Gunderson & Tepper’s Clinical Radiation Oncology [5 ed.] 9780323672467, 2019949699

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ASSOCIATE EDITORS Jeffrey A. Bogart, MD

Professor and Chair Department of Radiation Oncology SUNY Upstate Medical University Syracuse, New York

Minesh P. Mehta, MBChB, FASTRO Professor and Chair Department of Radiation Oncology FIU Herbert Wertheim College of Medicine Deputy Director and Chief Miami Cancer Institute Baptist Health South Florida Miami, Florida

Andrea K. Ng, MD, MPH

Professor Department of Radiation Oncology Harvard Medical School Dana-Farber Cancer Institute Brigham and Women’s Hospital Boston, Massachusetts

Abram Recht, MD

Professor Department of Radiation Oncology Harvard Medical School Vice Chair Department of Radiation Oncology Beth Israel Deaconess Medical Center Boston, Massachusetts

Christopher L. Tinkle, MD, PhD Assistant Member Department of Radiation Oncology St. Jude Children’s Research Hospital Memphis, Tennessee

Akila N. Viswanathan, MD, MPH

Professor Department of Radiation Oncology and Molecular Radiation Sciences Johns Hopkins University School of Medicine Baltimore, Maryland

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th

Gunderson & Tepper’s

EDITION

CLINICAL RADIATION ONCOLOGY SENIOR EDITORS Joel E. Tepper, MD, FASTRO

Hector MacLean Distinguished Professor of Cancer Research Department of Radiation Oncology University of North Carolina Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine Chapel Hill, North Carolina

Robert L. Foote, MD, FACR, FASTRO

Hitachi Professor of Radiation Oncology Research Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Jeff M. Michalski, MD, MBA, FACR, FASTRO Carlos A. Perez Distinguished Professor Vice Chair of Radiation Oncology Washington University School of Medicine in St. Louis St. Louis, Missouri

Elsevier 1600 John F. Kennedy Blvd. Ste. 1600 Philadelphia, PA 19103-2899

GUNDERSON & TEPPER’S CLINICAL RADIATION ONCOLOGY, FIFTH EDITION Copyright © 2021 by Elsevier Inc. All rights reserved.

ISBN: 978-0-323-67246-7

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. The Publisher Previous editions copyrighted © 2014, 2008, 2001, 1995, 1988, 1983 by Saunders and Churchill Livingstone, imprints of Elsevier Inc. Library of Congress Control Number: 2019949699

Executive Content Strategist: Robin Carter Senior Content Development Specialist: Anne Snyder Publishing Services Manager: Catherine Jackson Senior Project Manager: John Casey Book Designer: Patrick Ferguson Printed in China 9

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To my wife Laurie, for her support and for teaching me what is important in life, and who has made me a better person; and to my family, including Miriam, Adam, Abigail, Agustin, Zekariah, Zohar, Sammy, Marcelo, Jonah, and Aurelio for the love and support they have given me for many years. To my parents, who taught me the importance of education, learning, and doing that which should be done. To my many mentors who taught me in the past and those who continue to teach me. To my professional colleagues, both at the University of North Carolina and around the country, who have made me a better physician. JET To Kally, who, during our 40 years of marriage, has made innumerable, selfless, personal sacrifices for my patients and for my professional career. To my father, Leonard, who introduced me to the art, science, and practice of medicine. To John Earle, Len Gunderson and John Noseworthy. Their mentorship has enriched my professional life with experiences, opportunities, and growth beyond my wildest dreams. To the Mayo Clinic for providing a patient-centered, collegial, cooperative, compassionate, respectful, scholarly, integrated, professional, innovative, and healing environment in which to work and serve. RLF To Sheila, my loving wife of 31 years, for her steadfast support of my career and academic endeavors while also encouraging me to enjoy life with our family. To our children, Basia, Sophie, and Jeffrey, who have enriched my life with their love and support. To my parents, Richard and Rita, who both faced their own challenges of cancer therapy and taught me perspectives of care that you don’t get in medical school. To my mentors, especially Drs. Jim Cox and Larry Kun, who we lost this past year during the development of this new edition. They inspired me to reach higher. And finally, to my colleagues at Washington University in St. Louis who have patiently given me the time and support to contribute to this work. JMM Downloaded for [email protected] upr07 ([email protected]) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on April 23, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

CONTRIBUTORS Christopher D. Abraham, MD

Jonathan B. Ashman, MD, PhD

Philippe L. Bedard, MD, FRCPC

Assistant Professor Department of Radiation Oncology Washington University School of Medicine in St. Louis St. Louis, Missouri

Assistant Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science Phoenix, Arizona

Medical Oncologist Princess Margaret Cancer Centre Associate Professor Department of Medicine University of Toronto Toronto, Ontario, Canada

Matthew T. Ballo, MD Ross A. Abrams, MD Department of Radiation Oncology Rush University Medical Center Chicago, Illinois

Professor Radiation Oncology West Cancer Center and Research Institute Memphis, Tennessee

Aydah Al-Awadhi, MBBS

Lucia Baratto, MD

Department of Cancer Medicine University of Texas MD Anderson Cancer Center Houston, Texas

Research Fellow Department of Radiology Division of Nuclear Medicine and Molecular Imaging Stanford University Stanford, California

Kaled M. Alektiar, MD Member Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Jan Alsner, PhD Professor Department of Experimental Clinical Oncology Aarhus University Hospital Aarhus, Denmark

K. Kian Ang, MD, PhD† Professor and Gilbert H. Fletcher Endowed Chair Department of Radiation Oncology University of Texas MD Anderson Cancer Center Houston, Texas

Jonathan J. Beitler, MD, MBA, FACR, FASTRO Professor Departments of Radiation Oncology, Otolaryngology, and Hematology and Medical Oncology Emory University School of Medicine Georgia Research Alliance Clinical Scientist Winship Cancer Institute of Emory University NRG Institutional Principal Investigator Atlanta, Georgia

Christopher Andrew Barker, MD Radiation Oncologist Director of Clinical Investigation Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Sushil Beriwal, MD, MBA Professor Department of Radiation Oncology UPMC Hillman Cancer Center University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Adam Bass, MD Associate Professor of Medicine Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts

Ranjit S. Bindra, MD, PhD Associate Professor Therapeutic Radiology Yale Medical School New Haven, Connecticut

Brian C. Baumann, MD Assistant Professor Department of Radiation Oncology Washington University School of Medicine in St. Louis St. Louis, Missouri

Michael W. Bishop, MD

Beth M. Beadle MD, PhD

Rachel Blitzblau, MD, PhD

Associate Professor Department of Radiation Oncology Stanford University Stanford, California

Associate Professor Department of Radiation Oncology Duke University Medical Center Durham, North Carolina

Staci Beamer, MD

Jeffrey A. Bogart, MD

Assistant Professor Division of Cardiovascular and Thoracic Surgery Mayo Clinic College of Medicine and Science Phoenix, Arizona

Professor and Chair Department of Radiation Oncology SUNY Upstate Medical University Syracuse, New York

Assistant Member Department of Oncology St. Jude Children’s Research Hospital Memphis, Tennessee

Lilyana Angelov, MD, FAANS, FRCS(C) The Kerscher Family Chair for Spine Tumor Excellence Head, Section of Spine Tumors Professor, Department of Neurological Surgery Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Rose Ella Burkhart Brain Tumor and NeuroOncology Center Department of Neurosurgery Neurological Institute and Taussig Cancer Institute Cleveland Clinic Cleveland, Ohio

James A. Bonner, MD Chairman and Merle M. Salter Professor Department of Radiation Oncology The University of Alabama at Birmingham Birmingham, Alabama

†

Deceased

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CONTRIBUTORS

J. Daniel Bourland, PhD, MSPH

Bruce A. Chabner, MD

Stephen G. Chun, MD

Professor Radiation Oncology, Biomedical Engineering, and Physics Wake Forest School of Medicine Winston-Salem, North Carolina

Clinical Director, Emeritus Massachusetts General Hospital Cancer Center Massachusetts General Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts

Assistant Professor Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Joseph A. Bovi, MD Department of Radiation Oncology Medical College of Wisconsin Froedtert Memorial Lutheran Hospital Milwaukee, Wisconsin

Andrew G. Brandmaier, MD, PhD Assistant Professor Department of Radiation Oncology Weill Cornell Medical College New York, New York

John Breneman, MD Professor Department of Radiation Oncology University of Cincinnati Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Juan P. Brito, MD Assistant Professor of Medicine Division of Endocrinology, Diabetes, Metabolism, and Nutrition Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Michael D. Brundage, MD, MSc, FRCPC Professor Oncology and Public Health Sciences Queen’s University Radiation Oncologist Cancer Centre of Southeastern Ontario Kingston, Ontario, Canada

Matthew R. Callstrom, MD, PhD Professor of Radiology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Felipe A. Calvo, MD, PhD Professor and Chairman Department of Oncology Clinica Universidad de Navarra Madrid, Spain

George M. Cannon, MD Adjunct Assistant Professor Radiation Oncology University of Utah Salt Lake City, Utah

Michael D. Chan, MD Associate Professor and Vice Chairman Department of Radiation Oncology Wake Forest School of Medicine Winston-Salem, North Carolina

Samuel T. Chao, MD Associate Professor Department of Radiation Oncology Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center Cleveland Clinic Cleveland, Ohio

Christine H. Chung, MD Chair, Department of Head and Neck– Endocrine Oncology Moffitt Cancer Center Tampa, Florida

Peter W. M. Chung, MBChB, MRCP, FRCR, FRCPC Radiation Oncologist Princess Margaret Cancer Centre Associate Professor Department of Radiation Oncology University of Toronto Toronto, Ontario, Canada

Jeffrey M. Clarke, MD Anne-Marie Charpentier, MD, FRCPC Radiation Oncologist Centre Hospitalier de l’Université de Montréal Clinical Assistant Professor Université de Montréal Montréal, Quebec, Canada

Aadel A. Chaudhuri, MD Assistant Professor Department of Radiation Oncology Washington University School of Medicine in St. Louis St. Louis, Missouri

Nathan I. Cherny, MBBS, FRACP, FRCP Norman Levan Chair of Humanistic Medicine Cancer Pain and Palliative Medicine Service Shaare Zedek Medical Center Jerusalem, Israel

Assistant Professor Department of Medicine Division of Medical Oncology Duke University School of Medicine Durham, North Carolina

Louis S. Constine, MD, FASTRO, FACR The Philip Rubin Professor of Radiation Oncology and Pediatrics Vice Chair, Department of Radiation Oncology James P. Wilmot Cancer Center University of Rochester Medical Center The Judy DiMarzo Cancer Survivorship Program James P. Wilmot Cancer Institute University of Rochester Medical Center Rochester, New York

Benjamin W. Corn, MD

Assistant Professor Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Chairman Department of Radiation Medicine Shaare Zedek Medical Center Jerusalem, Israel; Professor Tel Aviv University School of Medicine Tel Aviv, Israel

John P. Christodouleas, MD, MPH

Allan Covens, MD, FRCSC

Attending Physician Department of Radiation Oncology University of Pennsylvania Philadelphia, Pennsylvania

Professor Department of Obstetrics and Gynecology Division of Gynecologic Oncology Sunnybrook Health Sciences Centre University of Toronto Toronto, Ontario, Canada

Fumiko Chino, MD

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CONTRIBUTORS

Christopher H. Crane, MD

Ryan W. Day, MD

Hugues Duffau, MD, PhD

Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Instructor of Surgery Mayo Clinic Scottsdale, Arizona; Senior Fellow Department of Surgical Oncology University of Texas MD Anderson Cancer Center Houston, Texas

Professor and Chairman Montpellier University Medical Center Institute for Neurosciences of Montpellier Hôpital Gui de Chauliac Montpellier, France

Carien L. Creutzberg, MD, PhD Professor Department of Radiation Oncology Leiden University Medical Center Leiden, Netherlands

Amanda J. Deisher, PhD Juanita M. Crook, MD, FRCP Professor Department of Radiation Oncology University of British Columbia Radiation Oncologist Center for the Southern Interior British Columbia Cancer Agency Kelowna, British Columbia, Canada

Brian G. Czito, MD Professor Department of Radiation Oncology Duke Cancer Institute Duke University Durham, North Carolina

Bouthaina S. Dabaja, MD Professor Section Chief, Hematology Department of Radiation Oncology University of Texas MD Anderson Cancer Center Houston, Texas

Thomas B. Daniels, MD Department of Radiation Oncology Mayo Clinic Arizona Assistant Professor of Radiation Oncology Mayo Clinic College of Medicine and Science Phoenix, Arizona

Marc David, MD Assistant Professor Department of Radiation Oncology McGill University Health Centre Montreal, Quebec, Canada

Laura A. Dawson, MD Professor Department of Radiation Oncology Princess Margaret Cancer Centre University of Toronto Toronto, Ontario, Canada

Instructor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Thomas F. DeLaney, MD Andres Soriano Professor of Radiation Oncology Harvard Medical School Associate Medical Director Francis H. Burr Proton Therapy Center Massachusetts General Hospital Boston, Massachusetts

Phillip M. Devlin, BPhil, MTS, EdM, MD, FACR, FASTRO, FFRRSCI (Hon) Chief, Division of Brachytherapy Dana-Farber/Brigham and Women’s Cancer Center Associate Professor of Radiation Oncology Harvard Medical School Institute Physician Dana-Farber Cancer Institute Boston, Massachusetts

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Thierry Duprez, MD Medical Imaging and Radiology Universite Catholique de Louvain Head of Neurology/Head and Neck Section Cliniques Universitaires Saint-Luc Brussels, Belgium

Peter T. Dziegielewski, MD, FRCS(C) Associate Professor Chief, Division of Head and Neck Oncologic Surgery Microvascular Reconstructive Surgery Kenneth W. Grader Professor University of Florida College of Medicine Gainesville, Florida

Charles Eberhart, MD, PhD Professor Pathology, Ophthalmology, and Oncology Johns Hopkins University School of Medicine Baltimore, Maryland

David W. Eisele, MD, FACS Andelot Professor and Director Department of Otolaryngology–Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

James J. Dignam, PhD Professor Department of Public Health Sciences University of Chicago Chicago, Illinois Statistics and Data Management Center NRG Oncology

Suzanne B. Evans, MD, MPH Associate Professor, Therapeutic Radiology Associate Director, Residency Program Yale University School of Medicine New Haven, Connecticut

Michael Farris, MD Don S. Dizon, MD Associate Professor Warren Alpert Medical School of Brown University Head of Women’s Cancers at Lifespan Cancer Institute Director of Medical Oncology Rhode Island Hospital Providence, Rhode Island

Assistant Professor Department of Radiation Oncology Wake Forest Baptist Health Winston-Salem, North Carolina

Mary Feng, MD Professor Department of Radiation Oncology University of California, San Francisco San Francisco, California

Jeffrey S. Dome, MD, PhD Chief Hematology and Oncology Children’s National Health System Washington, DC

Rui P. Fernandes, MD, DMD, FACS, FRCS(Ed) Associate Professor OMS, Neurosurgery, Orthopedics, Surgery University of Florida College of Medicine Jacksonville, Florida

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CONTRIBUTORS

Gini F. Fleming, MD

Adam S. Garden, MD

Dennis E. Hallahan, MD

Professor Department of Medicine University of Chicago Medical Center Chicago, Illinois

Professor Department of Radiation Oncology University of Texas MD Anderson Cancer Center Houston, Texas

Elizabeth H. and James S. McDonnell Distinguished Professor of Medicine Chair, Department of Radiation Oncology Washington University School of Medicine in St. Louis Barnes Jewish Hospital St. Louis, Missouri

John C. Flickinger, MD Professor Department of Radiation Oncology University of Pittsburgh Radiation Oncologist Department of Radiation Oncology UPMC Presbyterian-Shadyside Pittsburgh, Pennsylvania

Robert L. Foote, MD, FACR, FASTRO Hitachi Professor of Radiation Oncology Research Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Lilian T. Gien, MD Associate Professor Division of Gynecologic Oncology Odette Cancer Center Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Mary K. Gospodarowicz, MD, FRCPC, FRCR (Hon) Professor and Chair Department of Radiation Oncology University of Toronto Princess Margaret Hospital Toronto, Ontario, Canada

Christopher L. Hallemeier, MD Associate Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Michele Y. Halyard, MD Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Phoenix, Arizona

Cai Grau, MD, DMSc Silvia C. Formenti, MD Sandra and Edward Meyer Professor of Cancer Research Chairman, Department of Radiation Oncology Associate Director, Meyer Cancer Institute Weill Cornell Medical College Radiation Oncologist in Chief New York Presbyterian Hospital New York, New York

Benedick A. Fraass, PhD, FAAPM, FASTRO, FACR Vice Chair for Research, Professor and Director of Medical Physics Department of Radiation Oncology Cedars-Sinai Medical Center Health Sciences Professor Department of Radiation Oncology University of California, Los Angeles Los Angeles, California; Professor Emeritus Department of Radiation Oncology University of Michigan Ann Arbor, Michigan

Carolyn R. Freeman, MBBS, FRCPC, FASTRO Professor of Oncology and Pediatrics Mike Rosenbloom Chair of Radiation Oncology McGill University Montreal, Quebec, Canada

Professor Department of Oncology and Danish Centre for Particle Therapy Aarhus University Hospital Aarhus, Denmark

Marc Hamoir, MD Head and Neck Surgery Chairman of the Executive Board of the Cancer Center Saint-Luc University Hospital Cancer Center Brussels, Belgium

Vincent Grégoire, MD, PhD, FRCR Radiation Oncology Department Centre Léon Bérard Lyon, France

Timothy P. Hanna, MD, MSc, PhD, FRCPC

Professor Department of Radiation Oncology University of Texas Health Science Center at San Antonio San Antonio, Texas

Clinician Scientist Cancer Care and Epidemiology Cancer Research Institute at Queen’s University Radiation Oncologist Cancer Centre of Southeastern Ontario Kingston General Hospital Kingston, Ontario, Canada

Michael G. Haddock, MD

Paul M. Harari, MD

Professor of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Jack Fowler Professor and Chairman Human Oncology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

Chul S. Ha, MD

Ezra Hahn, MD, FRCPC Radiation Oncologist Department of Radiation Oncology Princess Margaret Cancer Centre Sunnybrook Health Sciences Centre of the University of Toronto Toronto, Ontario, Canada

Joseph M. Herman, MD, MSc, MSHCM

Matthew D. Hall, MD, MBA

Michael G. Herman, PhD

Radiation Oncology Miami Cancer Institute Baptist Health South Florida Miami, Florida

Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Professor Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

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CONTRIBUTORS

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Caroline L. Holloway, MD, FRCPC

Patricia A. Hudgins, MD

Brian D. Kavanagh, MD

Clinical Assistant Professor Department of Radiation Oncology BC Cancer Agency, Vancouver Island Centre Victoria, British Columbia, Canada

Professor Department of Radiology and Imaging Sciences Emory University School of Medicine Atlanta, Georgia

Professor and Chair Department of Radiation Oncology University of Colorado School of Medicine University of Colorado Comprehensive Cancer Center Aurora, Colorado

Bradford S. Hoppe, MD, MPH Associate Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Jacksonville, Florida

Michael R. Horsman, PhD, DMSc Professor Department of Experimental Clinical Oncology Aarhus University Hospital Aarhus, Denmark

Janet K. Horton, MD Adjunct Associate Professor Duke University Medical Center Durham, North Carolina

Julie Howle, MBBS, MS, FRACS, FACS Surgical Oncologist Westmead Private Hospital Westmead, New South Wales, Australia; Clinical Senior Lecturer Department of Surgery The University of Sydney Sydney, New South Wales, Australia

Christine A. Iacobuzio-Donahue, MD, PhD Director, David M. Rubenstein Center for Pancreatic Cancer Research Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Andrei Iagaru, MD Assistant Professor Department of Radiology Division of Nuclear Medicine and Molecular Imaging Stanford University Stanford, California

Nicole M. Iñiguez-Ariza, MD Division of Endocrinology, Diabetes, Metabolism, and Nutrition Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota; Department of Endocrinology and Metabolism Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City, Mexico

Brian A. Hrycushko, PhD Assistant Professor Department of Radiation Oncology UT Southwestern Medical Center Dallas, Texas

David Hsu, MD, PhD William Dalton Family Assistant Professor Division of Medical Oncology Department of Internal Medicine Duke Cancer Institute Duke University Durham, North Carolina

Chen Hu, PhD Assistant Professor of Oncology Division of Biostatistics and Bioinformatics Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University Baltimore, Maryland Statistics and Data Management Center NRG Oncology

Kara M. Kelly, MD Waldemar J. Kaminski Endowed Chair of Pediatrics Department of Pediatric Oncology Roswell Park Cancer Institute Division Chief, Pediatric Hematology/ Oncology and Research Professor Department of Pediatrics University of Buffalo School of Medicine and Biomedical Sciences Buffalo, New York

Amir H. Khandani, MD Associate Professor of Radiology Chief, Division of Nuclear Medicine Department of Radiology University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Deepak Khuntia, MD Vice President, Medical Affairs Oncology Systems Varian Medical Systems, Inc. Palo Alto, California; Radiation Oncologist Valley Medical Oncology Consultants Pleasanton, California

Jedediah E. Johnson, PhD Assistant Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Joseph G. Jurcic, MD Professor of Medicine Director, Hematologic Malignancies Section Department of Medicine Columbia University Irving Medical Center Attending Physician New York-Presbyterian Hospital/Columbia University Irving Medical Center New York, New York

John A. Kalapurakal, MD, FACR, FASTRO Professor Department of Radiation Oncology Northwestern University Chicago, Illinois

Ana Ponce Kiess, MD, PhD Assistant Professor Departments of Radiation Oncology and Molecular Radiation Sciences Johns Hopkins University School of Medicine Baltimore, Maryland

Joseph K. Kim, MD Resident Physician Department of Radiation Oncology New York University New York, New York

Susan J. Knox, MD, PhD Associate Professor Department of Radiation Oncology Stanford University Stanford, California

Wui-Jin Koh, MD Senior Vice President and Chief Medical Officer National Comprehensive Cancer Network (NCCN) Philadelphia, Pennsylvania

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CONTRIBUTORS

Rupesh R. Kotecha, MD

Nancy Lee, MD

Department of Radiation Oncology Miami Cancer Institute Baptist Health South Florida Department of Radiation Oncology FIU Herbert Wertheim College of Medicine Miami, Florida

Radiation Oncologist Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Matthew W. Krasin, MD Member Department of Radiation Oncology St. Jude Children’s Research Hospital Memphis, Tennessee

William J. Mackillop, MBChB, FRCR, FRCPC Professor Oncology and Public Health Sciences Queen’s University Kingston, Ontario, Canada

Percy Lee, MD Associate Professor Vice Chair of Education UCLA Department of Radiation Oncology University of California, Los Angeles Los Angeles, California

Kelly R. Magliocca, DDS, MPH Assistant Professor Department of Pathology and Laboratory Medicine Emory University School of Medicine Atlanta, Georgia

Benoît Lengelé, MD, PhD, FRCS, KB Larry E. Kun, MD† Professor and Director of Educational Programs Department of Radiation Oncology Professor, Department of Pediatrics UT Southwestern Medical Center Dallas, Texas

A. Nicholas Kurup, MD Associate Professor of Radiology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Head of Department Plastic and Reconstructive Surgery Cliniques Universitaires Saint-Luc Brussels, Belgium

Anuj Mahindra, MBBS Director, Malignant Hematology Division of Hematology/Oncology Scripps Clinic La Jolla, California

William P. Levin, MD Associate Professor Department of Radiation Oncology Abramson Cancer Center of the University of Pennsylvania Philadelphia, Pennsylvania

Anthony A. Mancuso, MD Professor and Chair Department of Radiology Professor of Otolaryngology University of Florida College of Medicine Gainesville, Florida

Jeremy H. Lewin, MBBS, FRACP Bindu Manyam, MD

Professor Chair, Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Medical Oncologist Peter MacCallum Cancer Centre Clinical Senior Lecturer Sir Peter MacCallum Department of Oncology University of Melbourne Melbourne, Victoria, Australia

Ann S. LaCasce, MD, MMSc

Dror Limon, MD

Associate Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute Boston, Massachusetts

Head of CNS Radiotherapy Service Radiotherapy Institute Tel-Aviv Sourasky Medical Center Tel-Aviv, Israel

Associate Professor and Division Chief Pediatric Radiation Oncology Dana-Farber/Boston Children’s Cancer and Blood Disorders Center Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts

Michael J. LaRiviere, MD

Jacob C. Lindegaard, MD, DMSc

Stephanie Markovina, MD, PhD

Resident Physician Department of Radiation Oncology University of Pennsylvania Philadelphia, Pennsylvania

Associate Professor Department of Oncology Aarhus University Hospital Aarhus, Denmark

Assistant Professor Department of Radiation Oncology Washington University School of Medicine in St. Louis St. Louis, Missouri

Andrew B. Lassman, MD

Daniel J. Ma, MD

Chief, Neuro-Oncology Division Columbia University Irving Medical Center Medical Director Clinical Protocol and Data Management Office Herbert Irving Comprehensive Cancer Center New York, New York

Associate Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Nadia N. Issa Laack, MD

Shannon M. MacDonald, MD Colleen A. Lawton, MD Vice Chair and Professor Department of Radiation Oncology Medical College of Wisconsin Milwaukee, Wisconsin

Associate Professor Department of Radiation Oncology Massachusetts General Hospital/Harvard Medical School Boston, Massachusetts

Department of Radiation Oncology Alleghany Health Network Pittsburgh, Pennsylvania

Karen J. Marcus, MD, FACR

Lawrence B. Marks, MD, FASTRO Dr. Sidney K. Simon Distinguished Professor of Oncology Research Chair, Department of Radiation Oncology University of North Carolina School of Medicine Chapel Hill, North Carolina

Martha M. Matuszak, PhD Associate Professor Department of Radiation Oncology University of Michigan Ann Arbor, Michigan

†

Deceased

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CONTRIBUTORS

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Mark W. McDonald, MD

Michael Mix, MD

Paul Okunieff, MD

Associate Professor Department of Radiation Oncology Emory University School of Medicine Atlanta, Georgia

Assistant Professor Department of Radiation Oncology SUNY Upstate Medical University Syracuse, New York

Professor and Chair Department of Radiation Oncology University of Florida Gainesville, Florida

Lisa A. McGee, MD

Amy C. Moreno, MD

Hilary L.P. Orlowski, MD

Assistant Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Phoenix, Arizona

Assistant Professor Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

Assistant Professor of Radiology Mallinckrodt Institute of Radiology Washington University School of Medicine in St. Louis St. Louis, Missouri

Paul M. Medin, PhD

William H. Morrison, MD

Sophie J. Otter, MD(Res), MRCP, FRCR

Professor Department of Radiation Oncology UT Southwestern Medical Center Dallas, Texas

Professor Department of Radiation Oncology University of Texas MD Anderson Cancer Center Houston, Texas

Consultant Clinical Oncologist Department of Oncology Royal Surrey County Hospital Guildford, Surrey, United Kingdom

Minesh P. Mehta, MBChB, FASTRO

Roger Ove, MD, PhD

Professor and Chair FIU Herbert Wertheim College of Medicine Deputy Director and Chief Department of Radiation Oncology Miami Cancer Institute Baptist Health South Florida Miami, Florida

Erin S. Murphy, MD

William M. Mendenhall, MD, FASTRO

Rashmi K. Murthy, MD, MBE

Professor Department of Radiation Oncology University of Florida College of Medicine Gainesville, Florida

Assistant Professor Department of Breast Medical Oncology University of Texas MD Anderson Cancer Center Houston, Texas

Assistant Professor Department of Radiation Oncology Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center Cleveland Clinic Cleveland, Ohio

Ruby F. Meredith, MD, PhD Professor Department of Radiation Oncology University of Alabama at Birmingham Senior Scientist UAB Comprehensive Cancer Center University of Alabama at Birmingham Birmingham, Alabama

Andrea K. Ng, MD, MPH Professor of Radiation Oncology Dana-Farber Cancer Institute Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts

Marianne Nordsmark, MD, PhD Jeff M. Michalski, MD, MBA, FACR, FASTRO Carlos A. Perez Distinguished Professor Vice Chair of Radiation Oncology Washington University School of Medicine in St. Louis St. Louis, Missouri

Michael T. Milano, MD, PhD Professor Department of Radiation Oncology University of Rochester Rochester, New York

Bruce D. Minsky, MD Professor of Radiation Oncology Frank T. McGraw Memorial Chair The University of Texas MD Anderson Cancer Center Houston, Texas

Senior Staff Specialist Department of Oncology Aarhus University Hospital Aarhus, Denmark

Yazmin Odia, MD, MS Lead Physician of Medical Neuro-Oncology Miami Cancer Institute Baptist Health South Florida Miami, Florida

Clinical Associate Professor Department of Radiation Oncology University Hospitals Case Medical Center Seidman Cancer Center Cleveland, Ohio

Jens Overgaard, MD, DMSc Professor Department of Experimental Clinical Oncology Aarhus University Hospital Aarhus, Denmark

Manisha Palta, MD Associate Professor Department of Radiation Oncology Duke Cancer Institute Duke University Durham, North Carolina

Luke E. Pater, MD Associate Professor Department of Radiation Oncology University of Cincinnati Cincinnati, Ohio

Todd Pawlicki, PhD, FAAPM, FASTRO Professor and Vice-Chair Department of Radiation Medicine and Applied Sciences Director, Division of Medical Physics and Technology University of California, San Diego La Jolla, California

Desmond A. O’Farrell, MSc, CMD Teaching Associate in Radiation Oncology Harvard Medical School Clinical Physicist Department of Radiation Oncology Dana-Farber/Brigham and Women’s Cancer Center Boston, Massachusetts

Jennifer L. Peterson, MD Department of Radiation Oncology Mayo Clinic Florida Associate Professor of Radiation Oncology Mayo Clinic College of Medicine and Science Jacksonville, Florida

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xiv

CONTRIBUTORS

Thomas M. Pisansky, MD

Pablo F. Recinos, MD

David P. Ryan, MD

Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Rochester, Minnesota

Assistant Professor Department of Neurological Surgery Cleveland Clinic Cleveland, Ohio

Clinical Director and Chief of Hematology/ Oncology Massachusetts General Hospital Cancer Center Professor of Medicine Harvard Medical School Boston, Massachusetts

Marsha Reyngold, MD, PhD Erqi Pollom, MD, MS Department of Radiation Oncology Stanford University Stanford, California

Radiation Oncologist Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Louis Potters, MD, FACR, FASTRO, FABS

Nadeem Riaz, MD

Professor and Chairperson Department of Radiation Medicine Northwell Health and the Zucker School of Medicine at Hofstra/Northwell Deputy Physician-in-Chief Northwell Health Cancer Institute Lake Success, New York

Assistant Attending Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Harry Quon, MD, MS Associate of Radiation Oncology and Molecular Radiation Sciences Johns Hopkins University School of Medicine Baltimore, Maryland

David Raben, MD Professor Department of Radiation Oncology University of Colorado Aurora, Colorado

Ezequiel Ramirez, MS, CMD RT(R)(T) Chief Medical Dosimetrist University of California, San Francisco San Francisco, California

Demetrios Raptis, MD Assistant Professor of Radiology Mallinckrodt Institute of Radiology Washington University School of Medicine in St. Louis St. Louis, Missouri

Michal Raz, MD Neuropathologist Pathology Department Tel-Aviv Sourasky Medical Center Tel-Aviv, Israel

Abram Recht, MD Professor Department of Radiation Oncology Harvard Medical School Vice Chair Department of Radiation Oncology Beth Israel Deaconess Medical Center Boston, Massachusetts

Kenneth B. Roberts, MD Professor Department of Therapeutic Radiology Yale University School of Medicine New Haven, Connecticut

Nabil F. Saba, MD Professor Departments of Hematology and Medical Oncology and Otolaryngology Emory University School of Medicine Atlanta, Georgia

Joseph K. Salama, MD Professor Department of Radiation Oncology Duke University School of Medicine Durham, North Carolina

John T. Sandlund Jr, MD

Associate Attending Physician Department of Pediatrics Memorial Sloan Kettering Cancer Center New York, New York

Member, Department of Oncology St. Jude Children’s Research Hospital Professor Department of Pediatrics University of Tennessee College of Medicine Memphis, Tennessee

Claus M. Rödel, MD

Michael Heinrich Seegenschmiedt, MD

Professor and Chairman Radiotherapy and Oncology University Hospital Frankfurt, Goethe University Frankfurt, Germany

Professor Strahlentherapie Osnabrück Osnabrück, Germany

Stephen S. Roberts, MD

Carlos Rodriguez-Galindo, MD Member and Chair Department of Global Pediatric Medicine Member, Department of Oncology St. Jude Children’s Research Hospital Memphis, Tennessee

Amy Sexauer, MD, PhD Dana-Farber Cancer Institute Division of Pediatrics Hematology/Oncology/Stem Cell Transplant Department of Pediatrics Boston Children’s Hospital Boston, Massachusetts

Jacob E. Shabason, MD C. Leland Rogers, MD Professor Department of Radiation Oncology Barrow Neurological Institute Phoenix, Arizona

Assistant Professor Department of Radiation Oncology Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Todd L. Rosenblat, MD

Chirag Shah, MD

Assistant Professor of Medicine Columbia University Irving Medical Center New York, New York

Department of Radiation Oncology Taussig Cancer Institute Cleveland Clinic Cleveland, Ohio

William G. Rule, MD Assistant Professor Department of Radiation Oncology Mayo Clinic College of Medicine and Science, Mayo Clinic Phoenix, Arizona

Jason P. Sheehan, MD Harrison Distinguished Professor Neurological Surgery University of Virginia Charlottesville, Virginia

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CONTRIBUTORS

Arif Sheikh, MD

John H. Suh, MD

Chiaojung Jillian Tsai, MD, PhD

Mount Sinai Health System New York, New York

Professor and Chairman Department of Radiation Oncology Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center Cleveland Clinic Cleveland, Ohio

Radiation Oncologist Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Anup S. Shetty, MD Assistant Professor of Radiology Mallinckrodt Institute of Radiology Washington University School of Medicine in St. Louis St. Louis, Missouri

Arun D. Singh MD Professor of Ophthalmology Department of Ophthalmic Oncology Cleveland Clinic Cleveland, Ohio

Winston W. Tan, MD Division of Hematology and Oncology Mayo Clinic Florida Associate Professor of Medicine Mayo Clinic College of Medicine and Science Jacksonville, Florida

Joel E. Tepper, MD, FASTRO

Professor and Chairman Department of Radiation Oncology Loyola University Chicago Stritch School of Medicine Chicago, Illinois

Hector MacLean Distinguished Professor of Cancer Research Department of Radiation Oncology University of North Carolina Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine Chapel Hill, North Carolina

Mike Soike, MD

Charles R. Thomas Jr, MD

Department of Radiation Oncology Wake Forest Baptist Health Winston-Salem, North Carolina

Professor and Chair Radiation Medicine Knight Cancer Institute Oregon Health & Science University Portland, Oregon

William Small Jr, MD, FACRO, FACR, FASTRO

C. Arturo Solares, MD Professor Department of Otolaryngology Emory University School of Medicine Atlanta, Georgia

Timothy D. Solberg, PhD Professor and Director, Medical Physics Department of Radiation Oncology University of California, San Francisco San Francisco, California

Alexandra J. Stewart, DM, MRCP, FRCR Consultant Clinical Oncologist St. Luke’s Cancer Centre Royal Surrey County Hospital Senior Lecturer University of Surrey Guildford, United Kingdom

Rebecca L. Stone, MD, MS Assistant Professor Department of Gynecology and Obstetrics Johns Hopkins Hospital Baltimore, Maryland

xv

Richard W. Tsang, MD, FRCPC Professor Department of Radiation Oncology University of Toronto Princess Margaret Hospital Toronto, Ontario, Canada

Mark D. Tyson, MD Department of Urology Mayo Clinic Arizona Assistant Professor of Urology Mayo Clinic College of Medicine and Science Phoenix, Arizona

Kenneth Y. Usuki, MS, MD Associate Professor Department of Radiation Oncology University of Rochester Rochester, Minnesota

Vincenzo Valentini, MD Professor and Chairman Radiation Oncology Policlinico Gemelli-Università Cattolica del Sacro Cuore Rome, Italy

Robert D. Timmerman, MD Professor and Vice-Chair Department of Radiation Oncology UT Southwestern Medical Center Dallas, Texas

Julie My Van Nguyen, MD, MSc, FRCSC Fellow Division of Gynecologic Oncology University of Toronto Toronto, Ontario, Canada

Christopher L. Tinkle, MD, PhD Assistant Member Department of Radiation Oncology St. Jude Children’s Research Hospital Memphis, Tennessee

Noam VanderWalde, MD, MS Assistant Professor Department of Radiation Oncology West Cancer Center and Research Institute Memphis, Tennessee

Betty C. Tong, MD Associate Professor Department of Surgery Division of Cardiovascular and Thoracic Surgery Duke University School of Medicine Durham, North Carolina

Ralph Vatner, MD, PhD Assistant Professor Department of Radiation Oncology University of Cincinnati Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Jordan A. Torok, MD Assistant Professor Department of Radiation Oncology Duke University School of Medicine Durham, North Carolina

Michael J. Veness, MD, MMed, FRANZCR Clinical Professor Department of Radiation Oncology Westmead Hospital The University of Sydney Sydney, New South Wales, Australia

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xvi

CONTRIBUTORS

Vivek Verma, MD

Lynn D. Wilson, MD, MPH, FASTRO

Joachim Yahalom, MD, FACR

Attending Physician Department of Radiation Oncology Allegheny General Hospital Pittsburgh, Pennsylvania

Professor, Executive Vice Chairman, Clinical Director Department of Therapeutic Radiology Professor, Department of Dermatology Staff Attending, Yale–New Haven Hospital Yale University School of Medicine Smilow Cancer Hospital New Haven, Connecticut

Professor Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Frank A. Vicini, MD Department of Radiation Oncology 21st Century Oncology Michigan Healthcare Professionals Farmington Hills, Michigan

Akila N. Viswanathan, MD, MPH Professor Department of Radiation Oncology and Molecular Radiation Sciences Johns Hopkins University School of Medicine Baltimore, Maryland

Daniel R. Wahl, MD, PhD Assistant Professor Department of Radiation Oncology University of Michigan Ann Arbor, Michigan

Padraig R. Warde, MBBCh, FRCPC Radiation Oncologist Princess Margaret Cancer Centre Professor Department of Radiation Oncology University of Toronto Toronto, Ontario, Canada

Christopher G. Willett, MD Professor and Chair Department of Radiation Oncology Duke Cancer Institute Duke University Durham, North Carolina

Christopher D. Willey, MD, PhD Associate Professor Department of Radiation Oncology The University of Alabama at Birmingham Birmingham, Alabama

Grant Williams, MD Assistant Professor Division of Hematology and Oncology and Gerontology, Geriatrics, and Palliative Care University of Alabama at Birmingham Birmingham, Alabama

Karen M. Winkfield, MD, PhD Associate Professor Department of Radiation Oncology Wake Forest Baptist Health Winston-Salem, North Carolina

Suzanne L. Wolden, MD Attending Physician Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York, New York

Eddy S. Yang, MD, PhD Professor Department of Radiation Oncology The University of Alabama at Birmingham Birmingham, Alabama

Y. Nancy You, MD, MHSc Associate Professor Department of Surgical Oncology Associate Medical Director Clinical Cancer Genetics Program The University of Texas MD Anderson Cancer Center Houston, Texas

Ye Yuan, MD, PhD Jeffrey Y.C. Wong, MD, FASTRO Professor and Chair Department of Radiation Oncology City of Hope National Medical Center Duarte, California

Resident Physician UCLA Department of Radiation Oncology University of California, Los Angeles Los Angeles, California

Elaine M. Zeman, PhD Terence Z. Wong, MD, PhD Professor of Radiology Chief, Division of Nuclear Medicine Department of Radiology Duke Cancer Institute Duke University Health System Durham, North Carolina

William W. Wong, MD Vice Chair, Department of Radiation Oncology Mayo Clinic Arizona Professor of Radiation Oncology Mayo Clinic College of Medicine and Science Phoenix, Arizona

Associate Professor Department of Radiation Oncology University of North Carolina School of Medicine Chapel Hill, North Carolina

Peixin Zhang, PhD Statistics and Data Management Center NRG Oncology

Tiffany C. Zigras, MD, MSc, MEng, FRCSC Fellow Division of Gynecologic Oncology University of Toronto Toronto, Ontario, Canada

Zhong Wu, MD, PhD Research Fellow in Medicine Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts

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F O R E WO R D Joel Tepper and I were approached by the senior medical editor of Churchill Livingstone in late 1995 about co-editing a textbook on clinical radiation oncology as a counterpart to the multidisciplinary textbook Clinical Oncology, edited by Abeloff, Armitage, Lichter, and Niederhuber. By May 1996, the decision had been made to proceed and a contract was signed in July. We were interested in producing a new radiation oncology textbook that was easily readable and useful to both residents and experienced radiation oncologists. As such, we introduced “Key Points” for each disease-site chapter, as well as algorithms for workup and treatment for each disease. We thought that, along with careful editing and organization, this would provide a new and valuable resource to the radiation oncology community. While providing a thorough coverage of all the topics, we made no attempt to cover all issues but rather emphasized what was important to the clinician. Since Joel and I had similar disease-site interests, the decision was made to select associate editors for eight other disease-site sections/ chapters “to enhance the scientific content and comprehensiveness of the textbook” (breast, central nervous system, childhood, gynecologic, genitourinary, head and neck, lymphoma/hematologic, thoracic). Associate editors were involved in helping select appropriate senior authors for each of the disease-site chapters, in editing the chapters for scientific content and accuracy, and in writing a section overview for their respective disease-sites. The first edition of Clinical Radiation Oncology (CRO), published in 2000 by Churchill Livingstone/Harcourt Science, was a 1300-page, black and white textbook containing 63 chapters in three major sections—Scientific Foundations of Radiation, Techniques and Modalities, Disease Sites. Subsequent editions (CRO2, CRO3, CRO4) were published in 2007 (Churchill Livingstone, Elsevier), 2012 (Saunders/Elsevier) and 2016 (Elsevier), with Joel and I as the co-senior editors, plus section editors for gastrointestinal and sarcoma, while continuing to involve associate editors for the other eight disease-site sections. CRO2 was a full-color textbook and expanded to 76 chapters with approximately 1800 pages. An exciting feature of CRO3 was the availability of an online version of the textbook that contained the entire print component of the textbook along with additional text, figures, tables, and a complete

set of cited references. This allowed a reduction in the length of the printed textbook by limiting the number of critical references in the print version of each chapter to 50. For CRO4 an exciting new feature was the periodic update of chapters in the online version of the textbook. Periodic changes were made in chapter senior authors and co-authors and in the associate editors for subsequent editions, as appropriate. While I was heavily involved in the clinical/content updates for CRO4, I promised my wife, Katheryn, that I would not edit further editions of CRO. Therefore, when the decision was made to proceed with CRO5, I conferred with Joel in selecting two new senior editors (Drs. Robert Foote and Jeff Michalski), which resulted in a more diverse group of senior editors by virtue of their respective disease-site expertise. At Joel’s request, I was involved with the three of them in the planning process for CRO5. As a group we decided to add six new chapters while keeping the length of the hardcopy textbook similar to CRO4 by reducing the number of critical references in the hardcopy version from 50 to 25. The intent of the first edition of CRO was “to be both comprehensive and authoritative, yet not exhaustive” by virtue of liberal use of tables, figures, and treatment algorithms as a supplement to the text. The comprehensive/authoritative intent of the print versions of the book persisted in subsequent editions, but the addition of an online version for CRO3 and subsequent editions has perhaps resulted in some “exhaustive” chapters online for those readers who found the additional information useful. It has been both a privilege and a pleasure to be associated with Clinical Radiation Oncology planning and editing in conjunction with Joel and many other national and international experts for over 20 years! The contributions of outstanding authors, associate editors, and senior editors will allow CRO5 to be a valuable resource for many readers in the coming years. Leonard L. Gunderson, MD, MS, FASTRO Professor Emeritus and Consultant Department of Radiation Oncology Mayo Clinic Rochester/Arizona Mayo Clinic College of Medicine and Science

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P R E FA C E The radiation oncology community has received the four previous editions of Clinical Radiation Oncology very well, and it has become the standard radiation oncology textbook for many physicians. For the fifth edition of Clinical Radiation Oncology, the major change that has been made is that Len Gunderson has decided to step down as a senior editor, a position he has held since the inception of this textbook. His insight and efforts have been essential over the years in making this book successful. Drs. Gunderson and Tepper thought carefully about who could replace Dr. Gunderson as a senior editor and decided that two people were needed to fill that role. We have been fortunate to have recruited Robert Foote and Jeff Michalski to be senior editors. As the field of radiation oncology has expanded in its scope, having a third senior editor allows us to have broader expertise. Despite this major change, our intent is to maintain the many excellent features of the previous editions while adding some new features, new chapters and chapter authors, and new associate editors. The fifth edition has maintained three separate sections—Scientific Foundations of Radiation Oncology, Techniques and Modalities, and Disease Sites. Within Scientific Foundations of Radiation Oncology, four new chapters have been added: “Radiation Physics: Charged Particle Therapy,” “Tumor Ablation in Interventional Radiology,” “Radiation Therapy in the Elderly,” and “Palliative Radiation Medicine,” reflecting the increasing clinical interest in all of these issues within the oncologic community. In the section on Techniques and Modalities, two new chapters have been added: “Quality and Safety in Radiation Oncology” and “Immunotherapy with Radiotherapy.” The associate editors for Disease Sites chapters were an important component of the success of the four previous editions and have been retained. Three associate editor positions have changed—Dr. Michalski has taken the lead on genitourinary diseases, Akila Viswanathan has become the associate editor for gynecologic tumors, and Abram Recht is the associate editor for breast tumors. Larry Kun functioned as the associate editor for pediatric tumors until his untimely death, and the remainder of his responsibilities were taken over by Christopher Tinkle and Jeff Michalski. Associate editors are involved in the selec-

tion of chapter authors and in editing the chapters for scientific content and accuracy. For most disease sites, the associate editors also wrote an overview in which they discuss issues common to various disease sites within the section and give their unique perspective on important issues. Features that are retained within Disease Sites section include an opening page format summarizing the most important issues, a full-color format throughout each chapter, liberal use of tables and figures, and a closing section with a discussion of controversies and problems and a treatment algorithm that reflects the treatment approach of the authors. Chapters have been edited not only for scientific accuracy, but also for organization, format, and adequacy of outcome data (disease control, survival, and treatment tolerance). We are again indebted to the many national and international experts who contributed to the fifth edition of Clinical Radiation Oncology as associate editors, senior authors, or co-authors. Their outstanding efforts combined with ours will hopefully make this new edition a valuable contribution and resource in the field in the coming years.

ACKNOWLEDGMENTS We wish to thank our wives, Laurie, Kally, and Sheila, and Dr. Tepper’s secretary, Betty Bush, for their patience and assistance during the many months we were involved in the preparation of the fifth edition of Clinical Radiation Oncology. We also thank the associate editors and the many senior authors and co-authors for their time, efforts, and outstanding contributions to this edition. We acknowledge the editors and production staff at Elsevier, especially Anne Snyder, Tara Delaney, and Robin Carter, who have done an outstanding job in collating and producing the fifth edition of Clinical Radiation Oncology. Joel E. Tepper Robert L. Foote Jeff M. Michalski

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VIDEO CONTENTS

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VIDEO CONTENTS Video 20.1 Video 22.1 Video 36.1 Video 65.1

Prostate Brachytherapy Intraoperative Radiation Ocular Melanoma Penile Brachytherapy

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PART A Radiobiology

1 The Biological Basis of Radiation Oncology Elaine M. Zeman

WHAT IS RADIATION BIOLOGY? In the most general sense, radiation biology is the study of the effects of electromagnetic radiation on biological systems. Three aspects of this definition deserve special mention. First, effects may include everything from DNA damage to genetic mutations, chromosome aberrations, cell killing, disturbances in cell cycle transit and cell proliferation, neoplastic transformation, early and late effects in normal tissues, teratogenesis, cataractogenesis, and carcinogenesis, to name but a few. Electromagnetic radiation refers to any type of radiant energy in motion with wave and/or particulate characteristics that has the capacity to impart some or all of its energy to the medium through which it passes. The amount of energy deposited can vary over some 25 orders of magnitude, depending on the type of electromagnetic radiation. For example, 1 kHz radio waves have energies in the range of 10–11 to 10–12 eV, whereas x-rays or γ-rays may have energies upwards of 10 MeV or more. The more energetic forms of electromagnetic radiation, the ionizing radiations, deposit energy as they traverse the medium by setting secondary particles in motion that can go on to produce further ionizations. Finally, biological systems may be, for example, quite simple cell-free extracts of biomolecules, or increasingly complex, from prokaryotes to single-celled eukaryotes, to mammalian cells in culture, to tissues and tumors in laboratory animals or humans, to entire ecosystems. Radiotherapy-oriented radiobiology focuses on that portion of the electromagnetic spectrum energetic enough to cause ionization of atoms. This ultimately results in the breaking of chemical bonds, which can lead to damage to important biomolecules. The most significant effect of ionizing radiation in this context is cell killing, which directly or indirectly is at the root of nearly all of the normal tissue and tumor responses noted in patients. Cytotoxicity is not the only significant biological effect caused by radiation exposure, although it will be the main focus of this chapter. Other important radiation effects—carcinogenesis, for example—will also be discussed, although the reader should be aware that radiation carcinogenesis is a large discipline in and of itself, involving investigators from fields as diverse as biochemistry, toxicology, epidemiology, environmental sciences, molecular biology, tumor biology, health and medical physics, as well as radiobiology. Most radiation protection standards are based on minimizing the risks associated with mutagenic and carcinogenic events. Therefore radiological health professionals are de facto educators of and advocates for the general

public when it comes to ionizing radiation, who need to be fully conversant in the potential risks and benefits of medical procedures involving radiation. The majority of this chapter will be devoted to so-called “foundational” radiobiology, that is, studies that largely predate the revolution in molecular biology and biotechnology during the 1980s and 1990s. While the reader might be tempted to view this body of knowledge as rather primitive by today’s standards, relying too heavily on phenomenology, empiricism, and descriptive models and theories, the real challenge is to integrate the new biology into the already-existing framework of foundational radiobiology. Chapter 2 endeavors to do this.

RADIOTHERAPY-ORIENTED RADIOBIOLOGY: A CONCEPTUAL FRAMEWORK Before examining any one aspect of radiobiology in depth, it is important to introduce several general concepts to provide a framework for putting the information in its proper perspective.

The Therapeutic Ratio The most fundamental of these concepts is what is termed the therapeutic ratio—in essence, a risk-versus-benefit approach to planning a radiotherapy treatment regimen. Many of the radiobiological phenomena to be discussed in this chapter are thought to play important roles in optimizing, or at least “fine tuning,” the therapeutic ratio. In theory, it should be possible to eradicate any malignant tumor simply by delivering a sufficiently high dose of radiation. Of course, in practice, the biological consequences for normal tissues that are necessarily irradiated along with the tumor limit the total dose that can be safely administered. As such, a balance must be struck between what is deemed an acceptable probability of a radiation-induced complication in a normal tissue and the probability of tumor control. Ideally, one would hope to achieve the maximum likelihood of tumor control that does not produce unacceptable normal tissue damage. The concept of therapeutic ratio is best illustrated graphically, by comparing dose-response curves for both tumor control and normal tissue complication rates plotted as a function of dose. Examples of this approach are shown in Fig. 1.1 for cases in which the therapeutic ratio is either “unfavorable,” “favorable,” or “optimal,” bearing in mind that these are theoretical curves. Actual dose-response curves derived from experimental or clinical data are much more variable, particularly for tumors, which tend to show much shallower dose responses.1 This

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CHAPTER 1

Probability of effect (%)

95

Desirable probability of tumor control

Unfavorable therapeutic ratio Normal tissue complication

50

Tumor control

5 40

A 95 Probability of effect (%)

Acceptable risk of normal tissue complication

60 Total dose (Gy)

Desirable probability of tumor control

Favorable therapeutic ratio Normal tissue complication

50

Tumor control

5

Acceptable risk of normal tissue complication

40

B 95 Probability of effect (%)

80

60 Total dose (Gy)

80

Desirable probability of tumor control

Optimal therapeutic ratio Normal tissue complication

50

Tumor control

5

Acceptable risk of normal tissue complication

60 80 Total dose (Gy) Fig. 1.1 Illustrating the concept of therapeutic ratio under conditions in which the relationship between the normal tissue tolerance and tumor control dose-response curves is unfavorable (A), favorable (B), and optimal (C).

C

40

serves to underscore how difficult it can be in practice to assign a single numerical value to the therapeutic ratio in any given situation. Many of the radiobiological properties of cells and tissues can have a favorable or adverse effect on the therapeutic ratio. Therefore, in planning a course of radiation therapy, the goal should be to optimize the therapeutic ratio as much as possible; in other words, using our graphical approach, increase the separation between the tumor control and normal tissue complication curves. This can be accomplished either by shifting the tumor control curve to the left with respect to the dose

The Biological Basis of Radiation Oncology

3

axis (toward lower doses, i.e., radiosensitization) or shifting the normal tissue complication curve to the right (toward higher doses, i.e., radioprotection) or, perhaps, some combination of both. The key, however, is to shift these curves differentially, not necessarily an easy task given that there are not that many exploitable differences in the radiobiology of cells derived from tumors and those derived from normal tissues.

The Radiation Biology Continuum There is a surprising continuity between the physical events that occur in the first few femtoseconds after ionizing radiation interacts with the atoms of a biomolecule and the ultimate consequences of that interaction on tissues. The consequences themselves may not become apparent until days, weeks, months, or even years after the radiation exposure. Some of the important steps in this radiobiology continuum are listed in Table 1.1. The orderly progression from one stage of the continuum to the next—from physical to physicochemical to biochemical to biological—is particularly noteworthy not only because of the vastly different time scales over which the critical events occur but also because of the increasing biological complexity associated with each of the endpoints or outcomes. Each stage of the continuum also offers a unique radiobiological window of opportunity: the potential to intervene in the process and thereby modify all of the events and outcomes that follow.

Levels of Complexity in Radiobiological Systems Another important consideration in all radiobiological studies is the nature of the experimental system used to study a particular phenomenon, the assay(s) used, and the endpoint(s) assessed. For example, one investigator might be interested in studying DNA damage caused by ionizing radiation, in particular, the frequency of DNA double-strand breaks (DSBs) produced per unit dose. As an experimental system, the investigator might choose DNA extracted from irradiated mammalian cells and, as an endpoint, use pulsed field gel electrophoresis to measure the distance and rate at which irradiated DNA migrates through the gel compared with unirradiated DNA. The DNA containing more DSBs migrates farther than DNA containing fewer breaks, allowing a calibration curve to be generated that relates migration to the dose received. A second investigator, meanwhile, may be interested in improving the control rate of head and neck cancers with radiation therapy by employing a nonstandard fractionation schedule. In this case, the type of experiment would be a clinical trial. The experimental system would be a cohort of patients, some of whom are randomized to receive nonstandard fractionation and the rest receiving standard fractionation. The endpoints assessed could be one or more of the following: locoregional control, long-term survival, disease-free survival, normal tissue complication frequency, and so forth, evaluated at specific times after completion of the radiation therapy. In considering both the strengths and weaknesses of these two investigators’ studies, any number of pertinent questions may be asked. Which is the more complex or heterogeneous system? Which is the more easily manipulated and controlled system? Which is more relevant for the day-to-day practice of radiation oncology? What kinds of results are gleaned from each and can these results be obtained in a timely manner? In this example, it is clear that human patients with spontaneously arising tumors represent a far more heterogeneous and complex experimental system than extracted mammalian DNA. However, the DNA system is much more easily manipulated, possible confounding factors can be more easily controlled, and the measurement of the desired endpoint (migration distance/rate) plus the data analysis can be completed within a day or two. Obviously, this is not the case with the human studies, in which numerous confounding factors can and do influence results,

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4

SECTION I

TABLE 1.1

Stages in the Radiobiology Continuum

Time Scale of Events (“Stage”) 10

−16

−12

to 10

Scientific Foundations of Radiation Oncology

second (“Physical”)

Initial Event

Final Event

Response Modifiers/Possible Interventions

Ionization of atoms

Free radicals formed in biomolecules

Type of ionizing radiation; shielding

10−12 to 10−2 second (“Physicochemical”)

Free radicals formed in biomolecules

DNA damage

Presence or absence of free radical scavengers, molecular oxygen and/or oxygen-mimetic radiosensitizers

1.0 second to several hours (“Biochemical”)

DNA damage

Unrepaired or misrejoined DNA damage

Presence or absence of functioning DNA damage recognition and repair systems; repair-inhibiting drugs; altering the time required to complete repair processes

Hours to years (“Biological”)

Unrepaired or misrejoined DNA damage

Clonogenic cell death, apoptosis, mutagenesis, transformation, carcinogenesis, “early and late effects” normal tissues, whole body radiation syndromes, tumor control, etc.

Cell-cell interactions, biological response modifiers, adaptive mechanisms, structural and functional organization of tissues, cell kinetics, etc.

manipulation of the system can be difficult, if not impossible, and the experimental results typically take years to obtain. The issue of relevance is an even thornier one. Arguably, both studies are relevant to radiation oncology in so far as the killing of cells is at the root of radiation’s normal tissue and tumor toxicity, and that cell killing usually is, directly or indirectly, a consequence of irreparable damage to DNA. As such, any laboratory findings that contribute to the knowledge base of radiation-induced DNA damage are relevant. Clearly, however, clinical trials with human patients not only are a more familiar experimental system to radiation oncologists but also, efficacy in conducting trials with cancer patients is ultimately what leads to new standards of care in clinical practice and becomes the gold standard against which all newer therapeutic strategies are judged. There is a time and place both for relatively simple systems and more complex ones. The relatively simple, homogeneous, and easily manipulated systems are best suited for the study of the mechanisms of radiation action, such as measuring DNA or chromosomal damage, changes in gene expression, activation of cell cycle checkpoints, or the survival of irradiated cells in vitro. The more complicated and heterogeneous systems, with their unique endpoints, are more clinically relevant, such as assays of tumor control or normal tissue complication rates. Both types of assay systems have inherent strengths and weaknesses, yet both are critically important if we hope to improve the practice of radiation therapy based on sound biological principles.

Heterogeneity Why is radiation therapy successful at controlling one patient’s tumor but not another’s when the two tumors in all other clinical respects seem identical? Why are we generally more successful at controlling certain types of cancers than others? The short answer to such questions is that, although the tumors may appear identical “macroscopically,” their component cells may be quite different genotypically and phenotypically. Also, there could be important differences between the two patients’ normal tissues. Because normal tissues by definition are composed of more than one type of cell, they are necessarily heterogeneous. However, tumors, owing both to the genomic instability of individual cells and to microenvironmental differences, are much more so. Different subpopulations of cells isolated from human and experimental cancers can differ with respect to differentiation, invasive and metastatic potential, immunogenicity, and sensitivity to radiation and chemotherapy, to name but a few. (For reviews, see Heppner and Miller2 and Suit et al.3) This heterogeneity is manifest both within a particular patient and, to a much greater extent, between patients with otherwise similar tumors. Both intrinsic and extrinsic factors contribute to this heterogeneity. Intrinsic factors

can include inherent radiosensitivity, genomic instability, gene expression patterns, DNA repair fidelity, mode(s) of cell death, cell cycle regulation, and how the tissue is structurally and functionally arranged. Extrinsic factors, on the other hand, are related to microenvironmental differences between tissues, such as the functionality of the vasculature, availability of oxygen and nutrients, pH, presence or absence of reactive oxygen species, cytokines and immune cells, energy charge, and cell-cell and cell-extracellular matrix interactions. What are the practical implications of normal tissue and tumor heterogeneity? First, if one assumes that normal tissues are the more uniform and predictable in behavior of the two, then tumor heterogeneity is responsible, either directly or indirectly, for most radiotherapy failures. If so, this suggests that a valid clinical strategy might be to identify the radioresistant subpopulation(s) of tumor cells and then tailor therapy specifically to cope with them—although, admittedly, this approach is much easier said than done. Some clinical studies—both prospective and retrospective—now include one or more determinations of, for example, extent of tumor hypoxia4,5 or potential doubling time of tumor clonogens6 or specific tumor molecular/genetic factors. The hope is that these and other biomarkers can identify subsets of patients bearing tumors with different biological characteristics and that, accordingly, patients with particular characteristics can be assigned prospectively to different treatment groups. Another consequence of tissue heterogeneity is that any radiobiological endpoint measured in an intact tissue necessarily reflects the sum total of the individual radiosensitivities of all of the subsets of cells, plus all other intrinsic and extrinsic factors that contribute to the overall response of the tissue. Since data on normal tissue tolerances and tumor control probabilities are also averaged across large numbers of patients, heterogeneity is even more pronounced.

Powers of Ten Tumor control is achieved only when all clonogenic cells are killed or otherwise rendered unable to sustain tumor growth indefinitely. In order to estimate the likelihood of cure, it is necessary to know, or at least have an appreciation for, approximately how many clonogenic cells the tumor contains, how radiosensitive these cells are (i.e., some measure of killing efficiency per unit radiation dose), and what the relationship is between the number of clonogenic cells remaining after treatment and the probability of recurrence. The latter is perhaps the easiest to ascertain given our knowledge of both the random and discrete nature of radiation damage and the general shape of dose-response curves for mammalian cells and tissues. For a given number of surviving cells per tumor, the probability of local control can be derived from Poisson statistics using the equation P = e−n, where P is the tumor

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CHAPTER 1 control probability and n is the average number of surviving clonogenic tumor cells. For example, when an average of one clonogenic cell per tumor remains at the end of radiation therapy, the tumor control rate will be about 37%. This means that about 6 out of 10 tumors of the same size and relative radiosensitivity will recur. Should the treatment reduce clonogenic cell numbers to an average of 0.1 per tumor, the tumor control probability would increase to 90%; 0.05 per tumor, 95%; and 0.01 per tumor, 99%, respectively. The tumor control probability for a given fraction of surviving cells is not particularly helpful when the total number of cells at risk is unknown; this is where an understanding of logarithmic relationships and exponential cell killing is useful. For example, estimates are that a 1-cm3 (1-g) tumor mass contains approximately 109 cells,7 admittedly a theoretical (and incorrect) value that assumes that all cells are perfectly packed and uniformly sized and that the tumor contains no stroma. A further assumption, that all such cells are clonogenic (rarely, if ever, the case), suggests that at least 9 logs of cell killing would be necessary before any appreciable tumor control (about 37%) would be achieved, and 10 logs of cell killing would be required for a high degree of tumor control (i.e., 90%). After the first log or two of cell killing, however, some tumors respond by shrinking, a so-called partial response. After two to three logs of cell killing, the tumor may shrink to a size below the current limits of clinical detection, that is, a complete response. While partial and complete responses are valid clinical endpoints, a complete response does not necessarily equal a tumor cure. At least six more logs of cell killing would still be required before any significant probability of cure would be expected. This explains why radiation therapy is not halted if the tumor disappears during the course of treatment; this concept is illustrated graphically in Fig. 1.2. Tumor mass 1 kg

1g

1 µg 1 ng

109 Number of tumor cells

1 mg

Number of 2.0-Gy fractions 10 20 30

Partial response

106 Complete response 103

100 Cure possible 10 0.9 Cure 0.37 probability 0.1

20

30 40 50 Total dose (Gy)

60

70

(Dose) Fig. 1.2 The relationship between radiation dose and tumor cell survival during fractionated radiotherapy of a hypothetical 1-g tumor containing 109 clonogenic cells. Although a modest decrease in cell-surviving fraction can cause the tumor to shrink (partial response) or disappear below the limits of clinical detection (complete response), few if any cures would be expected until at least 9 logs of clonogenic cells have been killed. In this example, a total dose of at least 60 Gy delivered as daily 2-Gy fractions would be required to produce a tumor control probability of 0.37, assuming that each dose reduced the surviving fraction to 0.5. (Modified from Steel G, Adams G, Peckham M, eds. The Biological Basis of Radiotherapy. New York: Elsevier; 1983.)

The Biological Basis of Radiation Oncology

5

Finally, it should be noted that while the goal of curative radiation therapy is to reduce tumor cell survival by at least nine logs, even for the smallest tumor likely to be encountered, it is much less clear how many logs of cell killing a particular normal tissue can tolerate before it loses its structural and/or functional integrity. This would depend on how the tissue is organized structurally, functionally, and proliferatively, which constituent cells are the most and least radiosensitive, and which cells are the most important to the integrity of the tissue. It is unlikely, however, that many normal tissues could tolerate a depletion of two logs (99%) of their cells, let alone nine or more logs.

RADIATION BIOLOGY AND THERAPY: THE FIRST 50 YEARS In fewer than 4 years after the discovery of x-rays by Roentgen,8 radioactivity by Becquerel,9 and radium by the Curies,10 the new modality of cancer treatment known as radiation therapy claimed its first cure of skin cancer.11 Today, more than 120 years later, radiotherapy is most commonly given as a series of small daily dose fractions of approximately 1.8 to 2.0 Gy each, 5 days per week, over a period of 5 to 7 weeks to total doses of 50 to 75 Gy. While it is true that the historical development of this conventional radiotherapy schedule was empirically based, there were a number of early radiobiological experiments that suggested this approach. In the earliest days of radiotherapy, both x-rays and radium were used for cancer treatment. Due to the greater availability and convenience of using x-ray tubes and the higher intensities of radiation output achievable, it was fairly easy to deliver one or a few large doses in short overall treatment times. Thus, from about 1900 into the 1920s, this “massive dose technique”12 was a common way of administering radiation therapy. Normal tissue complications were often quite severe and, to make matters worse, the rate of local tumor recurrence was still unacceptably high. Radium therapy was used more extensively in France. Because of the low activities available, radium applications necessarily involved longer overall treatment times in order to reach comparable total doses. Although extended treatments were less convenient, clinical results were often superior. Perceiving that the change in overall time was the critical factor, physicians began to experiment with the use of multiple, smaller x-ray doses delivered over extended periods. By that time, there was already a radiobiological precedent for expecting improvement in tumor control when radiation treatments were protracted. As early as 1906, Bergonié and Tribondeau observed histologically that the immature, dividing cells of the rat testis showed evidence of damage at lower radiation doses than the mature, nondividing cells of the stroma.13 Based on these observations, they put forth some basic “laws” stating that x-rays were more effective on cells that were (1) actively dividing, (2) likely to continue to divide indefinitely, and (3) undifferentiated.13 Since tumors were already known to contain cells that were not only less differentiated but also exhibited greater mitotic activity, they reasoned that several radiation exposures might preferentially kill these tumor cells but not their slowly proliferating, differentiated counterparts in the surrounding normal tissues. The end of common usage of the massive dose technique in favor of fractionated treatment came during the 1920s as a consequence of the pioneering experiments of Claude Regaud.14 Using the testes of the rabbit as a model tumor system (since the rapid and unlimited proliferation of spermatogenic cells simulated to some extent the pattern of cell proliferation in malignant tumors), Regaud showed that only through the use of multiple, smaller radiation doses could animals be completely sterilized without producing severe injury to the scrotum.15 Regaud suggested that the superior results afforded the multifraction irradiation scheme were related to alternating periods of relative radioresistance and sensitivity in the rapidly proliferating germ cells.16 These principles

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SECTION I

Scientific Foundations of Radiation Oncology

Total dose (Gy)

were soon tested in the clinic by Henri Coutard, who first used fractionated radiotherapy for the treatment of head and neck cancers, with spectacularly improved results, comparatively speaking.17,18 Largely as a result of these and related experiments, fractionated treatment subsequently became the standard form of radiation therapy. Time-dose equivalents for skin erythema published by Reisner,19 Quimby and MacComb,20 and others21,22 formed the basis for the calculation of equivalents for other tissue and tumor responses. By plotting the total doses required for each of these “equivalents” for a given level of effect in a particular tissue, as a function of a treatment parameter— such as overall treatment time, number of fractions, dose per fraction, and so forth—an isoeffect curve could be derived. All time-dose combinations that fell along such a curve theoretically would produce tissue responses of equal magnitude. Isoeffect curves, relating the total dose to the overall treatment time, derived in later years from some of these data,23 are shown in Fig. 1.3. The first published isoeffect curves were produced by Strandqvist in 194424 and are also shown in Fig. 1.3. When transformed on log-log coordinates, isoeffect curves for a variety of skin reactions and the cure of skin cancer were drawn as parallel lines, with common slopes of 0.33. These results implied that there would be no therapeutic advantage to using prolonged treatment times (i.e., multiple small fractions versus 80 70 60 50 40

oma

carcin

f skin ure o

C

30 20

”

nce

lera

“to Skin

ma

ythe

er Skin

10

A

1

2

3 4 5 10 20 40 60 80100 Overall treatment time (days)

Total dose (R)

10,000 sis necro oma Skin carcin in in k s of he sk Cure n of t io t a am esqu Dry d ema eryth Skin

5000 4000 3000 2000 1000 1

2 3 4 5 10 20 40 60 B Overall treatment time (days) Fig. 1.3 Isoeffect curves relating the log of the total dose to the log of the overall treatment time for various levels of skin reaction, and the cure of skin cancer. (A) Isoeffect curves constructed by Cohen in 1966, based on a survey of earlier published data on radiotherapy “equivalents.”19–22 See text for details. The slope of the curves for skin complications was 0.33 and that for tumor control, 0.22. (B) Strandqvist’s isoeffect curves, first published in 1944. All lines were drawn parallel and had a common slope of 0.33. (A, Modified from Cohen L. Radiation response and recovery: Radiobiological principles and their relation to clinical practice. In: Schwartz E, ed. The Biological Basis of Radiation Therapy. Philadelphia: J.B. Lippincott; 1966:208; B, modified from Strandqvist M. Studien uber die kumulative Wirkung der Roentgenstrahlen bei Fraktionierung. Acta Radiol Suppl. 1944;55:1.)

one, or a few, large doses) for the preferential eradication of tumors while simultaneously sparing normal tissues.25 It was somewhat ironic that the Strandqvist curves were so popular in the years that followed, when it was already known that the therapeutic ratio did increase (at least to a point) with prolonged, as opposed to very short, overall treatment times. However, the overarching advantage was that these isoeffect curves were quite reliable at predicting skin reactions, which were the dose-limiting factors at that time.

THE “GOLDEN AGE” OF RADIATION BIOLOGY AND THERAPY: THE SECOND 50 YEARS Perhaps the defining event that ushered in the golden age of radiation biology was the publication of the first survival curve for mammalian cells exposed to graded doses of x-rays. This first report of a quantitative measure of intrinsic radiosensitivity of a human cell line (HeLa, derived from a cervical carcinoma26) was published by Puck and Marcus in 1956.27 In order to put this seminal work in the proper perspective, it is first necessary to review the physicochemical basis for why ionizing radiation is toxic to biological materials.

The Interaction of Ionizing Radiation With Biological Materials As mentioned in the introductory section of this chapter, ionizing radiation deposits energy as it traverses the absorbing medium through which it passes. The most important feature of the interaction of ionizing radiation with biological materials is the random and discrete nature of the energy deposition. Energy is deposited in increasingly energetic packets referred to as spurs (≤100 eV deposited), blobs (100–500 eV), or short tracks (500–5000 eV), each of which can leave from approximately three to several dozen ionized atoms in its wake. This is illustrated in Fig. 1.4, along with a segment of (interphase) chromatin shown to scale. The frequency distribution and density of the different types of energy deposition events along the track of the incident photon or particle are measures of the radiation’s linear energy transfer (LET; see also the “Relative Biological Effectiveness” section to come). Because these energy deposition events are discrete, it follows that while the average energy deposited in a macroscopic volume of biological material is small, the distribution of this energy on a microscopic scale may be quite large. This explains why ionizing radiation is so efficient at producing biological damage; the total amount of energy deposited in a 70-kg human that Incident particle track

Chromatin fiber 30 nm

“Spur”: 0–100 eV “Blob”: 100–500 eV Short track: 500–5000 eV

Fig. 1.4 Hypothetical α-particle track through an absorbing medium, illustrating the random and discrete energy deposition “events” along the track. Each event can be classified according to the amount of energy deposited locally, which, in turn, determines how many ionized atoms will be produced. A segment of chromatin is also shown, approximately to scale. (Modified from Goodhead DT. Physics of radiation action: microscopic features that determine biological consequences. In: Hagen U, Harder D, Jung H, et al., eds. Radiation Research 1895-1995, Proceedings of the 10th International Congress of Radiation Research. Volume 2: Congress Lectures. Wurzburg: Universitatsdruckerei H. Sturtz AG; 1995:43–48.)

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CHAPTER 1 will result in a 50% probability of death is only about 70 calories, about as much energy as is absorbed by drinking one sip of hot coffee.28 The key difference is that the energy contained in the sip of coffee is uniformly distributed, not random and discrete. Those biomolecules receiving a direct hit from a spur or blob receive, relatively speaking, a huge radiation dose, that is, a large energy deposition in a very small volume. For photons and charged particles, this energy deposition results in the ejection of orbital electrons from atoms, causing the target molecule to be converted first into an ion pair and then into a free radical. Further, the ejected electrons—themselves energetic charged particles—can go on to produce additional ionizations. For uncharged particles such as neutrons, the interaction is between the incident particles and the nuclei of the atoms in the absorbing medium, causing the ejection of recoil protons (charged) and lower-energy neutrons. The cycle of ionization, free radical production, and release of secondary charged particles continues until all of the energy of the incident photon or particle is expended. These interactions are complete within a picosecond after the initial energy transfer. After that time, the chemical reactions of the resulting free radicals predominate the radiation response (see later discussion). Any and all cellular molecules are potential targets for the localized energy deposition events that occur in spurs, blobs, or short tracks. Whether the ionization of a particular biomolecule results in a measurable biological effect depends on a number of factors, including how probable a target the molecule represents from the point of view of the ionizing particle, how important the molecule is to the continued health of the cell, how many copies of the molecule are normally present in the cell and to what extent the cell can react to the loss of working copies, how important the cell is to the structure or function of its corresponding tissue or organ, and so on. DNA, for example, is obviously an important cellular macromolecule, and one that is present only as a single, doublestranded copy. On the other hand, other molecules in the cell may be less crucial to survival, yet are much more abundant than DNA and, therefore, have a much higher probability of being hit and ionized. By far, the most abundant molecule in the cell is water, comprising at least 70% to 80% of the cell on a per weight basis. The highly reactive free radicals formed by the radiolysis of water are capable of augmenting the DNA damage resulting from direct energy absorption by migrating to the DNA and damaging it indirectly. This mechanism is referred to as indirect radiation action to distinguish it from the aforementioned direct radiation action.29 The direct and indirect action pathways for ionizing radiation are illustrated below. Direct Effect DNA → [DNA + + e− ] → (irradiate )

(ion pair )

DNA •

(DNA free radical)

Indirect Effect H2O → [H2O+ + e− ] → (irradiate )

(ion pair )

( other radical reactions )

OH + DNA → DNA • + H2O

•

(DNA free radical and water)

The most highly reactive and damaging species produced by the radiolysis of water is the hydroxyl radical ( OH), although other free radical species are also produced in varying yields.30,31 Cell killing by indirect action constitutes some 70% of the total damage produced in DNA for low LET radiation. How do the free radicals produced by the direct and indirect action of ionizing radiation go on to cause the myriad lesions that have been identified in irradiated DNA? Since they contain unpaired electrons, free radicals are highly reactive chemically and will undergo multiple reactions in an attempt to either acquire new electrons or rid themselves of remaining unpaired ones. These reactions are considered quite slow

The Biological Basis of Radiation Oncology

7

compared with the time scale of the initial ionization events but are still fast relative to normal enzymatic processes in a typical mammalian cell. For all intents and purposes, free radical reactions are complete within milliseconds of irradiation. The OH radical is capable of both abstraction of hydrogen atoms from other molecules and addition across carbon-carbon or other double bonds. More complex macromolecules that have been converted to free radicals can undergo a series of transmutations in an attempt to rid themselves of unpaired electrons, many of which result in the breakage of nearby chemical bonds. In the case of DNA, these broken bonds may result in the loss of a base or an entire nucleotide, or a frank scission of the sugar phosphate backbone, involving either one or both DNA strands. In some cases, chemical bonds are broken initially but then rearranged, exchanged, or rejoined in inappropriate ways. Bases in DNA may be modified by the addition of one or more hydroxyl groups (e.g., the base thymine converted to thymine glycol), pyrimidines may become dimerized, and/or the DNA may become cross-linked to itself or to associated proteins. Again, because the initial energy deposition events are discrete, the free radicals produced also are clustered and, therefore, undergo their multiple chemical reactions and produce multiple damages in a highly localized area. This has been termed the locally multiply damaged site32 or cluster33 hypothesis. Examples of the types of damage found in irradiated DNA are shown in Fig. 1.5.

Biochemical Repair of DNA Damage DNA is unique insofar as it is the only cellular macromolecule with its own repair system. Until as recently as 35 years ago, little was known about DNA repair processes in mammalian cells, particularly because of the complexities involved and the relative lack of spontaneously occurring mutants defective in genes involved with DNA repair. As a consequence, most studies of DNA repair were carried out either in bacteria or yeasts and usually employed UV radiation as the tool for producing DNA damage. Although these were rather simple and relatively clean systems in which to study DNA repair, their relevance to mammalian repair systems and to the broader spectrum of DNA damage produced by ionizing radiation ultimately limited their usefulness. The study of DNA repair in mammalian cells received a significant boost during the late 1960s with publications by Cleaver34,35 that identified the molecular defect responsible for the human disease xeroderma pigmentosum (XP). Patients with XP are exquisitely sensitive to sunlight and highly (skin) cancer prone. Cleaver showed that cells derived from such patients were likewise sensitive to UV radiation and defective in the nucleotide excision repair pathway (see later discussion). These cells were not especially sensitive to ionizing radiation, however. Several years later, Taylor et al.36 reported that cells derived from patients with a second cancer-proneness disorder called ataxia telangiectasia (AT) were extremely sensitive to ionizing radiation and radiation-mimetic drugs, but not UV. In the years that followed, cell cultures derived from patients with these two conditions were used to help elucidate the complicated processes of DNA repair in mammalian cells. Today, dozens of other clinical syndromes associated with radiosensitivity, cancer proneness, or both have been identified.37,38 Today, many rodent and human genes involved in DNA repair have been cloned and extensively characterized.39 Some 30 to 40 proteins participate in excision repair of base damage; about half that many are involved in the repair of strand breaks.37 Many of these proteins function as component parts of larger repair complexes. Some are interchangeable and participate in other DNA repair and replication pathways as well. It is also noteworthy that some are not involved with the repair process per se, but rather link DNA repair to other cellular functions, including transcription, cell cycle arrest, chromatin remodeling, and apoptosis.40

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SECTION I

Scientific Foundations of Radiation Oncology with other cellular activities is termed the DNA Damage Response (DDR).37,41 For example, the defect responsible for the disease AT is not in a gene that codes for a repair protein but rather in a gene that acts in part as a damage sensor and signal transducer but also participates in a related pathway that normally prevents cells from entering S phase and beginning DNA synthesis while residual DNA damage is present. This is termed the G1 cell cycle checkpoint response.42 Because of this genetic defect, AT cells do not experience the normal G1 arrest after irradiation and enter S phase with residual DNA damage. This accounts both for the exquisite radiosensitivity of AT cells and the resulting genomic instability that can lead to cancer. The molecular and biochemical intricacies of DNA repair in mammalian cells are described in detail in Chapter 2. A brief overview is also presented next.

DNA-DNA Cross-link

Nucleotide loss (with strand break)

Base Excision Repair Base loss

Modified base Single-stranded break

Double-stranded break

A

The repair of base damage is initiated by DNA repair enzymes called glycosylases, which recognize specific types of damaged bases and excise them without otherwise disturbing the DNA strand.43 The action of the glycosylase results in the formation of another type of damage observed in irradiated DNA—an apurinic or apyrimidinic (AP) site. The AP site is then recognized by another repair enzyme, an endonuclease that nicks the DNA adjacent to the lesion, in effect creating a DNA single-stranded break. This break then becomes the substrate for an exonuclease, which removes the abasic site, along with a few additional bases. The small gap that results is patched by DNA polymerase using the opposite, hopefully undamaged, DNA strand as a template. Finally, DNA ligase seals the patch in place.

Nucleotide Excision Repair O

O CH3

HN O

HN O

N dR Thymine

N dR

Thymine glycol

O

O N

HN H2N

B

N Guanine

CH3 OH OH H

N dR

N

HN H2N

OH N

N dR

8-Hydroxyguanine

Fig. 1.5 Types of DNA damage produced by ionizing radiation. (A) Segment of irradiated DNA containing single- and double-stranded breaks, cross-links, and base damage. (B) Two types of modified bases observed in irradiated DNA include thymine glycol, which results from the addition of two hydroxyl (OH) groups across the carbon-carbon double bond of thymine, and 8-hydroxyguanine, produced by OH radical addition to guanine.

This attests to the fact that the maintenance of genomic integrity results from a complex interplay between not only the repair proteins themselves but also others that serve as damage sensors, signaling mediators and transducers, and effectors. Collectively, this complex network of proteins that sense, initiate, and coordinate DNA damage signaling and repair

The DNA glycosylases that begin the process of base excision repair do not recognize all known forms of base damage, however, particularly bulky or complex lesions.43 In such cases, another group of enzymes, termed structure-specific endonucleases, initiate the excision repair process. These repair proteins do not recognize the specific lesion but rather the structural distortions in DNA that necessarily accompany a complex base lesion. The structure-specific endonucleases incise the affected DNA strand on both sides of the lesion, releasing an oligonucleotide fragment made up of the damage site and several bases on either side of it. After this step, the remainder of the nucleotide excision repair process is similar to that of base excision repair. The gap is then filled by DNA polymerase and sealed by DNA ligase. For both types of excision repair, active genes in the process of transcription are repaired preferentially and more quickly. This has been termed transcription-coupled repair.44

Single-Strand Break Repair Single-strand breaks (SSBs) in the DNA backbone are common lesions, produced in the tens of thousands per cell per day as part of normal metabolism and respiration45 on top of any additional breaks introduced by radiation exposure. These are repaired using the machinery of excision repair, that is, gap filling by DNA polymerase and sealing by DNA ligase.

Double-Strand Break Repair Despite the fact that unrepaired or misrejoined double-strand breaks (DSBs) often have the most catastrophic consequences for the cell in terms of loss of reproductive integrity,46 how mammalian cells repair these lesions has been more difficult to elucidate than how they repair base damage. Much of what was originally discovered about these repair processes is derived from studies of x-ray-sensitive rodent cells that were later discovered to harbor specific defects in strand break repair.47 Since then, dozens of other rodent and human cells characterized

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CHAPTER 1 by DDR defects have been identified and are also used to help probe these fundamental processes. With respect to the repair of DSBs, the situation is more complicated in that the damage on each strand of DNA may be different and, therefore, no intact template would be available to guide the repair process. Under these circumstances, cells must rely on a somewhat error-prone process that rejoins the break(s) regardless of the loss of intervening base pairs for which there is no template (nonhomologous end joining [NHEJ]) or depend on genetic recombination in which a template for presumably error-free repair is obtained from recently replicated DNA of a sister chromatid (homologous recombination [HR]48) to cope with the damage. NHEJ occurs throughout the cell cycle, but predominates in cells that have not yet replicated their DNA, that is, cells in the G1 or G0 phases of the cell cycle. NHEJ involves a heterodimeric enzyme complex consisting of the proteins Ku-70 and Ku-80, the catalytic subunit of DNA protein kinase (DNA-PKCS), and DNA ligase IV. Cells that have already replicated most or all of their DNA—in the late S or G2 phases of the cell cycle—depend on HR to repair DSBs. HR involves the assembly of a nucleoprotein filament that contains, among others, the proteins Rad51 and Rad52. This filament then invades the homologous DNA sequence of a sister chromatid, which becomes the template for repair. The BRCA2 protein is also implicated in HR as it interacts with the Rad51 protein.38 Defects in either the BRCA1 (which helps determine which DSB repair pathway will be used in a particular situation) or BRCA2 genes are associated with hereditary breast and ovarian cancer.49

Mismatch Repair The primary role of mismatch repair (MMR) is to eliminate from newly synthesized DNA errors such as base/base mismatches and insertion/ deletion loops caused by DNA polymerase.50 This process consists of three steps: mismatch recognition and assembly of the repair complex, degradation of the error-containing strand, and repair synthesis. In humans, MMR involves at least five proteins, including hMSH2 and hMLH1, as well as other members of the DNA repair and replication machinery. Radiation-induced DNA lesions are not targets for mismatch repair per se. However, one manifestation of a defect in mismatch repair is germane to any study of oncogenesis: genomic instability,51 which renders affected cells hypermutable. This “mutator phenotype” is associated with several cancer predisposition syndromes, in particular, hereditary nonpolyposis colon cancer (HNPCC, a.k.a. Lynch syndrome).52,53 Genomic instability is considered one of the main enablers of normal cells to accumulate cancer-causing mutations and also drives tumor progression to more aggressive and potentially treatment-resistant phenotypes.

The DDR as a Clinical Target Historically, attempts to inhibit the repair of radiation-induced DNA damage were of interest to researchers probing these fundamental processes. However, clinical translation was typically lacking, mostly out of concern that normal tissues would also be affected in an adverse way. More recently, it has become clear that the cells of many tumors harbor one or more defects in the DDR (as a consequence of genomic instability) that are not present in normal cells and that this difference might be exploitable clinically. One approach along these lines is the use of inhibitors of the protein poly(ADP-ribose) polymerase (PARP).54,55 As of 2018, dozens of trials were underway using PARP inhibitors in combination with chemo- and immunotherapies.56,57 PARP is a damage sensor involved in both base excision and SSB repair that, if inhibited, leads to the persistence of SSBs. If left unrejoined, these breaks can cause the collapse of replication forks in DNA that then impede DNA replication, transcription, and HR repair,55 leading to radiosensitization and, ultimately, cell death.58

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9

In normal cells, little or no toxicity caused by PARP inhibition would be expected, as all DDR pathways are intact and salvage repair pathways to bypass PARP inhibition are active. In tumor cells already harboring defects in HR, however, PARP inhibition would be preferentially toxic. One clinical example is the targeting of breast cancers harboring cellular defects in the BRCA1/2 proteins—which either orchestrate or are directly involved in HR—for PARP inhibition. This overall approach of using the combined lethal effect of two genetic defects (one inherent HR defect plus one synthetic one induced by PARP inhibition) that are otherwise nonlethal singly is termed synthetic lethality.54,55,58 Synthetic lethality approaches targeting DDR proteins (including those other than PARP) likely will play increasingly important roles in the future.

Cytogenetic Effects of Ionizing Radiation When cells divide following radiation exposure, chromosomes frequently contain visible structural aberrations that are the result of any unrepaired or misrejoined DNA damage that persists from the time of irradiation. Most chromosome aberrations are lethal to the cell. In some cases, these aberrations physically interfere with the processes of mitosis and cytokinesis, resulting in prompt cell death. In other cases, cell division can occur but the loss or uneven distribution of genetic material between the cell’s progeny is ultimately lethal as well, although the affected cells may linger for several days before they die, with some even be able to go through a few more cell divisions in the interim. Most chromosome aberrations result from an interaction between two damage sites; therefore, they can be grouped into three different types of “exchange” categories. A fourth category is reserved for those chromosome aberrations that are thought to result from a single damage site.59 These categories are described here; representative types of aberrations from each category are shown in Fig. 1.6: 1. Intra-arm Exchanges: An interaction between lesions on the same arm of a single chromosome (example: interstitial deletion). 2. Inter-arm Exchanges: An interaction between lesions on opposite arms of the same chromosome (example: centric ring). 3. Interchanges: An interaction between lesions on different chromosomes (example: dicentric). 4. “Single Hit” Breaks: The complete severance of part of one arm of a single chromosome not obviously associated with any more than a single lesion (example: terminal deletion). These four categories can be further subdivided according to whether the initial radiation damage occurred before or after the DNA is replicated (a chromosome- vs. chromatid-type aberration, respectively) and, for the three exchange categories, whether the lesion interaction is symmetrical or asymmetrical. Asymmetrical exchanges always lead to the formation of acentric fragments that are usually lost in subsequent cell divisions and, therefore, are nearly always fatal to the cell. These fragments may be retained transiently in the cell’s progeny as extranuclear chromatin bodies called micronuclei. Symmetrical exchanges are more insidious in that they do not lead to the formation of acentric fragments and the accompanying loss of genetic material at the next cell division; thus, they do not always kill the cell. As such, they will be transmitted to all progeny of the original cell. Some types of symmetrical exchanges (e.g., a reciprocal translocation) have been implicated in radiation carcinogenesis insofar as they have the net effect of either bringing new combinations of genes together or separating preexisting groups of genes.28 Depending on where in the genome the translocation takes place, genes normally active could be turned off or vice versa, potentially with adverse consequences. Quantitation of the types and frequencies of chromosome aberrations in irradiated cells can be used to probe dose-response relationships for ionizing radiation and, to a first approximation, also can serve as a radiation dosimeter. For example, the dose-response curve for the

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Scientific Foundations of Radiation Oncology

Intra-arm exchanges

Inter-arm exchanges

Interchanges

“Single-hit” breaks

X-ray

Terminal deletion Centric ring and fragment

Dicentric and fragment

Asymmetrical

Symmetrical

Interstitial deletion

Paracentric inversion

Paracentric inversion

Reciprocal translocation

Fig. 1.6 Types of radiation-induced chromosome aberrations that are the result of unrepaired or misrejoined DNA damage. Aberrations are classified according to whether they involve a single or multiple chromosomes, whether the damage is thought to be caused by the passage of a single charged particle track (“one-hit” aberration), or by the interaction of damages produced by two different tracks (“two-hit” aberration), and whether the irradiation occurred prior to or after the chromosomes had replicated (chromosome- vs. chromatidtype aberrations, respectively; only chromosome-type aberrations are shown). The aberrations can be further subdivided according to whether broken pieces of the chromosome rearrange themselves symmetrically (with no net loss of genetic material) or asymmetrically (acentric fragments produced).

induction of exchange-type aberrations after exposure to low-LET radiation tends to be linear-quadratic in shape, whereas that for single-hit aberrations tends to be linear. In mathematical terms, the incidence, I, of a particular aberration as a function of radiation dose, D, can be expressed as I = αD + βD2 + c for exchange-type aberrations I = αD + c for single-hit aberrations, where α and β are proportionality constants related to the yields of the particular type of aberration and c is the spontaneous frequency of that aberration in unirradiated cells. For fractionated doses or continuous low dose rates of low-LET radiation, the yield of exchange-type aberrations decreases relative to that for acute doses, and the dose-response curve becomes more linear. For high-LET radiations, dose-response curves become steeper (higher aberration yields per unit dose) and more linear compared with those for low-LET radiations.

Cell Survival Curves and Survival Curve Theory What Is Meant by “Cell Death”?

The traditional definition of death as a permanent, irreversible cessation of vital functions is not the same as what constitutes “death” to the radiation biologist or oncologist. For proliferating cells—including those maintained in vitro, the stem cells of normal tissues, and tumor clonogens—cell death in the radiobiological sense refers to a loss of reproductive integrity, that is, an inability to sustain proliferation indefinitely. This type of “reproductive” or “clonogenic” death does not

preclude the possibility that a cell may remain physically intact, metabolically active, and continue its tissue-specific functions for some time after irradiation.60 Compared with nearly 65 years ago, when the term clonogenic death was first coined and used as an endpoint in assays of cellular radiosensitivity,27,61 by today’s standards it is clearly an operationally defined term that encompasses several distinct mechanisms by which cells die, all of which result in a cell losing its ability to divide indefinitely. These modes of cell death include mitotic catastrophe, apoptosis, necrosis, senescence, and autophagy. Strictly speaking, differentiation is included as well, because differentiated cells lose their ability to divide.62,63 Mitotic catastrophe is the major mode of radiation-induced death for most mammalian cells, occurring secondary to chromosome aberrations and/or spindle defects that interfere with the cell division process.64,65 Accordingly, this type of cell death occurs during or soon after an attempted cell division postirradiation (although not necessarily during the very first division attempt), leaving in its wake large, flattened, and multinucleated cells that are typically aneuploid. Apoptosis, or programmed cell death, is a type of nonmitotic or interphase death commonly associated with embryonic development and normal tissue remodeling and homeostasis.66 However, certain normal tissue and tumor cells also undergo apoptosis following irradiation, including normal cells of hematopoietic or lymphoid origin, crypt cells of the small intestine, salivary gland cells, plus a few tumor cell lines of gynecological and hematological origin.67 Cells undergoing apoptosis exhibit a number of characteristic morphological (nuclear condensation and fragmentation, membrane blebbing, etc.) and biochemical (DNA degradation) changes that culminate in the fragmentation of the cell, typically within 12 to

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CHAPTER 1 24 hours of irradiation and prior to the first postirradiation mitosis. The remains of apoptotic cells are phagocytized by neighboring cells; therefore, they do not elicit the type of inflammatory response, tissue destruction, and disorganization characteristic of necrosis. Apoptosis is an active and carefully regulated pathway that involves multiple proteins and an appropriate stimulus that activates the pathway. The molecular biology of apoptosis, the apoptosis-resistant phenotype noted for many types of tumor cells, and the role that radiation may play in the process are discussed in detail in Chapter 2. Senescence refers to a type of genetically controlled cellular growth arrest that, while not necessarily eliminating damaged cells, does halt permanently their continued movement through the cell cycle even in the presence of growth factors.68 Radiation can also induce senescence, presumably due to the permanent triggering of cell cycle checkpoints. However, it might better be termed radiation-induced permanent growth arrest to distinguish it from the normal process of cell age-related senescence.69 Autophagy is defined as the controlled lysosomal degradation of cytoplasmic organelles or other cytoplasmic components70,71 in response to cellular stressors, including nutrient deprivation, hypoxia, DNA damage, or an excess of reactive oxygen species. Likewise, necrosis—characterized by cell swelling followed by membrane rupture and the release of cellular contents into the extracellular space—can occur as a somewhat passive response to nutrient deprivation but also can follow a molecular program initiated by immune cells or various toxins.72,73 Most assays of radiosensitivity of cells and tissues, including those described later, use reproductive integrity, either directly or indirectly, as an endpoint. While such assays have served the radiation oncology community well in terms of elucidating dose-response relationships for normal tissues and tumors, the interrelationships between the different modes of cell death can be quite complex. For example, Meyn67 has suggested that a tumor with a high spontaneous apoptotic index may be inherently more radiosensitive because cell death might be triggered by lower doses than are usually required to cause mitotic catastrophe. Also, tumors that readily undergo apoptosis may have higher rates of cell loss, the net effect of which would be to partially offset cell production, thereby reducing the number of tumor clonogens. On the other hand, recent studies suggest that the very enzymes that orchestrate the removal of radiation-damaged cells via apoptosis also may stimulate tumor cell repopulation during and after radiotherapy.74 Studies also suggest that senescent cells can produce inflammatory cytokines that further contribute to immunosuppression in the tumor microenvironment.68

Cell Survival and Dose-Response Curve Models Survival curve theory originated in a consideration of the physics of energy deposition in matter by ionizing radiation. Early experiments with macromolecules and prokaryotes established that dose-response relationships could be explained by the random and discrete nature of energy absorption if it was assumed that the response resulted from critical “targets” receiving random “hits.”75 With an increasing number of shouldered survival and dose-response curves being described for cells irradiated both in vitro and in vivo, various equations were developed to fit these data. Target theory pioneers studied a number of different endpoints in the context of target theory, including enzyme inactivation in cell-free systems,29 cellular lethality, chromosomal damage, and radiation-induced cell cycle perturbations in microorganisms.29,76 Survival curves, in which the log of the “survival” of a certain biological activity was plotted as a function of the radiation dose, were found to be either exponential or sigmoid in shape, the latter usually noted for the survival of more complex organisms.29 Exponential survival curves were thought to result from the single-hit, “all or nothing” inactivation of a single target, resulting in the loss of

The Biological Basis of Radiation Oncology

11

activity. A mathematical expression used to fit this type of dose-response relationship is S = e−D D0 In this equation, S is the fraction of cells that survive a given dose, D, and D0 is the dose increment that reduces the cell survival to 37% (1/e) of some initial value on the exponential portion of the curve (i.e., a measure of the reciprocal of the slope). Target theory could also be applied to survival curves with shoulders at low doses if one assumed that either multiple targets or multiple hits in a single target were necessary for radiation inactivation. A mathematical expression based on target theory that provided a fairly good fit to survival data was S = 1− (1− e−D D0 )n with n being the back extrapolation of the exponential portion of the survival curve to zero dose. Implicit in this multitarget model was that damage had to accumulate before the overall effect was registered. It soon became apparent that some features of this model were inadequate.77 The most obvious problem was that the single-hit, multitarget equation predicted that survival curves should have initial slopes of zero, that is, that for vanishingly small doses (e.g., repeated, small doses per fraction or continuous low dose rate exposure), the probability of cell killing would approach zero. This is not what was observed in practice for either mammalian cell survival curves or as inferred from clinical studies in which highly fractionated or low dose rate treatment schedules were compared to more conventional fractionation. There was no fractionation schedule that produced essentially no cell killing, all other radiobiological factors being equal. A somewhat different interpretation of cell survival was proposed by Kellerer and Rossi78 in the late 1960s and early 1970s. The linearquadratic or “alpha-beta” equation, 2)

S = e−(αD+βD

was shown to fit many survival data quite well, particularly in the lowdose region of the curve, and also provided for the negative initial slope that investigators had described.77 In this expression, S is again the fractional cell survival following a dose D, α is the rate of cell kill by a single-hit process, and β is the rate of cell kill by a two-hit mechanism. The theoretical derivation of the linear-quadratic equation is based on two sets of observations. Based on microdosimetric considerations, Kellerer and Rossi78 proposed that a radiation-induced lethal lesion resulted from the interaction of two sublesions. According to this interpretation, the αD term is the probability of these two sublesions being produced by a single event (the “intra-track” component), whereas βD2 is the probability of the two sublesions being produced by two separate events (the “inter-track” component). Chadwick and Leenhouts79 derived the same equation based on a different set of assumptions, namely, that a DSB in DNA was a lethal lesion and that such a lesion could be produced by either a single energy deposition involving both strands of DNA or by two separate events, each involving a single strand. A comparison of the features and parameters of the target theory and linear-quadratic survival curve expressions is shown in Fig. 1.7.

Clonogenic Assays In Vitro As mentioned previously, it was not until the mid-1950s that mammalian cell culture techniques were sufficiently refined to allow quantitation of the radiation responses of single cells.61,80 Puck and Marcus’s acute

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Scientific Foundations of Radiation Oncology

S = 1 – (1 – e–D/D0)n

n Dq Surviving fraction

Surviving fraction

α Cell kill

0.01

β Cell kill S = e – (αD ! βD2)

α"β Ratio

1/e 0.0037

B

Dose (Gy)

D0

A

Dose (Gy)

Fig. 1.7 A comparison of two mathematical models commonly used to fit cell survival curve data. (A) The single-hit, multi-target model and its associated parameters, D0, n, and Dq. Although this model has since been invalidated, values for its parameters are still used for comparative purposes. (B) The linear-quadratic model and its associated parameters, α and β. This model provided the conceptual framework for current isoeffect formulae used in radiation therapy treatment planning.

Surviving fraction

100

10!1

10!2

10!3 1

2

3 4 5 6 7 Dose (Gy) Fig. 1.8 Clonogenic survival of HeLa cells in vitro as a function of x-ray dose. Like many mammalian cells of both tumorigenic and nontumorigenic origin, the HeLa cell survival curve is characterized by a modest initial shoulder region (n ≈ 2.0) followed by an approximately exponential final slope (D0 ≈ 1.0 Gy). (Modified from Puck TT, Marcus PI. Action of x-rays on mammalian cells. J Exp Med. 1956;103:653.)

dose, x-ray survival curve for the human tumor cell line HeLa is shown in Fig. 1.8. Following graded x-ray doses, the reproductive integrity of single HeLa cells was measured by their ability to form macroscopic colonies of at least 50 cells (corresponding to approximately 6 successful postirradiation cell divisions) on petri dishes. Several features of this survival curve were of particular interest. First, qualitatively at least, the curve was similar in shape to those previously determined for many microorganisms, being characterized by a shoulder at low doses and a roughly exponential region at high doses. Of note, however, was the finding that the D0 for HeLa cells was only 96 R, some 10- to 100-fold less than D0s determined for microorganisms and 1000- to 10,000-fold less than D0s for the inactivation of isolated macromolecules.60 Thus, cellular reproductive integrity was found to be a much more radiosensitive

endpoint for HeLa cells than for prokaryotes or primitive eukaryotes. The value of the extrapolation number, n, was approximately 2.0, indicating that the survival curve did have a small shoulder but, again, much smaller than typically observed for microorganisms. Puck and Marcus suggested that the n value was a reflection of the number of critical targets in the cell, each requiring a single hit before the cell would be killed, and further postulated that the targets were, in fact, the chromosomes themselves.27 However, the potential pitfalls of deducing mechanisms of radiation action from parameters of a descriptive survival curve model were soon realized.81,82 Survival curves for other types of mammalian cells, regardless of whether they were derived from humans or laboratory animals, or from tumors or normal tissues, have been shown to be qualitatively similar to the original HeLa cell survival curve.

Clonogenic Assays In Vivo In order to bridge the gap between the radiation responses of cells grown in culture and in an animal, Hewitt and Wilson developed an ingenious method to assay single-cell survival in vivo.83 Lymphocytic leukemia cells obtained from the livers of donor CBA mice were harvested, diluted, and inoculated into disease-free recipient mice. By injecting different numbers of donor cells, a standard curve was constructed that allowed a determination of the average number of injected cells necessary to cause leukemia in 50% of the recipient mice. It was determined that the endpoint of this titration, the 50% take dose (TD50), corresponded to an inoculum of a mere two leukemia cells. Using this value as a reference, Hewitt and Wilson then injected leukemia cells harvested from γ-irradiated donor mice into recipients and again determined the TD50 following different radiation exposures. In this way, the surviving fraction after a given radiation dose could be calculated from the ratio of the TD50 for unirradiated cells to that for the irradiated cells. Using this technique, a complete survival curve was constructed that had a D0 of 162 R and an n value close to 2.0, values quite similar to those generated for cell lines irradiated in vitro. For the most part, in vivo survival curves for a variety of cell types were also similar to corresponding in vitro curves.

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CHAPTER 1 A similar trend was apparent when in vivo survival curves for nontumorigenic cells were first produced. The first experiments by Till and McCulloch84,85 using normal bone marrow stem cells were inspired by the knowledge that failure of the hematopoietic system was a major cause of death following total body irradiation and that lethally irradiated animals could be “rescued” by a bone marrow transplant. The transplanted, viable bone marrow cells were observed to form discrete nodules or colonies in the otherwise sterilized spleens of irradiated animals. Subsequently, these authors transplanted known quantities of irradiated donor bone marrow into lethally irradiated recipient mice. They were able to count the resulting splenic nodules and then calculate the surviving fraction of the injected cells in much the same way as was done for in vitro experiments. The D0 for mouse bone marrow was 0. 95 Gy.84 Other in vivo assay systems based on the counting of colonies or nodules included the skin epithelium assay of Withers,86 the intestinal crypt assays of Withers and Elkind,87,88 and the lung colony assay of Hill and Bush.89 During the late 1960s and early 1970s, it also became possible to do excision assays, in which tumors irradiated in vivo were removed, enzymatically dissociated, and single cells plated for clonogenic survival in vitro. This allowed more quantitative measurement of survival, avoiding some of the pitfalls of in vivo assays (e.g., Rockwell and Kallman90).

Nonclonogenic Assays In Vivo Some normal tissues and tumors are not amenable to clonogenic assays. Thus, new assays were needed that had clinical relevance yet did not rely on reproductive integrity as an endpoint. Use of such assays required one leap of faith—namely, that the endpoints assessed would have to be a consequence of the killing of clonogenic cells, although not necessarily in a direct, one-to-one manner. Because nonclonogenic assays do not directly measure cell survival as an endpoint, data derived from them and plotted as a function of radiation dose are properly called dose-response curves rather than cell survival curves, although such data are often analyzed and interpreted similarly. Historically, among the first nonclonogenic assays was the mean lethal dose or LD50 assay, in which the (whole body) radiation dose to produce lethality in approximately 50% of the test subjects is determined, usually at a fixed time after irradiation, such as 30 (LD50/30) or 60 days (LD50/60). Clearly, the LD50 assay is not very specific in that the cause of death can result from damage to a number of different tissues. Another widely used nonclonogenic method to assess normal tissue radioresponse is the skin reaction assay, originally developed by Fowler et al.91 Pigs were often used because their skin is similar to that of humans in several respects. An ordinate scoring system was used to compare and contrast different radiation schedules, which was derived from the average severity of the skin reaction noted during a certain time period (specific to the species and whether the endpoint occurs early or late) following irradiation. For example, for early skin reactions, a skin score of 1 might correspond to mild erythema, whereas a score of 4 might correspond to confluent moist desquamation over more than half of the irradiated area. Finally, two common nonclonogenic assays for tumor response are the growth delay/regrowth delay assay92 and the tumor control dose assay.93 Both assays are simple and direct, are applicable to most solid tumors, and are clinically relevant. The growth delay assay involves measurements of a tumor’s dimensions or volume as a function of time after irradiation. For tumors that regress rapidly during and after radiotherapy, the endpoint scored is typically the time in days that it takes for the tumor to regrow to its original volume at the start of irradiation. For tumors that regress more slowly, a more appropriate endpoint might be the time that it takes for the tumor to grow or regrow to a specified size, such as three times its original volume.

The Biological Basis of Radiation Oncology

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Dose-response curves are generated by plotting the amount of growth delay as a function of radiation dose. The tumor control assay is a logical extension of the growth delay assay. The endpoint of this assay is the total radiation dose required to achieve a specified probability of local tumor control—usually 50% (TCD50)—in a specified period of time after irradiation. The TCD50 value is obtained from a plot of the percentage of tumors locally controlled as a function of total dose. The slope of the resulting doseresponse curve may be used for comparative purposes as a measure of the tumor’s inherent “radiosensitivity” and/or its degree of heterogeneity. More heterogeneous tumors tend to have shallower dose response curves than more homogeneous ones, as do spontaneous tumors relative to experimental ones maintained in inbred strains of mice.

Cellular “Repair”: Sublethal and Potentially Lethal Damage Recovery Taking the cue from target theory that the shoulder region of the radiation survival curve indicated that “hits” had to accumulate prior to cell killing, Elkind and Sutton94,95 sought to better characterize the nature of the damage caused by these hits and how the cell processed this damage. Even in the absence of any detailed information about DNA damage and repair at the time, a few things seemed obvious. First, those hits or damages that were registered as part of the accumulation process yet did not in and of themselves produce cell killing were, by definition, sublethal. Second, sublethal damage (SLD) became lethal only when it interacted with additional sublethal damage, that is, when the total amount of damage had accumulated to a sufficient level to cause cell killing. But what would be the result of deliberately interfering with the damage accumulation process by, for example, delivering part of the intended radiation dose, inserting a radiation-free interval, and then delivering the remainder of the dose? The results of such “split-dose” experiments turned out to be crucial to the understanding of why and how fractionated radiation therapy works as it does. The discovery and characterization of SLD, as low tech and operational the concept may be by today’s standards, still stands as arguably the single most important contribution that radiation biology has made to the practice of radiation oncology. By varying the time interval between two doses of approximately 5.0 Gy and plotting the log of the surviving fraction of cells after both doses (i.e., 10 Gy total dose) as a function of the time between the doses, the resulting split-dose recovery curve was observed to rise to a maximum after about 2 hours and then level off. In other words, the overall surviving fraction of cells following 10 Gy was higher if the dose was split into two fractions with a time interval in between than delivered as a single dose. Elkind interpreted these results as indicating that the cells that survived the initial dose fraction had “repaired” some of the damage during the radiation-free interval and, as such, this damage was no longer available to interact with the damage inflicted by the second dose. At the time, Elkind referred to this phenomenon as sublethal damage repair (SLDR). In retrospect, it is perhaps preferable to call it sublethal damage recovery, since biochemical DNA repair processes were not actually measured, only changes in cell survival. Of additional interest was the observation that the shape of the split-dose recovery curve varied with the temperature during the radiation-free interval (Fig. 1.9). When the cells were maintained at room temperature between the split doses, the SLDR curve rose to a maximum after about 2 hours and then leveled off. When the cells were returned to a 37° C incubator for the radiation-free interval, a different pattern emerged. Initially, the split-dose recovery curve rose to a maximum after 2 hours; then, the curve exhibited a series of oscillations, dropping to a second minimum for a split of about 4 to 5 hours, and then rising again to a higher maximum for split-dose intervals of 10

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SECTION I

Scientific Foundations of Radiation Oncology

hours or more. The interpretation of this pattern of SLDR was that other radiobiological phenomena operated simultaneously with cellular recovery. In this case, the fine structure of the split-dose recovery curve was not caused by an oscillating repair process but rather by a superimposed cell cycle effect: the so-called radiation “age response” through the cell cycle. This is discussed later in the “Ionizing Radiation and the Cell Cycle” section (see also Fig. 1.14). Since Elkind and Sutton’s original work, SLDR kinetics have been described for many different types of mammalian cells in culture,60 and for most normal and tumor tissues in vivo (e.g., Belli et al.96 and Emery et al.97). Pertinent findings include the following: 1. The amount of SLD capable of being repaired for a given cell type varies both with the radiation quality (less for radiations of increasing

"t 7.6 Gy 7.9 Gy V79 hamster cells

Surviving fraction

10!1

LET) and the oxygenation status of the cells (recovery reduced or absent at extremely low oxygen tensions).28 2. The half-time for SLDR in mammalian cells in culture is, on average, about 1 hour, although there is evidence that it may be somewhat longer for late-responding normal tissues in vivo.28 3. The survival increase between split doses is a manifestation of the “regeneration” of the shoulder of the radiation survival curve. After an initial radiation dose and an adequate time interval for SLDR, the response of surviving cells to graded additional doses is nearly identical to that obtained from cells without previous radiation exposure. Thus, the width of the shoulder of the survival curve came to be associated with the capacity of the cells for recovery from sublethal damage. This concept is illustrated in Fig. 1.10. 4. Cells are able to undergo repeated cycles of damage and recovery without a change in recovery capacity. As such, one would predict an equal effect per dose fraction during the course of fractionated radiotherapy. In a more practical sense, this means that a multifraction survival curve can be generated using the formula SFn = (SF1)n, where SF1 is the surviving fraction of cells after a single-dose fraction (determined from a single-dose survival curve), and SFn is the surviving fraction of cells after n dose fractions. Accordingly, multifraction survival curves are shoulderless and exponential (Fig. 1.11). 5. Sublethal damage recovery is largely responsible for the dose rate effect for low-LET radiation, which will be discussed in detail later in this chapter. As the dose per fraction (intermittent radiation) or dose rate (continuous irradiation) is decreased and the overall treatment time increased, the biological effectiveness of a given total dose is reduced. (Note that SLDR also occurs during continuous irradiation, i.e., that a radiation-free interval is not required per se.) A second type of cellular recovery following irradiation is termed potentially lethal damage repair or recovery (PLDR), and was first described for mammalian cells by Phillips and Tolmach98 in 1966. PLD is, by definition, a spectrum of radiation damage that may or may not result in cell killing depending on the cell’s postirradiation environment. Environmental conditions that favor PLDR include maintenance of cells in overcrowded conditions (plateau phase or contact-inhibited99,100) and

37° C

24° C

10!2

0

2

4 6 8 10 12 Time between doses (h) Fig. 1.9 “Split-dose” or sublethal damage recovery demonstrated in cultured hamster V79 cells that received a first x-ray dose at time = 0, followed by a second dose after a variable radiation-free interval. Cells were maintained at either room temperature (24° C) or at 37° C during the “split” time. (Modified from Elkind M, Sutton-Gilbert H, Moses W, et al. Radiation response of mammalian cells grown in culture. V. Temperature dependence of the repair of x-ray damage in surviving cells (aerobic and hypoxic). Radiat Res. 1965;25:359.)

Total dose (Gy) 2.5

5.0

7.5 10.0 12.5

100

10!1

100

10!2

10!1

10!3

10!2

3h

Surviving fraction

Surviving fraction

100

5 Gy 10!1

∆t 24° C

5 Gy

10!2 10!3

0h 1h 1 2 3 Time between doses (h) Fig. 1.10 Sublethal damage recovery is also manifest as a return of the shoulder on the radiation survival curve when a total dose is delivered as two fractions separated by a time interval (A). If the interfraction interval is shorter than the time it takes for this recovery to occur, the shoulder will be only partially regenerated (e.g., compare the shoulder regions of the survival curves for intervals of 1 h vs. 3 h). The regeneration of the shoulder accounts for the observed survival increase in the corresponding split-dose assay (B, and Fig. 1.9).

A

B

0

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CHAPTER 1

The Biological Basis of Radiation Oncology

Total dose (Gy) 2

4

6

8

10

15

Untransformed rodent fibroblasts (13 Gy)

12 10!2 Surviving fraction

Fxn 1 Fxn 2

10!1 Fxn 3 10!2

Transformed rodent fibroblasts (10 Gy)

10!3

10!3 10!4

etc.

Fig. 1.11 Hypothetical multifraction survival curve (dashed line) for repeated 3.0 Gy fractions under conditions in which sufficient time between fractions is allowed for full sublethal damage recovery, and cell cycle and proliferative effects are negligible. The multifraction survival curve is shallower than its corresponding single dose curve (solid lines) and has no shoulder, that is, surviving fraction is an exponential function of total dose.

incubation following irradiation at either reduced temperature101 in the presence of certain metabolic inhibitors98 or in balanced salt solutions rather than complete culture medium.101 What these treatment conditions have in common is that they are suboptimal for continued growth of cells. This gives resting cells more opportunity to repair DNA damage prior to cell division than cells that continue traversing the cell cycle immediately after irradiation. Phillips and Tolmach98 were the first to propose this repair-fixation or competition model to explain PLDR. While, admittedly, some of these postirradiation conditions are not likely to be encountered in vivo, slow growth of cells in general, with or without a large fraction of resting cells, is a common characteristic of many tissues. As might be expected, tumors (and, subsequently, select normal tissues amenable to clonogenic assay) were shown to repair PLD.100 Experiments using rodent tumors were modeled after comparable studies using plateau phase cells in culture, that is, a delayed-plating assay was used. For such an experiment, irradiated cell cultures or animal tumors are left in a confluent state (either in the overcrowded cell culture or in the intact tumor in the animal) for varying lengths of time before removing them, dissociating them into single-cell suspensions and plating the cells for clonogenic survival at a low density. The longer the delay between irradiation and the clonogenic assay, the higher the resulting surviving fraction of individual cells, even though the radiation dose is the same. In general, survival rises to a maximum within 4 to 6 hours and levels off thereafter (Fig. 1.12). The kinetics and extent of recovery from both SLD and PLD are correlated with the molecular repair of DNA and the rejoining of chromosome breaks.102,103 For the purposes of radiation therapy, however, the most important consideration is that both processes have the potential to increase the surviving fraction of cells between subsequent dose fractions. Such a survival increase could be manifest clinically as either increased normal tissue tolerance or decreased tumor control. It is also important to appreciate that small differences in recovery capacity between normal and tumor cells after a single-dose fraction are magnified into large differences after 30 or more dose fractions.

4 8 12 24 48 72 96 120 Time between irradiation and subculture (h)

A

Survival relative to tumor explanted immediately after irradiation

Surviving fraction

100

5 4

Large rodent tumor (20 Gy)

3 2

Small rodent tumor (15 Gy)

1

2 4 6 8 Time between irradiation and explant (h) Fig. 1.12 Potentially lethal damage recovery can be demonstrated using a “delayed-plating” assay in which a variable delay time is inserted between exposure to a large single dose of radiation and the harvesting of the cells for a clonogenic assay. If cells are maintained in overcrowded and/or nutrient-deprived conditions during the delay period, the surviving fraction increases relative to that obtained when there is no delay. (A) Potentially lethal damage recovery in vitro in a nontumorigenic rodent fibroblast cell line and its transformed tumorigenic counterpart. (B) Potentially lethal damage recovery in vivo in both small and large mouse fibrosarcomas. (A, Modified from Zeman E, Bedford J. Dose-rate effects in mammalian cells. V. Dose fractionation effects in noncycling C3H 10T1/2 cells. Int J Radiat Oncol Biol Phys. 1984;10:2089; B, modified from Little J, Hahn G, Frindel E, et al. Repair of potentially lethal radiation damage in vitro and in vivo. Radiology. 1973;106:689.)

B

Repair in Tissues When considering the repair phenomenon in intact tissues, it is important to remember that both the magnitude of the repair (related both to the shape of the shoulder region of the corresponding dose-response curve and the dose delivered) and the rate of the repair can influence how the tissue behaves during a course of radiation therapy. For example, a particular tissue—normal or tumor—may be quite capable of repairing most damage produced by each dose fraction, but if the interfraction interval is so short as to not allow all the damage to be repaired prior to the next dose, the tolerance of that tissue will be less than otherwise anticipated. Second, while the sparing effect of dose fractionation for

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Scientific Foundations of Radiation Oncology

both normal and tumor tissues can be explained largely by SLD recovery between fractions, at sufficiently small doses per fraction, the degree of sparing will reach a maximum below which no further sparing occurs, all other radiobiological factors being equal. This is a reflection of the fact that some radiation damage is necessarily lethal and not modifiable by either further fractionation or changing postirradiation conditions.

Ionizing Radiation and the Cell Cycle Another basic feature of the cellular response to ionizing radiation is perturbation of the cell cycle. Such effects can modify the radioresponsiveness of tissues either directly or indirectly depending on the fraction of cycling cells present in the tissue, their proliferation rates, and the kinetic organization of the tissue or tumor. Advances in techniques for the study of cell cycle kinetics during the 1950s and 1960s paved the way for the generation of survival curves as a function of cell “age.” Using a technique known as autoradiography, Howard and Pelc104 were able to identify the S, or DNA synthesis, phase of the cell cycle. When combined with the other obvious cell cycle marker, mitosis, they were able to discern the four phases of the cell cycle for actively growing cells: G1, S, G2, and M.

a “1X” DNA content would correspond to cells in G1 phase, cells with a “2X” DNA content in G2 or M phase, and cells with DNA contents between “1X” and “2X” in the S phase of the cell cycle. By performing a mathematical fit to the DNA histogram, the proportion of cells in each phase of the cell cycle can be determined, the phase durations can be derived, and differences in DNA ploidy can be identified. DNA flow cytometry is quite powerful in that a static measure of cell cycle distribution can be obtained for a cell population of interest and dynamic studies of, for example, transit through the various cell cycle phases or treatment-induced kinetic perturbations can be monitored over time (Fig. 1.13). Flow cytometers are often outfitted with a cell-sorting feature. In this case, cells analyzed for a property of interest can be collected in

A

Methodology Several techniques were subsequently developed for the collection of synchronized cells in vitro. One of the most widely used was the mitotic harvest or “shake-off ” technique first described by Terasima and Tolmach.105,106 By agitating cultures, mitotic cells, which tend to round up and become loosely attached to the culture vessel’s surface, can be dislodged, collected along with the overlying growth medium, and inoculated into new culture flasks. By incubating these flasks at 37° C, cells begin to proceed synchronously into G1 phase (and semisynchronously thereafter). Thus, by knowing the length of the various phase durations for the cell type being studied and then delivering a radiation dose at a time of interest after the initial synchronization, the survival response of cells in different phases of the cell cycle can be determined. A second synchronization method involved the use of DNA synthesis inhibitors such as fluorodeoxyuridine107 and, later, hydroxyurea108 to selectively kill S phase cells yet allow cells in other phases to continue cell cycle progression until they become blocked at the border of G1 and S phases. By incubating cells in the presence of these inhibitors for times sufficient to collect nearly all cells at the block point, large numbers of cells can be synchronized. The inhibitor technique has two other advantages: that some degree of synchronization is possible in vivo109 as well as in vitro and that, by inducing synchrony at the end of the G1 phase, a higher degree of synchrony can be maintained for longer periods than if synchronization had been at the beginning of G1. On the other hand, the mitotic selection method does not rely on the use of drugs that could perturb the normal cell cycle kinetics of the population. Developments in the early 1970s provided what is now considered among the most valuable tools for the study of cytokinetic effects: the flow cytometer and its offshoot, the fluorescence-activated cell sorter.110 These have largely replaced the aforementioned longer and more laborintensive cell cycle synchronization methods. Using this powerful technique, single cells are stained with a fluorescent probe that binds stoichiometrically to a specific cellular component, DNA in the case of cell cycle distribution analysis. The stained cells are then introduced into a pressurized flow cell and forced to flow single file and at a high rate of speed through a focused laser beam that excites the fluorescent dye. The resulting light emission from each cell is collected by photomultiplier tubes, recorded, and output as a frequency histogram of cell number as a function of relative fluorescence, with the amount of fluorescence directly proportional to DNA content. Accordingly, cells with

G1

G2/M M G2 G 1

B

S

G1

G2/M

G1

G2/M

G1

G2/M

C

D

Fig. 1.13 The analytical technique of flow cytometry has revolutionized the study of cell cycle kinetics by allowing rapid determination of DNA content in cells stained with a fluorescent dye that binds stoichiometrically to cellular DNA. (A) Frequency distribution for a population of exponentially growing cells. The large and small peaks correspond to cells with G1 (“1X”) and G2/M (“2X”) phase DNA content, respectively; those cells in S phase have an intermediate DNA content. (B–D) DNA histograms for a cell population synchronized initially in mitosis and then allowed to progress into G1 (B), S and G2/M (C and D). See text for details.

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CHAPTER 1 separate “bins” after they pass through the laser beam and, if possible, used for other experiments.

Age Response Through the Cell Cycle Results of Terasima and Tolmach’s106 age response experiment using synchronized HeLa cells are shown in the lower panel of Fig. 1.14.

0.2

V79 cells (rodent)

0.1

7.1 Gy

0.05 0.02 Surviving fraction

0.01 0.005 M

0.1

G1

G2

S

HeLa cells (human) 5.0 Gy

0.05 0.02 0.01 0.005 G1

G2

S

M

Cell “age” Fig. 1.14 Cell cycle age response for sensitivity to radiation-induced cell killing in a representative rodent cell line (V79, top) having a short G1 phase duration, and a representative human cell line (HeLa, bottom), having a long G1 phase duration. Both cell lines exhibit a peak of radioresistance in late S phase and maximum radiosensitivity in late G2/M phase. A second “trough” of radiosensitivity can be discerned near the G1/S border for cells with long G1 phase durations. (Modified from Sinclair W. Dependence of radiosensitivity upon cell age. In: Proceedings of the Carmel Conference on Time and Dose Relationships in Radiation Biology as Applied to Radiotherapy. BNL Report 50203. Upton, NY: Brookhaven National Laboratory; 1969.)

1.0

The Biological Basis of Radiation Oncology

Following a single dose of 5 Gy of x-rays, cells were found to be most radioresistant in late S phase. Cells in G1 were resistant at the beginning of the phase, but became sensitive toward the end of the phase, and G2 cells were increasingly sensitive as they moved toward the most sensitive M phase. In subsequent experiments by Sinclair,111,112 age-response curves for synchronized Chinese hamster V79 cells showed that the peak in resistance observed in G1 HeLa cells was largely absent for V79 cells. This is also illustrated in Fig. 1.14 (upper panel). Otherwise, the shapes of the age-response curves for the two cell lines were similar. The overall length of the G1 phase determines whether the resistant peak in early G1 will be present; in general, this peak of relative radioresistance is observed only for cells with long G1 phases. For cells with short G1 phases, the entire phase is often of intermediate radiosensitivity. An analysis of the complete survival curves for synchronized cells111,113 confirms that the most sensitive cells are those in the M and late G2 phases, in which survival curves are steep and largely shoulderless, and the most resistant cells are those in late S phase. The resistance of these cells is conferred by the presence of a broad survival curve shoulder rather than by a significant change in survival curve slope (Fig. 1.15). When high-LET radiations are used, the age-response variation through the cell cycle is significantly reduced or eliminated, since survival curve shoulders are either decreased or removed altogether by such exposures (see also “Relative Biological Effectiveness” section to come). Similar age-response patterns have been identified for cells synchronized in vivo.109 The existence of a cell cycle age response for ionizing radiation provided an explanation for the unusual pattern of SLDR observed for cells maintained at 37° C during the recovery interval (see Fig. 1.9). In Elkind and Sutton’s experiments, exponentially growing cells were used, that is, cells that were asynchronously distributed across the different phases of the cell cycle. The cells that survived irradiation tended to be those most radioresistant. Thus, the remaining population became enriched with the more resistant cells. For low-LET radiation, those cells that were most resistant were in S phase at the time of the first radiation dose. However, at 37° C, cells continued to progress through the cell cycle; those surviving cells in S phase at the time of the first dose may have moved into G2 phase by the time the second dose was delivered. Thus, the observed survival nadir in the SLDR curve was not due to a loss or reversal of repair but rather because the population of cells was now enriched in G2 phase cells, which are inherently more radiosensitive. For even longer radiation-free intervals, it is possible that the cells surviving the first dose would transit from G2 to M and

7.1 Gy

Surviving fraction

0.2 0.1

0.1 0.05 0.02

0.01

0.01 Late S 0.005 G2/M

0.001

G1 Early S

17

M

G1

S

G2

Cell “age” 5.0

10.0 15.0 Dose (Gy) Fig. 1.15 Cell survival curves for irradiated populations of Chinese hamster cells synchronized in different phases of the cell cycle (left), illustrating how these radiosensitivity differences translate into the age response patterns shown at right (and in Fig. 1.14).

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Scientific Foundations of Radiation Oncology

back into G1 phase, dividing and doubling their numbers. In this case, the SLDR curve again shows a surviving fraction increase because the number of cells has increased. None of these cell cycle-related phenomena occur when the cells are maintained at room temperature during the radiation-free interval, because continued movement through the cell cycle is inhibited under such conditions. In that case, all that is noted is the initial survival increase due to SLDR.

Radiation-Induced Cell Cycle Blocks and Delays Radiation is also capable of disrupting the normal proliferation kinetics of cell populations. This was recognized by Canti and Spear in 1927114 and studied in conjunction with radiation’s ability to induce cellular lethality. With the advent of mammalian cell culture and synchronization techniques along with time-lapse cinemicrography, it became possible for investigators to study mitotic and division delay phenomena in greater detail. Mitotic delay, defined as a delay in the entry of cells into mitosis, is a consequence of “upstream” blocks or delays in the movement of cells from one cell cycle phase to the next. Division delay, a delay in the time of appearance of new cells at the completion of mitosis, is caused by the combined effects of mitotic delay and any further lengthening of the mitosis process itself. Division delay increases with dose and is, on average, about 1 to 2 hours per gray106 depending on the cell line. The cell cycle blocks and delays primarily responsible for mitotic and division delay are, respectively, a block in the G2-to-M phase transition, and a block in the G1-to-S phase transition. The duration of the G2 delay, like the overall division delay, varies with cell type, but for a given cell type is both dose and cell cycle age dependent. In general, the length of the G2 delay increases linearly with dose. For a given dose, the G2 delay is longest for cells irradiated in S or early G2 phase, and shortest for cells irradiated in G1 phase.115 Another factor contributing to mitotic and division delay is a block in the flow of cells from G1 into S phase. For x-ray doses of at least 6 Gy, there is a 50% decrease in the rate of tritiated thymidine uptake (indicative of entry into S phase) in exponentially growing cultures of mouse L cells. Little116 reached a similar conclusion from G1 delay studies using human liver LICH cells maintained as confluent cultures. A possible role for DNA damage and its repair in the etiology of division delay was bolstered by the finding that certain cell types that either did not exhibit the normal cell cycle delays associated with radiation exposure (such as AT cells42) or, conversely, were treated with chemicals that ameliorated the radiation-induced delays117 tended to contain higher amounts of residual DNA damage and to show increased radiosensitivity. It is now known that the radiation-induced perturbations in cell cycle transit are under the control of cell cycle checkpoint genes, whose products normally govern the orderly (and unidirectional) flow of cells from one phase to the next. The checkpoint genes are responsive to feedback from the cell as to its general condition and readiness to transit to the next cell cycle phase. DNA integrity is one of

the criteria used by these genes to help make the decision whether to continue traversing the cell cycle or to pause—either temporarily or, in some cases, permanently. Cell cycle checkpoint genes are discussed in Chapter 2.

Redistribution in Tissues Because of the age response through the cell cycle, an initially asynchronous population of cells surviving a dose of radiation becomes enriched with S phase cells. Owing to variations in the rate of further cell cycle progression, however, this partial synchrony decays rapidly. Such cells are said to have “redistributed,”118 with the net effect of sensitizing the population as a whole to a subsequent dose fraction (relative to what would have been expected had the cells remained in their resistant phases). A second type of redistribution also has a net sensitizing effect, in which cells accumulate in G2 phase (in the absence of cell division) during the course of multifraction or continuous irradiation because of a buildup of radiation-induced cell cycle blocks and delays. This has been observed during continuous irradiation by several investigators.119 In some of these cases, a net increase in radiosensitivity is seen at certain dose rates. This so-called “inverse dose rate effect,” where certain dose rates are more effective at cell killing than other, higher dose rates, was extensively studied by Mitchell, Bedford and associates (for a review, see Bedford et al.120). The magnitude of the sensitizing effect of redistribution varies with cell type depending on what dose rate is required to stop cell division. For dose rates below the critical range that causes redistribution, some cells can escape the G2 block and proceed on to cell division.

Densely Ionizing Radiation Linear Energy Transfer

The total amount of energy deposited in biological materials by ionizing radiation (usually expressed in units of keV, ergs or joules per g or kg) is in and of itself insufficient to describe the net biological consequences of those energy deposition events. For example, 1 Gy of x-rays, while physically equivalent in terms of total energy imparted per unit mass to 1 Gy of neutrons or α-particles, does not produce equivalent biological effects. It is the microdosimetric pattern of that energy deposition, that is, the spacing or density of the ionization events, that determines biological effectiveness. This quantity—the average energy deposited locally per unit length of the ionizing particle’s track—is termed its linear energy transfer (LET). LET is a function both of the charge and mass of the ionizing particle. Photons set in motion fast electrons that have a net negative charge but a negligible mass. Neutrons, on the other hand, give rise to recoil protons or α-particles that possess one or two positive charges, respectively, and are orders of magnitude more massive than electrons. Neutrons, therefore, have a higher LET than photons and are considered densely ionizing, whereas the x-rays or γ-rays are considered sparsely ionizing. The LET concept is illustrated in Fig. 1.16 for both densely

Sensitive “target”

60 Co γ-rays 250 kVp x-rays α Particles

Fig. 1.16 Variation in the density of ionizing events along an incident particle’s track for radiations of differing linear energy transfer. The more closely spaced the ionizing events, the more energy will be deposited in the target volume and, to a point, the more biologically effective per unit dose the type of radiation will be.

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Insofar as the “quality” (LET) of the type of radiation influences its biological effectiveness, two questions immediately come to mind. First, why do seemingly subtle differences in microdosimetric energy deposition patterns lead to vastly different biological consequences? Second, how is this differing biological effectiveness manifest in terms of the commonly used assays and model systems of foundational radiobiology, and how can this difference be expressed in a quantitative way? Because high-LET radiations are more densely ionizing than their low-LET counterparts, it follows that energy deposition in a particular “micro”-target volume will be greater and therefore, more severe damage to biomolecules would be expected. In this case, the fraction of cell killing attributable to irreparable and unmodifiable DNA damage increases in relation to that caused by the accumulation of sublethal damage. Because of this, a number of radiobiological phenomena commonly associated with low-LET radiation are decreased or eliminated when high-LET radiation is used. For example, there is little, if any, sublethal60 or potentially lethal damage recovery.115 This is manifest as a reduction or loss of the shoulder of the acute dose survival curve, little or no sparing effect of dose fractionation or dose rate, and a corresponding reduction in the tolerance doses for normal tissue complications, particularly for late-responding tissues.121 Variations in the age response through the cell cycle also are reduced or eliminated for high-LET radiation,109 and the oxygen enhancement ratio (OER), a measure of the differential radiosensitivity of poorly versus welloxygenated cells (see later discussion), decreases with increasing LET.122 The dependence of OER on LET is illustrated in Fig. 1.17; at an LET of approximately 100 keV/μm, the relative radioresistance of hypoxic cells is eliminated. In light of these differences between high- and low-LET radiations, the term relative biological effectiveness (RBE) has been coined to compare and contrast two radiation beams of different LET. RBE is defined as the ratio of doses of a known type of low-LET radiation (historically, 250 kVp x-rays were the standard) to that of a higher-LET radiation to yield the same biological endpoint. RBE does not increase indefinitely with increasing LET, however, but rather reaches a maximum at approximately 100 keV/μm and then decreases again, yielding an approximately bell-shaped curve. One interpretation as to why the RBE reaches a maximum at an LET of approximately 100 keV/μm is that, at this ionization density, the average separation between ionizing events corresponds roughly to the diameter of the DNA double helix (approximately 2 nm). As such, radiations of this LET have the highest probability of producing DSBs in DNA, the putative lethal lesion, by the passage of a single charged particle. Lower-LET radiations have a smaller likelihood of producing such “two-hit” lesions from a single particle track and, therefore, are less biologically effective. Radiation beams of higher LET than the optimum are less efficient because some of the energy is wasted as more ionization events than minimally necessary to kill a cell are deposited in the same local area. This phenomenon has been termed the overkill effect.

Relative biological effectiveness

Relative Biological Effectiveness

3

10 8 6

2 4 2 1 1000

1 10 100 Linear energy transfer (keV/!m) X-rays and γ-rays

Argon Neon Carbon Neutrons

Fig. 1.17 Relative biological effectiveness (RBE, left Y-axis) as a function of linear energy transfer (LET) for a number of biological endpoints, including production of chromosomal aberrations, cell killing, and tissue reactions. The RBE rises to a maximum corresponding to an LET of approximately 100 keV/μm and then decreases as the LET continues to rise. Shown below the X-axis are the ranges of LET for photons plus several different types of particulate radiations that have been used clinically. Also shown is the dependence of the oxygen enhancement ratio (OER, right Y-axis) on LET.

100 RBE0.5!5.6

Surviving fraction

and sparsely ionizing radiations. For a given ionizing particle, the rate of energy deposition in the absorbing medium increases as the particle slows down. Therefore, a beam of radiation can only be described as having an average value for LET. Representative LET values for types of radiation that have been used for radiation therapy include 0.2 keV/μm for 60Co γ-rays; 2.0 keV/μm for 250 kVp x-rays; approximately 0.5 to 5.0 keV/μm for protons of different energies; approximately 50 to 150 keV/μm for neutrons; 100 to 150 keV/μm for α-particles; and anywhere from 100 to 2500 keV/μm for “heavy ions.”

19

The Biological Basis of Radiation Oncology

Oxygen enhancement ratio

CHAPTER 1

10!1 RBE0.05!3.6

10!2

Neutrons

X-rays

10!3

RBE0.0005!2.8

10!4 10!5 0

2

4

6 8 10 12 14 Dose (Gy) Fig. 1.18 Theoretical cell survival curves for x-rays and neutrons, illustrating the increase in relative biological effectiveness (RBE) with decreasing dose. This occurs because higher linear energy transfer radiations preferentially decrease or eliminate the shoulder on cell survival curves. (Modified from Nias A. Clinical Radiobiology. 2nd ed. New York: Churchill Livingstone; 1988.)

Factors That Influence Relative Biological Effectiveness RBE is highly variable and depends on several parameters, including the type of radiation, total dose, dose rate, dose fractionation pattern, and the biological effect being assayed. Therefore, when quoting an RBE value, the exact experimental conditions used to measure it must be stated. Because increasing LET differentially reduces the shoulder region of the radiation survival curve compared to its exponential or near-exponential high-dose region, the single-dose RBE increases with decreasing dose (Fig. 1.18). Second, the RBE determined by comparing

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20

SECTION I

100

2

4

Scientific Foundations of Radiation Oncology Total dose (Gy) 6 8 10

12

14

X-rays (multifraction) 10!1

Neutrons (multifraction)

X-rays (single doses)

Neutrons (single doses)

RBE = 4.1

Surviving fraction

Surviving fraction

Sensitive subpopulation

RBE = 2.7

10!2

Fig. 1.19 Increase in the relative biological effectiveness (RBE) of neutrons relative to x-rays when comparing single doses with fractionated treatment. For a given level of cell killing (or other approximately isoeffective endpoint), the more highly fractionated the treatment, the higher the RBE.

two isoeffective acute doses is less than the RBE calculated from two isoeffective (total) doses given either as multiple fractions or at a low dose rate. This occurs because the sparing effect of fractionation magnifies differences in the initial slope or shoulder region of cell survival or tissue dose-response curves (Fig. 1.19).

The Oxygen Effect Perhaps the best-known chemical modifier of radiation action is molecular oxygen. As early as 1909, Schwarz recognized that applying pressure to skin and thereby decreasing blood flow (and oxygen supply) caused a reduction in radiation-induced skin reactions.123 For many decades thereafter, radiation oncologists and biologists continued to suspect that the presence or absence of oxygen was capable of modifying radiosensitivity. In 1955, however, Thomlinson and Gray124 brought this idea to the forefront of radiation biology and therapy by proposing that tumors contain a fraction of still-clonogenic, hypoxic cells that, if persistent throughout treatment, would adversely affect clinical outcome. Although commonly considered a negative prognostic indicator for radiation therapy, hypoxia nevertheless has one particularly attractive feature: built-in specificity for tumors, to the extent that normal tissues contain few, if any, hypoxic cells. By studying histological sections of a human bronchial carcinoma, Thomlinson and Gray noted that necrosis was always seen in the centers of cylindrical tumor cords having a radius in excess of approximately 200 μm.124 Further, regardless of how large the central necrotic region was, the sheath of apparently viable cells around the periphery of this central region never had a radius greater than about 180 μm. The authors went on to calculate the expected maximum diffusion distance of oxygen from blood vessels and found that the value of 150 to 200 μm agreed quite well with the radius of the sheath of viable tumor cells observed histologically. With the advent of more sophisticated and quantitative methods for measuring oxygen utilization in tissues, the average diffusion distance of oxygen has since been revised downward to approximately 70 μm.28 Thus, the inference was that the oxygenation status of tumor cells varied from fully oxic to completely anoxic depending on where the cells were located in relation to the nearest blood vessels. Accordingly, tumor cells at intermediate distances from the blood supply would be hypoxic and radioresistant, yet remain clonogenic. The first unambiguous demonstration that a solid rodent tumor did contain clonogenic, radioresistant hypoxic cells was by Powers and

Fig. 1.20 Cell survival curve for a murine lymphosarcoma growing subcutaneously and irradiated in vivo. The biphasic curve suggests the presence of a small but relatively radioresistant subpopulation of cells, determined in accompanying experiments to represent the tumor’s clonogenic hypoxic fraction. (Modified from Powers WE, Tolmach LJ. A multicomponent x-ray survival curve for mouse lymphosarcoma cells irradiated. Nature. 1963;197:710.)

Tolmach125 in 1963. These authors used the dilution assay to generate an in vivo survival curve for mouse lymphosarcoma cells. The survival curve for this solid tumor was biphasic, having an initial D0 of about 1.1 Gy and a final D0 of 2.6 Gy (Fig. 1.20). Since the survival curve for lymphoid cells is shoulderless, it was simple to back-extrapolate the shallower component of the curve to the surviving fraction axis and determine that the resistant fraction of cells constituted about 1.5% of the total population. This was considered compelling evidence (yet did not unambiguously prove) that this subpopulation of cells was both hypoxic and clonogenic. The question then became how to prove that this small fraction of tumor cells was radioresistant because of hypoxia as opposed to being radioresistant for other reasons. An elegant, if somewhat macabre, method was developed to address this dilemma, called the paired survival curve technique.125,126 In this assay, laboratory animals bearing tumors were divided into three treatment groups, one group irradiated while breathing air, a second group irradiated while breathing 100% oxygen, and a third group killed first by cervical dislocation and then irradiated. Within each group, animals received graded radiation doses so that complete survival curves were generated for each treatment condition. When completed, the paired survival curve method yielded three different tumor cell survival curves: a fully oxic curve (most radiosensitive), a fully hypoxic curve (most radioresistant), and the survival curve for airbreathing animals which, if the tumor contained viable hypoxic cells, was biphasic and positioned between the other two curves. It was then possible to mathematically strip the fully aerobic and hypoxic curves from the curve for air-breathing animals and determine the radiobiologically hypoxic fraction.

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CHAPTER 1

Mechanistic Aspects of the Oxygen Effect A more rigorous analysis of the nature of the oxygen effect is possible with cells or bacteria grown in vitro. Historically, oxygen had been termed a dose-modifying agent, that is, that the ratio of doses to achieve a given survival level under hypoxic and aerobic conditions was constant regardless of the survival level chosen. This dose ratio to produce the same biological endpoint is termed the oxygen enhancement ratio (OER), and is used for comparative purposes (Fig. 1.21). The OER typically has a value of between 2.5 and 3.0 for large single doses of x-rays or γ-rays, 1.5 to 2.0 for radiations of intermediate LET, and 1.0 (i.e., no oxygen effect) for high-LET radiations. Increasingly, there is evidence that oxygen is not strictly dose modifying. Several studies have shown that the OER for sparsely ionizing radiation is lower at lower doses than at higher doses. Lower OERs for doses per fraction in the range commonly used in radiotherapy have been inferred indirectly from clinical and experimental tumor data and more directly in experiments with cells in culture.127,128 It has been suggested that the lower OERs result from an age response for the oxygen effect, not unlike the age responses for inherent radiosensitivity and cell cycle delay.28 Assuming that cells in G1 phase of the cell cycle have a lower OER than those in S phase and since G1 cells are also more radiosensitive, they would tend to dominate the low-dose region of the cell survival curve. While the exact mechanism(s) of the oxygen effect are obviously complex, a fairly simplistic model can be used to illustrate our current understanding of this phenomenon (Fig. 1.22). The radical competition model holds that oxygen acts as a radiosensitizer by forming peroxides in important biomolecules (including, but not necessarily limited to, DNA) already damaged by radiation exposure, thereby “fixing” the radiation damage. In the absence of oxygen, DNA can be restored to its preirradiated condition by hydrogen donation from endogenous reducing species in the cell, such as the free radical scavenger glutathione, a thiol compound. In essence, this can be considered a type of very fast chemical restitution or repair. These two processes, fixation and restitution, are considered to be in a dynamic equilibrium, such that changes in the relative amounts of either the radiosensitizer, oxygen, or the

Surviving fraction

100

OER ! 15.5 Gy/6.25 Gy ! 2.5

10"1

“Isoeffect” = 0.05 SF Aerobic

Hypoxic

radioprotector, glutathione, tip the scales in favor of either fixation (more damage, more cell killing, greater radiosensitivity) or restitution (less damage, less cell killing, greater radioresistance), respectively. Consistent with this free radical–based interpretation of the oxygen effect is the finding that, for all intents and purposes, oxygen need only be present during the irradiation (or no more than a few milliseconds after irradiation) in order to produce an aerobic radioresponse.129,130 The concentration of oxygen necessary to achieve maximum sensitization is quite small, evidence for the high efficiency of oxygen as a radiosensitizer. A sensitivity midway between a fully hypoxic and fully aerobic radioresponse is achieved at an oxygen tension of about 3 mm of mercury, corresponding to about 0.5% oxygen, much lower than partial pressures of oxygen usually encountered in normal tissues. This value of 0.5% has been termed oxygen’s k-value and is obtained from an oxygen k-curve of relative radiosensitivity plotted as a function of oxygen tension131 (Fig. 1.23).

X-rays or γ-rays

DNA

Endogenous or exogenous thiol compound

DNA

DNA

Oxygen

Radioprotection

DNA-OO Radiosensitization

Oxygen-mimetic radiosensitizer

DNA-sensitizer

Fig. 1.22 Schematic representation of the proposed mechanism of action for the oxygen effect. The radical competition model holds that oxygen acts as a radiosensitizer by forming peroxides in DNA already damaged by radiation, thereby “fixing” the damage. In the absence of oxygen, DNA can be restored to its preirradiated state by hydrogen donation from endogenous reducing species in the cell, such as the free radical scavenger glutathione. An oxygen-mimetic, hypoxic cell radiosensitizer may be used to substitute for oxygen in these fast free radical reactions or an exogenously supplied thiol compound may be used to act as a radioprotector.

3.0 Radiosensitivity relative to the fully anoxic response (= 1.0)

Across a variety of rodent tumors evaluated to date using the paired survival curve method, the percentage of hypoxic cells was found to vary between 0% and 50%, with an average of about 15%.126

21

The Biological Basis of Radiation Oncology

Air O2 “k”-value = 3 mm Hg (0.5%)

2.0

100% Oxygen

1.0 Range of normal tissue PO2

10"2 10 (6.25 Gy)

10"3 0

2

4

6

(15.5 Gy)

8 10 12 14 16 18 20 Dose (Gy) Fig. 1.21 Representative survival curves for cells irradiated with x-rays in the presence (aerobic) or virtual absence (hypoxic) of oxygen. The oxygen enhancement ratio (OER) is defined as the ratio of doses under hypoxic:aerobic conditions to yield the same biological effect, in this case, a cell surviving fraction of 0.05.

20

30 40 50 60 70 155 Oxygen tension (mm Hg at 37° C)

760

Fig. 1.23 An oxygen “k-curve” is used to illustrate the dependence of radiosensitivity on oxygen concentration. If a fully anoxic cell culture is assigned a relative radiosensitivity of 1.0, introducing even 0.5% (3 mm Hg) oxygen into the system increases the radiosensitivity of cells to 2.0; by the time the oxygen concentration reaches about 2.0%, cells respond as if they are fully aerated (i.e., radiosensitivity ≈ 3.0). The shaded area represents the approximate range of oxygen concentrations encountered in human normal tissues.

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22

SECTION I

Scientific Foundations of Radiation Oncology

Reoxygenation in Tumors After the convincing demonstration of hypoxic cells in a mouse tumor,125 it was assumed that human tumors contained a viable hypoxic fraction as well. However, if human tumors contained even a tiny fraction of clonogenic hypoxic cells, simple calculations suggested that tumor control would be nearly impossible with radiation therapy.132 Since therapeutic successes obviously do occur, some form of reoxygenation must take place during the course of multifraction irradiation. This was not an unreasonable idea since the demand for oxygen by sterilized cells would gradually decrease as they were removed from the tumor, and a decrease in tumor size, a restructuring of tumor vasculature, or intermittent changes in blood flow could make oxygen available to these previously hypoxic cells. The reoxygenation process was extensively studied by van Putten and Kallman,133 who serially determined the fraction of hypoxic cells in a mouse sarcoma during a course of clinically relevant multifraction irradiation. The fact that the hypoxic fraction was about the same at the end of treatment as at the beginning of treatment was strong evidence for a reoxygenation process because, otherwise, the hypoxic fraction would be expected to increase over time due to repeated enrichment with resistant cells after each dose fraction. Reoxygenation of hypoxic, clonogenic tumor cells during an extended multifraction treatment would increase the therapeutic ratio assuming that normal tissues remained well oxygenated. This is thought to be another major factor in the sparing of normal tissues relative to tumors during fractionated radiation therapy. What physiological characteristics would lead to tumor reoxygenation during a course of radiotherapy, and at what rate would this be expected to occur? One possible cause of tumor hypoxia and, by extension, a possible mechanism for reoxygenation, was suggested by Thomlinson and Gray’s pioneering work.124 The type of hypoxia that they described is what is now called chronic or diffusion-limited hypoxia. This results from the tendency of tumors both to have high oxygen consumption rates and to outgrow their blood supply. It follows that natural gradients of oxygen tension should develop as a function of distance from blood vessels. Cells situated beyond the diffusion distance of oxygen would be expected to be dead or dying secondary to anoxia; yet, in regions of chronically low oxygen tension, clonogenic and radioresistant hypoxic cells could persist. Should the tumor shrink as a result of radiation therapy or if the cells killed by radiation cause a decreased demand for oxygen, it is likely that this would allow some of the chronically hypoxic cells to reoxygenate. However, such a reoxygenation process could be quite slow—days at minimum—depending on how quickly tumors regress during treatment. The patterns of reoxygenation in some experimental rodent tumors are consistent with this mechanism of reoxygenation, but others are not. Other rodent tumors reoxygenate very quickly, from minutes to hours.134 This occurs in the absence of any measurable tumor shrinkage or change in oxygen utilization by tumor cells. In such cases, the model of chronic, diffusion-limited hypoxia, and slow reoxygenation does not fit the experimental data. During the late 1970s, Brown135 proposed that a second type of hypoxia must exist in tumors, an acute, perfusionlimited hypoxia. Based on the growing understanding of the vascular physiology of tumors, it was clear that tumor vasculature was often abnormal in both structure and function secondary to abnormal angiogenesis. If tumor vessels were to close transiently from temporary blockage, vascular spasm, or high interstitial fluid pressure in the surrounding tissue, the tumor cells in the vicinity of those vessels would become acutely hypoxic almost immediately. Then, assuming that blood flow resumed in minutes to hours, these cells would reoxygenate. However, this type of hypoxia also can occur in the absence of frank closure or blockage of tumor vessels (which is now considered a less

common cause of acute hypoxia) from, for example, vascular shunting, longitudinal oxygen gradients, decreased red cell flux or overall blood flow rate, abnormal vascular geometry, and so on.136 Because of this, the name perfusion-limited hypoxia is perhaps misleading; a better moniker might be fluctuant or intermittent hypoxia. While intermittent hypoxia would explain the rapid reoxygenation observed for some tumors, it does not preclude the simultaneous existence of chronic, diffusion-limited hypoxia. Intermittent hypoxia has since been demonstrated for rodent tumors by Chaplin et al.137 and human tumors by Lin et al.138 It is still not clear how many human tumors contain regions of hypoxia (although most do—see next section), what type(s) of hypoxia is present, whether this varies with tumor type or site, and whether and how rapidly reoxygenation occurs. However, the knowledge that tumor hypoxia is a diverse and dynamic process opens up a number of possibilities for the development of novel interventions designed to cope with, or even exploit, hypoxia.

Measurement of Hypoxia in Human Tumors Despite prodigious effort directed at understanding tumor hypoxia and developing strategies to combat the problem, it was not until the late 1980s that these issues could be addressed for human tumors because there was no way to measure hypoxia directly. Before that time, the only way to infer that a human tumor contained treatment-limiting hypoxic cells was by using indirect, nonquantitative methods. Some indirect evidence supporting the notion that human tumors contained clonogenic, radioresistant hypoxic cells includes the following: 1. An association between anemia and poor local control rates that, in some cases, could be mitigated by preirradiation blood transfusions139 2. Success of some clinical trials in which hyperbaric oxygen breathing was used to better oxygenate tumors140,141 3. Success of a few clinical trials of oxygen-mimetic hypoxic cell sensitizers combined with radiation therapy139,142 In 1988, one of the first studies showing a strong association between directly measured oxygenation status in tumors and clinical outcome was published by Gatenby et al.143 An oxygen-sensing electrode was inserted into the patient’s tumor, and multiple readings were taken at different depths along the probe’s track. The electrode was also repositioned in different regions of the tumor to assess intertrack variability in oxygen tension. Both the arithmetic mean Po2 value for a particular tumor and the tumor volume-weighted Po2 value directly correlated with local control rate. A high tumor oxygen tension was associated with a high complete response rate, and vice versa. In a similar prospective study, Höckel et al.4,144 concluded that pretreatment tumor oxygenation was a strong predictor of outcome among patients with intermediate and advanced-stage cervical carcinoma (Fig. 1.24). The use of oxygen electrodes has its limitations. One weakness is that relative to the size of individual tumor cells, the electrode is large, averaging an outer diameter of 300 μm, a tip recess of 120 μm, and a sampling volume of about 12 μm in diameter.145 Thus, not only is the oxygen tension measurement regional, but the insertions and removals of the probe no doubt perturb the oxygenation status. Another problem is that there is no way to determine whether the tumor cells are clonogenic or not. If such cells were hypoxic yet not clonogenic, they would not be expected to impact radiotherapy outcome. A second direct technique for measuring oxygenation status takes advantage of a serendipitous finding concerning how hypoxic cell radiosensitizers are metabolized. Certain classes of radiosensitizers, including the nitroimidazoles, undergo a bioreductive metabolism in the absence of oxygen that leads to their becoming covalently bound to cellular macromolecules.146,147 Assuming that the bioreductively bound drug

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Disease-free survival probability

CHAPTER 1

1.0 0.8

Median PO2 !10 mm Hg (n = 21)

0.6 Median PO2 "10 mm Hg (n = 23)

0.4 0.2

10

20

30 40 50 60 70 80 Time (months) Fig. 1.24 The disease-free survival probability of a small cohort of cervical cancer patients stratified according to pretreatment tumor oxygenation, as measured using an oxygen electrode. (Modified from Höckel M, Knoop C, Schlenger K, et al. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993;26:45.)

could be quantified by radioactive labeling148 or tagged with an isotope amenable to detection using positron emission tomography149 or magnetic resonance spectroscopy,150 a direct measure of hypoxic fraction can be obtained. Another approach to detecting those cells containing bound drug was developed by the Raleigh group (e.g., Cline et al.151 and Kennedy et al.152). This immunohistochemical method involved the development of antibodies specific for the bound nitroimidazole metabolites. After injecting the parent drug, allowing time for the reductive metabolism to occur, taking biopsies of the tumor, and preparing histopathology slides, the specific antibody is then applied to the slides and regions containing the bound drug are visualized directly. This immunostaining method has the distinct advantages that hypoxia can be studied at the level of individual tumor cells,153 spatial relationships between regions of hypoxia and other tumor physiological parameters can be assessed,154 and the drug does not perturb the tumor microenvironment. However, the method remains an invasive procedure, is labor intensive, does not address the issue of the clonogenicity of stained cells (although such cells do have to be metabolically active), and requires that multiple samples be taken because of tumor heterogeneity. One hypoxia marker based on the immunohistological method detects reductively bound pimonidazole hydrochloride and has been used in experimental and clinical studies around the world (e.g., Bussink et al.,155 Nordsmark et al.156). Human tumor specimens stained with the marker were found to have a wide range of hypoxic fractions (similar to that for experimental rodent tumors), with a mean value of approximately 15%.152,157 This marker can also be used to probe disease states other than cancer that may have the induction of tissue hypoxia as part of their etiology, such as cirrhosis of the liver158,159 and ischemiareperfusion injury in the kidney.160 There is also considerable interest in endogenous markers of tissue hypoxia161,162 that could reduce to some extent the procedural steps involved in, and the invasive aspects of, detecting hypoxia using exogenous agents. Among the endogenous cellular proteins being investigated in this regard are the hypoxia-inducible factor 1-alpha (HIF-1α, which acts as a transcription factor for hypoxia-regulated genes163), the enzyme carbonic anhydrase IX (CA-9 or CAIX, involved in respiration and maintenance of the proper acid–base balance in tissues164,165), glucose transporter-1 (GLUT-1, which facilitates glucose transport into cells and glycolysis166–168), lysyl oxidase (LOX, which oxidizes lysine residues in extracellular matrix proteins that can enhance

The Biological Basis of Radiation Oncology

23

the processes of tumor invasion and metastasis169,170), and osteopontin (OPN, a glycoprotein that facilitates tumor invasion and metastasis171–173). Clearly, although aberrant expression of some individual hypoxia markers has been associated with poor clinical outcome, no one marker is likely to be sufficiently robust or reproducible to either be diagnostic for the presence of a malignancy (or, at least, the presence of hypoxia in an already diagnosed tumor) or prognostic of treatment outcome. Thus, there has been increasing interest in the study of patterns of hypoxia-associated gene or protein expression for multiple markers simultaneously, for example, Le et al.,5 Erpolat et al.,173 and Toustrup et al.174

Radiosensitizers, Radioprotectors, and Bioreductive Drugs The perceived threat that tumor hypoxia posed spawned much research into ways of overcoming the hypoxia problem. One of the earliest proposed solutions was the use of high-LET radiations,175 which were less dependent on oxygen for their biological effectiveness. Other agents enlisted to deal with the hypoxia problem included hyperbaric oxygen breathing140; artificial blood substitutes with increased oxygen-carrying capacity176; oxygen-mimetic hypoxic cell radiosensitizers, such as misonidazole or etanidazole139; hyperthermia177; normal tissue radioprotectors, such as amifostine178; vasoactive agents that modify tumor blood flow, such as nicotinamide179; agents that modify the oxygen-hemoglobin dissociation curve, such as pentoxifylline180; and bioreductive drugs designed to be selectively toxic to hypoxic cells, such as tirapazamine.181,182

Radiosensitizers Radiosensitizers are loosely defined as chemical or pharmacological agents that increase the cytotoxicity of ionizing radiation. “True” radiosensitizers meet the stricter criterion of being relatively nontoxic in and of themselves, acting only as potentiators of radiation toxicity. “Apparent” radiosensitizers still produce the net effect of making the tumor more radioresponsive, yet the mechanism is not necessarily synergistic nor is the agent necessarily nontoxic when given alone. Ideally, a radiosensitizer is only as good as it is selective for tumors. Agents that show little or no differential effect between tumors and normal tissues do not improve the therapeutic ratio and, therefore, may not be of much clinical utility. Table 1.2 summarizes some of the classes of radiosensitizers (and radioprotectors—see later discussion) that have been used in the clinic. Hypoxic cell radiosensitizers. The increased radiosensitivity of cells in the presence of oxygen is believed to be due to oxygen’s affinity for the electrons produced by the ionization of biomolecules. Molecules other than oxygen also have this chemical property, known as electron affinity,183 including some agents that are not otherwise consumed by the cell. Assuming that such an electron-affinic compound is not used by the cell, it should diffuse further from capillaries and reach hypoxic regions of a tumor and, acting in an oxygen-mimetic fashion, sensitize hypoxic cells to radiation. One class of compounds that represented a realistic trade-off between sensitizer efficiency and diffusion effectiveness was the nitroimidazoles, which include such drugs as metronidazole, misonidazole, etanidazole, pimonidazole, and nimorazole. The nitroimidazoles consist of a nitroaromatic imidazole ring, a hydrocarbon side chain that determines the drug’s lipophilicity, and a nitro group that determines the drug’s electron affinity. Misonidazole was extensively characterized in cellular and animal model systems, culminating in its use in clinical trials. Clinical experiences with misonidazole and some of its successor compounds are discussed in Chapter 3. The relative efficacy of a particular hypoxic cell radiosensitizer is most often described in terms of its sensitizer enhancement ratio (SER),

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24

SECTION I

Scientific Foundations of Radiation Oncology

Selected Chemical Modifiers of Radiation Therapy

TABLE 1.2

Name (Type of Compound)

Chemical Structure O Br

NH

HO

O

Mechanism of Action

Clinic Status

5-Bromodeoxyuridine (halogenated pyrimidine)

Radiosensitizer of rapidly proliferating cells through incorporation into DNA during S phase. Uptake results in decrease or removal of the shoulder of the radiation survival curve.

No clear evidence of clinical efficacy has been established to date. The drug continues to be used in a research setting.

Misonidazole (2-nitroimidazole)

Radiosensitizer of hypoxic cells. Principal mechanism of action is mimicry of oxygen’s ability to “fix” free radical damage caused by exposure to radiation and some toxic chemicals.

Clinical trial results were disappointing overall except in selected sites, most notably, head and neck cancer. The drug’s failure largely has been ascribed to a dose-limiting toxicity, peripheral neuropathy.

Tirapazamine (organic nitroxide)

Bioreductive drug selectively toxic to hypoxic cells. The drug is reduced to a toxic intermediate capable of producing DNA strand breaks only in the relative absence of oxygen.

Phase II and Phase III clinical trials to date have been disappointing overall, except in select subsets of patients with head and neck or lung cancer. Some trials are still ongoing for the drug combined with radiotherapy and cis-platinum.

Amifostine (thiol free radical scavenger)

Radioprotector capable of “restituting” free radical damage caused by exposure to radiation and some toxic chemicals.

FDA-approved indications for amifostine include protection against the nephroand ototoxicity of platinum drugs and to reduce the incidence and severity of xerostomia in patients receiving radiotherapy for head and neck cancer.

O

N

OH OH N

N

O

O2N

O N N N

NH2

O

HO HO

P

S O

N H

NH2

FDA, U.S. Food and Drug Administration.

a parameter similar in concept to the OER. Whereas the OER is the ratio of doses to produce the same biological endpoint under hypoxic versus aerobic conditions, the SER is the dose ratio for an isoeffect under hypoxic conditions alone versus hypoxic conditions in the presence of the hypoxic cell sensitizer. If a dose of a sensitizer produces an SER of 2.5 to 3.0 for large single doses of low-LET radiation, it can be considered to a first approximation “as effective as oxygen.” This statement can be very misleading, however, in that the dose of the sensitizer required to produce the SER of 3.0 would be higher than the comparable “dose” of oxygen, high enough in some cases to preclude its use clinically. Finally, since the primary mechanism of action of the nitroimidazoles is substitution for oxygen in radiation-induced free-radical reactions, these drugs need only be present in hypoxic regions of the tumor at the time of irradiation. The nitroimidazoles also have characteristics that decrease their clinical usefulness. The hydrocarbon side chain of the molecule determines its lipophilicity; this chemical property affects the drug’s pharmacokinetics, which is a primary determinant of drug-induced side effects.184 The dose-limiting toxicity of the fairly lipophilic agent misonidazole is peripheral neuropathy, an unanticipated and serious side effect.139,185 Etanidazole was specifically designed to be less lipophilic186 in hopes of decreasing neurological toxicity. Although this goal was accomplished as a proof of concept, clinical results with etanidazole were otherwise disappointing187 (see also Chapter 3). Finally, in considering the prodigious amount of research and clinical effort that has gone into the investigation of hypoxic cell radiosensitizers over the past 50 years, it is difficult not to be discouraged by the predominantly negative results of the clinical trials. However, these negative

results have prompted a rethinking of the hypoxia problem and novel approaches to dealing with it as well as consideration of other factors that may have contributed to the lack of success of the nitroimidazole radiosensitizers.185 Among the more obvious questions raised are the following: 1. Did the patients entered in the various clinical trials actually have tumors that contained clonogenic hypoxic cells? At the time of most of these studies, hypoxia markers were not yet available; thus, it was not possible to triage patients into subgroups in advance of treatment. 2. Do hypoxic cells really matter to the outcome of radiotherapy? If reoxygenation is fairly rapid and complete during radiotherapy, the presence of hypoxic cells prior to the start of treatment may be of little consequence. 3. Given that the OER is lower for small doses versus large doses, it follows that the SER would be reduced as well. If so, a benefit in a subgroup of patients might not be readily observed, at least not at a level of statistical significance. Bioreductive drugs. In the wake of the failure of most hypoxic cell radiosensitizers to live up to their clinical potential, a new approach to combating hypoxia emerged: the use of bioreductive drugs that are selectively toxic to hypoxic cells. While these agents kill rather than sensitize hypoxic cells, the net effect of combining them with radiation therapy is an apparent sensitization of the tumor due to the elimination of an otherwise radioresistant subpopulation. Such drugs have been shown to outperform the nitroimidazole radiosensitizers in experimental studies with clinically relevant fractionated radiotherapy.188 To the extent that hypoxic cells are also resistant to chemotherapy because of tumor

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CHAPTER 1 microenvironmental differences in drug delivery, pH, or the cell’s proliferative status, complementary tumor-cell killing might be anticipated for combinations of bioreductive agents and anticancer drugs as well.189 Most hypoxia-specific cytotoxic drugs fall into three categories: the nitroheterocyclics, the quinone antibiotics, and the organic nitroxides.190 All require bioreductive activation by nitroreductase enzymes such as cytochrome P450, DT-diaphorase, and nitric oxide synthase to reduce the parent compound to its cytotoxic intermediate, typically an oxidizing free radical capable of damaging DNA and other cellular macromolecules. The active species is either not formed or immediately back-oxidized to the parent compound in the presence of oxygen, which accounts for its preferential toxicity under hypoxic conditions. Examples of nitroheterocyclic drugs with bioreductive activity include misonidazole and etanidazole191,192 and dual-function agents such as RSU 1069.193 The latter drug is termed “dual function” because its bioreduction also activates a bifunctional alkylating moiety capable of introducing crosslinks into DNA. Mitomycin C and several of its analogs (including porfiromycin and EO9) are quinones with bioreductive activity that have been tested in randomized clinical trials in head and neck tumors (e.g., Haffty et al.194). The lead compound for the third class of bioreductive drugs, the organic nitroxides, is tirapazamine (SR 4233, Table 1.2).181,182,188 The dose-limiting toxicity for single doses of tirapazamine is a reversible hearing loss; other effects observed include nausea and vomiting, and muscle cramps.195 Tirapazamine is particularly attractive because it both retains its hypoxia-selective toxicity over a broader range of (low) oxygen concentrations than the quinones and nitroheterocyclic compounds196 and its “hypoxic cytotoxicity ratio,” the ratio of drug doses under hypoxic versus aerobic conditions to yield the same amount of cell killing, averages an order of magnitude higher than for the other classes of bioreductive drugs.189 Laboratory and clinical data also support a tumor-sensitizing role for tirapazamine in combination with cisplatinum.195 To date, clinical trials with tirapazamine combined with radiotherapy and/or chemotherapy have yielded mixed results,195,197,198 although it has improved outcomes for some standard treatments. While it is disappointing that tirapazamine has not made a more significant impact on clinical practice, the search for more effective agents from the same or similar chemical class continues.199 Proliferating cell radiosensitizers. Another source of apparent radioresistance is the presence of rapidly proliferating cells. Such cells may not be inherently radioresistant but rather have the effect of making the tumor seem refractory to treatment because the production of new cells outpaces the cytotoxic action of the therapy. Analogs of the DNA precursor thymidine, such as bromodeoxyuridine (BrdUdR) or iododeoxyuridine (IdUdR), can be incorporated into the DNA of actively proliferating cells in place of thymidine because of close structural similarities between the compounds. Cells containing DNA substituted with these halogenated pyrimidines are more radiosensitive than normal cells, with the amount of sensitization directly proportional to the fraction of thymidine replaced.200 In general, the radiosensitization takes the form of a decrease in or elimination of the shoulder region of the radiation survival curve. To be maximally effective, the drug must be present for at least several rounds of DNA replication prior to irradiation. Although the mechanism by which BrdUdR and IdUdR exert their radiosensitizing effect remains somewhat unclear, it is likely that both the formation of more complex radiation-induced lesions in the vicinity of the halogenated pyrimidine molecules and interference with DNA damage sensing or repair are involved.201 The clinical use of halogenated pyrimidines began in the late 1960s with a major clinical trial in head and neck cancer.202 In retrospect, the

The Biological Basis of Radiation Oncology

25

choice of head and neck tumors for this study was far from ideal, because the oral mucosa is also a rapidly proliferating tissue and was similarly radiosensitized, causing severe mucositis and a poor therapeutic ratio overall. In later years, tumors selected for therapy with halogenated pyrimidines were chosen in the hopes of better exploiting the differential radiosensitization between tumors and normal tissues.203 Aggressively growing tumors surrounded by slowly growing or nonproliferating normal tissues, such as high-grade brain tumors or some sarcomas, have been targeted, for example.204,205 Later strategies for further improving radiosensitization by BrdUdR and IdUdR involved changing the schedule of drug delivery: giving the drug as a long, continuous infusion both before and during radiotherapy206; and administering the drug as a series of short, repeated exposures.207 Overall, however, the use of halogenated pyrimidines in the clinic has remained experimental and has not become mainstream. Chemotherapy drugs as radiosensitizers. Several chemotherapy agents have long been known to increase the effectiveness of radiotherapy despite not being “true” radiosensitizers, like the nitroimidazoles. This has driven the clinical practice of treating many more patients today than in the past with chemotherapy and radiation therapy concurrently. Two drugs in particular used for chemoradiotherapy are 5-fluorouracil (5-FU, effective against gastrointestinal malignancies208) and cisplatinum (effective against head and neck209 and cervix cancers210). Based on these clinical successes in combining radiation with concurrent chemotherapy, and with ever-increasing numbers of molecularly targeted drugs and biologics available today, it is naturally of interest whether any of these novel compounds could also act as radiosensitizers. Two classes of such drugs already have entered the clinical mainstream as sensitizers: the antiepidermal growth factor receptor (EGFR) inhibitors and the antivascular endothelial growth factor (VEGF) inhibitors. Cetuximab is a monoclonal antibody raised against the EGFR that has been shown to improve outcomes in advanced head and neck cancers when combined with radiation therapy211 and bevacizumab is a humanized monoclonal antibody raised against VEGF that prolongs overall and progression-free survival in patients with advanced colorectal cancer when combined with standard chemotherapy.212 It is hoped that these and other targeted agents will play greater roles in cancer therapy in the future.

Normal Tissue Radioprotectors Amifostine (WR 2721, see Table 1.2), is a phosphorothioate compound developed by the US Army for use as a radiation protector. Modeled after naturally occurring radioprotective sulfhydryl compounds such as cysteine, cysteamine, and glutathione,213 amifostine’s mechanism of action involves the scavenging of free radicals produced by ionizing radiation, radicals that otherwise could react with oxygen and “fix” the chemical damage. Amifostine can also detoxify other reactive species through the formation of thioether conjugates; in part because of this, the drug can also be used as a chemoprotective agent.214 Amifostine is a prodrug that is dephosphorylated by plasma membrane alkaline phosphatase to the free thiol WR 1065, the active metabolite. As is the case with the hypoxic cell radiosensitizers, amifostine need only be present at the time of irradiation to exert its radioprotective effect. In theory, if normal tissues could be made to tolerate higher total doses of radiation through the use of radioprotectors, then the relative radioresistance of hypoxic tumor cells would be less likely to limit radiation therapy. However, encouraging preclinical studies demonstrating radioprotection of a variety of cells and tissues notwithstanding,215,216 radioprotectors such as amifostine would not be expected to increase the therapeutic ratio unless they could be introduced selectively into normal tissues but not tumors. The pioneering studies of Yuhas et al.178,217,218 addressed this issue by showing that the drug’s active

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26

SECTION I

Scientific Foundations of Radiation Oncology

metabolite reached a higher concentration in most normal tissues than in tumors and that this mirrored the extent of radio- or chemoprotection. The selective protection of normal tissues results from slower tumor uptake of the drug and tumor cells being both less able to convert amifostine to WR 1065 (owing to lower concentrations of the required phosphatases) and less able to transport this active metabolite throughout the cell. Dose-reduction factors (DRFs; the ratio of radiation doses to produce an isoeffect in the presence vs. absence of the radioprotector) in the range of 1.5 to 3.5 are achieved for normal tissues, whereas the corresponding DRFs for tumors seldom exceed 1.2. Those normal tissues exhibiting the highest DRFs include bone marrow, gastrointestinal tract, liver, testes, and salivary glands.178 The brain and spinal cord are not protected by amifostine, and oral mucosa only marginally so.178 Comparable protection factors are obtained for some chemotherapy agents, including cyclophosphamide and cisplatin.219,220 The dose-limiting toxicities associated with the use of amifostine include hypotension, emesis, and generalized weakness or fatigue.221 Amifostine is currently indicated for the reduction of renal toxicity associated with repeated cycles of cisplatin chemotherapy in patients with advanced ovarian and non–small cell lung cancer. It is also approved for use in patients receiving radiotherapy for head and neck cancer in the hopes of reducing xerostomia secondary to exposure of the parotid glands. Finally, just as there are apparent radiosensitizers, there are also apparent radioprotectors that have the net effect of allowing normal tissues to better tolerate higher doses of radiation and chemotherapy but through mechanisms of action not directly related to the scavenging of free radicals. Various biological response modifiers, including cytokines, prostaglandins (such as misoprostol222,223), anticoagulants (such as pentoxifylline224,225), and protease inhibitors are apparent radioprotectors because they can interfere with the chain of events that normally follows the killing of cells in tissues by, for example, stimulating compensatory repopulation or preventing the development of fibrosis. Finally, there is also growing interest in the use of biologics that inhibit apoptosis as normal tissue radioprotectors.226,227 Such agents should have little or no effect on tumor cells, most of which are already apoptosis resistant.

CLINICAL RADIOBIOLOGY Growth Kinetics of Normal Tissues and Tumors In the simplest sense, normal tissues are normal because the net production of new cells, if it occurs at all, exactly balances the loss of old cells from the tissue. In tumors, the production of new cells exceeds cell loss, even if only by a modest amount. Although the underlying radiobiology of cells in vitro applies equally to the radiobiology of tissues, the imposition by growth kinetics of this higher level of organizational behavior makes the latter far more complex systems.

Descriptive Classification Systems Two qualitative classification systems based loosely on the proliferation kinetics of normal tissues are in use. Borrowing heavily from the pioneering work of Bergonié and Tribondeau,13 Rubin and Casarett’s228 classification system for tissue “radiosensitivity” consists of four main categories: Type I or vegetative intermitotic cells (VIMs) are considered the most radiosensitive, consisting of regularly dividing, undifferentiated stem cells such as are found in the bone marrow, intestinal crypts, and the basal layer of the epidermis of the skin. Type II or differentiating intermitotic cells (DIMs) are somewhat less radiosensitive, consisting of progenitor cells that are in the process of developing differentiated characteristics yet are still capable of a

limited number of cell divisions. Myelocytes of the bone marrow and spermatocytes of the testis are examples of Type II cells. Type III or reverting postmitotic cells (RPMs) are relatively radioresistant, consisting of those few types of cells that are fully differentiated and do not divide regularly yet under certain conditions can revert to a stem cell–like state and divide as needed. Examples of Type III cells include hepatocytes and lymphocytes, although the latter are unique in that they are a notable exception to the Rubin and Casarett classification system—an RPM cell type that is exquisitely radiosensitive. Type IV or fixed postmitotic cells (FPMs) are the most radioresistant, consisting of the terminally differentiated, irreversibly postmitotic cells characteristic of most normal tissue parenchyma, such as neurons and muscle cells. Should such cells be killed by radiation, they typically cannot be replaced. A second, simpler classification system, based on anatomical and histological considerations, has been proposed by Michalowski.229 Using this system, tissues are categorized on the basis of whether the tissue stem cells, if any, and the functional cells are compartmentalized (so-called Type H or hierarchical tissues, such as skin, gut epithelium, testis, etc.) or intermixed (Type F or flexible tissues, such as lung, liver, kidney, and spinal cord).

Growth Kinetic Parameters and Methodologies In order to predict the response of an intact tissue to radiation therapy in a more quantitative way, a number of kinetic parameters have been described that provide a better picture of the proliferative organization of tumors and normal tissues (Table 1.3). Growth fraction. Among the first kinetic characteristics described was the growth fraction (GF). The presence of a fraction of slowly cycling or noncycling cells in experimental animal tumors was first noted by Mendelsohn et al.230,231 and, subsequently, in human tumors by other investigators. While normal tissues do not grow and therefore do not have a GF per se, many are composed of noncycling cells that have differentiated in order to carry out tissue-specific functions. Some normal tissues do contain a small fraction of actively proliferating stem cells. Others contain apparently dormant or “resting” cells that are temporarily out of the traditional four-phase cell cycle but are capable of renewed proliferation in response to appropriate stimuli. Lajtha gave these resting but recruitable cells of normal tissues the designation G0.232 While a tumor counterpart of the G0 cell may or may not exist, the majority of slowly cycling or noncycling tumor cells are thought to be in such a state because of nutrient deprivation, not because of a normal cell cycle regulatory mechanism. Thus, Dethlefsen233 has suggested that the term Q cell be reserved for quiescent cells in tumors to distinguish them from the G0 cell of normal tissues. Measurement of a tumor’s GF is problematic,234,235 but an estimate can be obtained with a technique known as continuous thymidine labeling. Using this method, the tumor receives a continuous infusion of radiolabeled thymidine for a period of time long enough for all proliferating cells to have gone through at least one round of DNA synthesis and incorporated the radioactive label. Then, a biopsy of the tumor is obtained and tissue sections prepared for autoradiography. Once the slides are processed and scored, the continuous labeling index, that fraction of the total population of tumor cells containing tritiated thymidine, is calculated. This value is a rough estimate of the tumor’s GF. Cell cycle and volume doubling times. The percent labeled mitosis (PLM) technique of Quastler and Sherman236 was a key development in the study of the cell cycle in vivo because it provided a unique window into the behavior of that fraction of cells within a tissue that was actively proliferating. By focusing on cells in mitosis, the assay allowed both the overall cell cycle time (Tc) and the durations of the individual cell

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CHAPTER 1

TABLE 1.3

The Biological Basis of Radiation Oncology

27

Estimated Cell Cycle Kinetic Parameters for Human Tumors Representative Values for Human Solid Tumors

Parameter

Definition

How Measured

Notes

Tc

(Average) Cell cycle time

Percent labeled mitosis technique; flow cytometry

0.5–6.5 days (median ≈ 2.5)

Tc in vivo usually longer than for comparable cells cultured in vitro.

GF

Growth fraction

Estimated from continuous labeling technique

0.05–0.90 days (median ≈ 0.40?)

Difficult to measure directly; not much data available.

Tpot

Potential doubling time

Flow cytometry (relative movement method: Tpot = λTs/LI)

2–19 days (median ≈ 5)

Tpot ≈ Tc as GF approaches 1.0.

ϕ

Cell loss factor

1 − Tpot/Td

0.30–0.95 days (median ≈ 0.90?)

Thought to be the major cause of long Tds for human tumors; particularly high in carcinomas.

Td

Volume doubling time

Direct measurement of tumor dimensions over time

5–650 days (median ≈ 90)

Increases with increasing tumor size, often because of increases in Tc and f, and a decrease in GF.

Teff/Tp

Effective clonogen doubling time

Estimated from clinical data on the loss of local control with increasing overall treatment time

4–8 days

Tp approaches Tpot toward the end of a course of fractionated radiotherapy.

Data from Steel GG. Growth Kinetics of Tumours. Oxford: Clarendon Press; 1977, and Joiner M, van der Kogel A. Basic Clinical Radiobiology. 4th ed. London: Hodder Arnold; 2009.

cycle phases to be determined without the uncertainties introduced by the presence of noncycling cells in the population. Today, flow cytometric methods have largely replaced the arduous and time-consuming PLM assay. Briefly, the PLM technique involves tracking over time a cohort of proliferating cells that initially was in S phase (and exposed briefly to tritiated thymidine) and then proceeded through subsequent mitoses. Serial biopsy samples from the tissue of interest are obtained at regular intervals following labeling, and the fraction of cells both in mitosis (identified cytologically) and carrying the radioactive label is determined. A first peak of labeled mitoses is observed within 24 hours after labeling, and as cells pass through their second division, a second wave of labeled mitoses is noted. The average Tc for the population of proliferating cells corresponds to the peak-to-peak interval of the resulting PLM curve, a plot of the fraction of labeled mitoses as a function of time following the radioactive pulse. With sufficiently robust data, the durations of the individual cell cycle phases can be obtained as well. The PLM technique is illustrated schematically in Fig. 1.25. Historically, the interpretation of PLM curves was sometimes hampered by technical artifacts and by the fact that proliferating cell populations have distributed cell cycle times.234,235,237 Despite these limitations, it is clear that most cells in vivo proliferate more slowly than their in vitro counterparts. Although the variation in intermitotic times is quite large, a median value for Tc of 2 to 3 days is a reasonable estimate.234 While the cycle times of proliferating cells in vivo are long by cell culture standards, they are quite short when compared with the corresponding volume doubling times (Td) for human tumors. Although highly variable from tumor type to tumor type and somewhat difficult to measure, the Td for human solid tumors averages about 3 to 4 months.234 In many cases, sample calculations further suggest that the discrepancy between Tc for proliferating tumor cells and Td for the tumor as a whole cannot be accounted for solely by the tumor having a low GF. Cell loss factor. Cell kineticists initially adhered to the notion that the continued growth of tumors over time reflected abnormalities in

cell production. Pathologists and tumor biologists, meanwhile, had ample evidence that tumors routinely lost large numbers of cells, the result of cell death, maturation, and/or emigration.234,238,239 It is now clear that the overall rate of tumor growth, as reflected by its Td, is governed by the competing processes of cell production and cell loss. In fact, the cell loss factor, ϕ, the rate of cell loss expressed as a fraction of the cell production rate, is surprisingly high for both experimental and human tumors, as high as 0.9 or more for carcinomas and lower, on average, for sarcomas.234 Cell loss is usually the most important factor governing the overall volume Td of solid tumors. The clinical implications of tumors having high rates of cell loss are obvious. First, any attempts at making long-term predictions of treatment outcome based on short-term regression rates of tumors during treatment are misleading. Second, although regression rate may not correlate well with eventual outcome, it may be a reasonable indicator of when best to schedule subsequent therapy on the assumption that a smaller tumor will be more radio- and chemosensitive, as well as easier to remove surgically. Potential doubling time and “effective” doubling time. With the recognition that cell loss plays a major role in the overall growth rate of tumors and can mask a high cell production rate, a better measure of the potential repopulation rate of normal tissues and tumors was needed.240 One indicator of regenerative capacity is the potential doubling time (Tpot).234,241 By definition, Tpot is an estimate of the time that would be required to double the number of clonogenic cells in a tumor in the absence of cell loss. It follows that Td will usually be much longer than Tpot because of cell loss, and Tc will be shorter than Tpot because of the presence of nonproliferating cells.237 Tpot can be estimated from a comparison of the S phase pulse labeling index (LI) and the duration of S phase (TS) by using the following equation: Tpot = λ TS LI where λ is a correction factor related to the nonuniform distribution of cell “ages” in a growing population (usually, λ ≈ 0.8). TS and LI can

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G2 M G1 c

a

e

Percent labeled mitoses

b

d

TM

TC

100

TG2 ! TG2

50

0

b

TS

c

e

Percent labeled mitoses

s 80 60 40 20 0 10 20 30 Time after labeling (h)

40

TG2 a

d “Time” after labeling Fig. 1.25 The technique of labeled mitoses (PLM) for an idealized cell population with identical cell cycle times (left panels) and for a representative normal tissue or tumor with a dispersion in cell cycle times (right panel). Top left: Following a brief exposure to tritiated thymidine or equivalent at time = “a,” the labeled cohort of S phase cells continues (dark shading) around the cell cycle and is sampled at times = “b,” “c,” “d,” and “e,” respectively. Bottom left panel: For each sample, the percentage of cells both in mitosis and containing the thymidine label is determined and plotted as a function of time; from such a graph, individual cell cycle phase durations can be derived. Right panel: In this more realistic example, a mathematical fit to the PLM data would be needed to calculate the (average) cell cycle phase durations.

be determined by the relative movement method.241,242 This technique involves an injection of a thymidine analog, usually BrdUrd, which is promptly incorporated into newly synthesized DNA and whose presence can be detected using flow cytometry. The labeled cohort of cells is then allowed to continue movement through the cell cycle and a biopsy of the tumor is taken several hours later, at which point the majority of the BrdUrd-containing cells have progressed into G2 phase or beyond. A value for LI is determined from the fraction of the total cell population that contains BrdUrd, and TS is calculated from the rate of movement of the labeled cohort during the interim between injection of the tracer and biopsy. Values for Tpot for human tumors have been measured and, although quite variable, typically range between 2 and 20 days.234,240,243 These findings lend support to the important notion that slowly growing tumors can contain subpopulations of rapidly proliferating cells. To the extent that these cells retain unlimited reproductive potential, they may be considered the tumor’s stem cells (in a generic sense, at least) capable of causing recurrences after treatment. These cells represent a serious threat to local control of the tumor by conventional therapies, especially protracted treatments (that provide them additional time to proliferate). The use of a cell kinetic parameter such as Tpot as either a predictor of a tumor’s response to therapy or as a means of identifying subsets of patients particularly at risk for recurrence has been attempted, with some positive, but mostly negative, results.6,141,244 Lest these negative findings suggest that proliferation in tumors is unimportant, bear in mind that it is unlikely that a pretreatment estimate of Tpot—or any other single cell kinetic parameter (e.g., LI) for that matter—would be relevant once treatment commences and the growth kinetics of the tumor are perturbed. One approach to dealing with this problem is to measure proliferative activity during treatment. Although not without other limitations, the use of an “effective clonogen doubling time” (Teff or Tp) has been

advocated.245–247 Estimates of Tp can be obtained from two types of experiments. In an experimental setting, Tp can be inferred from the additional dose necessary to keep a certain level of tissue reaction constant as the overall treatment time is increased. (When expressed in terms of dose rather than time, the proper term would be Deff, although the underlying concept is the same.) For example, acute skin reactions usually both develop and begin to resolve during the course of radiation therapy, suggesting that the production of new cells in response to injury gradually surpasses the killing of existing cells by each subsequent dose fraction. By intensifying treatment once this repopulation begins, it theoretically should be possible to reach a steady state wherein the tissue reaction remains constant. In a clinical setting, Tp can be estimated from a comparison of tumor control rates for treatment schedules in which the dose per fraction and total dose used were held approximately constant but the overall treatment time varied. In some cases, the loss of local control with increasing overall treatment time provides an estimate not only of Tp but also of the delay time before the repopulation begins, sometimes referred to as Tk, the repopulation “kickoff” time.248–250 Repopulation in tumors and normal tissues. As discussed earlier, both normal tissues and tumors are capable of increasing their cell production rate in response to radiation-induced cell killing, a process known as regeneration or repopulation. The time of onset of the regenerative response varies with the turnover rate of the tissue or tumor since cell death (and depopulation) following irradiation is usually linked to cell division. Generally, tissues that naturally turn over fairly rapidly repopulate earlier and more vigorously than tissues that turn over slowly. However, it has been shown that the repopulation patterns of normal tissues and tumors following the start of irradiation tend to be characterized by a delay (of at least several weeks in many cases; see Tk discussed earlier) prior to the rapid proliferative response.248–250 Once this proliferative response begins, however, it can be quite vigorous. While this is clearly desirable for early-responding normal tissues attempting to recover from radiation injury, rapid proliferation in tumors

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CHAPTER 1 is obviously undesirable.251 For example, clinical studies of local control of head and neck tumors indicate that an average of about 0.6 Gy per day is lost to repopulation.245 Attempts to counteract this accelerated proliferation by dose intensification during the latter part of a treatment course can be problematic because late-responding normal tissues do not benefit from accelerated repopulation during treatment and risk incurring complications.

EARLY AND LATE EFFECTS IN NORMAL TISSUES “Early” Versus “Late” Normal tissue complications observed following radiation therapy are the result, either directly or indirectly, of the killing of critical target cells within the tissue that are crucial to the tissue’s continued functional and/or structural integrity. The loss of these cells can occur either as a direct consequence of the cytotoxic action of the radiation or indirectly due to the radiation injury or killing of other cells. In some cases, the tissue’s response to the depletion of its component cells can exacerbate the injury, for example, when a hyperproliferation of fibroblasts and the resulting collagen deposition replace a tissue’s parenchymal cells, resulting in fibrosis. It is important to realize that a particular tissue or organ may contain more than one type of target cell, each with its own radiosensitivity. One tissue may manifest more than one complication following radiation therapy, with the severity of each determined by the radiosensitivity of the particular target cell and the time-dose-fractionation schedule employed. It follows from this that the severity of one complication does not necessarily predict the severity of another complication, even within the same tissue (although “consequential” late effects secondary to severe early reactions are possible in some cases252). For example, dry or moist desquamation of the skin results from the depletion of the basal cells of the epidermis, fibrosis results from damage to dermal fibroblasts, and telangiectasia results from damage to small blood vessels in the dermis. For many tissues, however, the cell(s) whose death is (are) responsible for a particular normal tissue injury remain(s) unclear. While the radiosensitivity of the putative target cells determines the severity of an early or late effect in a normal tissue, the “earliness” or “lateness” of the clinical manifestation of that injury is related to the tissue’s proliferative organization (discussed above). The distinction between the radiosensitivity of a tissue’s cells and the radioresponsiveness of the tissue as a whole can be a source of confusion. Bergonié and Tribondeau’s “laws,”13 for example, confused the concepts of radiosensitivity and radioresponsiveness to some extent, referring to tissues that responded to damage early as “radiosensitive,” when this is not necessarily the case.

Whole Body Radiation Syndromes Many human beings have been exposed to total body irradiation, including the survivors of Hiroshima and Nagasaki, Polynesian Islanders and military personnel present during above ground nuclear tests during the 1950s, and victims of accidental exposures in the workplace (e.g., Chernobyl). Of the latter, about 100 fatalities due to radiation accidents have been documented since the mid-1940s.253–255 The whole body radiation syndromes described here only occur when most or all of the body is irradiated. Also, although total body irradiation (TBI) is a prerequisite for the manifestation of these syndromes, neither the dose received nor its biological consequences are necessarily uniform. The radiosensitivities of the respective target cells determine the effective threshold dose below which the syndrome does not occur, whereas the onset time of individual symptoms is governed more by the proliferative organization of the tissue.

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The mean lethal dose (LD50) is defined as the (whole body) dose that results in mortality for 50% of an irradiated population. The LD50 value is often expressed in terms of the time scale over which the deaths occur, such as at either 30 or 60 days postirradiation. For humans, the single-dose LD50/60 for x-rays or γ-rays is approximately 3.5 Gy in the absence of medical intervention and about twice that with careful medical management.28,255 The LD50 increases with decreasing dose rate of low-LET radiation and decreases for radiations of higher LET. The prodromal syndrome. The prodromal syndrome consists of one or more transient, neuromuscular, and gastrointestinal symptoms that begin soon after irradiation and persist for up to several hours. The symptoms, which can include anorexia, nausea, vomiting, diarrhea, fatigue, disorientation, and hypotension, and their severity and duration, increase with increasing dose. Because in most radiation accident situations the dose that victims received is unknown initially, careful attention to the prodromal syndrome can be used as a crude dosimeter. The cerebrovascular syndrome. The cerebrovascular syndrome occurs for total body doses in excess of 50 Gy. The onset of signs and symptoms is almost immediate following exposure, consisting of severe gastrointestinal and neuromuscular disturbances—including nausea and vomiting, disorientation, ataxia, and convulsions.28,255 The cerebrovascular syndrome is invariably fatal; survival time is seldom longer than about 48 hours. Only a few instances of accidental exposure to such high doses have occurred, two of which (a nuclear criticality accident at Los Alamos National Laboratory in 1958 and a 235U reprocessing plant accident in Rhode Island in 1964) have been extensively documented in the medical literature.256,257 The immediate cause of death for the cerebrovascular syndrome is likely vascular damage leading to progressive brain edema, hemorrhage, and/or cardiovascular shock.255 Following such high doses delivered acutely, even cells traditionally considered radioresistant, such as neurons and the parenchymal cells of other tissues and organs, will be killed along with the more radiosensitive vascular endothelial cells and the various glial cells of the central nervous system. The gastrointestinal syndrome. For doses upwards of about 8 Gy, the gastrointestinal syndrome predominates, characterized by lethargy, vomiting and diarrhea, dehydration, electrolyte imbalance, malabsorption, weight loss, and, ultimately, sepsis. These symptoms begin to appear within a few days of irradiation and are progressive in nature, culminating in death after 5 to 10 days. The target cells for the gastrointestinal syndrome are principally the crypt stem cells of the gut epithelium. As mature cells of the villi are lost over a several-day period, no new cells are available to replace them; thus, the villi begin to shorten and eventually become completely denuded. This greatly increases the risk of bleeding and sepsis, both of which are aggravated by declining blood counts. Prior to the Chernobyl accident, in which approximately a dozen firefighters received total doses sufficient to succumb to the gastrointestinal syndrome, there was only one other documented case of a human dying of gastrointestinal injury.28,255 To date, no human has survived a documented whole body dose of 10 Gy of low-LET radiation. The hematopoietic syndrome. Acute doses of approximately 2.5 Gy or more are sufficient to cause the hematopoietic syndrome, a consequence of the killing of bone marrow stem cells and lymphocytes. This syndrome is characterized by a precipitous (within 1–2 days) reduction in the peripheral blood lymphocyte count, followed by a more gradual reduction (over a period of 2–3 weeks) in the numbers of circulating leukocytes, platelets, and erythrocytes. The granulocytopenia and thrombocytopenia reach a maximum within 30 days after exposure; death, if it is to occur, is usually a result of infection and/or hemorrhage.28,255 Theoretically, the use of antibiotics, blood transfusions, and bone marrow transplantation can save the lives of individuals who receive doses at or near the LD50. In practice, however, the exact dose

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is seldom known, and should it be high enough to reach the threshold for the gastrointestinal syndrome, such heroic measures would be in vain. This was the case for all but 2 of the 13 Chernobyl accident victims who received bone marrow transplants.28 Of the two survivors, only one technically had his life saved by the transplant; the other survivor showed autologous bone marrow repopulation.

Teratogenesis One of the most anxiety-provoking risks of irradiation in the eyes of the general public is prenatal exposure of the developing embryo or fetus.254,255 In part, such concern is warranted because teratogenic effects are quite sensitive to induction by ionizing radiation, with readily measurable neurological abnormalities noted in individuals exposed prenatally to doses as low as approximately 0.06 Gy.28 The radiationinduced excess relative risk of teratogenesis during the most sensitive phase of gestation is approximately 40% per Gy.28 By comparison, the spontaneous incidence of a congenital abnormality occurring during an otherwise normal pregnancy is about 5% to 10%.255 Information on the teratogenic effects of radiation in humans come from two major sources, the Japanese atomic bomb survivors and patients who received diagnostic or therapeutic irradiation either prior to the establishment of modern radiation protection standards or in clinical emergency situations. While a range of abnormalities have been identified in individuals irradiated in utero (including anecdotal reports of miscarriages and stillbirths, cataracts and other ocular defects, gross malformations, sterility, etc.), the most commonly reported are microcephaly, intellectual/cognitive impairment, and growth retardation.28,254,255 Each of these teratogenic effects has a temporal relationship to the stage of gestation at the time of irradiation as well as a radiation dose and dose rate dependency. Lethality is the most common consequence of irradiation during the preimplantation stage (within 10 days of conception), growth retardation has been noted for irradiation during the implantation stage (10–14 days after conception), and during the organogenesis period (about 15–50 days after conception), the embryo is sensitive to both lethal, teratogenic, and growth retarding effects.255 Radiation-induced gross abnormalities of the major organ systems do not occur during the fetal period (more than 50 days postconception), although generalized growth retardation and some neurological defects have been noted for radiation doses in excess of 1 Gy.

Radiation-Induced Cataracts Late effects resulting from irradiation of the eye were noted within a few years of the discovery of x-rays,228,255 with cataracts being the most frequent pathological finding. From a clinical perspective, the induction of a cataract following radiotherapy is a normal tissue complication that can be corrected surgically and, as such, is not considered quite as dire as other late effects. From a radiobiological perspective, however, cataracts are unique among the somatic effects of radiation in several respects. First, although the lens of the eye is a self-renewing tissue complete with a stem cell compartment of epithelial cells that divide and gradually differentiate into mature lens fibers, there is no clear mechanism of cell loss.28 As such, the stem cells damaged by radiation (which manifest themselves as abnormal, opaque lens fibers) persist, eventually leading to a cataract. Second, cataracts are among the few radiation-induced lesions that can be distinguished pathologically from their spontaneously occurring counterparts; radiation cataracts first appear in the posterior pole of the lens, whereas spontaneous cataracts usually begin in the anterior pole.258,259 Third, radiogenic cataracts exhibit a variable latency period (anywhere from about a year to several decades, averaging 5–8 years) that decreases with increasing radiation dose. Finally, cataract formation is a nonstochastic (deterministic) process; that is, there is a threshold dose below which no cataracts occur, but above the

threshold, the frequency and severity of cataracts increases with increasing dose.258,259 For low-LET radiation, the single-dose threshold for a cataract in humans is approximately 2 Gy, which increases to about 4 Gy for fractionated exposures. These dose thresholds apply to any detectable cataract, although not necessarily a symptomatic one, which generally requires a fractionated dose of at least 10 Gy. Neutrons are also known to be quite effective at inducing cataracts, with RBEs of about 5 to 10 commonly observed in laboratory rodents.255

Radiation Carcinogenesis Unrepaired or misrejoined DNA damage caused by radiation exposure is usually lethal to the cell, although this is not invariably the case, particularly when the genetic material is simply rearranged rather than deleted. Whether such changes have further implications for the cell bearing them depends on the location of the damage in the genome, the nature and extent of the mutational event, whether working copies of proteins can still be produced from the gene or genes involved, what function these proteins normally have, and the type of cell. There is compelling evidence that some of these radiation-induced genetic rearrangements—particularly ones that activate oncogenes or inactivate tumor suppressor genes—either alone or in combination with other such changes predispose a cell to neoplastic transformation, a necessary early step in the process of tumor induction.254,260 Laboratory studies. Although ionizing radiation is one of the most studied and best understood carcinogens, it is not a particularly potent one. This fact hampers studies of radiation carcinogenesis in humans, because investigators must identify a modest radiogenic increment of excess risk with a long latency period against a high background spontaneous cancer rate and multiple confounding factors. Nevertheless, from a public health perspective, carcinogenesis is the most important somatic effect of radiation for doses of 1.5 Gy or less.28 The use of cell cultures and laboratory rodents to study carcinogenesis avoids some of the pitfalls of human epidemiological studies but have their own inherent limitations. Cell culture systems employ neoplastic transformation as the endpoint, which is a prerequisite for, but by no means equal to, carcinogenesis in vivo. Neoplastic transformation is defined as the acquisition of one or more phenotypic traits in nontumorigenic cells that are usually associated with malignancy, such as immortalization, reduced contact inhibition of growth, increased anchorage-independent growth, reduced need for exogenously supplied nutrients and growth factors, various morphological and biochemical changes, and, in nearly all cases, the ability to form tumors in histocompatible animals.237 Such systems can be used to study relatively early events in the carcinogenesis process, have much greater sensitivity and statistical resolution than in vivo assays, and can be used to measure dose-response relationships. Laboratory animal studies, however, are considered more relevant in that tumor formation is the endpoint, latency periods are shorter, statistical variability is reduced, and the carcinogen exposure conditions can be carefully controlled. Pertinent results from laboratory studies of radiation carcinogenesis include the following: 1. Carcinogenesis is a stochastic effect, that is, a probabilistic function of the dose received, with no evidence of a dose threshold. Increasing the radiation dose increases the probability of the effect, but not its severity.254,260 2. The neoplastic transformation frequency increases linearly with dose, at least over the low-dose range (about 1.5 Gy or less). 3. There is a dose rate effect for transformation and carcinogenesis (for low-LET radiations); protracted exposures carry a reduced risk relative to acute exposures. 4. The processes of neoplastic transformation and carcinogenesis are necessarily in competition with the cell-killing effects of ionizing

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CHAPTER 1 radiation.28 As such, dose-response curves for tumor formation in vivo tend to be bell shaped as a function of dose (e.g., Upton261). In vitro, where cytotoxicity can be assessed separately from transformation and appropriate corrections made, dose-response curves tend to be linear. Epidemiological studies in humans. In humans, most of the information useful for risk estimation is derived from epidemiological studies, with the dose almost always exceeding 0.1 Gy and often exceeding 1.0 Gy. However, most of the controversy concerns doses less than 0.1 Gy, delivered over protracted, rather than acute, time periods. Therefore, in order to infer low-dose effects from high-dose data, epidemiologists make extrapolations and assumptions about dose-response relationships that may or may not be valid in all cases. Many sources of error can also plague epidemiological data, including selection bias, small sample size, heterogeneous population characteristics, and dose uncertainties.255 The human populations that have been and continue to be evaluated for radiation-induced excess cancers are Japanese atomic bomb survivors; persons exposed to fallout from nuclear tests or accidents; radiation workers receiving occupational exposure; populations living in areas characterized by above average natural background radiation or in proximity to man-made sources of radiation; and patients exposed to repeated diagnostic or therapeutic radiation. Pertinent findings from these studies include the following. 1. Within the limits of statistical resolution, the shape of the doseresponse curve is not inconsistent with a linear, no-threshold model.254,260 2. Different tissues have different sensitivities to radiation-induced carcinogenesis, with bone marrow (leukemias other than chronic lymphocytic), breast (female), salivary glands, and thyroid especially susceptible.255 3. The latency period between irradiation and the clinical presentation of a solid tumor averages 20 years or more, and about half that for hematological malignancies. However, the latency period varies with the age of the individual, generally increasing with decreasing age at exposure. Latency periods tend to be shorter for radiation-induced second malignancies, in which patients had received much higher doses. 4. Two risk projection models have been used to predict the risk of radiation carcinogenesis in the human population: the absolute risk model, and the relative risk model. Using the absolute risk model, excess risk in an irradiated population begins after the latency period has passed and is added to the age-adjusted spontaneous cancer risk. After a period of time, the cancer risk returns to spontaneous levels. The relative risk model predicts that the excess cancer risk is a multiple of the spontaneous incidence. At present, the epidemiological data tend to support the relative risk model for most solid tumors and the absolute risk model for leukemia. 5. The current recommendations of the International Commission on Radiological Protection (ICRP) state that the nominal probability of radiation-induced cancer death is approximately 4% per Sievert (Sv) for working adults and about 5% per Sv for the whole population under conditions of frequent, low-dose exposure over extended periods.262 These risk estimates double for acute, high-dose exposures. The Sievert is a unit of dose equivalent used for radiation protection purposes and is equal to the radiation dose (in Gy) multiplied by a radiation weighting (WR) factor specific for the type of radiation (with WR roughly equivalent to the radiation’s RBE). As warranted, a second correction to the equivalent dose can be made to account for the differing radiosensitivities of the different tissues exposed, termed the tissue weighting factor (WT). Once this correction is applied, equivalent dose becomes effective dose, also expressed in units of Sv.

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31

Carcinogenic risk from prenatal irradiation. The risk of carcinogenesis as a result of prenatal radiation exposure is made even more controversial by conflicting results of epidemiological studies. One major study cohort consisted of several thousand children (plus a demographically similar population of unirradiated children) who received prenatal exposure from diagnostic procedures during the 1950s and 1960s. The Oxford Survey of Childhood Cancer263 reported nearly twice the incidence of leukemia in children who had received prenatal irradiation. Although other epidemiological studies lend credence to the Oxford Survey’s findings,254,260 it is still possible that factors other than the x-ray exposure may have caused, or at least contributed to, the excess cancer risk. On the other hand, children of the Japanese atomic bomb survivors who were pregnant at the time of the bombing did not support the Oxford Survey’s findings of increased risk of childhood malignancy; however, they did support an increased risk of malignancy later in life.28 On the assumption that it is preferable to overestimate rather than underestimate risk, it is prudent to assume that the carcinogenic risk of radiation exposure to an embryo or fetus is about twice that for postnatal exposure. Carcinogenic risk from medical imaging procedures. Recent data gleaned from the Japanese atomic bomb survivors indicate a small but statistically significant excess cancer risk even for doses as low as 35 to 150 mSv.264,265 That this is in the range of doses delivered during a computed tomography (CT) scan—in particular, a pediatric CT scan266,267—has made headlines and both sparked controversy268 as well as increased awareness269 of radiation’s risks. Estimates are that an abdominal helical CT scan of a pediatric patient results in a risk of a fatal cancer later in life of approximately one in a thousand.265 A very small risk of radiation carcinogenesis from a CT scan may seem trivial, especially to the radiation oncologist who typically delivers more than 10 times that dose to a patient each day (albeit not to the whole body). Nevertheless, the finding of a radiation-induced excess cancer risk associated with a medical imaging procedure whose use has skyrocketed over the past 35 years265 has the makings of a public health issue. Currently, over 70 million CT scans are performed annually in the United States.265 That, disproportionately, this increase in CT scanning has been in a pediatric population both inherently more sensitive to ionizing radiation and with the longest lifespan in which to express those radiation-induced malignancies is all that much more concerning. Because of this, radiation oncologists, as de facto experts on the health and medical effects of ionizing radiation, should be willing to serve as educators of the public as to both the benefits and risks associated with the common procedures that they employ.

Early and Late Effects Following Radiotherapy It is not the intent of this section to provide an exhaustive review of the various histopathological changes observed in the irradiated normal tissues of radiation therapy patients; the reader is referred to several textbooks and pertinent review articles on the subject (e.g., Rubin and Casarett,228 Mettler and Upton,255 and Fajardo270). This section will focus instead on more recent developments that promise to increase our understanding of the etiology of normal tissue injury and, hopefully, provide clues as to how to decrease or even prevent their occurrence. Cytokines, reactive oxygen species, and inflammation. As mentioned previously, the early and late effects that occur in irradiated normal tissues result directly or indirectly from the killing of critical target cells. Although this statement is true in a general sense, it is clearly a gross oversimplification of what is now known to be a highly complex and dynamic process of signaling cascades, radiation-induced gene expression, cell death (by any of several possible mechanisms), and compensatory proliferative responses. Cytokines, chemokines, and growth factors, inducible proteins released by irradiated cells that stimulate

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Scientific Foundations of Radiation Oncology

other cells to produce a biological response, participate in many of these processes. Although produced locally within the irradiated volume and chiefly intended to influence the behavior of cells in the local microenvironment, some cytokines do enter the circulation and can mobilize cells distant from the irradiated site. In addition to cytokines, another important player in an irradiated tissue’s microenvironment and that also contributes to the development of the complication, is persistent, sometimes cyclic, oxidative stress and inflammation that, after the initial radiation insult, can become self-perpetuating.271 By way of example, lung irradiation causes the release of, among others, cytokines transforming growth factor β (TGF-β), basic fibroblast growth factor (bFGF), and interleukin-6 (IL-6), all of which participate in the etiology of radiation pneumonitis and fibrosis. Of these, TGF-β’s role in promoting lung fibrosis is perhaps the best understood, as is its potential to serve as an early biomarker of radiation-induced lung injury.272 It drives fibrosis development by affecting the survival, proliferation, differentiation, and extracellular matrix production by fibroblasts, while at the same time producing reactive oxygen species that further contribute to oxidative stress and inflammation in the tissue’s microenvironment.271,273 Functional subunits and volume effects. Radiation oncologists traditionally reduce the total dose when the irradiation field involves a large volume of normal tissue. Although this practice evolved empirically, the biological basis for decreasing normal tissue tolerance with increasing irradiation volume remains unclear. Withers240,274 proposed a descriptive model for the pathogenesis of radiation injury in normal tissues based on the structural and functional organization of the tissue at risk for a complication. Conceptually, tissues are considered to be organized into functional subunits (FSUs), which can be inactivated by radiation exposure secondary to the killing of their constituent target cell(s). These FSUs may be anatomically defined, such as an alveolar sac of the lung, a nephron of the kidney, or lobule of the liver, or anatomically undefined (skin, gut, nervous system).28 The main difference between the two is that surviving cells from surrounding FSUs can migrate and help repopulate anatomically undefined FSUs but not anatomically defined ones, presumably due to the lack of any structural demarcation. This could have the net effect of making anatomically undefined FSUs able to tolerate higher radiation doses. Whether the inactivation of one or more FSUs impacts the overall tissue function (in the form of a radiation-induced complication) depends on how many of the tissue’s FSUs are in the irradiation field and their spatial arrangement. The spinal cord responds to changing irradiation volume as if its corresponding FSUs are arranged “in series.” There is a steep reduction in the tolerance dose for white matter necrosis of the rat spinal cord with increasing treatment volume for small radiation fields (up to about 2 cm exposed cord length), but little or no volume dependence for larger treatment fields, presumably because inactivation of one FSU inactivates the entire cord.141 The lung, on the other hand, seems to have a large functional reserve; it is only when much larger volumes are irradiated, and correspondingly large numbers of FSUs inactivated, that a functional deficit develops. This is more in keeping with a tissue whose functional subunits operate relatively independently and are arranged “in parallel.” Some other organs are believed to behave as if they have both serial and parallel components. One immediate clinical implication for tissues with parallel versus serially arranged FSUs is that a small dosimetric hotspot would be relatively innocuous for a parallel tissue but potentially catastrophic for a serial tissue. Reirradiation tolerance. A common problem that radiation oncologists face is whether or not to risk reirradiation of a previously treated site. If a decision is made to retreat, even in the most ideal case in which

the previous treatment course is well documented and the treatment fields still identifiable, the clinician is nevertheless left with the uncertainty of what time, dose, and fractionation pattern to use. Radiobiology research in this area has been slow in coming (given the very nature of studies involving late effects), but some progress has been made and some of the factors thought to be important in normal tissue tolerance to retreatment have been identified. These include whether the initial treatment course was to “full tolerance” or not, the likelihood that residual damage from the first treatment course has persisted, the amount of time that has elapsed between the first course and the second, the target volume to be reirradiated compared to the original target volume, and the structural and functional makeup of the tissue at risk. A few general concepts are beginning to emerge from studies with laboratory rodents (for reviews, see Thames and Hendry,275 Travis and Terry,276 and Joiner and van der Kogel141): 1. For rapidly proliferating tissues such as skin, bone marrow, or testis, recovery following the first course of treatment is rapid such that the tissue can be reirradiated to near the full tolerance dose within about 2 to 3 months. However, it must be borne in mind that these tissues do not exist in isolation; thus, damage to nearby tissues that they depend on could affect tolerance. 2. Some slowly proliferating tissues, such as spinal cord and lung, are capable of long-term recovery after the first course of treatment and can be retreated to a partial (25%–70%) tolerance dose, with the dose generally increasing the longer the time between the two treatments (3–6 months minimum). 3. Other slowly dividing tissues, such as bladder, seem to show permanent residual injury from the first treatment such that the total dose for a second course must be reduced by at least half regardless of how much time has elapsed between treatments. In addition, there is evidence that complications arising from retreatment tend to occur much earlier (relative to the second treatment) than they would have from a single treatment. 4. One apparent exception to this type of classification system is the kidney, for which retreatment tolerance decreases with time between the first and second treatment courses. A model that is consistent with these observations suggests that target cells that survive the initial treatment course have three possible fates. Some may regenerate their numbers over time, making the tissue as a whole better able to tolerate a second treatment, with the rate of regeneration determining how much time should elapse between the two treatments and what total dose can be delivered safely during the second course. Other target cells may maintain a steady-state number of survivors after the first treatment; therefore, the tissue would appear to harbor “residual damage” and never be able to tolerate a full second course of radiation therapy. Finally, some target cells may undergo continued depletion after the first treatment such that tolerance to a second treatment course will actually decrease the longer the time between treatments. This may be related to a progressive expression of otherwise subclinical residual damage from the initial treatment. Radiation-induced second malignancies. With increasing numbers of long-term cancer survivors, the risk of second malignancies arising as a consequence of prior treatment becomes significant. Leukemia is thought to account for about 20% of second malignancies, with the remainder usually presenting as solid tumors in and around the previously irradiated site.277,278 Certain subpopulations of previously treated patients are at an even higher risk than the majority and deserve special attention, including children and young adults, those with a known genetic predisposition to cancer, immunocompromised individuals, and those with known exposure to other carcinogens (including chemotherapy).

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CHAPTER 1

33

The Biological Basis of Radiation Oncology

For example, large epidemiological studies have assessed the breast and lung cancer risk in Hodgkin lymphoma survivors,279,280 leukemia and sarcomas in cervical cancer survivors,281 and sarcomas in long-term survivors of childhood retinoblastoma.282

0

10

20

Total dose (Gy) 30 40

50

60

100

Dose Rate and Dose Fractionation Effects 10!1 Surviving fraction

While the sparing effects of fractionated, external beam radiotherapy and brachytherapy are assumed to be a result of the repair of SLD, other factors may be involved as well, most notably, repopulation. In the isoeffect relationship derived by Strandqvist,24 however, the “time factor” included both the effects of dose fractionation (presumably, the result of SLDR) and overall treatment time (presumably, repopulation). It was not until 1963 that Fowler and colleagues91,132,283 attempted to separate the contributions of these two factors by performing fractionation experiments with pig skin. In their experiments, 5 equal dose fractions were given in overall treatment times of either 4 or 28 days. In changing from an overall time of 4 days to 28 days, an additional 6 Gy was required to reach the same level of skin response. This was thought to reflect the contribution of overall time (i.e., repopulation) to the isoeffect total dose since the size and number of fractions were kept constant. In a parallel series of experiments in which the overall time was kept constant (28 days) but the number of fractions was increased from 5 to 21, it was found that an additional 13 Gy was required to reach the skin isoeffect level. This increase was almost as great as the 16-Gy additional dose required when changing from a single-dose treatment to a treatment protocol of 5 fractions in 4 days, implying that the change in fraction number was more important than the change in the overall treatment time. During the 1960s and 1970s, dose rate effects were studied extensively. The clinical community was also becoming more attuned to the biological underpinnings of radiation therapy, especially the “Four Rs of Radiotherapy”: repair, reoxygenation, redistribution, and repopulation.284 These are considered key radiobiological phenomena that influence the outcome of multifraction radiotherapy. (In later years, a fifth R was added, radiosensitivity.285) Bedford and Hall286,287 generated in vitro survival curves for HeLa cells irradiated at various dose rates between about 0.1 Gy per hour and 7.3 Gy per minute. The killing effectiveness per unit dose decreased as the dose rate was reduced; however, a limit to this dose rate or dose fractionation effect was reached under conditions in which cell cycle and proliferative effects were eliminated by the use of lower temperatures288 or by growing cells to plateau phase prior to irradiation289–291 (Fig. 1.26). Similar conclusions about the nature of dose rate and dose fractionation effects were reached from clinical studies. Dutreix et al.292 studied dose fractionation effects in human skin under conditions in which cell cycle and proliferative effects were minimized (i.e., short interfraction intervals and overall treatment times). Their data indicated that the incremental dose recovered due to SLDR when a single dose was replaced by two equal fractions became very small when the size of the dose per fraction dropped below approximately 2 Gy (Table 1.4). This finding is consistent with the hypothesis that survival curves have negative (rather than zero) initial slopes and, therefore, that a limit to the repair-dependent dose fractionation effect should be reached for increasingly smaller-sized dose fractions or dose rates. Accordingly, these authors cautioned that isoeffect equations in common clinical use at the time (the NSD model—see discussion to come) would be inaccurate for predicting tolerances when doses per fraction were quite small. Further, small differences in the initial slopes of survival curves for different cell types could be magnified into large differences in the limiting slopes for continuous or multifraction survival curves.

10!2 0.29 Gy/h 0.17 Gy/h 0.06 Gy/h

10!3

10!4

55.8 Gy/h

0.49 Gy/h

2.4 Gy/h

10!5 Fig. 1.26 The dose rate effect for nonproliferating C3H 10T1/2 mouse cells maintained in vitro. As the dose rate decreases from about 56 to 0.3 Gy/h, survival curves become progressively shallower, reflecting the repair of radiation damage during the continuous irradiation interval. However, for dose rates less than about 0.3 Gy/h, no further sparing effect of dose protraction is observed, suggesting that there is an effective limit to the repair-dependent dose rate effect. This is considered compelling evidence that cell survival curves have nonzero initial slopes. (Modified from Wells R, Bedford J. Dose-rate effects in mammalian cells. IV. Repairable and nonrepairable damage in non-cycling C3H 10T1/2 cells. Radiat Res. 1983;94:105.)

“Recovered Dose” as a Function of Dose per Fraction for Skin Reactions in Human Radiotherapy Patients

TABLE 1.4

Split Dose (2 Di)a

Recovered Dose (Dr = 2Di − Ds)

15 Gy

2 × 8.5 Gy

2 Gy

13 Gy

2 × 7.5 Gy

2 Gy

8 Gy

2 × 5.5 Gy

3 Gy

6 Gy

2 × 4 Gy

2 Gy

3.5 Gy

2 × 2 Gy

≤0.5 Gy

Single Dose (Ds)

a

Interfraction interval (i) was 6 h. Data from Dutreix J, Wambersie A, Bounik C. Cellular recovery in human skin reactions: application to dose fraction number overall time relationship in radiotherapy. Eur J Cancer. 1973;9:159–167.

Time-Dose-Fractionation Relationships The NSD Model

Based on Strandqvist’s isoeffect curves,24 Fowler and Stern’s pig skin experiments,91,283 and other laboratory and clinical findings,23 Ellis293,294 formulated the NSD concept in 1969. The NSD equation, D = (NSD) N0.24 T 0.11 where D is the total dose delivered, N the number of fractions used, T the overall treatment time, and NSD the nominal standard dose (a proportionality constant thought to be related to the tolerance of the tissue being irradiated), became widely used for the design of biologically equivalent treatment schedules, particularly when its more mathematically

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Scientific Foundations of Radiation Oncology

convenient derivatives, such as the TDF295 or CRE296 equations became available. The introduction of the NSD equation theoretically allowed radiotherapy prescriptions worldwide to be compared and contrasted with respect to “biological equivalence.” It also permitted the calculation of dose equivalents for split-course treatments and brachytherapy, and provided a means of revising treatment prescriptions in the event of unforeseen treatment interruptions. Because the NSD formula was based on observations of early-onset radiation effects, it was quite useful as a predictor of some tissue tolerances, as long as it was not used for treatments involving extremes of fraction number or overall time. On the other hand, the NSD formula was ill equipped to deal with some clinical problems, particularly the prediction of late effects in normal tissues (especially at nonstandard doses per fraction) and the patterns of repopulation in normal tissues and tumors.243 The use of a fixed exponent for the overall time component, T, gave the false impression that an extra dose to counteract proliferation would be needed from the outset of treatment, rather than after a delay of several weeks, which is what is observed in practice (e.g., Denekamp297). In light of the growing frustration with the NSD model and research at the time focusing on the shape of the shoulder region of cell survival curves and the nature of dose rate and dose fractionation effects, new radiobiology-based approaches to isoeffect modeling were developed during the late 1970s and early 1980s.

The Linear-Quadratic Isoeffect Model In ambitious multifraction experiments using mice in which a broad range of fraction sizes and interfraction intervals was used, Douglas and Fowler298 developed a novel method of data analysis in which they assumed that their resulting isoeffect curves for skin damage in the mouse foot were a reflection of the shape of the underlying tissue dose-response curve for the effect. The shape of this dose-response curve was assumed to be linear-quadratic, effectively “repurposing” the cell survival curve expression for in vivo use. Because overall treatment times were kept quite short, proliferative effects were assumed to be negligible, such that inherent radiosensitivity and repair were the main factors governing the tissue’s response. The underlying dose-response curves were deduced by plotting 1/D, where D was the total dose delivered (D = n × d), as a function of d, the dose per fraction. This was termed a reciprocal dose plot and was used to derive values for the α/β ratio, a novel metric proposed to express a tissue’s fractionation sensitivity.298 A representative reciprocal dose plot is shown in Fig. 1.27. This new approach to isoeffect analysis, in which attention was focused on repair parameters and dose-response curve shapes, emphasized that the critical parameter in radiotherapy is the size of the dose per fraction, more so than the overall treatment time. During the course of experimental and clinical fractionation studies, it became clear that there was a systematic difference between early- and late-responding normal tissues and tumors in their responses to different fractionation patterns. Isoeffect curves for the slowly or nonproliferating normal tissues—kidney and spinal cord, for example—are steeper in general than those for more rapidly proliferating, early-responding tissues, such as skin and gut epithelium and, significantly, most tumors (Fig. 1.28).299,300 A steep isoeffect curve implies that late effects were more sensitive to changes in the size of the dose per fraction, experiencing greater sparing with decreasing fraction size than their early-effects counterparts (Fig. 1.29). This difference is also reflected in the α/β ratios derived for these tissues, which are usually low for late-responding tissues (on the order of 1–6 Gy, with an average of about 3 Gy), and high for early-responding tissues and tumors (typically 7–20 Gy, with an average of about 10 Gy; Tables 1.5 and 1.6). There are exceptions, however.

0.04 Intercept/slope = α/β Reciprocal total dose (Gy)

SECTION I

0.03 Slope = β/ln S 0.02

Intercept = α/ln S

0.01

0

5

10

15

20

Dose per fraction (Gy) Fig. 1.27 The reciprocal dose or “Fe” plot technique of Douglas and Fowler,298 used to determine a normal tissue or tumor’s α/β ratio. Using this method, the reciprocal of the total dose necessary to reach a given isoeffect is plotted as a function of the dose per fraction. Assuming that the killing of target cells responsible for the tissue effect can be modeled using the linear-quadratic expression, S = e–(αD + βD ), the α/β ratio can be obtained from the ratio of the isoeffect curve’s intercept:slope. See text for details. (Modified from Douglas B, Fowler J. The effect of multiple small doses of x rays on skin reactions in the mouse and a basic interpretation. Radiat Res. 1976;66:401.) 2

Total dose for various isoeffects (Gy)

34

80 70 60

Skin necrosis

40 30

Skin contraction

)

50

ra

pa

d(

or

c al

is lys

Los

S

ss tis (lo

20

lon

co s of

pin

Lung (LD50, Pneumonitis)

lls

t ce

cryp

Kidney (LD50)

ia) gon

ato

erm

of sp

Skin desquamation

Loss of jejunal crypt cells

Tes

Local control of fibrosarcoma Vertebral growth inhibition

10

Bone marrow ablation (LD50)

8 6 10

8

6

4

2

1 0.8

0.6

Dose per fraction (Gy) Fig. 1.28 Isoeffect curves in which the total dose necessary to produce a certain normal tissue or tumor endpoint (as indicated) is plotted as a function of the dose per fraction under conditions in which cell proliferation is negligible. Isoeffect curves for late-responding normal tissues (solid lines) tend to be steeper than those for early-responding normal tissues and tumors (dashed lines). This suggests that, for the same total dose, late reactions may be spared by decreasing the size of the dose per fraction used. It also follows that by using smaller-sized dose fractions, a somewhat higher total dose could be given for the same probability of a late reaction but, hopefully, with a higher tumor control probability. (Modified from Withers H, Thames H, Peters L, et al. Normal tissue radioresistance in clinical radiotherapy. In: Withers H, Thames H, Peters L, eds. Biological Basis and Clinical Implications of Tumor Radioresistance. New York: Masson; 1983:139.)

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CHAPTER 1 Dose per fraction of size “A” or “B”

35

Representative α/β Ratios for Human Normal Tissues and Tumors

TABLE 1.5 Total dose “C”

Early-responding tissues (α/β is large)

Effect

The Biological Basis of Radiation Oncology

Late-responding tissues (α/β is small)

Total dose Fig. 1.29 Hypothetical dose response curves for either an acute (top) or late (bottom) effect in an irradiated normal tissue, depending on whether the total dose “C” is delivered using dose fractions of size “A” or “B.” Because of the difference in the initial slopes of the corresponding single-dose survival curves for these cell types, reducing the fraction size from “B” to “A” preferentially spares late-responding normal tissues (shaded areas). (Modified from Withers H, Thames H, Peters L. Differences in the fractionation response of acutely responding and late-responding tissues. In: Karcher K, Kogelnik H, Reinartz G, eds. Progress in Radio-Oncology II, New York: Raven Press; 1982:287.)

Clinical Applications of the Linear-Quadratic Isoeffect Model The shapes of tissue and tumor isoeffect curves and their calculated α/β ratios have a number of clinical applications. It is possible using α/β ratios to equate treatment schedules employing different-sized doses per fraction in order to match the probability of causing a tissue injury, assuming that the overall treatment times are similar in both schedules or the tissue at risk of a complication is relatively insensitive to treatment duration.249 The equation

Tissue Type (and Endpoint)

α/β Ratio (±95% Confidence Interval)

Early-Responding Normal Tissues Skin: erythema Desquamation

10.6 (1.8; 22.8) Gy 11.2 (8.5; 17.6) Gy

Lung: pneumonitis ≤90 days after radiotherapy

>8.8 Gy

Oral Mucosa: mucositis

8–15 Gy

Late-Responding Normal Tissues Skin: telangiectasia Fibrosis

~2.7 (−0.1; 8.1) Gy 1.7 (0.6; 3.0) Gy

Breast: cosmesis Fibrosis

3.4 (2.3; 4.5) Gy 3.1 (1.8; 4.4) Gy

Lung: pneumonitis >90 days after radiotherapy Fibrosis

4.0 (2.2; 5.8) Gy

Bowel: perforation/stricture Various other

3.9 (2.5; 5.3) Gy 4.3 (2.2; 9.6) Gy

Spinal cord: myelopathy

13.9 Gy

Skin: squamous cell carcinoma Melanoma

8.5 (4.5; 11.3) Gy 0.6 (−1.1; 2.5) Gy

Prostate

1.1 (−3.3; 5.6) Gy

Breast (early-stage invasive ductal, lobular, and mixed)

4.6 (1.1; 8.1) Gy

Esophagus

4.9 (1.5; 17) Gy

Liposarcoma

0.4 (−1.4; 5.4) Gy

3.1 (−0.2; 8.5) Gy

Data from Joiner M, van der Kogel A. Basic Clinical Radiobiology. 4th ed. London: Hodder Arnold; 2009.

D2 D1 = (α β + d1) (α β + d2 ) can be used for this purpose, where D1 and d1 are, respectively, the total dose and dose per fraction (in Gy) of one radiotherapy treatment plan, D2 and d2 are the total dose and dose per fraction for an alternate treatment plan designed to be biologically equivalent for a particular tissue effect, and with the fractionation sensitivity of that tissue defined by its unique α/β ratio. Of course, avoiding a normal tissue complication is not the sole criterion used in treatment planning; in considering a particular time, dose, and fraction size combination, the responses of the tumor and all incidentally irradiated normal tissues should be taken into account simultaneously.

An important implication of the steeper isoeffect curves for lateresponding tissues compared to those for tumors is that it might be possible to increase the therapeutic ratio by using larger numbers of smaller fractions to a somewhat higher total dose than traditionally used.248,249,301 Although such treatments could exacerbate acute effects in normal tissues, late effects would be spared preferentially and tumor control could be improved, thereby increasing the therapeutic ratio. The use of multiple fractions per day of smaller than conventional size (less than about 1.6 Gy) but to a somewhat higher total dose, with little or no change in overall treatment time, is called hyperfractionation.

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36

SECTION I

TABLE 1.6

Scientific Foundations of Radiation Oncology

Summary of the Linear-Quadratic Isoeffect Model Parameters and Concepts

Tissue Type

α/β Ratioa

Dose-Response Curve Shapeb

Isoeffect Curve Shapec

Early-responding normal tissues and most tumors

High (6–30 Gy)

Steep initial slope (α is large)

Shallow

Late-responding normal tissues

Low (1–6 Gy)

Shallow initial slope (α is small)

Steep

a

Determined from the reciprocal dose plot technique of Douglas and Fowler.298 Based on the assumption that differences in the calculated α/β ratio are usually caused by differences in the α component. c Using the Thames et al.299 isoeffect curve plot (see Fig. 1.28).

b

With particularly aggressive tumors that proliferate rapidly, multiple treatments per day might also be useful in order to decrease the overall treatment time, thereby allowing less time for repopulation of clonogenic tumor cells.302,303 Treatment with multiple daily fractions of approximately standard size and number (and to about the same total dose), but in shorter overall times, is termed accelerated fractionation. In practice, however, a combination of accelerated and hyperfractionated treatment is often used, as purely accelerated treatment tends to be poorly tolerated.275 Finally, hypofractionation, the use of one or a few large dose fractions delivered over short periods of time—for example, stereotactic radiosurgery (SRS), stereotactic body radiation therapy (SBRT), or intraoperative radiation therapy (IORT)—is also an option. Indications for such include cases in which the frank ablation of a small primary tumor or metastasis is the goal or in the relatively unusual circumstance in which the tumor is suspected of having a low, rather than high, α/β ratio. Prostate cancer and melanoma are tumor types that meets these criteria, as does, to a lesser extent, breast cancer. It is clear that hypofractionation has been quite successful for the treatment of multiple types of (small) tumors, while at the same time causing no worse normal tissue complications.304–306 However, the biological underpinnings associated with its use remain poorly defined and the subject of considerable controversy.307–310 Regardless, today’s use of hypofractionation would not be possible were it not for innovations in physics and imaging that now allow nearly all normal tissue to be excluded from the radiation field because, otherwise, complications in late-responding normal tissues would be dose limiting. This was amply demonstrated during the early days of radiotherapy. The decision to opt for one of these fractionation protocols would depend not only on the α/β ratios for the tissues being irradiated but also on their relative repair rates and proliferative responses before, during, and after exposure. At present, while α/β ratios for human normal tissues and tumors are fairly well characterized, data on proliferative behavior and repair rates, especially for tumors, are less robust.243,303 With “non-standard” fractionation now the standard, radiation oncologists find themselves confronted with the same problem faced by their 1930s counterparts, that is, how to compare and contrast different treatment schedules for presumptive isoeffectiveness. The “biologically effective dose,” or BED method,250,311 another derivative of the LQ model, attempts to address this issue. Knowing that cell survival and doseresponse curves have negative initial slopes and that, for a sufficiently low dose per fraction or dose rate, a limit to the repair-dependent dose fractionation effect occurs that “traces” this initial slope, this question may be asked: “In the limit, for an infinite number of infinitely small dose fractions, what total radiation dose will correspond to normal tissue tolerance, tumor control, or any other endpoint of interest?” Clearly, this theoretical dose will be quite large for a tissue characterized by a dose-response curve with a shallow initial slope (like many lateresponding normal tissues) and appreciably smaller for a tissue characterized by a dose-response curve with a steep initial slope (like most tumors and early-responding normal tissues). It is also important to bear in mind that BEDs are not real doses but rather extrapolates based on the

α/β ratios for the tissues at risk. For this reason, the units used to describe these extrapolated doses are, for example, Gy3 and Gy10 rather than Gy, in which the subscripts 3 and 10 refer to the assumed α/β ratio of the tissue at risk. A second caveat is that, while two different radiotherapy treatment schedules can be compared qualitatively on the basis of their respective Gy3 or Gy10 doses, Gy3 and Gy10 cannot be intercompared. A mathematical rearrangement of the linear-quadratic expression S = e−(αD + βD ) yields 2

BED = E α = nd (1+ d α β) where E is the (iso)effect being measured (E is divided by α to obtain the BED value in units of dose), n is the number of fractions, d is the dose per fraction, and the α/β ratio is specific for the tissue being irradiated. The factor (1 + d / α/β) has been called the relative effectiveness term because, in essence, it is a correction for the fact that treatment is not really given as an infinite number of infinitely small dose fractions but rather as a finite number of fractions of a finite size. Perhaps the best way to illustrate the use of the BED equation is by example. Suppose that a radiation oncologist is developing a clinical protocol in head and neck cancer comparing standard fractionation (30 fractions of 2 Gy to a total dose of 60 Gy in an overall treatment time of about 6 weeks) to a schedule of 50 fractions of 1.4 Gy to a total dose of 70 Gy in approximately the same overall treatment time. The tissues of most concern for radiation injury are the tumor, the oral mucosa, and the spinal cord, that is, two early-responding tissues and one late-responding tissue. Finally, assume that an α/β ratio of 10 Gy is appropriate for the tumor and oral mucosa and an α/β ratio of 3 Gy is appropriate for the spinal cord. For calculation purposes, an α/β ratio of 10 Gy can be used for most early-responding normal tissues and tumors and 3 Gy for most late-responding normal tissues unless more robust, better vetted values are available. For example, an α/β ratio of 4 Gy may be more appropriate for breast cancer; 20 Gy for non–small cell lung cancer; approximately 2 Gy for CNS, kidney, and prostate cancer; and approximately 0.6 Gy for melanoma.247 For the standard fractionation schedule, therefore: For tumor and mucosa: E α = 60 Gy (1+ 2 Gy 10 Gy) = 72 Gy10 For the spinal cord: E α = 60 Gy (1+ 2 Gy 3 Gy) = 100 Gy 3 For the more highly fractionated schedule (rounded off to the nearest whole number): For tumor and mucosa: E α = 70 Gy (1+ 1.4 Gy 10 Gy) = 80 Gy10

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CHAPTER 1

The Biological Basis of Radiation Oncology

37

Current Status of Existing and Proposed Parameters of the Linear-Quadratic Isoeffect Model for Human Normal Tissues and Tumors

TABLE 1.7

AVAILABILITY OF DATA WITH RESPECT TO Parameter

Property Governed

Early Effects

Late Effects

Tumors

α/β Ratio

Fractionation sensitivity

Can assume 10 Gy for most

Can assume 3 Gy for most

Can assume 10 Gy for most

T1/2 (repair half-time)

Repair kinetics

Poor/fair

Poor

None/poor

Tp (effective clonogen doubling time) and/or Tk (“kickoff” time—time proliferation begins relative to the start of treatment)

Dose lost to accelerated proliferation during radiotherapy

Fair

Poor/NA

Poor/fair

Volume effect

Variation in tissue tolerance with increasing target volume

Poor

Poor

None/poor

γ (normalized dose-response gradient)

Steepness of dose-response curve for effect; can be used to estimate the normal tissue complication probability

Fair

Fair

Fair

Modified from Bentzen SM. Estimation of radiobiological parameters from clinical data. In: Hagen U, Jung H, Streffer C, eds. Radiation Research 1895-1995. Volume 2, Congress Lectures. Wurzburg: Universitatsdruckerei H. Sturtz AG; 1995:833–838.

For the spinal cord: E α = 70 Gy (1+ 1.4 Gy 3 Gy) = 103 Gy 3 Although little quantitative information can be gleaned from this exercise, a few qualitative statements can be made. First, a comparison of the Gy10 values for the two treatment schedules suggests that the more highly fractionated schedule should result in somewhat better tumor control, albeit at the expense of more vigorous mucosal reactions (i.e., 72 Gy10 compared with 80 Gy10, an 11% increase in “biodose”). However, the comparison of the Gy3 values for the two schedules suggests that the spinal cord tolerance would be essentially unchanged (i.e., 100 Gy3 compared to 103 Gy3, a 3% increase). Even with the BED concept being only semi-quantitative at best, its use for treatment planning purposes over the past 3 decades has provided a wealth of clinical data that has allowed a better definition of what is or is not tolerable for particular normal tissues in terms of Gy3 or Gy10. Using head and neck cancer as an example, Fowler et al.247,312,313 have suggested that the tolerance dose for acute mucosal reactions is in the range of 59 to 63 Gy10 and for late reactions in the range of 110 to 117 Gy3. It would be remiss to conclude any discussion of the LQ isoeffect model, or any biologically based model with potential clinical application, without a few words of warning. First, this model, although certainly more robust than the NSD model and much better grounded in biological principles, is still a theoretical model. Some limitations of the basic model are obvious: an overly simplistic assumption that an isoeffect in a tissue corresponds to an isosurvival of a particular cell type; no provision for the influence of cell cycle, proliferative or microenvironmental effects in the overall dose-response relationship; no way to account for differences in repair rates between different tissues; no consideration of volume effects; uncertainty surrounding the model’s applicability for extremes of fractionation; and a limited understanding of how to apply the model in patients receiving multimodality therapy. Various add-ons to the LQ model have been proposed,314–316 especially with respect to compensating for tumor cell repopulation and correcting for differing tissue repair rates when multiple fractions per day or

brachytherapy are used. However, the lack of robust values at present for the parameters introduced in such calculations (e.g., potential doubling times, repopulation “kick-off” times, and half-times for repair) can limit their usefulness. The current status of some of the existing and proposed parameters of the LQ model for human tumors and normal tissues is summarized in Table 1.7.

RADIATION BIOLOGY IN THE 21ST CENTURY Since the mid-1980s, most graduate students pursuing careers in oncology necessarily trained as molecular, cellular, or tumor biologists and not as radiation biologists per se, although some may have worked with ionizing radiation as a tool for probing fundamental cellular processes or as part of translational research designed to develop new cancer therapies. Even fewer have taken a formal course in radiation biology, let alone in its more clinical aspects. This shift in focus and training that effectively has blurred the line between “radiation biologist” and “cancer biologist” is part of the natural evolution of the oncologic sciences over the years and surely not an unexpected or unwarranted one. However, the fact remains that the field of radiation biology as a distinct entity, with its rich 120-year history that has made major contributions to fields as diverse as carcinogenesis, epidemiology, toxicology, DNA damage and repair, genetics and cytogenetics, cell cycle biology and radiation oncology, to name but a few, is threatened with extinction. In many respects, the extinction is in name only, as the radiationrelated research enterprise continues regardless of the backgrounds of its investigators and how they self-identify. What is being lost, and at an increasingly rapid rate, is competent radiation biology educators. This is especially troubling, as there remains a need for all radiological science professionals to be at least reasonably well versed in the basic principles of radiation biology. Radiation oncologists, in particular, need to be familiar both with the foundational and modern aspects of the field and, since the events of September 11, 2001, a new mandate has emerged: the need to provide expertise in the basics of radiation biology and radiation protection to emergency responders, civic leaders, and the general public in the event of a radiological or nuclear terrorist attack.

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From a research perspective, fundamental studies of genomic instability,317,318 epigenetics,319,320 and cell signaling as it applies to radiation response321,322 continue to be active areas of investigation. Our growing understanding of the complex roles played by cytokines in the etiology of normal tissue complications following radiation exposure323,324 promises to someday deliver novel, molecularly based radioprotectors that may benefit radiation accident victims, first responders during radiation emergencies, and astronauts on deep-space missions. Radiation scientists also have been important contributors to the fields of genomics and proteomics, functional and molecular imaging, and molecularly targeted cancer therapy, and to the search for tumor-specific biomarkers that can aid in cancer diagnosis, staging, and the monitoring of treatment progress. In early 2018, a new agenda was proposed325 that provides an ambitious roadmap for the next 10 to 20 years of radiation biology research. New priority areas for research include combining radiotherapy (especially hypofractionation) with immunotherapy; targeting DNA repair, cancer metabolism, tumor stem cells, and the tumor microenvironment; and developing novel high-throughput in vitro screening systems and animal models.

CRITICAL REFERENCES 15. Regaud C, Ferroux R. Discordance des effets de rayons X, d’une part dans le testicule, par le peau, d’autre part dans la fractionnement de la dose. C R Soc Biol. 1927;97:431–434. 17. Coutard H. Roentgen therapy of epitheliomas of the tonsillar region, hypopharynx and larynx from 1920 to 1926. Am J Roentgenol Radium Ther Nucl Med. 1932;28:313–331. 27. Puck TT, Marcus PI. Action of X-rays on mammalian cells. J Exp Med. 1956;103:653–666. 78. Kellerer AM, Rossi HH. The theory of dual radiation action. Curr Top Radiat Res Q. 1972;8:85–158. 84. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14:213–221. 94. Elkind MM, Sutton H. X-ray damage and recovery in mammalian cells. Nature. 1959;184:1293–11295. 105. Terasima T, Tolmach LJ. Changes in X-ray sensitivity of HeLa cells during the division cycle. Nature. 1961;190:1210–1211. 122. Barendsen GW. Responses of cultured cells, tumors and normal tissues to radiations of different linear energy transfer. Curr Top Radiat Res Q. 1968;4:293–356. 124. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955;9:539–549.

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A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 1

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159. Arteel GE, Thurman RG, Raleigh JA. Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state. Eur J Biochem. 1998;253:743–750. 160. Yin M, Zhong Z, Connor HD, et al. Protective effect of glycine on renal injury induced by ischemia-reperfusion in vivo. Am J Physiol Renal Physiol. 2002;282:417–423. 161. Vordermark D, Brown JM. Endogenous markers of tumor hypoxia: predictors of clinical radiation resistance? Strahlenther Onkol. 2003;179:801–811. 162. Vergis R, Corbishley CM, Norman AR, et al. Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol. 2008;4:342–351. 163. Vordermark D, Katzer A, Baier D, et al. Cell type-specific association of hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein accumulation and radiobiologic tumor hypoxia. Int J Radiat Oncol Biol Phys. 2004;58:1242–1250. 164. Lindskog S. Structure and mechanism of carbonic anhydrase. Pharmacol Ther. 1997;74:1–20. 165. Olive PL, Aquino-Parsons C, MacPhail SH, et al. Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. Cancer Res. 2001;61:8924–8929. 166. Airley R, Loncaster J, Davidson S, et al. Glucose transporter GLUT-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin Cancer Res. 2001;7:928–934. 167. Airley R, Loncaster J, Raleigh JA, et al. GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int J Cancer. 2003;104:85–91. 168. Cooper R, Sarioglu S, Sokmen S, et al. Glucose transporter-1 (GLUT-1): a potential marker of prognosis in rectal carcinoma? Br J Cancer. 2003;89:870–876. 169. Xiao Q, Ge G. Lysyl oxidase, extracellular matrix remodeling and cancer metastasis. Cancer Microenviron. 2012;5:261–273. 170. Nishioka T, Eustace A, West C. Lysyl oxidase: from basic science to future cancer treatment. Cell Struct Funct. 2012;37:75–80. 171. Hoogsteen IJ, Marres HA, Bussink J, et al. Tumor microenvironment in head and neck squamous cell carcinomas: predictive value and clinical relevance of hypoxic markers. A review. Head Neck. 2007;29:591–604. 172. Bache M, Kappler M, Said HIM, et al. Detection and specific targeting of hypoxic regions within solid tumors: current preclinical and clinical strategies. Curr Med Chem. 2008;15:322–338. 173. Erpolat OP, Gocun PU, Akmansu M, et al. Hypoxia-related molecules HIF-1alpha, CA9, and osteopontin : predictors of survival in patients with high-grade glioma. Strahlenther Onkol. 2013;189:147–154. 174. Toustrup K, Sorensen BS, Alsner J, et al. Hypoxia gene expression signatures as prognostic and predictive markers in head and neck radiotherapy. Semin Radiat Oncol. 2012;22:119–127. 175. Hall EJ. High-LET radiations. In: Becker FF, ed. Cancer: A Comprehensive Treatise. Vol. 6. New York: Plenum Press; 1977:281–315. 176. Rockwell S, Baserga SJ, Knisley PS. Artificial blood substitutes in radiotherapy. In: Hagen U, Harder D, Jung H, et al, eds. Radiation Research 1895-1995: Proceedings of the Tenth International Congress of Radiation Research. Vol. 2. Wurzburg: Universitätsdruckerei H. Stürtz AG; 1996:795–798. 177. Gerweck LE, Gillette EL, Dewey WC. Killing of Chinese hamster cells in vitro by heating under hypoxic or aerobic conditions. Eur J Cancer. 1974;10:691–693. 178. Yuhas JM, Spellman JM, Culo F. The role of WR 2721 in radiotherapy and/or chemotherapy. In: Brady L, ed. Radiation Sensitizers. New York: Masson; 1980:303–308. 179. Horsman MR, Chaplin DJ, Overgaard J. The use of blood flow modifiers to improve the treatment response of solid tumors. Radiother Oncol. 1991;20:47–52. 180. Lee I, Kim JH, Levitt SH, et al. Increases in tumor response by pentoxifylline alone or in combination with nicotinamide. Int J Radiat Oncol Biol Phys. 1992;22:425–429.

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Scientific Foundations of Radiation Oncology

251. Hermens AF, Barendsen GW. Changes of cell proliferation characteristics in a rat rhabdomyosarcoma before and after X-irradiation. Eur J Cancer. 1969;5:173–189. 252. Dorr W, Hendry JH. Consequential late effects in normal tissues. Radiother Oncol. 2001;61:223–231. 253. Hemplemann LH, Lisco H, Hoffman JG. The acute radiation syndrome: a study of nine cases and a review of the problem. Ann Intern Med. 1952;36:279–510. 254. United Nations Scientific Committee on the Effects of Atomic Radiation: Sources and effects of ionizing radiation. Report to the General Assembly with Annexes. 1994. 255. Mettler FA, Upton AC. Medical Effects of Ionizing Radiation. 3rd ed. Philadelphia: WB Saunders Company; 2008. 256. Shipman TL, Lushbaugh CC, Peterson D, et al. Acute radiation death resulting from an accidental nuclear critical excursion. J Occup Med. 1961;3:146–192. 257. Karas JS, Stanbury JB. Fatal radiation syndrome from an accidental nuclear excursion. N Engl J Med. 1965;272:755–761. 258. Cogan CJ, Donaldson DD, Reese AB. Clinical and pathological characteristics of the radiation cataract. Arch Ophthalmol. 1952;47: 55–70. 259. Shrieve DC, Loeffler JS. Human Radiation Injury. Philadelphia: Lippincott Williams & Wilkins; 2011. 260. Committee on Biological Effects of Ionizing Radiation: Health effects of exposure to low levels of ionizing radiation. 1990. 261. Upton AC. The dose-response relation in radiation-induced cancer. Cancer Res. 1961;21:717–729. 262. International Commission on Radiological Protection. 1990 Recommendations, Publication Number 60. Oxford: Pergamon Press; 1991. 263. Stewart A, Webb D, Hewitt B. A survey of childhood malignancies. Br Med J. 1958;1:1495. 264. Brenner DJ, Doll R, Goodhead DT, et al. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci USA. 2003;100:13761–13766. 265. Brenner DJ, Hall EJ. Computed tomography - an increasing source of radiation exposure. N Engl J Med. 2007;357:2277–2284. 266. Brenner D, Elliston C, Hall E, et al. Estimated risks of radiation-induced fatal cancer from pediatric CT. Am J Roentgenol Radium Ther Nucl Med. 2001;176:289–296. 267. Brenner DJ. Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative. Pediatr Radiol. 2002;32:228–233. 268. Tubiana M, Aurengo A, Averbeck D, et al. The debate on the use of linear no threshold for assessing the effects of low doses. J Radiol Prot. 2006;26:317–324. 269. Larson DB, Rader SB, Forman HP, et al. Informing parents about CT radiation exposure in children: it’s OK to tell them. Am J Roentgenol Radium Ther Nucl Med. 2007;189:271–275. 270. Fajardo LF. Pathology of Radiation Injury. New York: Masson Publishing; 1982. 271. Straub JM, New J, Hamilton CD, et al. Radiation-induced fibrosis: mecanisms and implications for therapy. J Cancer Res Clin Oncol. 2015;141:1985–1994. 272. Fleckenstein K, Gauter-Fleckenstein B, Jackson IL, et al. Using biological markers to predict risk of radiation injury. Semin Radiat Oncol. 2007;17:89–98. 273. Citrin DE, Mitchell JB. Mechanisms of normal tissue injury from irradiation. Semin Radiat Oncol. 2017;27:316–324. 274. Withers HR, Taylor JMG, Maciejewski B. Treatment volume and tissue tolerance. Int J Radiat Oncol Biol Phys. 1988;14:751. 275. Thames HD, Hendry JH. Fractionation in Radiotherapy. Philadelphia: Taylor and Francis; 1987. 276. Travis EL, Terry NHA. Cell depletion and initial and chronic responses in normal tissues. In: Vaeth JM, Meyer JL, eds. Radiation Tolerance of Normal Tissues. Frontiers of Radiation Therapy and Oncology. Vol. 23. Basel: Karger; 1989:41–59. 277. Ng AK, Travis LB. Subsequent malignant neoplasms in cancer survivors. Cancer J. 2008;14:429–434.

278. Tubiana M. Can we reduce the incidence of second malignancies occurring after radiotherapy? A critical review. Radiother Oncol. 2009;91:4–15. 279. Travis LB, Gospodarowicz M, Curtis RE, et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin’s Disease. J Natl Cancer Inst. 2002;94:182–192. 280. Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin’s Disease. JAMA. 2003;290:465–475. 281. Kleinerman RA, Boice JD, Storm HH, et al. Second primary cancer after treatment for cervical cancer. Cancer. 1995;76:442–452. 282. Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005;23:2272–2279. 283. Fowler JF, Stern BE. Dose-time relationships in radiotherapy and the validity of cell survival curve models. Br J Radiol. 1963;36:163–173. 284. Withers HR. The four R’s of radiotherapy. In: Adler H, Lett JT, Zelle M, eds. Advances in Radiation Biology. Vol. 5. New York: Academic Press; 1975:241–271. 285. Steel GG, McMillan TJ, Peacock JH. The 5Rs of radiobiology. Int J Radiat Biol. 1989;56:1045–1048. 286. Bedford JS, Hall EJ. Survival of HeLa cells cultured in vitro and exposed to protracted gamma irradiation. Br J Radiol. 1964;39:896–900. 287. Hall EJ, Bedford JS. Dose-rate: its effect on the survival of HeLa cells irradiated with gamma-rays. Radiat Res. 1964;22:305–315. 288. Szechter A, Schwarz G. Dose-rate effects, fractionation and cell survival at lower temperatures. Radiat Res. 1977;71:593–613. 289. Mitchell JB, Bedford JS, Bailey SM. Dose-rate effects in plateau-phase cultures of S3 HeLa and V79 cells. Radiat Res. 1979;79:552–567. 290. Wells RL, Bedford JS. Dose-rate effects in mammalian cells. IV. Repairable and nonrepairable damage in noncycling C3H 10T1/2 cells. Radiat Res. 1983;94:105–134. 291. Zeman EM, Bedford JS. Dose-rate effects in mammalian cells: V. Dose fractionation effects in noncycling C3H 10T1/2 cells. Int J Radiat Oncol Biol Phys. 1984;10:2089–2098. 292. Dutreix J, Wambersie A, Bounik C. Cellular recovery in human skin reactions: application to dose fraction number overall time relationship in radiotherapy. Eur J Cancer. 1973;9:159–167. 293. Ellis F. Relationship of biological effect to dose-time-fractionation factors in radiotherapy. In: Ebert M, Howard M, eds. Current Topics in Radiation Research. Amsterdam: North Holland Publishing; 1968:357–397. 294. Ellis F. Dose, time and fractionation: a clinical hypothesis. Clin Radiol. 1969;20:1–8. 295. Orton CG, Ellis F. A simplification in the use of the NSD concept in practical radiotherapy. Br J Radiol. 1973;46:529–537. 296. Kirk J, Gray WM, Watson R. Cumulative radiation effect. Part I - Fractionated treatment regimes. Clin Radiol. 1971;22:145–155. 297. Denekamp J. Changes in the rate of proliferation in normal tissues after irradiation. In: Nygaard O, Adler HI, Sinclair WK, eds. Radiation Research: Biomedical, Chemical and Physical Perspectives. New York: Academic Press, Inc.; 1975:810–825. 298. Douglas BG, Fowler JF. The effect of multiple small doses of X-rays on skin reactions in the mouse and a basic interpretation. Radiat Res. 1976;66:401–426. 299. Thames HD, Withers HR, Peters LJ, et al. Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships. Int J Radiat Oncol Biol Phys. 1982;8:219–226. 300. Withers HR, Thames HD, Peters LJ. Differences in the fractionation response of acutely and late-responding tissues. In: Karcher KH, Kogelnik HD, Reinartz G, eds. Progress in Radio Oncology II. New York: Raven Press; 1982:287–296. 301. Fowler JF. Review: total doses in fractionated radiotherapy—implications of the new radiobiological data. Int J Radiat Oncol Biol Phys. 1984;46:103–120. 302. Thames HD, Peters LJ, Withers HR, et al. Accelerated fractionation vs. hyperfractionation: rationale for several treatments per day. Int J Radiat Oncol Biol Phys. 1983;9:127–138.

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CHAPTER 1 303. Thames HD, Bentzen SM, Turesson I, et al. Time-dose factors in radiotherapy: a review of human data. Radiother Oncol. 1990;19: 219–235. 304. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303:1070–1076. 305. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14:1086–1094. 306. Yamada Y, Katsoulakis E, Laufer I, et al. The impact of histology and delivered dose on local control of spinal metastases treated with stereotactic radiosurgery. Neurosurg Focus. 2017;42:E6. 307. Brenner DJ. The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction. Semin Radiat Oncol. 2008;18:234–239. 308. Kirkpatrick JP, Meyer JJ, Marks LB. The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery. Semin Radiat Oncol. 2008;18:240–243. 309. Brown JM, Carlson DJ, Brenner DJ. The tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved. Int J Radiat Oncol Biol Phys. 2014;88:254–262. 310. Song CW, Kim MS, Cho LC, et al. Radiobiological basis of SBRT and SRS. Int J Clin Oncol. 2014;19:570–578. 311. Barendsen GW. Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys. 1982;8:1981–1997. 312. Lee AWM, Sze W-M, Fowler JF, et al. Caution on the use of altered fractionation for nasopharyngeal carcinoma. Radiother Oncol. 1999;52:201–211. 313. Fowler JF, Harari PM, Leborgne F, et al. Acute radiation reactions in oral and pharyngeal mucosa: tolerable levels in altered fractionation schedules. Radiother Oncol. 2003;69:161–168.

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314. Fowler JF. Repair between dose fractions: a simpler method of analyzing and reporting apparently bioexponential repair. Radiat Res. 2002;158:141–151. 315. Fowler JF, Welsh JS, Howard SP. Loss of biological effect in prolonged fraction delivery. Int J Radiat Oncol Biol Phys. 2004;59: 242–249. 316. Gasinska A, Fowler JF, Lind BK, et al. Influence of overall treatment time and radiobiological parameters on biologically effective doses in cervical cancer patients treated with radiation alone. Acta Oncol. 2004;43:657–666. 317. Ellsworth DL, Ellsworth RE, Liebman MN, et al. Genomic instability in histologically normal breast tissues: implications for carcinogenesis. Lancet Oncol. 2004;5:753–758. 318. Streffer C. Bystander effects, adaptive response and genomic instability induced by prenatal irradiation. Mutat Res. 2004;568:79–87. 319. Ballestar E, Esteller M. Epigentic gene regulation in cancer. Adv Genet. 2008;61:247–267. 320. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10:704–714. 321. Rodemann HP, Blaese MA. Responses of normal cells to ionizing radiation. Semin Radiat Oncol. 2007;17:81–88. 322. Prise KM, O’Sullivan JM. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer. 2009;9:351–360. 323. Coleman CN, Stone HB, Moulder JE, et al. Modulation of radiation injury. Science. 2004;304:693–694. 324. Singh VK, Garcia M, Seed TM. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status. Int J Radiat Biol. 2017;93:870–884. 325. Kirsch DG, Diehn M, Kesarwala AH, et al. The future of radiobiology. J Natl Cancer Inst. 2018;110:329–340.

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2 Molecular and Cellular Biology Stephanie Markovina and Dennis E. Hallahan

The “hallmarks of cancer” were described by Hanahan and Weinberg in 2000 and detail the features required for a tumor to progress to an invasive malignancy.1 The “next generation” hallmarks, published in 2011, include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and escaping immune destruction.1 Boss et al. framed the hallmarks with the historical context of radiation biology.2 Tumors need to overcome numerous natural barriers in order to survive. Understanding the molecular events underlying each of these features is key not only to cancer prevention but also to achieving cancer control. This chapter provides an overview of the fundamentals of cancer biology as well as emerging areas of understanding how this knowledge might be used to improve cancer therapy, with a focus on radiation biology.

MOLECULAR BASIS OF CANCER DEVELOPMENT AND PROGRESSION Oncogene Activation, Tumor Suppressor Loss, and Multistep Carcinogenesis Cancer development is a multistep process marked by accumulation of multiple genetic and molecular changes, resulting in dysregulation of a number of normal cellular and organism processes. A common initiating event in tumor formation is either a gain of function mutation or amplification of a proto-oncogene, or loss of function mutation or deletion of a tumor suppressor gene. Oncogene activation requires alteration of only one allele and often results in increased proliferation and/or prevention of cell death. Commonly affected genes include those in the myc family, ras family, and bcl-2. Loss of tumor suppressor activity requires functional loss of both alleles. Examples of commonly altered tumor suppressors include p53 and Rb, which are both critical regulators of the DNA-damage response (DDR) and can direct cell fate following DNA-damaging chemotherapies and ionizing radiation (IR). p53, the most common somatic tumor mutation, is considered a “gatekeeper” gene, as its function is important for maintaining the fidelity of the genome, and for inducing cell death in cases in which genome fidelity is threatened. Upstream inactivation of gatekeeper genes allows accumulation and propagation of additional genetic abnormalities, ultimately resulting in tumor formation. This concept of multistep carcinogenesis is perhaps best illustrated through the natural history of familial colon cancer. Early loss of DNA mismatch repair genes, including MSH2 or MLH1, result in a “mutator phenotype” and persistent DNA mismatches. Additional mutations occur in the precancerous adenomas over the course of several years that allow the development of invasive cancer. The Cancer Genome Atlas (TCGA), an expansive multiplatform effort to molecularly characterize 32 different types of cancer, has

uncovered significant information not only about the genetic landscape and heterogeneity of human tumors but also the mRNA and protein expression profiles associated with different mutational backgrounds (https://cancergenome.nih.gov/). In some cases, comprehensive clinical data is also available, allowing analysis of omics data in the context of therapies including radiation and disease and survival outcomes following treatment.

Growth Promotion Alterations of proto-oncogenes through activating genetic mutations, translocation, or gene amplification can result in increased proliferation. Similarly, genetic loss of tumor suppressors that normally keep cellular proliferation in check contributes to abnormal progression through the cell cycle. Cellular proliferation is stimulated by soluble growth factors. Cancer cells overexpress growth factors or bypass the need for a ligand through activating mutations within the growth factor receptors or downstream factors. For example, BRAF mutations are common in melanoma and differentiated thyroid cancers and are thought to result in constitutive activation of the mitogen-activated protein (MAP)-kinase pathway.3 Mutations in the phosphoinositide 3-kinase (PI3-kinase) family of proteins are common in several cancer subtypes and result in downstream activation of Akt/protein kinase B (PKB).4 In cervical cancer, mutations along the PI3K/Akt pathway are associated with glucose avidity and cancer recurrence, suggesting that these growth-promoting genetic alterations can also affect tumor response to standard therapy.5

Cell Death Suppression Regulated cell death (RCD) is a process by which cells die in order to maintain physiological homeostasis and is governed in part by master regulator proteins, such as p53. Loss of proapoptotic factors and upregulation or increased activity of antiapoptotic factors, most commonly of the Bcl-2 family, allow tumor cells to evade these regulated cell death signals.6 Accumulated DNA damage in the setting of hyperproliferation is one known trigger of RCD in normal cells, but this process is dysregulated in many tumor cells, allowing propagation of cells with increasingly abnormal genomes. Tumor cell evasion of this response occurs through the loss of tumor suppressor p53, through either genetic mutation, or epigenetic silencing, which functions as a critical sensor of DNA damage.7 Dysregulation of autophagy in cancer is also common; however, this process can permit tumor cell survival or promote cell death.

Angiogenesis With rapid proliferation and generally increased metabolic turnover, developing tumors can quickly outpace their blood supply. In order to avoid nutrient and oxygen deprivation and to allow elimination of toxic metabolic byproducts, tumors induce an “angiogenic switch,”

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Scientific Foundations of Radiation Oncology

inducing formation of neovasculature from quiescent mature blood vessels. A balance between proangiogenic factors such as vascular endothelial growth factor-A (VEGF-A) and members of the fibroblast growth factor (FGF) family and antiangiogenic factors, including thrombospondin-1 (TSP-1) and endostatin, is tipped in favor of angiogenesis in many expanding cancers and characteristic tumor neovasculature results.8 These new vessels are recognizably abnormal, with premature capillaries, convoluted vessel branching, and vessel leakiness.9 Several therapeutic strategies take advantage of the differences between tumor vasculature and normal blood vessels, including a monoclonal antibody against the receptor for VEGF, VEGFR, called bevacizumab, which is approved by the US Food and Drug Administration for a number of cancer indications. It has become increasingly clear, however, that simple inhibition of VEGF signaling is not sufficient to destroy a tumor’s blood supply, and the concept of the angiogenic switch and the factors that regulate it is likely to be tumor type and individual specific.10

Telomere Dysfunction and Replicative Immortality Telomeres are an array of 6-nucleic acid sequence repeats (TTAGGG in humans) bound by the shelterin complex that prevent chromosomal ends from being recognized as damaged DNA.11 The shortening of telomeres with each cell division constitutes the main mechanism of somatic cellular aging. With respect to cancer development, terminal telomere shortening has two main and opposing consequences: (1) the tumor-suppressor effect of activation of the ATM/ATR kinase cascade and resultant halting of proliferation; and (2) the telomeric crisis, marked by extensive genome instability and cancer progression.11 This interplay is complex and incompletely understood but may partially explain the increased risk of cancer development associated with aging. Telomerase reverse transcriptase (TERT) can reverse the process of telomere shortening by adding GGTTAG repeats to the chromosomal 3′ DNA terminus. TERT is genetically silenced in most somatic cells during development,11 resulting in programmed telomere shortening and either senescence or apoptosis following activation of the DDR by the unprotected ends of chromosomes. Available evidence suggests that, in some cancer cells, activation of the telomeric crisis results in reactivation of TERT, extending the proliferative capacity of cells with extensive mutations and chromosomal instability and malignant progression. Using markers of previous telomeric crisis as a determinant, TERT reactivation is thought to contribute to the development of chronic lymphocytic leukemia (CLL), breast cancer, colorectal adenomas, and other solid tumors.12,13 Mutations in the TERT promoter are the most commonly recognized mechanism of TERT activation in cancers. However, in many cases, the mechanism of activation is unclear. Despite reactivation of TERT in up to 90% of human cancers, there is evidence that telomeric dysfunction persists, and the resultant combination of perpetuated chromosomal instability and unrestrained proliferation supports the malignant phenotype.11

Invasion and Metastases The multistep process of invasion and metastasis is a series of required steps, known as the invasion-metastasis cascade.14,15 Cancer cells first locally invade the basement membrane, intravasate into nearby blood and lymphatic vessels, and transit through the lymphatic and circulation systems.1 Tumor cell survival in the circulation requires prosurvival signals from the extracellular matrix (ECM), hemodynamic sheer forces, and attacks by the immune system.16 Subsequent extravasation of these cells from the blood or lymphatic vessels into the tissues of distant organs involves adhesion to endothelial cells, disruption of and invasion through the endothelial barrier. This can occur with single cells in larger vessels or small groups of cells that have proliferated in end capillaries.16

Once in the tissue parenchyma, these cells must proliferate to form small micrometastases.1 Disrupted cell polarity, loss of basement membrane integrity, and cell motility all contribute to this process. Decreased expression of cell surface adhesion molecules, such as E-cadherin, that mediate cell-to-cell and cell-to-ECM connections is found in many cancer types1 and is mediated by many of the same transcription factors that direct embryogenesis and wound healing, including Snail, Slug, Twist, and Zeb1/2. Transforming growth factor-β (TGFβ), a strong antiproliferative signal in normal cells, instead appears to participate in this process, termed the epithelial-tomesenchymal transition (EMT) when present in transformed epithelial cells.17 In addition to loss of adherence to adjacent cells and the ECM, cells with activation of EMT take on a mesenchymal-like morphology; secrete enzymes, including matrix metalloproteases that break down the basement membrane; and display increased motility.1 While the relationship between tumor cells and the surrounding microenvironment is heterotypic, tumor-associated fibroblasts can promote this process of invasion.1,18 Once in the metastatic niche, tumor cells adapt a number of mechanisms to make the often uninviting environment more welcoming. In one elegant study, Valiente and colleagues demonstrated that plasmin acts as a natural defense mechanism against establishment of brain metastases. They further demonstrated that lung tumor cell metastasis to the brain through the hematological vasculature, in turn, secretes plasminogen-activating inhibitor serpins, including neuroserpin and serpinB2, to counteract this effect and allow colonization of the brain.19 Similar instances of opposing forces offers some explanation of the predilection of certain tumor cell types for colonization of specific distant sites.

Metabolic Rewiring/Plasticity Most cancers have adapted the preference for glucose metabolism by glycolysis, even in the presence of oxygen, in at least a subset of tumor cells. First recognized in the early half of the 1900s by Otto Warburg, this process of aerobic glycolysis, or the “Warburg phenomenon,” is a cancer phenotype characterized by greater uptake and metabolism of glucose in cancer cells, resulting in lactic acidosis even in the presence of oxygen. Tumor cells compensate for the 18-fold lower yield of ATP derived from aerobic glycolysis mainly by increased surface expression of the GLUT1 glucose transporter.1,20 Fluorodeoxyglucose positron emission tomography (FDG-PET) scanning exploits the significant increase in glucose uptake, as 18F-deoxyglucose is phosphorylated upon uptake into cells and accumulates in cancer cells, allowing detection by PET imaging.21,22 The “metabolic switch” to a significantly less efficient glycolysis pathway may be a byproduct of oncogene activation in some cancers. Ras oncogene activation and hypoxia increase activity of HIF-1α and HIF-1β transcription factors, leading to enhancement of the glycolytic pathway.23 Nevertheless, with evidence of aerobic glycolysis in cancers even without these direct links, a physiological advantage seems certain. In the last several years, it has become increasingly clear that metabolic reprogramming in tumors is a dynamic and overall advantageous trait of main cancers. A revisited hypothesis that byproducts generated through glycolysis such as pyruvate can be redirected to enhance amino acids and other critical cellular components is increasingly supported by emerging evidence.1 In a comprehensive review, Pavlova and Thompson propose six metabolic hallmarks of cancer, stating that not all cancers display all six hallmarks, but most display many of these.24 Many features of altered metabolism in human cancers are a result of either mutation or altered expression of one or more of the various enzymes involved in cellular energy metabolism. An example of this is IDH1, which is mutated in many low-grade gliomas and overexpressed in glioblastoma. By altering lipid metabolism and redox stress, IDH1 promotes tumor

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CHAPTER 2 cell growth and therapeutic resistance in vitro and in vivo and can be targeted molecularly with antitumor effect.25 In keeping with the recognized importance of the tumor microenvironment and host contributions, one of these hallmarks is metabolic interactions with the microenvironment. Although the mechanism is not yet understood, obesity, an increasing comorbidity among cancer patients particularly in the developed world, is thought to affect not only cancer risk but also response to primary therapies, including IR.26–28 The intimate relationship between energy utilization and redox balance could account for response to therapy.

Immune Evasion Although anticancer immunotherapy has recently come into the forefront, as discussed later in this chapter, the recognition of the role of the immune system in prevention of cancer establishment and synergy with standard cytotoxic therapies is more than a century old. Immunosurveillance appears to play an important role in eradication of transformed cells and prevention of tumor development. Cancers that develop despite this surveillance have adapted various mechanisms to evade an anticancer immune response. The details and extent of these mechanisms are coming to light and involve tumor cell expression of negative immunoregulatory cell surface receptors, soluble factors, and nonimmunogenic cell death. Most cancer cells have acquired a significant number of genetic mutations, providing a wealth of potential tumor-specific antigens to be recognized as foreign by the immune system. At the same time and potentially as a consequence, tumors have also evolved a number of mechanisms to evade or actively inhibit the immune system, so-called immune checkpoints, which normally modulate immune tolerance.29 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is a key mediator of antitumor immune response as it is upregulated by tumor cells and inhibits T-cell activation. Programmed cell death protein 1 (PD1) and its ligand programmed cell death protein ligand 1 (PDL1) are increased in many tumor types and, when bound to each other, inhibit T-cell effector functions in the surrounding tumor microenvironment. Therapies targeting these two checkpoint pathways have seen recent success in a variety of cancers, with seemingly higher response rates in tumors with significant mutational burdens.30 Despite dramatic responses documented even in patients with metastatic multiply chemoresistant disease, the overall response rate for these therapies as single agents hovers around only 10% to 15%, with very poor response rates in certain cancers, such as pancreatic cancer and metastatic prostate cancer.31 Thus, in addition to understanding these varied responses, much of the focus has turned to combination therapy, not only with combinations of immunotherapies targeting different aspects of the tumor immune evasion network, but also with anticancer therapies that enhance the general immune response, including IR. The effect of IR on components of the immune system and immune response is complex. A simplified schematic of this complex effect is presented in Fig. 2.1, depicting the myriad signaling events induced within tumor cells exposed to IR that effect expression of tumor neoantigens, cytokines, and chemokines. Subsequent tumor cell death itself acts as a signal that generally enhances the immune response. Radiation is also a potent inducer of lymphocyte apoptosis; cells within the irradiated field at the time of treatment delivery are likely to die from very low doses, a potential negative impact on the immune response.32,33 Given these complexities and the excitement behind combining immunotherapies with radiation that already comprises the standard of care therapy for many cancers, efforts are underway to identify the optimal dose, fractionation, and timing in order to produce the maximal antitumor response. Recent work in mouse models of cancer immunotherapy by Vanpouille-Box et al. identified the DNA exonuclease Trex1 as a negative regulator of antitumor immune response induced

Molecular and Cellular Biology

41

by radiation doses higher than 12 to 18 Gy34. Expression of Trex1, which degrades cytosolic DNA in radiated cells, thus downregulating the cGas-STING-mediated immune activation, is induced only by certain radiation schemes and may be one molecular biomarker that could be used in deciding optimal clinical regimens for combination with immunotherapy. The radiation therapy-immunotherapy combination is an enticing possibility to improve response in many different cancer types.

CELLULAR AND MOLECULAR BASIS OF RADIATION DAMAGE High doses of radiation are effective in ablating pathological tissues that include diseases other than cancer, such as ventricular tachycardia, arteriovenous malformation, trigeminal neuralgia, and benign neoplasms. The molecular basis to radiation ablation involves several physiological responses. For example, doses above 10 Gy activate enzymatic cleavage of sphingomyelin to produce cytotoxic concentrations of ceramide.35 Ceramide, in turn, activates regulated cell death. The molecular basis to the efficacy of stereotactic radiosurgery is, in part, due to production of ceramide following a single high dose of radiation. A radiation dose–dependent induction of cell surface proteins occurs within cancer. The general principle for this molecular response includes damage-associated molecular patterns (DAMPs), such as surface proteins that mark irradiated cells. An example is calreticulin, which can activate macrophage-mediated phagocytosis. In addition, cytokines that are induced by radiation include tumor necrosis factor (TNF) and interleukins (ILs). Cell adhesion molecules such as ICAM-1, P-selectin, E-selectin, and others are radiation-inducible proteins that are expressed on the surface of cancer endothelium.36 DAMPs are physiological processes that occur in response to tissue injuries, such as thermal, mechanical, radiation, and other causes of injury. DAMPs include molecules that signal adjacent cells and distant cells and compartments, such as immune effector cells and hematopoietic stem cells.

DNA Damage Response As discussed in Chapter 1, both direct ionization events and development of oxygen free radicals lead to an almost instantaneous cellular response. Various types of physical DNA damage can occur, including DNA cross-linking, nucleotide loss, base modification, and single- and doublestranded breaks. Different damage events initiate distinct signaling cascades that ultimately are intended to halt progression through the cell cycle to allow DNA repair. These pathways are presented in simplified schematic form in Fig. 2.2. A series of proteins—categorized as sensors, effectors, and transductors—participate in the orchestration of DNA damage repair mechanisms. Defects in DNA repair can cause hypersensitivity to radiation and/or propagation of misrepaired mutations, as discussed in Chapter 1. Single-strand breaks are relatively straightforward for cells to repair, as the alternate sense strand is intact as a repair template. Similarly, base loss or damage can be repaired through the base excision repair (BER) pathway. Double-strand breaks (DSBs), on the other hand, require significantly more machinery and intricate signaling to repair with fidelity by one of two major pathways, nonhomologous end joining (NHEJ) and homologous recombination (HR). Within seconds of DNA damage, sensor proteins Mre11/Rad50/Nbs1 (MRN) complex is recruited to the DSB foci, and ataxia telangiectasia mutated kinase (ATM) is activated, phosphorylating the MRN complex. Whether the repair process then proceeds through HR or NHEJ is at least partially dependent on the phase of the cell cycle, with HR preferentially occurring when a homologous sister chromatid is available for recombination during late S and G2 phases.37 Bias toward NHEJ repair is seen during the G1 phase when

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SECTION I

Scientific Foundations of Radiation Oncology IR

In-Field Lymphocyte Toxicity Potential negative effect on immune response?

Tumor Cell Membrane damage

Tumor Microenvironment Acid sphingomyelinase DNA damage Ceramide

Tumor, microenvironment production, release of cytokines, chemokines

ROS production

PI3K/Akt activation

Recruitment of humoral immune cells Recruitment of Treg cells TCR

mTOR Cytosolic DNA

T-Cell

Mitochondria

cGAS

NF-κB

STING pathway

Cell death and antigen release

Increased protein synthesis, antigen processing

TLR

MHC

IFNγ, proinflammatory, cell death, cytokine and chemokine production

B-Cell DC APC travels to lymph node for tumor antigen-specific T-cell activation and proliferation

Release of DAMPs DC activation, T-cell priming

Fig. 2.1 Radiation-induced immune effects: Ionizing radiation (IR) induces a number of signaling events that result in multiple signals that can affect the immune response. These effects can both promote and inhibit an antitumor immune response. The goal of current radiation therapy–immunotherapy combinations is to create the conditions under which this global response largely promotes an antitumor immune response. Within the tumor cells, IR induces DNA damage, which can induce the stimulator of interferon genes (STING) pathway and directly induce nuclear factor-kappa B (NF-κB) activity, a master transcription regulator that controls the expression of myriad genes involved in immune response, namely, interferon-gamma (IFNγ). Tumor cell membrane damage initiates cell death pathway(s) dependent on the mitochondria, thus, facilitating release of tumor-specific antigens and damage-associated molecular patterns (DAMPs). These molecules can lead to dendritic cell (DC) cell maturation and activation and T-cell priming. These mature antigen presenting cells (APCs) then migrate to nearby lymph nodes, where they induce a tumor-antigen-specific T-cell response. ROS production leads to increased protein synthesis through a phosphoinositide 3-kinase/protein kinase B/ mammalian target of rapamycin (PI3K/Akt/mTOR) dependent pathway and increased neoantigen processing and presentation. Within the tumor microenvironment, IR results in increased production and release of cytokines and chemokines responsible for recruitment of humoral immune cells. Some factors recruit regulatory T-cells (Tregs) that inhibit the function of cytotoxic T-cells. A potentially important part of the balanced effect of IR on the immune response is the direct lymphocytotoxic effect of IR on lymphocytes within the radiation field at the time of treatment delivery. cGas, Cyclic GMP-AMP synthase; MHC, major histocompatibility complex; TLR, toll-like receptor; TCR, T-cell receptor.

sister chromatids are unavailable and is mediated by localization of 53BP1 to the DSBs, inhibiting ATM-dependent activation of the MRN complex. In the absence of 53BP1, RPA coats the processed single-strand ends, followed by recruitment of mediator proteins Rad52, BRCA1/2, and Rad51, which facilitates strand invasion of the homologous strand of the sister chromatid. In G1 phase, 53BP1 inhibits ATM-mediated processing of the blunt DSB ends. Instead, DNA ends are capped by Ku70/Ku80 heterodimers, thus recruiting and activating the catalytic subunit of DNAPK (DNA-PKcs). After approximation of the Ku-protein capped ends, ligase complexes are recruited to complete the strand repair process.38 Drugs that inhibit DNA repair are reviewed in Chapter 5. Cells that are in mitosis at the time of DNA damage are prone to mutations, with mitosis-specific phosphorylation events actively inhibiting both HR and NHEJ. Inhibition of classic repair pathways can mean that cells surviving the first mitosis may allow propagation of DNA defects to subsequent progeny.39 Defects in the components of these repair pathways are manifested in radiation sensitivity; pharmacological

inhibitors of ATM, ATR, and other members of the DSB repair pathway are being pursued as therapeutic radiosensitizers.40 Moreover, there is recent evidence that noncoding RNAs can also participate in regulating the DDR.41 In parallel, ATM/ATR kinases phosphorylate key cell cycle checkpoint proteins, facilitating cell cycle arrest and preventing cells from entering mitosis with unrepaired DNA, as discussed further later in the chapter.

Cell Cycle Checkpoints As a direct consequence of IR-induced DNA damage, and potentially in response to other cellular damage, cells with intact cell cycle checkpoints will arrest at some phase dependent on their location in the cell cycle at the time of injury and prior to entry into mitosis, primarily at the G1, S, and G2 checkpoints. Cells in G1 at the time of IR exposure are arrested prior to entry into S phase with ATM-mediated activation of p53, which induces transcriptional upregulation of p21, thus inhibiting cyclins D/E and cyclin-dependent kinases (CDKs) 4/6 and 2, resulting

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Nucleus SSB (nonlethal) SB sensing PARP activation

DSB (potentially lethal)

PARP1

NER, BER pathways

PARP1 MRN

HR

Ku

3’ 5’

DNAKu PKcs

3’ 5’

BRCA1

PCtlP

P-

Ku

-P

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Alternative pathways (alt-EJ, SSA)

CDK2

-P

NHEJ

-P

P-

ARTEMIS

-P

-P

-P

DNAKu PKcs

XRCC4 LIG4

-P

3’ 5’

1

Ku

D5

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RA

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CHK1

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Ligation P-

ATR

-P

Strand invasion, HJ formation

P-

3’ 5’

DNAKu PKcs -P

1 D5 RA

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1 D5

5’ 3’

End processing

RA

P-

P-

ATM RPA

BRCA2

P-

Ku

-P

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P-

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HJ resolution

Fig. 2.2 DNA damage response: Simplified schematic of DNA damage response pathways. Single strand breaks (SSBs) are largely nonlethal and repaired by nucleotide excision repair (NER) or base excision repair (BER) pathways. Double strand breaks (DSBs) are potentially lethal and induce a number of repair pathways, including nonhomologous end joining (NHEJ), homologous recombination (HR), and less common alternative pathways, including alternative end joining (alt-EJ) and single-strand annealing (SSA). Selection of repair pathways is not only cell cycle dependent, but the pathways are highly interactive and can modulate one another. Defects in DSB repair pathways result in sensitivity to ionizing radiation. ARTEMIS, Artemis complex; ATM, ataxia telangiectasia mutated kinase; ATR, ataxia telangiectasia and Rad3-related protein; BRCA1, BRCA1 DNA repair associated; BARD1, BRCA1-associated RING domain 1; BRCA2, BRCA2 DNA repair associated; CDK2, cyclin-dependent kinase 2; CHK1, checkpoint kinase 1; CtlP, RB binding protein 8; DNA-PKcs, DNA-dependent protein kinase, catalytic subunit; Ku, Ku70/Ku80; LIG4, DNA ligase 4; MRN, MRN complex (Mre11, Rad50, Nbs1 = nibrin); PARP1, poly(ADP-ribose) polymerase 1; RAD51, Rad51 recombinase; RPA, replication protein A; XRCC4, x-ray repair cross-complementing 4.

in G1 arrest.38 For cells in S phase, RPA appears to recruit the MRN complex also to sites of replication, thus slowing DNA replication. CHK2 is also activated by ATM, preventing the loading of CDC45 onto replication origins, together resulting in halting of the cell cycle in S phase. Finally, G2 arrest is thought to occur as a result of ATM-mediated activation of CHK1 and CHK2, which phosphorylate and inactivate the phosphatase CDC25c and sequester it in the cytoplasm. CDC25C target CDK1 remains phosphorylated and inactive, preventing progression beyond G2.38 Cell-cycle checkpoint inhibitors, particularly CHK1 inhibitors, are being explored as potential radiosensitizers for the treatment of cancer, although it is unclear whether the mechanism of efficacy of these agents is strictly by inhibition of cell cycle arrest or dependent on other roles of CHK1.40 Ultimately, in the case of cell cycle checkpoint defects or if these concerted efforts fail, cells that progress to mitosis with residual unrepaired DNA damage are likely to undergo mitotic catastrophe.

Radiation-Induced Cell Death and Nonlethal Fates Clonogenic cell death is defined as the inability of a single cell to undergo about 5 to 6 cell divisions such that 50 cells are formed. Multiple modes

of cell death and other nonlethal terminal processes can contribute to clonogenic cell death. The importance of understanding these specific mechanisms induced—or resisted—in cancer cells following exposure to IR is to identify susceptibilities for tumor cell death such that novel therapies can be developed to sensitize tumors to IR.

Mechanisms of Cell Death Mechanisms of cell death can be categorized as accidental cell death and regulated cell death, with additional nonlethal processes, such as mitotic catastrophe and senescence, constituting a third category of clonogenic cell death. Based on the Recommendations of the Nomenclature Committee on Cell Death 2018, at least 12 distinct forms of regulated cell death occur under specific circumstances.42 Regulated cell death by definition can be modulated pharmacologically and/or genetically, while accidental cell death is irreversible. Many of these cell death mechanisms—including nonautonomous cell death, such as immunogenic cell death and netosis—are thought to occur in human malignant cells. Programmed cell death, also known as apoptosis, describes a group of several processes in which intracellular enzymes degrade protein

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and DNA without the activation of the immune response. Several pathways that regulate apoptosis have been described. Regulated cell death processes that activate immune response include necroptosis and pyroptosis. These forms of regulated cell death release signals that activate immune effector cells and inflammation.43 Therefore, channeling cell death along necroptosis and pyroptosis pathways can be exploited to enhance immunotherapy. Radiation is known to induce apoptosis of lymphocytes and hematological malignancies, including lymphoma and multiple myeloma, but is thought to induce apoptosis in only a small population of tumor cells derived from solid tissues. This is likely in large part due to inactivation of p53 in many solid tumors either through p53 gene mutation or posttranslational modulation by oncogenic viruses such as human papillomavirus (HPV). In solid tumors, the proportion of cell death mechanisms seen following various doses of IR have been difficult to discern because of the multiple death pathways likely induced simultaneously and the relatively long time course of several days following IR. Mitotic catastrophe is believed to lead to cell death or senescence in a large portion of solid tumor cell bulk, but radiation has been shown to also induce tumor cell necroptosis.42,44 Moreover, pyroptosis is a regulated cell death mechanism believed to be responsible for at least some radiation normal tissue toxicity.45

Nonlethal Fates—Senescence, Mitotic Catastrophe Postmitotic cell death (PMCD) and mitotic catastrophe occur when cancer cells progress through mitosis despite unrepaired DNA damage. Mitotic catastrophe is used to describe cells that have attempted and failed to undergo mitosis. Mitotic catastrophe itself is not considered to be a form of regulated cell death but often proceeds to PMCD via apoptosis or other regulated cell death mechanisms. Mitotic catastrophe is an important component to radiation-induced cell death in many solid tumors and is characterized by the presence of multinucleated giant cells that are metabolically active but either die by secondary regulated cell death mechanisms such as necrosis or apoptosis or remain in terminal proliferation arrest, termed senescence. Cellular senescence is characterized by the inability to replicate while the cell remains metabolically active and cells show positive staining for β-galactosidase. Senescence occurs in both cancer and normal tissue cells and contributes to biological response to radiotherapy.46

Radiation-Induced Lymphopenia The abscopal effect is reviewed in Chapter 1. This is a radiation biology principal in which a tissue or cancer is irradiated and a biological response is observed in a distant unirradiated tumor or tissue. The molecular basis for the abscopal effect involves several mechanisms that include the release of cytokines and microvesicles (MVs). For example, tumor necrosis factor, TGFβ, and other cytokines are released from irradiated cells. MVs are membranous extracellular vesicles that contain protein and microRNA. MVs are released from irradiated cells and fuse with distant target cells to transfer signals. For example, irradiated peripheral blood leukocytes (PBLs) release MV into the circulation. MVs traffic to hematopoietic stem cells (HSCs), where they activate biological responses in unirradiated HSCs. In this regard, iatrogenic immunosuppression results from the chronic depletion of lymphocytes, which persists for many months beyond the completion of radiotherapy.47–49 The mechanisms of radiation-induced lymphopenia involve the depletion of CD11a stem cells within the bone marrow compartment. CD11a stem cells are precursors to lymphocytes. MVs and irradiated leukocytes traffic to HSCs and deplete CD11a stem cells within the bone marrow.50,51 Radiation-induced apoptosis was characterized in lymphoid cells.37 In fact, iatrogenic immunosuppression can be recapitulated by irradiation of peripheral blood leukocytes (ex vivo) that are subsequently injected

into unirradiated naïve mice. Following irradiation, extracellular MV and irradiated leukocytes traffic to the bone marrow and fuse with HSCs, thereby delivering microRNA and cytokines to HSCs. MV signals are involved in the depletion of CD11a stem cells.

Radiation-Induced Normal Tissue Stem Cell Depletion Embryonic stem cells (ESCs) undergo an apoptotic response after low-dose irradiation52,53 and a dramatic decrease in cell viability.54 The protection of ESCs from apoptosis following irradiation has been investigated and many biological pathways contribute to radiationinduced cell death.55–59 ESCs show a higher apoptotic response as compared with their differentiated isogenic progeny60,61 together with high levels of the pro-apoptotic protein Bax and low levels of antiapoptotic protein Bcl-2.62 HSCs respond to radiation with a high level of apoptosis63 through the participation of Bcl-2, p53 and ASPP1.64 Radiation also drives HSCs to quiescence, without an apoptotic response.65 Neural stem cells (NSCs) undergo regulated cell death after irradiation53,61,66,67 in a dose-dependent manner,67 with the surviving cells undergoing senescence.68 The apoptosissusceptible nature of the irradiated neuronal stem cells has been associated with TRAIL-R2-mediated signaling cascade with activation of caspase-369 and with prolonged upregulation of phosphorylated p53.70 p53-dependent apoptosis has also been observed in intestinal stem cells after irradiation by Wang et al.71 In vivo experiments on mice show that 10% of intestinal stem cells initiate apoptosis after low doses, although cell death had no appreciable effect on tissue architecture.72,73 Intestinal stem cells in ex vivo organoid cultures undergo massive apoptosis after 6 Gy irradiation while non-stem cells in the same organoids showed higher radioresistance.62 Phosphoprotein phosphatase 2A (PP2A) is a potential DDR-signaling antagonist associated with normal stem cell radiosensitivity.62 PP2A deactivates DDR by dephosphorylating pATM and γH2AX and dephosphorylates Akt with consequent apoptotic pathway activation. Stem cells constitutively express high PP2A levels, which causes impaired DDR activation and increased apoptotic responses in several in vivo niches and stem cell cultures.62 Epigenetic mechanisms of stem cell hypersensitivity to DDR include histone modifications (acetylation and methylation) and regulatory noncoding RNAs (reviewed in Li74). Epigenetic alterations have been found to contribute to the pathogenesis of radiation-induced carcinogenesis75,76 by the reactivation of oncogenes and the silencing of tumor suppressor genes.77,78 These events can result in genomic instability and consequent carcinogenesis in many models.79–82

Molecular Targeted Radiation Protection There are several mechanisms of radiation-induced tissue injury that include cell death, stem cell depletion, inflammation, edema, and fibrosis, each of which impair the function of irradiated organs. Molecular targeted radiation protection is a strategy that is similar to molecular targeted cancer therapy in that specific molecules are inhibited to prevent normal tissue injury. The challenge of molecular targeted radioprotection is that the drugs must protect normal tissues without diminishing the cytotoxic effects of radiation on cancer. “Druggable” molecular targets that specifically prevent normal tissue radiation injury exploit the differential response in normal tissue stem cells and do not attenuate cell death in cancer. Normal stem cells are susceptible to RCD following irradiation, while cancer and cancer stem cells are resistant to RCD. Strategies to reduce RCD in normal stem cells include the inhibition of enzymes that regulate apoptosis. For example, GSK3β inhibition alters the expression level of proteins that regulate apoptosis, Bax, and Bcl-2. GSK3β inhibitors thereby attenuate radiation-induced apoptosis in normal stem cells without altering cancer cell response to radiation.

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CHAPTER 2 Similarly, PP2A is an enzyme overexpressed in normal stem cells and participates in signal transduction in irradiated normal stem cells leading to PCD. Inhibition of PP2A attenuates apoptosis and prevents depletion of normal tissue stem cells. For example, intestinal stem cell depletion results in the shortening of intestinal villi and subsequent intestinal malabsorption.83 The susceptibility of intestinal stem cells is associated with the epigenomics that is responsible for maintaining the “stem cell phenotype.” Stem cells show increased PP2A and genetic silencing of PP2A markedly reduces susceptibility of stem cells. Stem cells can be protected from radiation-induced apoptosis by epigenetic downregulation of Bax and upregulation of Bcl-2. Inhibition of glycogen synthase kinase 3b (GSK3b) prevents apoptosis both in vitro and in brain, intestine, and skin of mice treated with GSK3b-specific inhibitors.84 Radiation-induced inflammation can impair organ function. Most notable is radiation pneumonitis, which impairs oxygen exchange in the lung. Radiation induces pneumonitis through the induction of inflammatory mediators such as ICAM-1, cytokines (e.g., TNF, ILs) and DAMPs. The mechanism of the delay in the onset of pneumonitis is not entirely clear. Pneumonitis can occur weeks after the completion of radiotherapy, which implicates the delay required for immune effector cell expansion. Radiation-induced edema is attenuated by glucocorticoids (GCs), which bind to glucocorticoid receptors on the endothelium and leukocytes to reduce inflammation and minimize vascular permeability. GCs also reduce the osmotic pressure gradient across microvasculature in irradiated cancers and normal tissues. Thus, GCs are an important component in the treatment of cancers that compress the brain, spine, and airway. GCs cause harmful side effects, such as hyperglycemia, hypertension, insomnia, irritability, and gastritis. Alternative drugs that have the potential to attenuate radiation-induced edema include inhibitors of receptors and enzymes that mediate edema. The molecular biology of radiation-induced edema is a complex of signals that include vascular permeability factors, VEGF, and LPA. These radiation-induced molecules bind to receptors on the endothelium to increase permeability. Inhibitors of these signaling pathways could be developed to reduce radiationinduced edema in patients who are intolerant to GCs. The molecular basis of radiation-induced fibrosis is multifactorial and involves the chronic production of cytokines such as TGF-β. The role of inflammation in the pathogenesis of radiation-induced fibrosis is indicated by improved pulmonary elasticity in irradiated mice that lack ICAM-1. ICAM-1 is a cell adhesion molecule that regulates leukocyte extravasation within irradiated tissues. Blocking ICAM-1 function is a potential means of attenuating radiation-induced inflammation and fibrosis.

BIOMARKERS FOR RADIATION RESPONSE PREDICTION AND PERSONALIZED ONCOLOGY Personalized patient care in oncology refers to the use of biomarkers and genomic testing to determine what is the best management for each individual patient. Genetic analysis of tumors to determine “actionable” or “druggable” mutations is a way of identifying tumors that may be resistant to standard therapies but are likely responsive to molecular targeted therapy. The importance of biomarkers that detect or predict cancer is best demonstrated by prostate specific antigen (PSA), which is exclusively expressed by prostate epithelial cells and, thus, is both a sensitive biomarker for prostate cancer and very useful for monitoring treatment response and detection of recurrence.85 Few biomarkers are truly cancer specific but are used along with other tumor and patient features to stratify patients for outcomes and response to treatment. Examples of these include serum CA-125 as a marker of ovarian cancer that can be helpful in the assessment of cytoreductive surgery and response to

Molecular and Cellular Biology

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systemic chemotherapy,86 and serum CA-19-9, which is measurable in patients with pancreaticobiliary cancers. CA-19-9 elevated above 90 U/ mL after surgery for pancreatic cancer is associated with significantly worse overall survival.87 In cervical cancer, for example, elevated serum squamous cell carcinoma antigen (SCCA) is one of few biomarkers with independent prognostic value in addition to International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node status prior to either surgical treatment for early-stage disease or definitive chemoradiation therapy (CRT) for locally advanced cervical cancer.88,89 Factors such as SCCA that are detectable in the blood/serum or other biologic fluids are appealing as biomarkers because they are noninvasive and amenable to repeat sampling with relatively little cost and burden to patients. Emerging circulating biomarkers include detection of circulating tumor cells (CTCs) or cell fragments, circulating tumor DNA (ctDNA), metabolites, and viral titers or viral-specific proteins. The TCGA effort has produced a wealth of information about tumor heterogeneity and, for some tumor types such as endometrial cancer and central nervous system tumors, significant insight into prognostic groups that can be identified from de novo tumor mutational patterns, gene expression profiles, and/or proteomic signatures. For cancer types treated predominantly with radiation, such as cervical cancer and head and neck cancers, such omics approaches can possibly provide predictive biomarkers and begin to unlock potential mechanisms of radiation sensitivity and radiation resistance. However, for some tumor types, the TCGA is limited in this regard, emphasizing the importance of generating datasets from cohorts that also have well-annotated clinical outcomes after definitive irradiation. PSA levels in blood samples from prostate cancer patients can be used along with other pathological features to predict a risk of metastasis to lymph nodes and distant sites. PSA levels are also used to monitor recurrence after prostatectomy. However, tumor-specific molecular signatures capable of predicting response to therapy are only recently being validated. The 24-gene expression signature Post-Operative Radiation Therapy Outcomes Score (PORTOS) was recently validated as a molecular tool to predict response to post-prostatectomy radiotherapy in men independently of previously known prognostic factors such as Gleason Score and PSA. Similar comprehensive analysis of noncoding RNA species has identified prognostic signatures from what are now known to be functional nucleic acid species.90 Wong et al. identified a prognostic microRNA signature from the TCGA head and neck squamous cell carcinoma cohort, demonstrating significance for patients with either HPV-positive or HPV-negative tumors.91 Epigenomics and metabolomics analyses of tumors and their hosts are also advancing our understanding of measurable biological markers that can provide prognostic information, including risk of recurrence and development of metastatic disease and/or predictive information about response to a specific therapy.91a For virus-associated tumors, expression of viral proteins, viral titers, and viral subtype can all serve as biomarkers for outcomes and therapeutic response. Perhaps the best example of this is HPV, an important biomarker for cancers of the cervix, head and neck, anus, vulva, vagina, and penis. Nonsmoking patients with HPV detected within cancer show elevated levels of p16 and have improved prognosis compared to patients with no HPV detection.92 Further, recent evidence suggests that infection with HPV α-9 strains (including HPV 16, 31, 33, 52, and 58) is associated with improved disease-free survival and distant metastasis-free survival following definitive radiotherapy for patients with cervical cancer as compared with those infected with HPV α-7 strains (HPV 18, 39, 45, 59, and 68).93 Clearance of the virus over the course of chemoradiation in cervical cancer is associated with significantly improved outcomes as

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shown by Mahantshetty et al. in their prospective analysis, suggesting that persistent viral infection may play a role in radiation resistance.94

to release the drug within cancer cells. Extracellular cleavage of cytotoxic drugs from antibodies is under development.

Imaging Biomarkers

Radiation-Inducible Antigens on Cancer

Pretreatment imaging assessment can also provide useful biomarkers not only for anatomical location of the tumor and treatment planning but also for outcomes potentially indicative of underlying biology. FDG-PET is probably the best example of such an imaging biomarker. Metrics such as SUVmax of the primary tumor have been shown to correlate with outcomes in cervical cancer, lung cancer, and vulvar cancer, among others.95–99 Non-FDG-PET radiotracers are also under development, particularly those that can detect intratumoral hypoxia (such as FAZA and Cu-ATSM). These agents may prove particularly useful for predicting response to IR. Functional magnetic resonance imaging (MRI) can also be used to determine tumor heterogeneity, diffusion, and treatment response in a noninvasive manner, with evidence of prognostic value already seen in prostate, cervical, pancreatic, and endometrial cancers.100–104 Additional imaging modalities—including hyperpolarized MRI, optical imaging with cancer-specific tracers, focused ultrasound, and radiomic and radiogenomic analyses—are on the horizon and promise a wealth of information promoting personalized medicine.

Radiation induces the surface expression of antigens and thereby expands the number of antigens that are useful in therapeutic antibody development. Scaffold proteins that function to tether DAMP signals such as calreticulin to the cell include tax-interacting protein (TIP-1). TIP-1 is transported to the surface of cancer cells during radiotherapy. Cell adhesion molecules—such as P-selectin, E-selectin, and others—are radiation-inducible proteins that are expressed on the surface of cancer endothelium. Antibodies that are specific to each of these inflammatory regulators bind selectively within irradiated cancer to achieve directed drug delivery. GRP78 is a radiation-inducible antigen in many cancer subtypes and antibodies to GRP78 enhance the efficacy of radiation in cancer.105

Cancer-Specific Neoantigens The development of effective therapeutic antibodies is expanding rapidly and includes antibody drug conjugates, radioimmunoconjugates, immunotoxins, and bispecific antibodies (Fig. 2.3). These antigens are expressed on the surface of cancer cells. Neoantigens that are specific to cancer include mutations within surface proteins, such as the EGF receptor. Other surface proteins that are molecular targets for antibody development for cancer therapy include overexpressed proteins such as her2/neu. The clinical importance of cancer-specific neoantigens is the improved outcome in patients treated with therapeutic antibodies (e.g., EGFR; cetuximab). Antibody-drug conjugates (ADC) target cytotoxic drugs specifically to cancer antigens. ADCs undergo endocytosis, where the linker is cleaved

Immunotherapy Immune effector cells that are activated by antibodies include macrophages during antibody-dependent cell-mediated cytotoxicity (ADCC) and NK cells during antibody-dependent cell-mediated phagocytosis (ADCP). ADCC and ADCP have played only a minor role in cancer immunotherapy. In contrast, T-cell activation has been harnessed through several strategies: anti-PD1, anti-CTLA4, CAR-T cells, BITEs, and cancer vaccines. Cancer vaccines promise to activate immune responses against antigens that are unique to cancer. PD1 and CTLA4 are immune checkpoints and are a means by which cancer can evade immunosurveillance. These proteins signal to the immune system that cancer is “self ” and inactivate immune effector cells to prevent autoimmunity. Anti-PD1 antibodies block immune checkpoints and markedly improve outcomes during cancer therapy. Likewise, anti-CTLA4 antibodies block another immune checkpoint that recognizes cancer as “self” and improve cancer outcomes. Predictive biomarkers that can predetermine cancer response to PD-1 blocking antibodies include tumor mutational burden (TMB),

Radioactive ligand

Naked MAb ADCC CDC Radionuclide Radioimmunoconjugate

Bispecific MAb

Cancer Cell Cytokine

Killer cell

Immunocytokine

Immune effector cell or CAR Cells

Immunotoxin

Liposome

scFv-enzyme Prodrug

scFv Drug

Immunoliposome

Fig. 2.3 Classification of therapeutic antibodies. VH/VL are the antigen-binding domains. CH is the Fc or complement and Fc receptor binding domain. ADCC, Antibody-dependent cell-mediated cytotoxicity; CAR, chimeric antigen receptor; CDC, complement dependent cytotoxicity; MAb, monoclonal antibody; scFv, singlechain variable fragment.

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CHAPTER 2 which is a measure of the number of genetic mutations within a cancer.106 This finding suggests that mutations that are specific to cancer could be targets for the immunobiological response to PD-1 blockade. It is not yet known whether radiation-induced mutations in cancer can enhance the biological response to checkpoint blockade. CAR-T cells are genetically engineered T-cells with antibodies that bind to cancer antigens and subsequently activate these immune effector cells. Similarly, BITEs are antibodies that bind simultaneously to cancer surface antigens and T-cell receptors, thereby activating T-cell response against the cancer. The development of IgGs, CAR-T, and BITEs that bind to radiation-inducible antigens are under development. The goal of these radiation-targeted strategies is to augment current immunotherapy (see Chapter 5).

Cell Viability Signaling Pathways Molecular targeted drug development is defined as chemical inhibition of enzymes that are specific to cancer without “off-target” effects on normal tissues. The goal of molecular targeted radiosensitization is to specifically enhance the efficacy of radiotherapy in cancer without worsening radiation injury in normal tissues. The classic targets are those that prevent DNA damage repair during radiotherapy (see Chapter 4). One advantage in this approach is that DNA DSB repair is rapid; thus, the pharmacokinetics of inhibitors need not exceed a couple of hours. Molecular targets include DNA-PK and ATM, along with other enzymes. PI3K and AKT are enzymes that are activated by radiation and enhance cell viability. Inhibitors of these enzymes enhance the efficacy of radiotherapy in preclinical models of cancer. Radiation also induces prosurvival signaling. For example, radiation induces the activation of PLA2, which cleaves membrane lipids to form prosurvival second messengers, such as LPC and LPA. LPA binds to LPA receptors on cancer cells and endothelial cells. LPAR activates cell survival signals within irradiated cells. GRP78 is a radiation-inducible, transmembrane protein that enhances cancer cell viability. Anti-GRP78 antibodies bind specifically to cancer and enhance the efficacy of radiotherapy. In summary, studies of the molecular biology of cancer have led to new radiation-sensitizing drugs. Studies of biomarkers have uncovered new ways to personalize cancer therapy for each individual patient. Radiation injury to normal tissues can be attenuated by molecular targeted radiation-protecting drugs. Other chapters in this textbook will describe each of these strategies in greater depth.

CRITICAL REFERENCES 1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 2. Boss MK, Bristow R, Dewhirst MW. Linking the history of radiation biology to the hallmarks of cancer. Radiat Res. 2014;181(6):561–577. 5. Schwarz JK, et al. Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer. Clin Cancer Res. 2012;18(5):1464–1471. 16. Strilic B, Offermanns S. Intravascular survival and extravasation of tumor cells. Cancer Cell. 2017;32(3):282–293. 20. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703–707.

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22. Siegel BA, Dehdashti F. Oncologic PET/CT: current status and controversies. Eur Radiol. 2005;15(suppl 4):D127–D132. 27. Grigsby P, et al. Clinical outcomes and differential effects of PI3K pathway mutation in obese versus non-obese patients with cervical cancer. Oncotarget. 2018;9(3):4061–4073. 28. Park J, et al. Obesity and cancer–mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014;10(8):455–465. 35. Haimovitz-Friedman A, et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med. 1994;180(2):525–535. 36. Hallahan D, Kuchibhotla J, Wyble C. Cell adhesion molecules mediate radiation-induced leukocyte adhesion to the vascular endothelium. Cancer Res. 1996;56(22):5150–5155. 37. Kastan MB, et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992;71(4):587–597. 39. Bakhoum SF, et al. Mitotic DNA damage response: at the crossroads of structural and numerical cancer chromosome instabilities. Trends Cancer. 2017;3(3):225–234. 40. Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med. 2015;66:129–143. 47. Campian JL, et al. Severe treatment-related lymphopenia in patients with newly diagnosed rectal cancer. Cancer Invest. 2018;36(6):356–361. 61. Meyer B, et al. Histone H3 lysine 9 acetylation obstructs ATM activation and promotes ionizing radiation sensitivity in normal stem cells. Stem Cell Reports. 2016;7(6):1013–1022. 62. Fabbrizi MR, et al. Transient PP2A inhibition alleviates normal tissue stem cell susceptibility to cell death during radiotherapy. Cell Death Dis. 2018;9(5):492. 67. Acharya MM, et al. Consequences of ionizing radiation-induced damage in human neural stem cells. Free Radic Biol Med. 2010;49(12):1846– 1855. 71. Wang X, et al. Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation. Sci Rep. 2015;5:8566. 72. Zhu Y, et al. Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations. Cell Stem Cell. 2013;12(3):298–303. 84. Thotala DK, et al. A new class of molecular targeted radioprotectors: GSK-3beta inhibitors. Int J Radiat Oncol Biol Phys. 2010;76(2): 557–565. 89. Markovina S, et al. Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer. Br J Cancer. 2018;118(1):72–78. 97. Miller TR, Grigsby PW. Measurement of tumor volume by PET to evaluate prognosis in patients with advanced cervical cancer treated by radiation therapy. Int J Radiat Oncol Biol Phys. 2002;53(2):353–359. 98. Rao YJ, Grigsby PW. The role of PET imaging in gynecologic radiation oncology. PET Clin. 2018;13(2):225–237. 99. Xue F, et al. F-18 fluorodeoxyglucose uptake in primary cervical cancer as an indicator of prognosis after radiation therapy. Gynecol Oncol. 2006;101(1):147–151. 105. Dadey DYA, et al. Antibody targeting GRP78 enhances the efficacy of radiation therapy in human glioblastoma and non-small cell lung cancer cell lines and tumor models. Clin Cancer Res. 2017;23(10): 2556–2564.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 2

REFERENCES 1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 2. Boss MK, Bristow R, Dewhirst MW. Linking the history of radiation biology to the hallmarks of cancer. Radiat Res. 2014;181(6):561–577. 3. Davies H, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–954. 4. Gray LH, et al. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953;26(312):638–648. 5. Schwarz JK, et al. Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer. Clin Cancer Res. 2012;18(5):1464–1471. 6. Adams BR, et al. Dynamic dependence on ATR and ATM for doublestrand break repair in human embryonic stem cells and neural descendants. PLoS ONE. 2010;5(4):e10001. 7. Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature. 2004;432(7015):307–315. 8. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401–410. 9. Baeriswyl V, Christofori G. The angiogenic switch in carcinogenesis. Semin Cancer Biol. 2009;19(5):329–337. 10. Ye W. The complexity of translating anti-angiogenesis therapy from basic science to the clinic. Dev Cell. 2016;37(2):114–125. 11. Maciejowski J, de Lange T. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol. 2017;18(3):175–186. 12. Capper R, et al. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev. 2007;21(19):2495–2508. 13. Lin TT, et al. Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis. Blood. 2010;116(11):1899–1907. 14. Talmadge JE, Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 2010;70(14):5649–5669. 15. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–458. 16. Strilic B, Offermanns S. Intravascular survival and extravasation of tumor cells. Cancer Cell. 2017;32(3):282–293. 17. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–829. 18. Yamaguchi H, Sakai R. Direct Interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion. Cancers (Basel). 2015;7(4):2054–2062. 19. Valiente M, et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014;156(5):1002–1016. 20. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703–707. 21. Kelloff GJ, et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res. 2005;11(8):2785–2808. 22. Siegel BA, Dehdashti F. Oncologic PET/CT: current status and controversies. Eur Radiol. 2005;15(suppl 4):D127–D132. 23. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13(6):472–482. 24. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23(1):27–47. 25. Calvert AE, et al. Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation. Cell Rep. 2017;19(9):1858–1873. 26. Berger NA. Obesity and cancer pathogenesis. Ann N Y Acad Sci. 2014;1311:57–76. 27. Grigsby P, et al. Clinical outcomes and differential effects of PI3K pathway mutation in obese versus non-obese patients with cervical cancer. Oncotarget. 2018;9(3):4061–4073. 28. Park J, et al. Obesity and cancer–mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014;10(8):455–465.

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29. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. 30. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17(12):e542–e551. 31. Li X, et al. Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. J Hematol Oncol. 2018;11(1):31. 32. Sharabi AB, et al. Stereotactic radiation therapy combined with immunotherapy: augmenting the role of radiation in local and systemic treatment. Oncology (Williston Park). 2015;29(5):331–340. 33. Spiotto M, Fu YX, Weichselbaum RR. The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications. Sci Immunol. 2016;1(3). 34. Vanpouille-Box C, et al. DNA exonuclease Trex1 regulates radiotherapyinduced tumour immunogenicity. Nat Commun. 2017;8:15618. 35. Haimovitz-Friedman A, et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med. 1994;180(2):525–535. 36. Hallahan D, Kuchibhotla J, Wyble C. Cell adhesion molecules mediate radiation-induced leukocyte adhesion to the vascular endothelium. Cancer Res. 1996;56(22):5150–5155. 37. Kastan MB, et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992;71(4):587–597. 38. Morgan MA, Lawrence TS. Molecular pathways: overcoming radiation resistance by targeting DNA damage response pathways. Clin Cancer Res. 2015;21(13):2898–2904. 39. Bakhoum SF, et al. Mitotic DNA damage response: at the crossroads of structural and numerical cancer chromosome instabilities. Trends Cancer. 2017;3(3):225–234. 40. Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med. 2015;66:129–143. 41. d’Adda di Fagagna F. A direct role for small non-coding RNAs in DNA damage response. Trends Cell Biol. 2014;24(3):171–178. 42. Galluzzi L, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486–541. 43. Davidovich P, Kearney CJ, Martin SJ. Inflammatory outcomes of apoptosis, necrosis and necroptosis. Biol Chem. 2014;395(10): 1163–1171. 44. Wang Z, et al. Progress in studies of necroptosis and its relationship to disease processes. Pathol Res Pract. 2018;214(11):1749–1757. 45. Liao H, et al. Mesenchymal stem cells attenuate radiation-induced brain injury by inhibiting microglia pyroptosis. Biomed Res Int. 2017;2017: 1948985. 46. Citrin DE, Mitchell JB. Mechanisms of normal tissue injury from irradiation. Semin Radiat Oncol. 2017;27(4):316–324. 47. Campian JL, et al. Severe treatment-related lymphopenia in patients with newly diagnosed rectal cancer. Cancer Invest. 2018;36(6):356–361. 48. Campian JL, et al. Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Cancer Invest. 2013;31(3):183–188. 49. Campian JL, et al. Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer. Head Neck. 2014;36(12):1747–1753. 50. Kapoor V, Hallahan D, Thotala D. Radiation induces extracellular vesicles that suppress hematopoiesis leading to iatrogenic immunosuppression. Cancer Res. 2018. 51. Szatmari T, et al. Extracellular vesicles mediate radiation-induced systemic bystander signals in the bone marrow and spleen. Front Immunol. 2017;8:347. 52. Sokolov MV, Neumann RD. Human embryonic stem cell responses to ionizing radiation exposures: current state of knowledge and future challenges. Stem Cells Int. 2012;2012:579104. 53. Barazzuol L, Jeggo PA. In vivo sensitivity of the embryonic and adult neural stem cell compartments to low-dose radiation. J Radiat Res. 2016;57(suppl 1):i2–i10.

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SECTION I

Scientific Foundations of Radiation Oncology

54. Filion TM, et al. Survival responses of human embryonic stem cells to DNA damage. J Cell Physiol. 2009;220(3):586–592. 55. Yang C, et al. Opposing putative roles for canonical and noncanonical NFkappaB signaling on the survival, proliferation, and differentiation potential of human embryonic stem cells. Stem Cells. 2010;28(11):1970–1980. 56. Bai H, et al. Bcl-xL enhances single-cell survival and expansion of human embryonic stem cells without affecting self-renewal. Stem Cell Res. 2012;8(1):26–37. 57. Conklin JF, Baker J, Sage J. The RB family is required for the self-renewal and survival of human embryonic stem cells. Nat Commun. 2012;3:1244. 58. Ardehali R, et al. Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors. Proc Natl Acad Sci USA. 2011;108(8):3282–3287. 59. Edel MJ, et al. Rem2 GTPase maintains survival of human embryonic stem cells as well as enhancing reprogramming by regulating p53 and cyclin D1. Genes Dev. 2010;24(6):561–573. 60. Jacobs KM, et al. Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses. Mol Biol Cell. 2016;27(8):1332–1345. 61. Meyer B, et al. Histone H3 lysine 9 acetylation obstructs ATM activation and promotes ionizing radiation sensitivity in normal stem cells. Stem Cell Reports. 2016;7(6):1013–1022. 62. Fabbrizi MR, et al. Transient PP2A inhibition alleviates normal tissue stem cell susceptibility to cell death during radiotherapy. Cell Death Dis. 2018;9(5):492. 63. Katoh O, et al. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res. 1995;55(23):5687–5692. 64. Milyavsky M, et al. A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell. 2010;7(2):186–197. 65. Chang J, et al. Low doses of oxygen ion irradiation cause acute damage to hematopoietic cells in mice. PLoS ONE. 2016;11(7):e0158097. 66. Katsura M, et al. Effects of chronic low-dose radiation on human neural progenitor cells. Sci Rep. 2016;6:20027. 67. Acharya MM, et al. Consequences of ionizing radiation-induced damage in human neural stem cells. Free Radic Biol Med. 2010;49(12):1846–1855. 68. Zou Y, et al. Responses of human embryonic stem cells and their differentiated progeny to ionizing radiation. Biochem Biophys Res Commun. 2012;426(1):100–105. 69. Ivanov VN, Hei TK. Radiation-induced glioblastoma signaling cascade regulates viability, apoptosis and differentiation of neural stem cells (NSC). Apoptosis. 2014;19(12):1736–1754. 70. Isono M, et al. Carbon-ion beams effectively induce growth inhibition and apoptosis in human neural stem cells compared with glioblastoma A172 cells. J Radiat Res. 2015;56(5):856–861. 71. Wang X, et al. Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation. Sci Rep. 2015;5:8566. 72. Zhu Y, et al. Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations. Cell Stem Cell. 2013;12(3):298–303. 73. Metcalfe C, et al. Lgr5+ stem cells are indispensable for radiationinduced intestinal regeneration. Cell Stem Cell. 2014;14(2):149–159. 74. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002;3(9):662–673. 75. Weil MM, et al. Incidence of acute myeloid leukemia and hepatocellular carcinoma in mice irradiated with 1 GeV/nucleon (56)Fe ions. Radiat Res. 2009;172(2):213–219. 76. Loree J, et al. Radiation-induced molecular changes in rat mammary tissue: possible implications for radiation-induced carcinogenesis. Int J Radiat Biol. 2006;82(11):805–815. 77. Jones PA, Liang G. Rethinking how DNA methylation patterns are maintained. Nat Rev Genet. 2009;10(11):805–811. 78. Howard G, et al. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene. 2008;27(3):404–408.

79. Yamazaki J, et al. The epigenome of AML stem and progenitor cells. Epigenetics. 2013;8(1):92–104. 80. Wakita S, et al. Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia. Leukemia. 2013;27(5):1044–1052. 81. Shih AH, et al. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer. 2012;12(9):599–612. 82. Holz-Schietinger C, Matje DM, Reich NO. Mutations in DNA methyltransferase (DNMT3A) observed in acute myeloid leukemia patients disrupt processive methylation. J Biol Chem. 2012;287(37):30941–30951. 83. Withers HR, Brennan JT, Elkind MM. The response of stem cells of intestinal mucosa to irradiation with 14 MeV neutrons. Br J Radiol. 1970;43(515):796–801. 84. Thotala DK, et al. A new class of molecular targeted radioprotectors: GSK-3beta inhibitors. Int J Radiat Oncol Biol Phys. 2010;76(2): 557–565. 85. Fenton JJ, et al. Prostate-specific antigen-based screening for prostate cancer: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;319(18):1914–1931. 86. Pignata S, et al. Follow-up with CA125 after primary therapy of advanced ovarian cancer: in favor of continuing to prescribe CA125 during follow-up. Ann Oncol. 2011;22(suppl 8):viii40–viii44. 87. Berger AC, et al. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol. 2008;26(36):5918–5922. 88. Charakorn C, et al. The association between serum squamous cell carcinoma antigen and recurrence and survival of patients with cervical squamous cell carcinoma: a systematic review and meta-analysis. Gynecol Oncol. 2018;150(1):190–200. 89. Markovina S, et al. Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer. Br J Cancer. 2018;118(1):72–78. 90. Krishnan P, Damaraju S. The challenges and opportunities in the clinical application of noncoding RNAs: the road map for miRNAs and piRNAs in cancer diagnostics and prognostics. Int J Genomics. 2018;2018:5848046. 91. Wong N, et al. Prognostic microRNA signatures derived from The Cancer Genome Atlas for head and neck squamous cell carcinomas. Cancer Med. 2016;5(7):1619–1628. 91a. Zhao SG, Chang SL, Spratt DE, et al. Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol. 2016;17(11): 1612–1620. 92. Lewis A, et al. The new face of head and neck cancer: the HPV epidemic. Oncology (Williston Park). 2015;29(9):616–626. 93. Okonogi N, et al. Human papillomavirus genotype affects metastatic rate following radiotherapy in patients with uterine cervical cancer. Oncol Lett. 2018;15(1):459–466. 94. Mahantshetty U, et al. Impact of HPV 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy - A prospective observational study. Gynecol Oncol. 2018;148(2):299–304. 95. Berghmans T, et al. Primary tumor standardized uptake value (SUVmax) measured on fluorodeoxyglucose positron emission tomography (FDG-PET) is of prognostic value for survival in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis (MA) by the European Lung Cancer Working Party for the IASLC Lung Cancer Staging Project. J Thorac Oncol. 2008;3(1):6–12. 96. Kidd EA, et al. The standardized uptake value for F-18 fluorodeoxyglucose is a sensitive predictive biomarker for cervical cancer treatment response and survival. Cancer. 2007;110(8):1738–1744. 97. Miller TR, Grigsby PW. Measurement of tumor volume by PET to evaluate prognosis in patients with advanced cervical cancer treated by radiation therapy. Int J Radiat Oncol Biol Phys. 2002;53(2):353–359. 98. Rao YJ, Grigsby PW. The role of PET imaging in gynecologic radiation oncology. PET Clin. 2018;13(2):225–237.

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CHAPTER 2 99. Xue F, et al. F-18 fluorodeoxyglucose uptake in primary cervical cancer as an indicator of prognosis after radiation therapy. Gynecol Oncol. 2006;101(1):147–151. 100. Deike-Hofmann K, et al. Sensitivity of different MRI sequences in the early detection of melanoma brain metastases. PLoS ONE. 2018;13(3):e0193946. 101. Fraum TJ, et al. PET/MRI for gastrointestinal imaging: current clinical status and future prospects. Gastroenterol Clin North Am. 2018;47(3):691–714. 102. Mahajan A, et al. Magnetic resonance imaging of gynecological malignancies: role in personalized management. Semin Ultrasound CT MR. 2017;38(3):231–268.

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103. De Robertis R, et al. Prognostication and response assessment in liver and pancreatic tumors: the new imaging. World J Gastroenterol. 2015;21(22):6794–6808. 104. Furlan A, Borhani AA, Westphalen AC. Multiparametric MR imaging of the prostate: interpretation including prostate imaging reporting and data system version 2. Urol Clin North Am. 2018;45(3):439–454. 105. Dadey DYA, et al. Antibody targeting GRP78 enhances the efficacy of radiation therapy in human glioblastoma and non-small cell lung cancer cell lines and tumor models. Clin Cancer Res. 2017;23(10):2556–2564. 106. Hellmann MD, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell. 2018;33(5):853–861, e4.

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3 Dose-Response Modifiers in Radiation Therapy Michael R. Horsman, Jacob C. Lindegaard, Cai Grau, Marianne Nordsmark, Jan Alsner, and Jens Overgaard

When cancer patients undergo radiation therapy, there is a clear doseresponse relationship between the dose delivered and the response of the tumor to the radiation. This is illustrated in Fig. 3.1. There is also an increase in normal tissue damage with increasing radiation dose; it is this complication that limits the total radiation dose that can be given safely. Substantial effort has been made to modify these dose-response relationships in order to increase the separation between the tumor and normal tissue dose-response curves. The approach has been either to selectively increase the radiation damage in tumors without affecting the normal tissues or by protecting the normal tissues without having a similar protective effect in tumors. Agents capable of enhancing radiation response include certain conventional chemotherapeutic agents, the halogenated pyrimidines, and treatments that specifically overcome radioresistance resulting from the presence of hypoxic cells that occur as a result of the environmental conditions within most solid tumors. The most widely investigated method applied to the hypoxia problem is radiosensitization of the hypoxic cells with either electron-affinic sensitizing drugs or hyperthermia. Another approach often used to reduce hypoxia—especially in experimental systems—involves increasing oxygen availability (1) by having patients breathe high-oxygen-content gas; (2) introducing perfluorochemical emulsions into the vascular system to increase the oxygen-carrying capacity of the blood; (3) modifying oxygen transport or delivery by using agents that affect hemoglobin; (4) using drugs that increase tumor blood perfusion; or (5) a more recent approach of decreasing the oxygen consumption rate of the “nonhypoxic” cell population, thereby increasing the oxygen diffusion distance. Many experimental studies have also demonstrated that hypoxic cells can be preferentially destroyed by bioreductive drugs that are active under reduced oxygen conditions or, again, using hyperthermia. Each of these hypoxic-cell cytotoxins improve the radiation response of tumors. Another group of agents with the potential to enhance radiation damage are vascular targeting agents. These include drugs that inhibit angiogenesis, the process by which tumors develop their own vascular supply, or agents that preferentially damage the already established tumor vessels. More recent studies indicate the potential of combining radiation with immunotherapy. Radiation protectors fall into several categories based on the timing of their administration in relation to radiotherapy. There are the true “radiation protectors,” in particular, sulfhydryl compounds, which are used as a prophylactic strategy and administered before radiotherapy. They primarily appear to interact with radicals that are formed as a result of radiation exposure. Another group consists of “radiomitigators” that reduce the effects on normal tissues before the emergence of symptoms if given during or shortly after radiotherapy. Finally, there are “therapeutic agents,” which are administered

after radiotherapy to treat symptoms that have already developed, especially fibrosis. Radiosensitization by conventional chemotherapeutic agents (e.g., cisplatin, 5-fluorouracil, and mitomycin C), halogenated pyrimidines (e.g., 5-bromodeoxyuridine and 5-iododeoxyuridine), and hyperthermia are discussed in detail elsewhere in this book. In this chapter, the focus will be on hypoxic cell modifiers, immunotherapy, vascular targeting drugs, and radioprotectors.

THE HYPOXIA PROBLEM Importance of Oxygen In 1909, Gottwald Schwarz,1 in a simple but elegant experiment, demonstrated that the radiation response of skin was markedly decreased if the blood flow in the irradiated area was reduced by compression. Although he did not state that the phenomenon was the result of a lack of oxygen, his study was probably the first radiobiologically oriented clinical study implicating the importance of environmental parameters in the outcome of radiotherapy. This finding was used to introduce the concept of “kompressionsanämie” by which the skin was made anemic, thereby allowing a higher dose to be given to deeply situated tumors. Following the work of Schwarz, in 1910, Müller2 reported that tissues in which the blood flow was stimulated by diathermia showed a more prominent response to radiation. This early study not only demonstrated the importance of oxygen supply in radiotherapy but it was also the first clinical approach showing how resistance could be overcome by using hyperthermia. Subsequently, sporadic clinical and experimental observations indicated the importance of sufficient blood supply to secure an adequate radiation response. These observations led Gray et al.3 in the early 1950s to postulate that oxygen deficiency (hypoxia) was a major source of radiation resistance. The first clinical indication that hypoxia existed in tumors was made around the same time by Thomlinson and Gray4 when, from histological observations in carcinoma of the bronchus, they reported seeing viable tumor regions surrounded by vascular stroma from which the tumor cells obtained their nutrients and oxygen. As the tumors grew, the viable regions expanded and areas of necrosis appeared at the center. The thickness of the resulting shell of viable tissue was found to be between 100 and 180 μm, which was within the same range as the calculated diffusion distance for oxygen in respiring tissues. It suggested that as oxygen diffused from the stroma, it was consumed by the cells and, although those beyond the diffusion distance were unable to survive, the cells immediately bordering the necrotic area might be viable yet hypoxic. In 1968, Tannock5 described an inverted version of the Thomlinson and Gray picture, with functional blood vessels surrounded by cords of viable tumor cells outside of which were areas of necrosis.

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CHAPTER 3 100

Dose-Response Modifiers in Radiation Therapy

49

Response (%)

The current use of chronic or acute to explain hypoxia in tumors is probably an oversimplification of the real situation. Chronic hypoxia generally refers to prolonged and reduced oxygen concentrations that influence radiation response, but there is evidence that oxygen concentrations that are higher, yet below normal physiological levels, are often found.10 Furthermore, reduced perfusion can be both partial and total.11 While cells under the former condition would be oxygen deprived, with the latter they would be starved of oxygen and nutrients. As such, their survival and response to therapy would be expected to be different. Tumor Normal tissue

0

Radiation dose (Gy) Fig. 3.1 Schematic illustration of the proportion of patients cured and patients with normal tissue complications as a function of the total radiation dose received.

Diffusion-limited chronic hypoxia Perfusion-limited acute hypoxia

Transiently Functional occluded blood vessel blood vessel Fig. 3.2 Schematic representation of the interrelationship between tumor cells and the vascular supply. On the left, cells are seen growing as a “corded” structure around a functional vessel from which the cells receive their oxygen supply. As oxygen diffuses out from the vessel, it is used up. Thus, the outermost viable cells (shown by shading) are oxygen deprived or chronically hypoxic. A similar arrangement is seen on the right; here, however, flow through the vessel is transiently stopped, thus making all of the cells oxygen deprived. (From Horsman MR. Measurement of tumor oxygenation. Int J Radiat Oncol Biol Phys. 1998;42:701–714.)

This “corded” structure, illustrated in Fig. 3.2, is the more typical picture found in most solid tumors.6 It arises because the tumor blood vessels, which are derived from the normal tissue vessels by a process of angiogenesis, are inadequate to meet the needs of the rapidly growing tumor cells. This hypoxia is more commonly called chronic hypoxia. It was also suggested that hypoxia in tumors could be acute in nature.7 However, it was not until later that Chaplin et al.8 were able to confirm the existence of acutely hypoxic cells in tumors and demonstrate that these cells were the result of transient stoppages in tumor blood flow (see Fig. 3.2). To date, these temporary cessations in blood flow have been observed in mouse and rat tumors as well as human tumor xenografts, with anywhere from around 4% to 8% of the total functional vessels involved,9 although the exact causes of these stoppages are not known.

Evidence for Hypoxia in Tumors In experimental tumors, it is not only relatively easy to identify hypoxia but one can also quantitatively estimate the percentage of cells that are hypoxic. Three major techniques are routinely used.12 These are the paired survival curve, the clamped tumor growth delay, and the clamped tumor control assays. All involve a comparison of the response of tumors when irradiated under either normal air-breathing conditions or when tumors are artificially made hypoxic by clamping. Using these procedures, hypoxia has been directly identified in most animal solid tumors, with the values ranging from less than 1% to well more than 50% of the total viable cell population.12 None of these procedures can be applied to the clinical situation, however. One therefore must rely on indirect techniques. Estimating hypoxia in human tumors has generally involved the use of indirect methods.13 Some of the earliest attempts focused on the vascular supply because it was only via the tumor vasculature that oxygen could be delivered. The endpoints included immunohistochemical estimates of intercapillary distance, vascular density, and distance from tumor cells to the nearest blood vessel14–16; oxyhemoglobin saturation determined using cryophotometry or noninvasively with near-infrared spectroscopy or magnetic resonance imaging (MRI)17–19; or measurements of tumor perfusion using MRI, computed tomography (CT), or positron emission tomography (PET).20–22 With the finding that hypoxia could upregulate gene/protein expression, it was suggested that endogenous markers could be used to identify hypoxia.23 The principal markers have included hypoxia-inducible factor 1 (HIF-1), carbonic anhydrase IX (CAIX), the glucose transporters GLUT-1 and GLUT-3, and osteopontin (OPN).24–27 Attempts to relate their expression levels with established hypoxia assays have reported mixed results, which is not entirely unexpected since the expression of many endogenous markers can be regulated by factors other than hypoxia.28 A more reliable hypoxia indicator involves combining endogenous markers in a gene signature.29–34 Although such signatures have typically been derived from cell lines exposed to hypoxia versus normoxia, they have been further developed in clinical material through associations with more direct indicators of hypoxia or outcome.29–34 More popular techniques for identifying hypoxia involve measurements of the binding of exogenous markers.13 This can be achieved following immunohistological analysis of biopsied sections using, for example, pimonidazole or EF5.35,36 It can also be done noninvasively with PET, single-photon emission computed tomography (SPECT), or MRI analysis of radioactively labeled nitroimidazoles (i.e., [18F] labeled misonidazole or FAZA; [123I] labeled azomycin arabinoside), or PET imaging of [60–64Cu]-ATSM.37–40 The most direct method involves determining oxygen partial pressure (PO2) distributions with polarographic electrodes.41–46 How this approach can be used to detect hypoxia and relate the measurements to radiotherapy outcome is illustrated in Fig. 3.3. In this international multicenter study in head and neck cancer patients, their tumor’s PO2 was measured before radiation therapy and was found to correlate with overall survival in that those patients with lower tumor oxygenation status did significantly worse.47

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Scientific Foundations of Radiation Oncology

Probably the best evidence for the existence of hypoxia in human tumors comes from the large number of clinical trials in which hypoxic modification has shown some benefit.48 The latter situation constitutes a circular argument: if hypoxic modification shows an improvement, then hypoxic clonogenic cells must have been present in tumors. However, it is likely that even tumors with the same histological makeup and of the same type have substantial heterogeneity with respect to the extent of hypoxia. It must be admitted that today, a century after the first clinical description, the importance of hypoxia and its influence on the outcome of radiotherapy is still the subject of substantial debate. We will now discuss in detail how the different

hypoxic modifiers have been used to modify the radiation dose response of tumors.

OVERCOMING TUMOR HYPOXIA High-Oxygen-Content Gas Breathing Because the oxygen supply to tumors is insufficient to meet the needs of all of the tumor cells, radiation-resistant hypoxia develops. Therefore, an obvious solution to improving the tumor’s radiation response would be to increase the oxygen supply. This has been tried, both experimentally and clinically, by simply allowing the tumor-bearing host to breathe high-oxygen-content gas mixtures before and during irradiation. Early experimental studies reported that breathing either oxygen or carbogen (95% O2 + 5% CO2) could substantially enhance the response of murine tumors to radiation and that the best effect was generally seen when the gasses were inspired under hyperbaric (typically 3 atmospheres [3 atm]) rather than normobaric conditions.49,50 This is not surprising because hyperbaric conditions would be expected to saturate the blood with oxygen more than normobaric conditions. However, later studies indicated that the radiosensitizations produced by normobaric oxygen or carbogen were quite substantial.51–53 Because it is quicker and easier to breathe gas under normobaric conditions, the use of cumbersome, expensive, and complex hyperbaric chambers is probably not necessary. Clinically, the use of high-oxygen-content gas breathing, specifically under hyperbaric conditions, was introduced relatively early by Churchill-Davidson.54 Most trials were fairly small and suffered from the applications of unconventional fractionation schemes, but it appeared that the effect of hyperbaric oxygen was superior to radiotherapy given in air, especially when few and large fractions were applied.54–56 In the large, multicenter clinical trials conducted by the British Medical Research Council (Table 3.1), the results from both uterine cervix and advanced head and neck tumors showed a significant benefit in local tumor control and subsequent survival.55,57–59,60 The same findings were not observed in bladder cancer nor were they seen in a number of smaller studies.60 In retrospect, the use of hyperbaric oxygen was stopped somewhat prematurely. This was partly the result of the introduction of hypoxic radiosensitizers and partly because of problems with patients’ compliance. It has been claimed that hyperbaric treatment caused significant suffering, but the discomfort associated with such a treatment

100

Overall survival (%)

80

60

40

20

0 0

1

2

3

Follow-up (years) Fig. 3.3 Oxygen levels were measured with Eppendorf electrodes before radiation therapy in 397 patients with squamous cell carcinomas of the head and neck. Tumors were stratified by whether the fraction of pO2 values ≤2.5 mm Hg (HP2.5) were above or below the median value for the whole group (i.e., 19%). The lines show Kaplan-Meier estimates of actuarial overall survival probability for patients with less hypoxic tumors (HP2.5 ≤ 19%; violet line) compared with more hypoxic tumors (HP2.5 > 19%; blue line), p = 0.006. (From Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol. 2005;77:18–24.)

TABLE 3.1

Multicenter Randomized Trials With Hyperbaric Oxygen No. of Patients

Endpointa

HBO

Head and Neck Carcinoma MRC 1st trial (1977)

294

Control (5 y)

53%

30% (p < 0.01)

MRC 2nd trial (1986)

106

Control (5 y)

60%

41% (p < 0.05)

Uterine Cervix Carcinoma MRC (1978)

320

Control (5 y)

67%

47% (p < 0.001)

Bronchogenic Carcinoma MRC; 60 Gy/40 fx (1978)

51

Survival (2 y)

15%

8% (NS)

MRC; 36 Gy/6 fx (1978)

123

Survival (2 y)

25%

12% (p < 0.05)

Carcinoma of the Bladder MRC (1978)

241

Survival (5 y)

28%

30% (NS)

Site and Study

a

Air

60

Endpoints were control (locoregional control) or survival. See Overgaard for additional information. fx, Fractions; MRC, Medical Research Council; NS, not significant.

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CHAPTER 3 must be considered minor compared to the often life-threatening complications associated with chemotherapy, which is used with less restrictive indications. The use of high-oxygen-content gas breathing under normobaric conditions to radiosensitize human tumors has also been tried clinically, but it failed to show any dramatic improvement.61–63 In the most recent study, this may have been the result of size limitation.63 In previous studies, it may have been caused by the failure to achieve the optimum preirradiation gas breathing time.61,62 Experimental studies have shown that the amount of time is critical for the enhancement of radiation damage and that it can vary from tumor to tumor.50–52,64

Hypoxic Cell Radiosensitizers An alternative approach to the hypoxia problem is the use of chemical agents that mimic oxygen and preferentially sensitize the resistant population to radiation. The advantage of these drugs over oxygen is that they are not rapidly metabolized by the tumor cells through which they diffuse; thus, the drugs can penetrate farther than oxygen and reach all of the tumor cells. In the early 1960s, researchers found that the efficiency of radiosensitization was directly related to electron affinity,65 which ultimately led to in vitro studies demonstrating preferential radiosensitization of hypoxic cells by highly electron-affinic nitroaromatic compounds.66,67 Several of these compounds were later shown to be effective at enhancing radiation damage in tumors in vivo.68 As a result, they underwent clinical testing.

TABLE 3.2

Dose-Response Modifiers in Radiation Therapy

51

The drugs reaching clinical evaluation include metronidazole, misonidazole, benznidazole, desmethylmisonidazole, etanidazole, pimonidazole, nimorazole, ornidazole, sanazole, and doranidazole. Initial clinical studies were done with metronidazole in brain tumors, followed by a boom in clinical trials exploring the potential of misonidazole as a radiosensitizer in the latter part of the 1970s.60,68,69 The results from the multicenter randomized trials are summarized in Table 3.2. Most of the trials with misonidazole were unable to generate any significant improvement in radiation response, although a benefit was seen in some trials, especially the second Danish Head and Neck Cancer study (DAHANCA 2), which found a highly significant improvement in the stratification subgroup of pharynx tumors but not in the prognostically better glottic carcinomas.70 The overall impression of the “misonidazole era” was a prolongation of the inconclusive experience from the hyperbaric oxygen trials, namely, that the problems related to hypoxia had not been ruled out indefinitely.68 Therefore, the search for more efficient or less toxic hypoxic sensitizers continues. Furthermore, the experience from the misonidazole trials has been taken into account to select a more homogeneous tumor population in which hypoxia is more likely to be present. Results from subsequent randomized trials with other nitroaromatic compounds have been conflicting. The European pimonidazole trial in uterine cervix cancer was disappointing,71 whereas the two other multicenter trials in head and neck cancer, using etanidazole, showed no benefit.68,72 On the other hand, studies with the low toxic drug

Multicenter Randomized Trials With Nitroimidazoles

Site and Study

No. of Patients

Sensitizer

Endpointa

RT and Sensitizer

RT Alone

Head and Neck Carcinoma DAHANCA 2 (1989)

626

MISO

Control (5 y)

41%

34% (p < 0.05)

MRC (1984)

267

MISO

Control (>2 y)

40%

36% (NS)

EORTC (1986)

163

MISO

Control (3 y)

52%

44% (NS)

RTOG (1987)

306

MISO

Control (3 y)

19%

24% (NS)

RTOG 79-04 (1987)

42

MISO

Control (2 y)

17%

10% (NS)

DAHANCA 5 (1992)

414

NIM

Control (5 y)

49%

34% (p < 0.002)

RTOG 85-27 (1995)

500

ETA

Control (2 y)

39%

38% (NS)

European multicenter (1991)

374

ETA

Control (2 y)

57%

58% (NS)

Uterine Cervix Carcinoma Scandinavian study (1989)

331

MISO

Control (5 y)

50%

54% (NS)

MRC (1984)

153

MISO

Control (>2 y)

59%

58% (NS)

RTOG (1987)

119

MISO

Control (3 y)

53%

54% (NS)

MRC (1993)

183

PIM

Control (4 y)

64%

80% (p < 0.01)

Glioblastoma Scandinavian study (1985)

244

MISO

Survival

10

10 (NS)

MRC (1983)

384

MISO

Survival

8

9 (NS)

EORTC (1983)

163

MISO

Survival

11

12 (NS)

RTOG (1986)

318

MISO

Survival

11

13 (NS)

Bronchogenic Carcinoma RTOG (1987)

117

MISO

Survival

7

7 (NS)

RTOG (1989)

268

MISO

Survival

7

8 (NS)

a

Endpoints were control (locoregional control) and survival (median survival in months). See Overgaard68 for additional information. DAHANCA, Danish Head and Neck Cancer study; EORTC, European Organization for Research and Treatment of Cancer; ETA, etanidazole; MISO, misonidazole; MRC, Medical Research Council; NIM, nimorazole; NS, not significant; PIM, pimonidazole; RT, radiation therapy; RTOG, Radiation Therapy Oncology Group.

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52

SECTION I

Scientific Foundations of Radiation Oncology

nimorazole given to patients with supraglottic and pharynx carcinomas (DAHANCA 5) showed a highly significant benefit in terms of improved locoregional tumor control and disease-free survival rates (Fig. 3.4),73 thereby confirming the result of the DAHANCA 2 study. More recent trials with the 3-nitrotriazole compound, sanazole (AK-2123), in uterine cervical cancer74 and doranidazole in pancreatic cancer75 demonstrated significant improvements in both local tumor control and overall survival. The potential benefit of using hypoxic radiosensitizers to improve radiotherapy is probably best illustrated from a recent meta-analysis of randomized clinical studies in squamous cell carcinoma of the head and neck.76 These results are summarized in Fig. 3.5 and clearly showed

100

Nimorazole (219 patients) 49% Placebo (195 patients) 33%

Disease-specific survival (%)

Locoregional control (%)

100

that radiosensitizer modification of tumor hypoxia significantly improved locoregional tumor control and overall survival, with odds ratios of 0.71 and 0.87, respectively. Although the overall observed gains were small (5%–10% for local control and 0%–6% for survival), they are actually relevant. We can conclude that the nonsignificant outcome of most clinical trials (see Table 3.2) is not the result of a biological lack of importance of hypoxia, but in most cases is considered a consequence of poor clinical trials methodology with an overly optimistic study design and an expected treatment gain that goes far beyond what is reasonable. Overall, the results with nitroimidazoles add to the general consensus that if a nontoxic hypoxic modification can be applied, then such treatments may certainly be relevant as a baseline therapy together

80

60

40

20

Nimorazole (219 patients) 52% Placebo (195 patients) 41%

80

60

40

20 p = 0.01

p = 0.002 0

0 0

12 24 36 48 Months after treatment

60

0

12 24 36 48 60 Months after treatment Fig. 3.4 Actuarial estimated locoregional tumor control and disease-specific survival rate in patients randomized to receive nimorazole or placebo in conjunction with conventional radiotherapy for carcinoma of the pharynx and supraglottic larynx. (From Overgaard J, Sand Hansen H, Overgaard M, et al. A randomised double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer study [DAHANCA] protocol 5-85. Radiother Oncol. 1998;46:135–146.)

Head and Neck Cancer–Meta-Analysis–Summary Events/Total Endpoint Locoregional control Disease-specific survival Overall survival Distant metastasis Radiotherapy complications

Hypoxic Modification

Control

1203/2406 1175/2335 1450/2312 159/1427 307/1864

1383/2399 1347/2329 1519/2305 179/1391 297/1822

Odds Ratio

Risk Reduction

NNT**

0.71 (0.63–0.80) * 0.73 (0.64–0.82) 0.87 (0.77–0.98) 0.87 (0.69–1.09) 1.00 (0.82–1.23)

8% (5–10%) * 7% (5–10%) 3% (0–6%) 2% (–1–4%) 0% (–3–2%)

13 14 31 57 >>

Odds Ratio and 95% Cl

0.5 Hypoxic modification better

1

2 Control better

Meta-analysis–hypoxic modification of radiotherapy in HNSCC

* 95% confidence interval. ** Numbers of patients needed to treat to achieve benefit in one patient. Fig. 3.5 Meta-analysis of hypoxic modification of radiotherapy in squamous cell carcinomas of the head and neck. Results show summary data from 32 randomized trials (including 4805 patients). Patients received radiation alone or radiation with a hypoxic modifier that included high-oxygen-content gas breathing under normobaric or hyperbaric conditions, or a hypoxic radiosensitizer. HNSCC, Head and neck squamous cell carcinoma. (Modified from Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck—a systemic review and meta-analysis. Radiother Oncol. 2011;100:22–32.)

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CHAPTER 3

Dose-Response Modifiers in Radiation Therapy

53

with radiotherapy for cancers such as advanced head and neck cancer. Such a strategy has been adopted in Denmark, where nimorazole has become part of the standard radiotherapy treatment in cancer of the head and neck.

or using antilipidemic drugs.88 Although each of these approaches has been shown to improve the oxygenation status of experimental tumors or enhance radiation damage, none has yet reached controlled clinical testing. Thus, their potential usefulness in the clinic is uncertain.

Dose Modification Based on Hemoglobin

Changing Oxygen Consumption

One of the major factors influencing the delivery of oxygen to tumors is the concentration of hemoglobin. Therefore, it is not surprising that low hemoglobin concentration in general has a negative impact on tumor radiation response. In a review of 51 studies involving 17,272 patients, the prognostic relationship between hemoglobin concentration and local tumor control was analyzed. Of these, 39 studies (14,482 patients) showed a correlation, whereas only 12 (2790 patients) did not.77 However, the relationship between hemoglobin concentration and tumor oxygenation status is not clear because a large (397 patients) international multicenter study in head and neck cancer failed to show a correlation between these parameters.47 Although a well-documented causal relationship between hemoglobin concentration, tumor oxygenation, and response to radiotherapy has not been shown, it is likely that such a relationship does exist. Thus, there is a rationale for investigating the possibility of improving the outcome of radiotherapy in relevant tumor sites in patients with low hemoglobin concentration given curative radiotherapy. This was investigated in two randomized trials using transfusion to raise hemoglobin levels.73,78 Despite an initial positive report from the Canadian trial in uterine cervix carcinoma, both studies concluded that the use of such transfusions did not significantly improve treatment outcome. In the DAHANCA 5 study, transfusion was given several days before radiotherapy and adaptation may have occurred. Based on preclinical data, it was hypothesized that any increase in tumor hypoxic fraction induced by anemia will be only transient, with tumors adapting to the lowered oxygen delivery79; transfusing anemic animals decreased tumor hypoxia, but this effect also was only transient and the tumors were able to adapt to the increased oxygen level. This suggests that, when correcting for anemia, it may not necessarily be the final hemoglobin concentration by itself that is important. Rather, an increasing hemoglobin concentration occurring at the time when the tumors are regressing during radiotherapy may be more likely to result in an increased oxygen supply to tumors and a subsequent improvement in response to radiotherapy. Increasing hemoglobin concentration by stimulation with erythropoietin (EPO), a hormone normally secreted from the kidney in response to tissue hypoxia and low serum levels, has also been investigated. Several preclinical studies have shown that the induction of anemia in animals could be corrected by serial injection with EPO and that this EPO treatment also overcame the anemia-induced radiation resistance.80,81 The concept of using EPO to correct for anemia has also been tested in several clinical trials. However, although low hemoglobin can be effectively and safely improved by EPO,82,83 patients treated with radiation and EPO had a poorer outcome than the control arms not treated with EPO.84 Although this clearly raises concerns about the use of such agents to improve radiation therapy through a manipulation of hemoglobin levels, it does not make the concept of having a high hemoglobin concentration during radiation therapy an irrelevant issue. Other “hemoglobin-related” methods for improving tumor oxygenation have been investigated.85 These include the use of artificial blood substances, such as perfluorocarbons,86 which are small particles capable of carrying more oxygen than hemoglobin, or by manipulating the oxygen unloading capacity of blood by modifying the oxyhemoglobin dissociation curve. This can be achieved either by increasing the red blood cell 2,3-DPG content,87 2,3-DPG being one of the most important allosteric factors controlling the hemoglobin-oxygen dissociation curve,

A novel approach that is currently receiving attention focuses on reducing tumor hypoxia by decreasing the oxygen consumption of cells close to blood vessels and thereby increasing the oxygen diffusion distance, which makes more oxygen available to the hypoxic cells. This may be achieved using the drug metformin, which has undergone extensive clinical evaluation for the treatment of diabetes and has been linked to decreased rates of certain types of cancer.89 One preclinical study has clearly shown that high doses of metformin can decrease cellular oxygen consumption in vitro.90 Additional in vivo data from that study demonstrated that metformin could improve tumor radiation response, but whether or not this was the direct result of reduced oxygen consumption is not entirely known. Further studies in this area are clearly warranted.

Dealing With the Problem of Fluctuating (Acute) Hypoxia Although several of the procedures used to combat radiation resistance caused by hypoxic cells have met with some success, the results are far from satisfactory. A possible explanation is that most of the procedures used clinically seem to operate primarily against diffusion-limited chronic hypoxia and have little or no influence on fluctuating hypoxia, which is caused by transient variations in tumor blood flow.9 Experimental studies have clearly demonstrated that the vitamin B3 analog, nicotinamide, can enhance radiation damage in a variety of murine tumor models using both single and fractionated treatments (Fig. 3.6).9 The enhancement of radiation damage appears to depend on the tumor type, drug dose, and time of irradiation after drug administration.9 The drug can also enhance radiation damage in certain normal tissues, but generally the effects are less pronounced than those seen in tumors.9 Nicotinamide seems to primarily prevent or reduce the transient fluctuations in tumor blood flow that normally lead to the development of acute hypoxia.9 This finding led to the suggestion that the optimal approach would be to combine nicotinamide with treatments that specifically overcome chronic hypoxia. This was subsequently demonstrated with hyperthermia,91 perfluorochemical emulsions,92 and carbogen breathing.64,93–95 Combining nicotinamide with carbogen has undergone testing in a number of European clinical studies. The results in head and neck96 and bladder cancer97 demonstrated an improved response to radiation therapy.

Bioreductive Drugs The early preclinical studies with electron-affinic radiosensitizers showed that these agents, which were relatively nontoxic to cells under normal oxygenated conditions, were reduced to a more toxic form under hypoxia.98 This led to the development of various bioreductive drugs that preferentially killed the radiation-resistant hypoxic tumor cell population. These drugs can be divided into three major groups, as illustrated in Fig. 3.7. They are the quinones, nitroaromatics, and N-oxides.99 The quinine derivative, mitomycin C (MMC), is probably the prototype bioreductive drug.100 It has been used clinically for many years as a chemo-radiosensitizer, long before it was realized that it had preferential effects against hypoxic cells. It is activated by bioreduction to form products that cross-link DNA and, therefore, produce cell killing. Several randomized clinical trials in patients with squamous cell carcinoma of the head and neck were undertaken, specifically using MMC to counteract the effects of hypoxia, but not all showed a benefit.101–105

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54

SECTION I

Scientific Foundations of Radiation Oncology

100

100 Single Rad Nic + Rad

Tumor control (%)

80

80

60

60

40

40

20

20

Fractionated Rad Nic + Rad

0

0 80 20 40 60 80 100 Radiation dose (Gy) Fig. 3.6 Effect of nicotinamide (500–1000 mg/kg) on local tumor control measured as a function of the total radiation dose given either as a single treatment to C3H mammary carcinomas or in fractionated schedule to the carcinoma NT. The drug was i.p. injected 30 to 60 minutes before irradiation. (Modified from Horsman MR, Chaplin DJ, Overgaard J. Combination of nicotinamide and hyperthermia to eliminate radioresistant chronically and acutely hypoxic tumor cells. Cancer Res. 1990;50:7430–7436; and Kjellen E, Joiner MC, Collier JM, et al. A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated x-ray treatments. Radiother Oncol. 1991;22:81–91.) 0

20

40

60

1

Surviving fraction

10-1 10-2 10-3

10-4

10-5

Mitomycin C 10-4

10-3

RSU-1069

Tirapazamine

10-2

10-1 10-3 10-2 10-1 1 10 10-3 10-2 10-1 1 10 Drug concentration (mmol/dm3) Fig. 3.7 Survival of mammalian cells exposed to mitomycin C, RSU-1069, or tirapazamine under aerobic (violet symbols) of hypoxic (blue symbols) conditions. (Modified from Stratford IJ, Stephens MA. The differential hypoxic cytotoxicity of bioreductive agents determined in vitro by the MTT assay. Int J Radiat Oncol Biol Phys. 1989;16:973–976; and Hall EJ. Radiobiology for the Radiobiologist. 4th ed. Philadelphia: J.B. Lippincott; 1994.)

This may not be surprising when one considers that MMC actually has a small differential killing effect between aerobic and hypoxic cells (see Fig. 3.7) and was administered only once or twice during the entire course of radiotherapy. Attempts to find more efficient quinones have been undertaken; to that end, porfiromycin, RH1, and EO9 were developed.99 Of these, EO9 is currently being evaluated in a Phase II trial in bladder cancer.

The finding that misonidazole was preferentially toxic toward hypoxic cells led to numerous efforts to find other nitroimidazoles that were better. The first drug developed was RSU-1069 (see Fig. 3.7). This compound has the classic 2-nitroimidazole radiosensitizing properties but also an aziridine ring at the terminal end of the chain, which gave the molecule substantial potency as a hypoxic cell cytotoxin both in vitro and in vivo.106 In large-animal studies, it was found to cause

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CHAPTER 3 gastrointestinal toxicity. Therefore, a less toxic prodrug was developed (RB-6145), which is reduced in vivo to RSU-1069. Although this drug was found to have potent antitumor activity in experimental systems, further animal studies revealed that this drug induced blindness. This is perhaps not surprising when one realizes that the retina is hypoxic; thus, further development of this drug was halted. However, other nitro-containing compounds have been developed, including NLCQ-1, CB 1954, SN 23862, PR-104, and TH-302,99 of which the latter is currently under Phase II/Phase III clinical evaluation, albeit in combination with chemotherapy. Perhaps the most promising group of bioreductives is the organic nitroxides, of which the benzotriazene di-N-oxide, tirapazamine, is the lead compound (see Fig. 3.7). The parent moiety shows limited toxicity toward aerobic cells, but after reduction under hypoxic conditions, a product is formed that has been shown to be highly toxic and can substantially enhance radiation damage to tumors in vivo.107 Most clinical studies have involved combining tirapazamine with chemotherapy, although there have been a few trials with radiation with or without chemotherapy.99 The results from the Phase II trials generally showed promise; however, in the few randomized trials that have been completed, the results were somewhat disappointing. It has now been suggested that the benefit of tirapazamine might be achieved if one could select patients who had hypoxic tumors before treatment. Other N-oxides currently under development include chlorambucil N-oxide, SN30000, and AQ4N (Banoxantrone), the latter being combined with radiation in a number of clinical trials.99

RADIOTHERAPY AND IMMUNOTHERAPY Although radiotherapy is generally used for local-regional control of solid malignancies, the cellular damage produced by radiation results in the release of tumor antigens that could stimulate the host immune system to attack both the irradiated tumor and distant metastases.108 The latter mechanism is generally known as an abscopal effect.109 Unfortunately, the abscopal effect associated with radiation alone is considered a rare clinical event.110 However, numerous preclinical studies have shown that an abscopal effect can be observed if radiation is combined with various cancer immunotherapy strategies.108,111,112 This is especially true for immunotherapies that target immunosuppressive checkpoint receptors CTLA-4 or PD-1 and its ligand PD-L1. CTLA-4 is an inhibitory molecule present on T-cells that inhibits the development of an active immune response by acting primarily at the level of T-cell development and proliferation.113 Blocking CTLA-4 (i.e., using ipilimumab) releases the inhibitory effect leading to unrestricted T-cell activation.114 PD-1 is a receptor expressed in activated T-cells; the interaction between PD-1 and its ligand PD-L1 is an innate mechanism to reduce autoimmunity and promote tolerance.115 Tumor cells that express PD-L1 interact with PD-1 positive tumor-infiltrating lymphocytes, which helps reduce the antitumor response. Blocking PD-1/PD-L1 interaction (i.e., using nivolumab and pembrolizumab) can restore antitumor immunity.116 These approaches have resulted in improved outcome with CTLA-4 blockade in malignant melanoma117,118 and with PD-1/PD-L1 blockade in non–small cell lung cancer and renal cell cancer.115 Other cancer types—including bladder, head and neck, and ovarian—are under clinical evaluation.115 Clinical evaluation of radiation and immunomodulators is ongoing.119–121 Yet, it is unclear as to the timing and sequencing of the radiation and immunomodulator, or the radiation dose or fractionation schedule, necessary to induce an optimal effect. One preclinical study suggested that although a large single radiation dose of 20 Gy induced growth inhibition of the irradiated tumor, it did not induce an abscopal effect.122 This could be attributed to large single doses (around 15 Gy and above) increasing splenic Treg cells123 that have an immunosuppressive

Dose-Response Modifiers in Radiation Therapy

55

effect.124 However, administering 15 Gy as 5 × 3 Gy produced an identical increase in Treg cells,123 yet a similar 8 × 3 Gy treatment combined with anti-CTLA-4 antibody resulted in a significant abscopal effect.122 The presence of tumor hypoxia may further complicate this issue since there is evidence that hypoxia in tumors can have a negative effect on immunogenicity by altering the function of immune cells and/or increasing resistance of tumor cells to the cytolytic activity of immune effectors.125,126 This would suggest that when the optimal combination of radiation and immunotherapy is established, it might further benefit from the inclusion of some form of hypoxic modification in the treatment schedule.

VASCULAR TARGETING AGENTS Angiogenesis Inhibitors The tumor’s vascular supply plays a critical role in determining the tumor’s microenvironmental factors that influence radiotherapy.127 This vasculature develops from the normal tissue vessels via the process of angiogenesis,128 which is a highly complex process triggered by the release of specific growth factors from the tumor cells.129 These growth factors initiate a series of physical steps, including local degradation of the basement membrane surrounding capillaries, invasion of surrounding stroma by the endothelial cells in the direction of the angiogenic stimulus, proliferation of the endothelial cells, and, finally, organization of the endothelial cells into three-dimensional structures that connect with other similar structures to form the new blood vessel network.129 The importance of this process makes it an attractive target for therapy; numerous approaches for inhibiting the various steps in the angiogenic process have been tested in preclinical models.130,131 Many of these therapies have now moved into clinical evaluation.132 Of these therapies, the antivascular endothelial growth factor (anti-VEGF) antibody bevacizumab (Avastin) has been shown to improve outcome in a number of chemotherapy-based trials.133 Preclinical studies using rodent and human tumor xenografts show that certain angiogenesis inhibitors can be effectively combined with radiation to improve tumor response (Table 3.3).131 As a result, a limited number of clinical studies have been initiated combining certain angiogenesis inhibitors with radiation therapy.132

List of Vascular Targeting Agents That Have Been Combined With Radiation

TABLE 3.3

Angiogenesis Inhibitors

Vascular Disrupting Agents

Suramin TNP-470 Angiostatin Endostatin Arginine deiminase Thrombospondin Thalidomide Anginex Anti-VEGF(R) antibodies SU 5416 SU 6668 SU 11248 SU 11657 PTK787/ZK 222584 ZD 6474 Metastat

Hyperthermia Photodynamic therapy Colchicine Tumor necrosis factor Arsenic trioxide Flavone acetic acid 5,6-dimethylxanthenone acetic acid Combretastatin A-4 phosphate AVE 8062 ZD 6126 OXi4503 MN-029 NPI-2358

See Horsman and Siemann131 for additional information.

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56

SECTION I

Scientific Foundations of Radiation Oncology

The consensus opinion is that the improvement in radiation response found in preclinical studies is the consequence of normalization of the tumor vasculature, resulting in a decrease in tumor hypoxia.134 Although there are certainly preclinical studies showing an improved tumor oxygenation status with such treatment, there are just as many studies showing no change and even a decrease in tumor oxygenation.131 These findings not only make it unclear as to the role of vessel normalization in influencing the combination of angiogenesis inhibitors with radiation, but they also indicate that timing and sequencing of the two modalities may be critical for an optimal benefit.

RADIATION PROTECTORS

Vascular Disrupting Agents An alternative approach for targeting tumor vasculature involves using agents that can damage the already established tumor vessels.130,131 This is not a new concept; it was first demonstrated with the tubulin-binding agent colchicine back in the 1940s.135 Since then, a number of vascular disrupting agents (VDAs) have been proven capable of preferentially damaging tumor vessels, leading to a reduction in tumor perfusion that results in an increase in tumor ischemia and necrosis, subsequently producing an inhibitory effect on tumor growth.131 The VDAs include physical treatments (e.g., hyperthermia, photodynamic therapy, and even radiation), chemotherapeutic agents (e.g., tumor necrosis factor, vinca alkaloids, and arsenic trioxides), and small-molecule agents (e.g., flavonoid derivatives such as 5,6-dimethylxanthenone-4-acetic acid; tubulin-binding drugs such as Combretastatin A-4 phosphate). As with the angiogenesis inhibitors, several of the VDAs have been combined with radiation (see Table 3.3), and significant improvements in response have been seen in preclinical models.131 This is illustrated in Fig. 3.8 using a C3H mammary carcinoma grown in CDF1 mice. The radiation dose needed to control 50% of treated animals (±95% confidence intervals [CI]) following single-dose radiation treatment alone was found to be 53 Gy (95% CI, 51–56). This was significantly reduced (Chi-squared test; p < 0.05) to 46 Gy (95% CI, 42–49) when tumors were locally irradiated. However, 30 minutes later, mice were given a single intraperitoneal injection of a large but nontoxic dose of Combretastatin A-4 phosphate (CA4P), the lead VDA in clinical evaluation.131,133 On its own, in this tumor model, such a drug dose will slow

Sulfhydryl-Containing Compounds More than 50 years ago, it was realized that certain amino acids, glutathione, and ascorbic acid were able to modulate radiation-induced inactivation of biological material. Based on those observations, Patt et al. investigated the effect of treating mice with the thiol-containing amino acid, cysteine.136 They found that administering this compound to mice before whole-body irradiation resulted in a remarkable increase in animal survival (Fig. 3.9). In contrast, no effect was observed when cysteine was given after irradiation. During the Cold War, this finding led to a large research program at the Walter Reed Army Institute of Research aimed at developing a drug that could protect soldiers from nuclear weapons.137 Numerous sulfhydryl-containing substances with substantial radioprotective properties were detected, but only WR-2771 (amifostine) was found to exhibit acceptable toxicity. The idea of using amifostine in oncology arose when preclinical studies, performed mainly in the 1970s and 1980s, suggested a selective protection of normal tissue from damage induced not only by irradiation but also from chemotherapy.138,139 Despite these findings, the interest in amifostine over the years has waxed and waned, although this interest was boosted by commercialization of the drug, US Food and Drug Administration (FDA) approval, and the establishment of authoritative guidelines.140 The lack of interest was probably related to the fact that there is no fail-safe modification of traditional radiotherapy.141 Many normal tissues are dose limiting; therefore, evaluating the therapeutic benefit of a radioprotector requires either that the protector have absolute normal

100

Moist desquamation (%)

100

Tumor control (%)

the growth of the tumors by only about 2 days. The enhancement of tumor radiation damage is known to be time and schedule dependent, with the greatest effect seen when the drug is given within a few hours after irradiating.131 It is also tumor specific, with no enhancement of radiation response seen in normal tissues. This has been shown for CA4P in acutely responding normal skin (see Fig. 3.8) or late-responding bladder and lung.131 These differences between the tumor and normal tissue results are entirely consistent with the drugs’ ability to induce damage in tumor vessels but not vessels in normal tissue.131

75

50

25

0

50

25

0 20

A

75

50 Radiation dose (Gy)

80

0

30 Radiation dose (Gy)

60

B

Fig. 3.8 Effect of Combretastatin A-4 disodium phosphate (250 mg/kg) on either local control of a C3H mammary carcinoma (A) or the development of moist desquamation in the foot skin of CDF1 mice (B) following radiation treatment. Radiation was either given alone (violet symbols) or 30 minutes before intraperitoneal injection of the drug (blue symbols). (Modified from Murata R, Siemann DW, Overgaard J, et al. Interaction between Combretastatin A-4 disodium phosphate and radiation in murine tumors. Radiother Oncol. 2001;60:155–161.)

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CHAPTER 3

57

Dose-Response Modifiers in Radiation Therapy 2.00

100

Air

1.90 80

1.80

Protection factor

1.70 Survival

60

40

20

1.60 1.50 1.40 1.30 1.20 1.10

0 0

1 2 3 4 5 Time after irradiation (weeks) Fig. 3.9 Percentage of rodents surviving after whole-body irradiation with 8 Gy. Animals were either control irradiated (blue symbols) or given radiation after injection with 575 mg of cysteine (violet symbols). (Modified from Patt HM, Tyree EB, Straub RL, et al. Cysteine protection against X irradiation. Science. 1949;110:213–214.)

tissue selectivity (and, thus, fewer complications with an unchanged rate of tumor control for a given radiation dose) or, if selectivity is uncertain, that an increase in radiation dose may be needed to maintain the same rate of tumor control. However, this scenario requires that the protective effect on tumor tissues is predictable and exceeded by the protection offered to all relevant normal tissues. In addition, the “perfect” radioprotector must have an acceptable toxicity profile and must be easy to handle if generalized clinical use is to be expected with routine fractionated radiotherapy.142–144 It is not entirely clear how amifostine induces radioprotection. The drug must first undergo dephosphorylation to its active metabolite WR-1065, which is further metabolized to the disulfide WR-33278. The latter metabolite may also afford some protection, although to a lesser extent.145 Several mechanisms are involved in radioprotection, depending on the quality of the radiation. Protection against sparsely ionizing radiation, such as x-rays, is mainly obtained by scavenging of free radicals146,147; such scavenging has also been observed with glutathione, superoxide dismutase and its mimetics, and isoflavones such as genistein. Because WR-1065 and WR-33278 react with free radicals in competition with oxygen, the protection obtained by scavenging is highly influenced by oxygen tension (Fig. 3.10). Here, the protection is maximal at intermediate levels of oxygen (20%–50% oxygen in the inspired air). At higher oxygen tensions, WR-1065 is counterbalanced by excess oxygen and the protection is gradually lost. The degree of protection is also diminished at low-oxygen tensions, for which scavenging of free radicals is no longer important because the lack of oxygen by itself provides radioprotection. Additional and complex mechanisms are undoubtedly involved. Some of these may involve hypoxia created locally by direct interaction of thiols with oxygen, chemical repair by thiol donation of hydrogen, or decreased accessibility of radiolytic attack sites by induction of DNA packaging.142 Preclinical studies have shown that many tissues can be protected from radiation damage by amifostine (Table 3.4). However, the protection observed in different normal tissues is heterogeneous. Some normal tissues—such as central nervous system, which often is dose limiting in radiotherapy—are not protected because amifostine probably does not cross the blood-brain barrier.148 In other normal tissues, such as

1.00 100 10 % Oxygen in inspired gas Fig. 3.10 The variation in normal skin protection in mice given 400 mg/ kg WR-2721 30 to 45 minutes before irradiation in mice that breathed various oxygen concentrations. (Modified from Denekamp J, Michael BD, Rojas A, et al. Radioprotection of mouse skin by WR-2721: the critical influence of oxygen tension. Int J Radiat Oncol Biol Phys. 1982;8:531–534.) 1

Protection Factors Achieved by Amifostine in Different Normal Tissues and Tumors

TABLE 3.4

Tissue

Protection Factor

Salivary gland

2.3–3.3

Bone marrow

1.8–3.0

Jejunum

1.5–2.1

Skin

1.4–2.1

Testis

1.5–1.6

Kidney

1.3–1.5

Bladder

1.3–1.5

Lung

1.2–1.4

Heart

>1.0

Tumor

1.0–2.8

Data from references 141, 147, and 149–153.

salivary glands and the hematopoietic system, amifostine affords significant radioprotection. These variations are probably explained by tissue variations in oxygen concentration, dephosphorylation activity, and distribution of amifostine and its metabolites.145,147,149 To make things even more complicated, tumor protection has been impossible to rule out by preclinical experiments.141 In addition, large single doses of irradiation have often been used, and relevant comparison with tumor effects have been absent or difficult to translate into a meaningful clinical context.142 On the clinical side, there have been far too many publications of Phase I and Phase II studies with a limited number of patients and a few underpowered randomized studies. In addition, chemotherapy has often been applied together with radiotherapy, making it difficult to evaluate the results (Table 3.5). Despite the long list of preclinical normal

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58

SECTION I

Scientific Foundations of Radiation Oncology

Randomized Clinical Trials Investigating the Effect of Amifostine on Outcome in Radiotherapy Administered Alone or With Chemotherapy

TABLE 3.5 Author

Year

Reference

Site

Treatment

No. Patients

Buntzel et al.

1998

160

Head and neck

RT and CT

39

Bourhis et al.

1999

161

Head and neck

RT

26

Brizel et al.

2000

154

Head and neck

RT

315

Momm et al.

2001

162

Head and neck

RT

73

Wasserman et al.

2005

163

Head and neck

RT

303

Buentzel et al.

2006

164

Head and neck

RT and CT

132

Anné et al.

2007

165

Head and neck

RT and CT

54

Haddad et al.

2009

166

Head and neck

RT and CT

Antonadou et al.

2001

167

Lung

RT

Antonadou et al.

2003

168

Lung

RT and CT

73

Leong et al.

2003

169

Lung

RT and CT

60

Komaki et al.

2004

170

Lung

RT and CT

62

Movsas et al.

2005

171

Lung

RT and CT

242

Lawrence et al.

2013

172

Lung

RT and CT

243

Bohuslavizki et al.

1999

173

Thyroid

RT (I-131)

Liu et al.

1992

174

Rectum

RT

100

Athanassiou et al.

2003

175

Pelvis

RT

205

Kouloulias et al.

2004

176

Prostate

RT

67

Koukourakis et al.

2000

177

Various

RT

140

58 146

50

CT, Chemotherapy; RT, radiotherapy.

Modifiers of the Oxygen Supply Decreasing the availability of oxygen to normal tissues may be an alternative approach to achieving radiation protection. This might be achieved by modifying hemoglobin-oxygen affinity. The substituted benzaldehyde, BW12C, and derivatives178,179 preferentially bind to oxyhemoglobin, increasing the affinity of the hemoglobin for oxygen,180,181 thus decreasing the amount of oxygen available to the tissues. Carbon monoxide gas can also reduce oxygen transport to tissues by binding to hemoglobin, thereby decreasing the amount available for oxygen transport as well as causing a left shift of the hemoglobin-oxygen dissociation curve. Therefore, any oxygen that binds to the hemoglobin does so more strongly,182 which has been documented to increase hypoxia and reduce radiation response.183,184 However, modification of the oxygen supply, whether by drugs or gas breathing, will radioprotect tumors as

100

Overall survival (%)

tissue studies with a proven effect of amifostine, disappointingly few have been confirmed in the clinical setting. Amelioration of acute radiation toxicity has been observed in studies that often employed various types of treatment intensification, such as concomitant chemotherapy or accelerated radiotherapy. However, definite confirmation regarding late morbidity, such as fibrosis, has not been obtained. A pivotal trial by Brizel et al.154 showed that amifostine significantly protected against radiation-induced xerostomia with no apparent loss of tumor control in head and neck cancers. That was followed by amifostine being approved by the FDA for use in patients undergoing postoperative fractionated radiotherapy in the head and neck region to decrease the incidence of acute and chronic xerostomia. A number of meta-analyses have concluded that amifostine could significantly reduce acute and late side effects associated with radiation therapy155–158 without changing radiation-induced overall survival or progression-free survival.156,159 However, several studies questioned the benefit of intervention with amifostine when weighed against its high cost and side effects.157,158

75

50

25

0

43% Never/quit

Events Never/quit 39 Moderate smk 39 Heavy smk 79

All 70 54 108

28% Moderate smk 27% Heavy smk

0

24 48 72 96 120 Time after treatment (months) Fig. 3.11 Influence of smoking (smk) during treatment on the outcome of radiotherapy in 232 patients with advanced head and neck carcinoma. Results show 10-year survival when comparing nonsmokers and quitters to moderate or heavy smokers (>20 cigarettes or one pack per day). (Modified from Hoff CM. Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy. Acta Oncol. 2012;51:419–432.)

well as normal tissues.178,179–185 Clinical evidence for this is shown in Fig. 3.11, in which patients with head and neck carcinomas who were smokers (and, therefore, had higher carboxyhemoglobin levels) had a poorer response to radiation therapy than nonsmokers. This may not be true for pentoxifylline, a drug that alters red blood cell deformability and inhibits platelet aggregation and fibrinolytic activity.186 As a result, red blood cells are better able to transverse narrowed

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CHAPTER 3 arterioles and capillaries. When given before irradiation, pentoxifylline enhances radiation damage in tumors187 presumably because of an improvement in oxygen delivery,188,189 but it has no effect on the response of normal tissues.187 However, when administered on a daily basis after irradiation, pentoxifylline had no effect on early skin reactions in mice but did significantly reduce the incidence of late reactions.190

Other Radioprotectors Various other agents have been reported to be capable of radioprotecting certain normal tissues.191–193 These include cytokines, such as granulocytemacrophage colony-stimulating factor, interleukin-1, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and basic fibroblast growth factor.194,195–198 Another interesting group of agents inhibits the process of apoptosis. Many tumors have acquired mutations that prevent them from undergoing radiation-induced apoptosis. Proliferating normal cells, however, are often killed by radiation-induced apoptosis, and several apoptosis inhibitors have shown radioprotective potentials in animal models. These include p53 inhibitors (pifithrin-α and pifithrin-μ), growth factors (KGF-1 [palifermin], KGF-2 [repifermin], FGF-20 [velafermin]), activators of NRF2 (triterpenoids), and inhibitors of NF-κB (CBLB502).191–193 Another approach, designed to take advantage of a typically acquired defect in tumor cells, is to induce a G1 cell cycle arrest in normal cells, thereby temporarily arresting them in the relatively radioresistant G1 phase, allowing for improved DNA repair (e.g., PD0332991 and 2BrIC).191–193 Agents are also being developed that target molecular pathways involved in radiation-induced effects, including the TGF-β1/Smad, CTGF/RHO/ROCK, TNF-α, and PDGF/PDGFR pathways.191–193 Finally, there is a group of miscellaneous inhibitors that includes the angiotensin-converting enzyme inhibitor captopril, corticosteroids, prostaglandins, and essential fatty acids.199–203 However, the mechanisms of action are not entirely clear, nor is there evidence that these agents do not also radioprotect tumors.

SUMMARY The use of radiation to treat certain types of cancer with curative intent is a well-established and effective therapy, but there is still room for improvement. The additional use of treatments that can either increase radiation damage in tumors without affecting normal tissues or protect normal tissues without having a similar protective effect in tumors is clearly warranted. Because the vasculature and microenvironment of tumors differs from those of normal tissues, targeting these parameters should lead to tumor specificity. Many preclinical studies have demonstrated this to be a viable approach. However, despite numerous clinical studies confirming the potential of such methods to significantly improve outcome to radiation therapy, only one agent has become established in standard radiation therapy protocols. That agent is the radiosensitizer nimorazole, which is used only in Denmark and only in head and neck cancers. The use of radioprotectors is more controversial. Experimentally, several agents have been shown to radioprotect certain normal tissues, but data also demonstrate that some of these agents induce radiation protection in tumors. Results from clinical studies investigating the potential of radioprotectors have also been inconclusive. Until good human data demonstrating radioprotection of normal tissues—but not tumors—become available, the use of radioprotectors must be considered experimental.

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Dose-Response Modifiers in Radiation Therapy

59

3. Gray LH, Conger AD, Ebert M, et al. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953;26:638–648. 4. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955;9:539–549. 5. Tannock IF. The relationship between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer. 1968;22:258–273. 8. Chaplin DJ, Olive PL, Durand RE. Intermittent blood flow in a murine tumor: radiobiological effects. Cancer Res. 1987;47:597–601. 9. Horsman MR. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours. Acta Oncol (Madr). 1995;34:571–587. 12. Moulder JE, Rockwell S. Hypoxic fractions of solid tumour. Int J Radiat Oncol Biol Phys. 1984;10:695–712. 13. Horsman MR, Mortensen LS, Petersen JB, et al. Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol. 2012;9: 674–687. 30. Toustrup K, Sørensen BS, Alsner J, et al. Hypoxia gene expression signatures as prognostic and predictive markers in head and neck radiotherapy. Semin Radiat Oncol. 2012;22:119–127. 32. Harris BH, Barberis A, West CM, et al. Gene expression signatures as biomarkers of tumour hypoxia. Clin Oncol (R Coll Radiol). 2015;27:547–560. 47. Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol. 2005;77:18–24. 48. Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol. 1996;6:10–21. 50. Suit HD, Marshall N, Woerner D. Oxygen, oxygen plus carbon dioxide, and radiation therapy of a mouse mammary carcinoma. Cancer. 1972;30:1154–1158. 60. Overgaard J. Sensitization of hypoxic tumour cells—clinical experience. Int J Radiat Biol. 1989;56:801–811. 64. Chaplin DJ, Horsman MR, Siemann DW. Further evaluation of nicotinamide and carbogen as a strategy to reoxygenate hypoxic cells in vivo: importance of nicotinamide dose and pre-irradiation breathing time. Br J Cancer. 1993;68:269–273. 65. Adams GE, Cooke MS. Electron-affinic sensitization. I. A structural basis for chemical radiosensitizers in bacteria. Int J Radiat Biol. 1969;15:457–471. 66. Asquith JC, Watts ME, Patel K, et al. Electron-affinic sensitization V. Radiosensitization of hypoxic bacteria and mammalian cells in vitro by some nitroimidazoles and nitropyrazoles. Radiat Res. 1974;60:108–118. 68. Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res. 1994;6:509–518. 73. Overgaard J, Sand Hansen H, Overgaard M, et al. A randomised double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer study (DAHANCA) protocol 5–85. Radiother Oncol. 1998;46:135–146. 74. Dobrowsky W, Huigol NG, Jayatilake RS, et al. Ak-2123 (Sanazol) as a radiation sensitizer in the treatment of stage III cervical cancer: results of an IAEA multicentre randomized trial. Radiother Oncol. 2007;82:24–29. 75. Karasawa K, Sunamura M, Okamoto A, et al. Efficacy of novel hypoxic cell sensitizer doranidazole in the treatment of locally advanced pancreatic cancer—long-term results of a placebo-controlled randomized study. Radiother Oncol. 2008;87:326–330. 76. Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinomas of the head and neck—a systematic review and meta-analysis. Radiother Oncol. 2011;100:22–32. 77. Grau C, Overgaard J. Significance of haemoglobin concentration for treatment outcome. In: Molls M, Vaupel P, eds. Medical Radiology: Blood Perfusion and Microenvironment of Human Tumours. Heidelberg, Germany: Springer-Verlag; 1998:101–112.

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145. Savoye C, Swenberg C, Hugot S, et al. Thiol WR-1065 and disulphide WR-33278, two metabolites of the drug ethyol (WR-2721), protect DNA against fast neutron-induced strand breakage. Int J Radiat Biol. 1997;71:193–202. 146. Denekamp J, Michael BD, Rojas A, et al. Radioprotection of mouse skin by WR-2721: the critical influence of oxygen tension. Int J Radiat Oncol Biol Phys. 1982;8:531–534. 147. Travis EL. The oxygen dependence of protection by aminothiols: implications for normal tissues and solid tumors. Int J Radiat Oncol Biol Phys. 1984;10:1495–1501. 159. Bourhis J, Blanchard P, Maillard E, et al. Effect of amifostine on survival among patients treated with radiotherapy: a meta-analysis of individual patient data. J Clin Oncol. 2011;29:2590–2597. 178. Adams GE, Barnes DW, du Boulay C, et al. Induction of hypoxia in normal and malignant tissues by changing the oxygen affinity of hemoglobin—implications for therapy. Int J Radiat Oncol Biol Phys. 1986;12:1299–1302. 183. Siemann DW, Hill RP, Bush RA. The importance of the pre-irradiation breathing times of oxygen and carbogen (5% CO2; 95% O2) on the in vivo radiation response of a murine sarcoma. Int J Radiat Oncol Biol Phys. 1977;2:903–911. 186. Ward A, Clissold SP. Pentoxifylline: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs. 1987;34:50–97. 187. Lee I, Kim JH, Levitt SH, et al. Increases in tumor response by pentoxifylline alone or in combination with nicotinamide. Int J Radiat Oncol Biol Phys. 1992;22:425–429. 190. Dion MW, Hussey DH, Osborne JW. The effect of pentoxifylline on early and late radiation injury following fractionated irradiation in C3H mice. Int J Radiat Oncol Biol Phys. 1989;17:101–107. 191. Stewart FA, Akleyev AV, Hauer-Jensen M, et al. ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs–threshold doses for tissue reactions in a radiation protection context. Ann ICRP. 2012;41:211–286. 194. Hendry JH. Biological response modifiers and normal tissue injury after irradiation. Semin Radiat Oncol. 1994;4:123–132.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 3

REFERENCES 1. Schwarz G. Über Desensibilisierung gegen Röntgen- und Radiumstrahlen. Munch Med Wochenschr. 1909;24:1–2. 2. Müller C. Eine neue Behandlungsmethode bösartiger Geschwülste. Munch Med Wochenschr. 1910;28:1490–1493. 3. Gray LH, Conger AD, Ebert M, et al. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953;26:638–648. 4. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955;9:539–549. 5. Tannock IF. The relationship between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer. 1968;22:258–273. 6. Horsman MR, Overgaard J. Overcoming tumour radiation resistance resulting from acute hypoxia. Eur J Cancer. 1992;28A:717–718. 7. Brown JM. Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br J Radiol. 1979;52:650–656. 8. Chaplin DJ, Olive PL, Durand RE. Intermittent blood flow in a murine tumor: radiobiological effects. Cancer Res. 1987;47:597–601. 9. Horsman MR. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours. Acta Oncol (Madr). 1995;34:571–587. 10. Helmlinger G, Yuan F, Dellian M, et al. Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat Med. 1997;3:177–182. 11. Kimura H, Braun RD, Ong ET, et al. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 1996;56:5522–5528. 12. Moulder JE, Rockwell S. Hypoxic fractions of solid tumour. Int J Radiat Oncol Biol Phys. 1984;10:695–712. 13. Horsman MR, Mortensen LS, Petersen JB, et al. Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol. 2012;9:674–687. 14. Kolstad P. Intercapillary distance, oxygen tension and local recurrence in cervix cancer. Scand J Clin Lab Invest. 1968;106:145–157. 15. Révész L, Siracka E, Siracky J, et al. Variation of vascular density within and between tumors of the uterine cervix and its predictive value for radiotherapy. Int J Radiat Oncol Biol Phys. 1989;11:97–103. 16. Lauk S, Skates S, Goodman M, et al. Morphometric study of the vascularity of oral squamous cell carcinomas and its relation to outcome of radiation therapy. Eur J Cancer Clin Oncol. 1989;25:1431–1440. 17. Mueller-Kleiser W, Vaupel P, Manz R, et al. Intracapillary oxyhemoglobin saturation of malignant tumors in humans. Int J Radiat Oncol Biol Phys. 1981;7:1397–1404. 18. Vikram DS, Zweier JL, Kuppusamy P. Methods for noninvasive imaging of tissue hypoxia. Antioxid Redox Signal. 2007;9:1745–1756. 19. Padhani AR, Krohn KA, Lewis JS, et al. Imaging oxygenation of human tumours. Eur Radiol. 2007;17:861–872. 20. Mayr NA, Wang JZ, Zhang D, et al. Longitudinal changes in tumor perfusion pattern during the radiation therapy course and its clinical impact in cervical cancer. Int J Radiat Oncol Biol Phys. 2010;77: 502–508. 21. Bisdas S, Ngyuyen SA, Anand SK, et al. Outcome prediction after surgery and chemoradiation of squamous cell carcinoma in the oral cavity, oropharynx, and hypopharynx: use of baseline perfusion CT microcirculatory parameters vs. tumor volume. Int J Radiat Oncol Biol Phys. 2009;73:1313–1318. 22. Lehtio K, Eskola O, Vijanen T, et al. Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004;59:971–982. 23. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47. 24. Haugland HK, Vukovic V, Pintilie M, et al. Expression of hypoxiainducible factor-1alpha in cervical carcinomas: correlation with tumor oxygenation. Int J Radiat Oncol Biol Phys. 2002;53:854–861. 25. Hui EP, Chan ATC, Pezzella F, et al. Coexpression of hypoxia-inducible factors 1α and 2α, carbonic anhydrase IX, and vascular endothelial

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138. Yuhas JM. Active versus passive absorption kinetics as the basis for selective protection of normal tissues by S-2(3-aminopropylamino)ethylphosphorothioic acid. Cancer Res. 1980;40:1519–1524. 139. Yuhas JM. Protective drugs in cancer therapy: optimal clinical testing and future directions. Int J Radiat Oncol Biol Phys. 1982;8:513–517. 140. Schuchter LM, Hensley ML, Meropol NJ, et al. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2002;20:2895–2903. 141. Denekamp J, Stewart FA, Rojas A. Is the outlook grey for WR-2721 as a clinical radioprotector. Int J Radiat Oncol Biol Phys. 1983;9:595–598. 142. Lindegaard JC, Grau C. Has the outlook improved for amifostine as a clinical radioprotector? Radiother Oncol. 2000;57:113–118. 143. Rades D, Fehlauer F, Bajrovic A, et al. Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients. Radiother Oncol. 2004;70:261–264. 144. Brizel DM, Overgaard J. Does amifostine have a role in chemoradiation treatment? Lancet Oncol. 2003;4:378–381. 145. Savoye C, Swenberg C, Hugot S, et al. Thiol WR-1065 and disulphide WR-33278, two metabolites of the drug ethyol (WR-2721), protect DNA against fast neutron-induced strand breakage. Int J Radiat Biol. 1997;71:193–202. 146. Denekamp J, Michael BD, Rojas A, et al. Radioprotection of mouse skin by WR-2721: the critical influence of oxygen tension. Int J Radiat Oncol Biol Phys. 1982;8:531–534. 147. Travis EL. The oxygen dependence of protection by aminothiols: implications for normal tissues and solid tumors. Int J Radiat Oncol Biol Phys. 1984;10:1495–1501. 148. Washburn LC, Rafter JJ, Hayes RL. Prediction of the effective radioprotective dose of WR-2721 in humans through an interspecies tissue distribution study. Radiat Res. 1976;66:100–105. 149. Yuhas JM, Afzal SMF, Afzal V. Variation in normal tissue responsiveness to WR-2721. Int J Radiat Oncol Biol Phys. 1984;10:1537–1539. 150. Kruse JJ, Strootman EG, Wondergem J. Effects of amifostine on radiation-induced cardiac damage. Acta Oncol. 2003;42:4–9. 151. Bohuslavizki KH, Klutmann S, Jenicke L, et al. Radioprotection of salivary glands by S-2-(3-aminopropylamin)-ethylphosphorothioic (amifostine) obtained in a rabbit animal model. Int J Radiat Oncol Biol Phys. 1999;45:181–186. 152. Rojas A, Denekamp J. The influence of X ray dose level on normal tissue radioprotection by WR-2721. Int J Radiat Oncol Biol Phys. 1984;10:2351–2356. 153. Rojas A, Stewart FA, Soranson JA, et al. Fractionated studies with WR-2721: normal tissues and tumour. Radiother Oncol. 1986;6: 51–60. 154. Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol. 2000;18:3339–3345. 155. Sasse AD, Clark LG, Sasse EC, et al. Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int J Radiat Oncol Biol Phys. 2006;64:784–791. 156. Gu J, Zhu S, Li X, et al. Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. PLoS ONE. 2014;9(5):e95968. doi:10.1371/journal.pone0095968. 157. Devine A, Marignol L. Potential of amifostine for chemoradiotherapy and radiotherapy-associated toxicity reduction in advanced NSCLC: a meta-analysis. Anticancer Res. 2016;36:5–12. 158. Riley P, Glenny AM, Hua F, et al. Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy. Cochrane Database Syst Rev. 2017;(7):CD012744, doi:10.1002/14651858.CD012744. 159. Bourhis J, Blanchard P, Maillard E, et al. Effect of amifostine on survival among patients treated with radiotherapy: a meta-analysis of individual patient data. J Clin Oncol. 2011;29:2590–2597. 160. Buntzel J, Kuttner K, Frohlich D, et al. Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer. Ann Oncol. 1998;9:505–509.

161. Bourhis J, De Crevoisier R, Abdulkarim B, et al. A randomized of very accelerated radiotherapy with and without amifostine in advanced head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 1999;46:1105–1108. 162. Momm F, Bechtold C, Rudat V, et al. Alteration of radiation-induced hematotoxicity by amifostine. Int J Radiat Oncol Biol Phys. 2001;51:947–951. 163. Wasserman TH, Brizel DM, Henke M, et al. Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and-neck cancer: 2-year follow-up of a prospective, randomized, phase III trial. Int J Radiat Oncol Biol Phys. 2005;63:985–990. 164. Buentzel J, Micke O, Adamietz IA, et al. Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebocontrolled phase III study. Int J Radiat Oncol Biol Phys. 2006;64: 684–691. 165. Anné PR, Machtay M, Rosenthal DI, et al. A phase II trial of subcutaneous amifostine and radiation therapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2007;67:445–452. 166. Haddad R, Sonis S, Posner M, et al. Randomized phase 2 study of concomitant chemoradiotherapy using weekly carboplatin/paclitaxel with or without daily subcutaneous amifostine in patients with locally advanced head and neck cancer. Cancer. 2009;115:4514–4523. 167. Antonadou D, Coliarakis N, Synodinou M, et al. Randomized phase III trial of radiation treatment ± amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys. 2001;51:915–922. 168. Antonadou D, Throuvalas N, Petridis A, et al. Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non–small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2003;57:402–408. 169. Leong SS, Tan EH, Fong KW, et al. Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non–small-cell lung cancer. J Clin Oncol. 2003;2003:1767–1774. 170. Komaki R, Lee JS, Milas L, et al. Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non–small-cell lung cancer: report of a randomized comparative trial. Int J Radiat Oncol Biol Phys. 2004;58:1369–1377. 171. Movsas B, Scott C, Langer C, et al. Randomized trial of amifostine in locally advanced non–small-cell lung cancer patients receiving chemotherapy and hyper fractionated radiation: Radiation Therapy Oncology Group trial 98–01. J Clin Oncol. 2005;23:2145–2154. 172. Lawrence YR, Paulus R, Langer C, et al. The addition of amifostine to carboplatin and paclitaxel based chemoradiation in locally advanced non–small cell lung cancer: long-term follow-up of Radiation Therapy Oncology Group (RTOG) randomized trial 9801. Lung Cancer. 2013;80:298–305. 173. Bohuslavizki KH, Klutmann S, Bleckmann C, et al. Salivary gland protection by amifostine in high-dose radioiodine therapy of differentiated thyroid cancer. Strahlenther Onkol. 1999;175: 57–61. 174. Liu T, Liu Y, He S, et al. Use of radiation with or without WR-2721 in advanced rectal cancer. Cancer. 1992;69:2820–2825. 175. Athanassiou H, Antonadou D, Coliarakis N, et al. Protective effect of amifostine during fractionated radiotherapy in patients with pelvic carcinomas: results of a randomized trial. Int J Radiat Oncol Biol Phys. 2003;56:1154–1160. 176. Kouloulias VE, Kouvaris JR, Pissakas G, et al. A phase II randomized study of topical intrarectal administration of amifostine for the prevention of acute radiation-induced rectal toxicity. Strahlenther Onkol. 2004;180:557–562. 177. Koukourakis MI, Kyrias G, Kakolyris S, et al. Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study. J Clin Oncol. 2000;18:2226–2233. 178. Adams GE, Barnes DW, du Boulay C, et al. Induction of hypoxia in normal and malignant tissues by changing the oxygen affinity of hemoglobin—implications for therapy. Int J Radiat Oncol Biol Phys. 1986;12:1299–1302.

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CHAPTER 3 179. Adams GE, Stratford IJ, Nethersell AB, et al. Induction of severe tumor hypoxia by modifiers of the oxygen affinity of hemoglobin. Int J Radiat Oncol Biol Phys. 1989;16:1179–1182. 180. Beddell CR, Goodford PJ, Kneen G, et al. Substituted benzaldehydes designed to increase the oxygen affinity of human haemoglobin and inhibit the sickling of sickle erythrocytes. Br J Pharmacol. 1984;82:397–407. 181. Keidan AJ, Franklin IM, White RD. Effect of BW12C on oxygen affinity of haemoglobin in sickle cell disease. Lancet. 1986;1:831–834. 182. Roughton FJW, Darling RC. The effect of carbon monoxide on the oxyhemoglobin dissociation curve. Am J Phys. 1944;141:17–31. 183. Siemann DW, Hill RP, Bush RA. The importance of the pre-irradiation breathing times of oxygen and carbogen (5% CO2; 95% O2) on the in vivo radiation response of a murine sarcoma. Int J Radiat Oncol Biol Phys. 1977;2:903–911. 184. Grau C, Khalil AA, Nordsmark M, et al. The relationship between carbon monoxide breathing, tumour oxygenation and local tumour control in the C3H mammary carcinoma in vivo. Br J Cancer. 1994;69:50–57. 185. Van den Aardweg GJMJ, Hopewell JW, Barnes DWH, et al. Modification of the radiation response of pig skin by manipulation of tissue oxygen tension using anaesthetics and administration of BW12C. Int J Radiat Oncol Biol Phys. 1989;16:1191–1194. 186. Ward A, Clissold SP. Pentoxifylline: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs. 1987;34:50–97. 187. Lee I, Kim JH, Levitt SH, et al. Increases in tumor response by pentoxifylline alone or in combination with nicotinamide. Int J Radiat Oncol Biol Phys. 1992;22:425–429. 188. Honess DJ, Andrews MS, Ward R, et al. Pentoxifylline increases RIF-1 tumour pO2 in a manner compatible with its ability to increase relative tumour perfusion. Acta Oncol. 1995;34:385–389. 189. Price MJ, Li LT, Tward JD, et al. Effect of nicotinamide and pentoxifylline on normal tissue and FSA tumor oxygenation. Acta Oncol. 1995;34:391–395. 190. Dion MW, Hussey DH, Osborne JW. The effect of pentoxifylline on early and late radiation injury following fractionated irradiation in C3H mice. Int J Radiat Oncol Biol Phys. 1989;17:101–107.

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191. Stewart FA, Akleyev AV, Hauer-Jensen M, et al. ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs–threshold doses for tissue reactions in a radiation protection context. Ann ICRP. 2012;41:211–286. 192. Bourgier C, Levy A, Vozenin M-C, et al. Pharmacological strategies to spare normal tissues from radiation damage: useless or overlooked therapeutics? Cancer Metastasis Rev. 2012;31:699–712. 193. Maier P, Wenz F, Herskind C. Radioprotection of normal tissue cells. Strahlenther Onkol. 2014;Epub ahead of print. 194. Hendry JH. Biological response modifiers and normal tissue injury after irradiation. Semin Radiat Oncol. 1994;4:123–132. 195. Bernstein EF, Harisiadis L, Salomon G, et al. Transforming growth factor-β improves healing of radiation-impaired wounds. J Invest Dermatol. 1991;97:430–434. 196. Hancock SL. Effects of tumor necrosis factor α on the radiation response of murine intestinal stem cells and lung. Radiation Research Society Meeting, Salt Lake City, Utah, March 1992 (abstract P-06–5). 197. Hancock SL, Chung RT, Cox RS, et al. Interleukin 1β initially sensitizes and subsequently protects murine intestinal stem cells exposed to photon radiation. Cancer Res. 1991;51:2280–2285. 198. Okunieff P, Abraham EH, Moini M, et al. Basic fibroblast growth factor radioprotects bone marrow and not RIF-1 tumor. Acta Oncol. 1995;34:435–438. 199. Robbins MEC, Hopewell JW. Physiological factors affecting renal radiation tolerance: a guide to the treatment of late effects. Br J Cancer. 1986;53:265–267. 200. Halnan KE. The effect of corticosteroids on the radiation skin reaction. Br J Radiol. 1962;35:403–408. 201. Walden TL, Patchen M, Snyder SL. 16,16-dimethyl prostaglandin-E2 increases survival in mice following irradiation. Radiat Res. 1987;109:540–549. 202. Hansen WR, Pelka AE, Nelson AK, et al. Subcutaneous or topical administration of 16,16 dimethyl prostaglandin-E2 protects from radiation-induced alopecia in mice. Int J Radiat Oncol Biol Phys. 1992;23:333–337. 203. Hopewell JW, Robbins MEC, van den Aardweg GJMJ. The modulation of radiation-induced damage to pig skin by essential fatty acids. Br J Cancer. 1993;68:1–7.

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4 Interaction of Chemotherapy and Radiation Christopher D. Willey, Eddy S. Yang, and James A. Bonner

Oncology has increasingly become a multidisciplinary field: (1) surgery remains the definitive local treatment modality; (2) chemotherapy remains the definitive systemic treatment modality; and (3) radiation therapy is the definitive locoregional treatment modality. Although, historically, these approaches have predominantly been used exclusively of one another, the past 30 years have seen an explosion of both preclinical and clinical efforts to combine these therapies for improved outcomes, including improved local and regional control, overall survival, cosmesis, and organ preservation. We have learned a great deal about the interactions between chemotherapy and radiation from clinical trials that have combined these treatment modalities in sequential and concomitant regimens. In addition, laboratory investigations have demonstrated key molecular targets and pathways that can potentially be exploited for improved outcome. The combination of chemotherapy and radiation has changed the management approach in several disease sites, which are broadly reviewed here.

HISTORICAL PERSPECTIVE Radiosensitization and chemosensitization are complex concepts that have many different interpretations and have been used to describe many different interactions.1,2 The use of radiation and chemotherapy for mutual or even simultaneous sensitization adds to the intricacies of these interactions. Over 100 years ago, radiation treatment and benzene systemic therapy were combined for leukemia treatment.3 However, probably the best historical model of chemotherapy and radiation therapy interaction is that of 5-fluorouracil (5-FU).

5-Fluorouracil In the 1950s, the halogenated pyrimidine, 5-FU, was combined with external beam irradiation (EBRT) after this class of drug was determined to have anticancer properties.4 In the last fifty years, 5-FU has been successfully combined with radiation to treat a variety of gastrointestinal cancers, as well as cervical cancer and head and neck cancer.5 The route of administration and scheduling of 5-FU has been manipulated many times in an attempt to reduce toxicity and maximize tumor control. What began as bolus delivery at the beginning and end of a fractionated radiation treatment course (Moertel regimen) has progressed to protracted venous infusion (PVI) and now to twice-daily oral 5-FU analog formulations. These approaches have allowed for an increase in cumulative dose of the drug, decreased chemotherapy toxicity, and improved radiosensitization. 5-FU has proven to be a staple drug in the armamentarium of medical oncologists and a key radiosensitizer for the radiation oncologist.

RATIONALE Limitations in Current Therapeutic Approach Over the past several decades, we have seen great technological advances in surgery and radiation while novel systemic agents are being developed at a pace never seen before. Nevertheless, cancer morbidity and mortality remain major problems. The advent of combined modality therapy has sought to improve on the limitations that surgery, chemotherapy, and radiation carry independently. For several decades, radiation has complemented surgery by improving loco regional control. Tumor-specific and patient-specific factors limit the success of both surgical and radiation treatments, however. In this chapter, we will focus on the multiple ways that systemic therapies are used in an attempt to overcome the shortcomings of radiation treatment. The presence of micrometastatic disease, disease outside of our treatment fields, and the inability to deliver adequate dose to the target region owing to normal tissue toxicity risk are some of the most frequently cited reasons. In addition, tumors may contain regions of relative hypoxia or subpopulations of cells with intrinsic or acquired resistance to radiation damage. We will briefly review the current understanding of these topics.

Tumor Detection If ionizing radiation (IR) was without normal tissue toxicity, tumor detection would be immaterial and radiotherapy could be delivered to the entire body, much like chemotherapy. Obviously, this is not the case; much like surgeons, we must be able to identify the tumor so that we can precisely and accurately target it with radiation, akin to “carving out” a tumor with a scalpel. Advances in radiology have dramatically improved our ability to detect tumor location and extent. Whereas computed tomography (CT) and magnetic resonance imaging (MRI) provide excellent anatomical information, when combined with biological or functional imaging such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), the radiation oncologist can more confidently define tumor versus nontumor. Emerging MRI sequences—including dynamic contrast enhanced and fast imaging employing steady-state acquisition (FIESTA) ultrafast pulse sequence approaches, MR spectroscopy, and MR/PET— are providing improved anatomical and biological imaging for surgeons and radiation oncologists. Nevertheless, the resolution of our current techniques (on the order of 5 mm for PET resolution6) and high false-negative rates with small tumors still limit our ability to identify microscopic tumor extent and micrometastatic disease. Novel radiopharmaceuticals may provide additional improvements in the future.

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Inherent and Acquired Resistance We know empirically that certain tumors have inherent radiation resistance pathways that manifest with high rates of local failure following irradiation. In some cases, such as in pancreatic cancer, it is difficult to deliver adequate doses of radiation to the target owing to the limitations in dose tolerance of surrounding bowel, kidney, and liver. However, there are other tumors with extremely high local failure rates despite dose escalation. A prime example is glioblastoma multiforme, which has local recurrence rates approaching 100%. Biological factors within the tumor or tumor microenvironment also generate resistance (discussed in other chapters). Later in this chapter, we will describe how chemotherapeutics can potentially mitigate some of these resistance pathways.

Increased Toxicity In the original treatise by Steel and Peckham on combining chemotherapy and radiation,7 it was assumed that each modality functioned independently in both beneficence and toxicity. However, it is abundantly clear that concurrent chemoradiation has increased toxicity, suggesting some level of overlapping toxicity, chemosensitization by radiation, or radiosensitization by the chemotherapy. Since chemoradiation is often used when tumors have wide anatomical extension (thus, precluding surgery), the volume of normal tissue irradiated—and, therefore, at risk of toxicity—is larger. In some cases, a patient has comorbid conditions that prevent aggressive therapy as well.

Therapeutic Index The features described earlier generate the need for a metric to determine efficacy relative to toxicity so that newer approaches can be compared. This metric, known as the therapeutic index (or therapeutic ratio) refers to the ratio of the probability of tumor control to the probability of normal tissue toxicity and has been covered in previous chapters. Typically, the ratio is calculated based on the 50% control rate of tumor versus the 50% normal tissue toxicity. These sigmoidal-shaped curves determine the estimated efficacy versus toxicity of treatment. Therapeutic index has been, and will continue to be, the “holy grail” of cancer therapy. For this reason, it is no surprise that it takes careful treatment planning to try to achieve maximal tumor cell kill while also sparing normal tissue in hopes of preserving function. There are a host of technological factors that impact this therapeutic ratio. Certainly, our ability to correctly identify tumor versus normal tissue will affect therapeutic ratio. The expanding use of PET, MRI, and SPECT imaging, as described earlier, are allowing radiation oncologists to better differentiate target from nontarget. Obviously, the ability to precisely deliver radiation through techniques such as intensity-modulated radiation therapy (IMRT), stereotactic procedures, and particle therapy allow us to avoid normal tissue while targeting tumor. Moreover, our ability to accurately deliver radiation via image-guided radiation therapy (IGRT) has grown by leaps and bounds; this enables smaller margin expansions, which will also limit dose to normal tissue. Nevertheless, based on the anatomical location of the tumor, there are technological limits to what can be accomplished with radiation in and of itself. Therefore, additional improvement will likely rely on the interaction of systemic agents with our technologically advanced radiation delivery methods.

Strategies to Improve Therapeutic Index The fundamental approach to improving outcomes through combined modality therapy has its basis in the theoretical strategies set forth by Steel and Peckham in 1979.7 Their seminal paper defined four potential means by which combined therapy could improve the therapeutic index: (1) independent toxicity, (2) normal tissue protection, (3) spatial cooperation, and (4) enhanced tumor response. As discussed later, the

first theoretical concept may not actually function as in the original intent. However, the latter three concepts are relevant for modern strategies of combining drugs with radiation. Additional mechanistic considerations have been identified in recent years that expand on Steel and Peckham’s “exploitable mechanisms in combined radiotherapychemotherapy” that was described 4 decades ago.7 These newer concepts of biological cooperation and temporal modulation are impacting current investigative strategies for improving the therapeutic index.

Independent Toxicity One of the main concepts suggested by Steel and Peckham as a means to improve the therapeutic index is to select a chemotherapeutic regimen with a distinct toxicity profile from that of radiation. This ideal selection of nonoverlapping toxicities could allow for increased tumor cell kill with minimal impact in terms of tissue toxicity. Although this has been pursued in therapy selection, the actual success in finding independent toxicity has been elusive. However, the inverse relationship has been implemented to a great extent. The avoidance of drugs with overlapping toxicities is standard of care practice—for instance, avoiding methotrexate with cranial irradiation, adriamycin with breast irradiation, or bleomycin with lung irradiation.

Normal Tissue Protection The identification of clinically relevant agents that promote normal tissue protection without protecting tumors has provided very little in terms of therapeutics. Limited success has been achieved with the free radical scavenging agent, amifostine (WR-2721), which appears to be selectively taken up by normal tissue relative to tumor, where it is converted into the active thiol metabolite, WR-1065.8 Although amifostine has been shown to protect against xerostomia in head and neck cancer treatment (Table 4.1) and to limit renal toxicity from cisplatin, several clinical trials have failed to show an advantage to amifostine use. Investigations into novel radioprotectors will continue, with the potential to impact the therapeutic ratio.

Spatial Cooperation The concept of spatial cooperation implies that chemotherapy and radiation therapy are independent players with systemic therapy acting systemically, that is, targeting micrometastatic disease, and radiation therapy acting locoregionally. Because these therapies function independently, it could be assumed that a full dose of each will be required to achieve the desired outcome. If the drug and radiation did function completely independently, then concurrent administration should be possible with nonoverlapping toxicities. It is unclear whether a completely independent action can actually be achieved with the chemotherapies that are currently used with radiation treatment, however, since in-field toxicities do occur, suggesting some level of localized radiation sensitization. Therefore, sequential therapy is probably the best means to exploit spatial cooperation. Many clinical examples exist for this approach, such as breast cancer with adjuvant chemotherapy followed by radiation, consolidative radiation to bulky disease in lymphoma, or prophylactic cranial irradiation in small cell lung cancer (see Table 4.1).

Enhanced Tumor Response (Cytotoxic Enhancement) Currently, a tremendous amount of investigative effort is focused on achieving cytotoxic enhancement with combined modality treatment. In other words, the combination of therapies leads to an interaction on some level that generates improved antitumor effect relative to each treatment alone. Interestingly, we have some clinical examples that subtherapeutic or radiosensitizing doses of chemotherapy can impact distant disease control, suggesting either that increased locoregional control can diminish distant metastatic disease potential or that

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CHAPTER 4

TABLE 4.1

Interaction of Chemotherapy and Radiation

63

Possible Drug-Radiation Interactions

Mechanism

Example

Notes

Normal tissue protection

Amifostine in head and neck cancer

Reduces xerostomia rates from RT alone

Spatial cooperation

Early-stage breast cancer with adjuvant chemotherapy PCI in SCLC

RT provides locoregional control for breast cancer but no impact on DM SCLC chemo does not effectively cross BBB → RT can effectively treat the brain

Biological cooperation

Targeted therapies inhibit prosurvival/proliferation pathways within tumors

Kinase-targeted agents, including tyrosine kinase inhibitors such as dasatinib and sunitinib as well as monoclonal antibodies such as cetuximab and bevacizumab; mTOR inhibitors

Temporal modulation

Drugs that impact tumor response in between fractions, namely, targeting repair, repopulation, reoxygenation, and redistribution

This is essentially a composite of several of the other mechanisms but requires concomitant delivery of the drug rather than sequential

Increased DNA damage

Drugs that incorporate into DNA

5-FU and platinum are classic examples

Inhibition of DNA repair

DNA intercalators and nucleoside analogs can disrupt repair and enhance radiation cytotoxicity

Alkylators, antimetabolites, platinum, and topoisomerase inhibitors are a few examples

Cell cycle effects

Most chemotherapeutics are cell cycle specific (except alkylators) Cell cycle arrest in radiosensitive phases (microtubule-targeting agents at M phase) Elimination of radioresistant cells (S phase)

Taxanes, epothilones, 5-FU, gemcitabine, topoisomerase inhibitors are good examples

Targeting repopulation

Conceivably any systemic agent that has at least cytostatic properties can prevent repopulation

Molecularly targeted agents as well as chemotherapeutics (particularly antimetabolites) can function this way

Hypoxia targeting

Mitomycin C and tirapazamine selectively targeting hypoxic cells Tumor shrinkage by chemotherapy decreases interstitial pressure and improves oxygenation

Taxanes and other chemotherapies that can produce tumor shrinkage are indirect means (given as induction therapy) while mitomycin C and tirapazamine are directly affecting hypoxic cells

Tumor microenvironment targeting

Antiangiogenesis promotes vascular renormalization

Bevacizumab in glioma

BBB, Blood brain barrier; DM, distant metastasis; 5-FU, 5-fluorouracil; PCI, prophylactic cranial irradiation; RT, radiation therapy; SCLC, small-cell lung carcinoma.

lower-dose chemotherapy can treat micrometastatic disease (i.e., spatial cooperation).

radiobiology factors in between fractionated radiation treatments (see Table 4.1).9,11

Biological Cooperation

POTENTIAL BIOLOGICAL MECHANISMS OF DRUG RADIATION INTERACTION

The term biological cooperation is a newer concept9 that involves independent targeting of subpopulations of cells within the tumor itself (see Table 4.1). Although similar to the spatial cooperation concept, biological cooperation implies that some portion of the actual radiation target (i.e., in-field) is resistant to radiation, which is the target of the drug given concomitantly. The most prominent example for biological cooperation is hypoxic cell cytotoxins such as tirapazamine. Since hypoxia is a known radiation resistance condition, tirapazamine will target these subpopulations of cells since it is most potent in anoxic conditions.

There are a host of potential mechanisms by which a drug may impact radiation efficacy, summarized in Table 4.1. Classical definitions of radiosensitizers indicated an enhancement of DNA damage as the critical factor. However, with increased understanding of cancer cell biology, it is apparent that targets other than DNA damage can enhance radiation efficacy. Therefore, a broader defined “radiation enhancer” can impact several potential mechanisms to increase radiation effect.

Temporal Modulation

Increasing Radiation Damage

The four Rs of classical radiobiology—reoxygenation, repair, redistribution, and repopulation10—refer to factors that are particularly important for fractionated radiation therapy. For example, antiproliferative therapies could prevent accelerated repopulation between fractions, which might not be detectable using single-fraction assays in vitro. Conversely, although DNA damage repair blockade may enhance radiation sensitivity in the tumor, if DNA repair is also inhibited in normal tissue, outcomes may be worse in fractionated therapy.9 Depending on which factors are most prominent in normal and tumor cells, the therapeutic index can be shifted in either beneficial or detrimental directions. Therefore, temporal modulation implies therapeutics that optimize these four

The classical radiobiology definition of a radiosensitizer implied that the drug would enhance DNA damage. This is accomplished when the drug incorporates itself into the DNA or causes damage to the DNA itself by forming adducts, thereby increasing susceptibility of the DNA to radiation damage. Examples of this type of interaction include 5-FU and cisplatin.

Inhibition of DNA Repair Cancer cells that can effectively repair DNA damage will have resistance to radiation effect. Therefore, compounds that can interfere with DNA damage repair can potentially enhance radiation damage. Several

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chemotherapeutics target this process, particularly those that disrupt nucleotide biosynthesis and utilization. Modified nucleotides such as 5-FU, bromodeoxyuridine, gemcitabine, fludarabine, methotrexate, etoposide, hydroxyurea, and cisplatin fall into this category. Additionally, as described later, compounds that alter the cell cycle may indirectly inhibit DNA repair.

Cell Cycle Effects A multitude of preclinical studies has identified the G2/M as the most radiation-sensitive and S as the most radiation-resistant phases of the cell cycle.12,13 In addition, many cytotoxic chemotherapeutics are cell cycle specific. Therefore, agents that can maintain cells in radiationsensitive phases or eliminate those cells in radiation-resistant phases will cooperate with radiation for enhanced efficacy. Although this is clearly seen in preclinical settings, there is much less direct evidence for this phenomenon in clinical data. Nevertheless, taxanes and nucleoside analogs and modified pyrimidines appear to work in this manner.14–17

Repopulation In normal adult tissue, the rate of cell loss is balanced by that of cell proliferation. When increased cell loss occurs from injury, including radiation treatment, signaling for proliferation occurs, resulting in a repopulation. Cancers, however, have an excess of cell proliferation relative to cell loss by their very nature. Therefore, when a subtotal cell loss occurs during fractionated radiation, cancers can also promote increased proliferation. This is known as accelerated repopulation. Chemotherapeutics with cytotoxic or even cytostatic effects, when given concurrently with radiation, can counteract this repopulation and enhance efficacy.

Hypoxia/Tumor Microenvironment As discussed in other chapters, the tumor microenvironment is thought to modulate treatment response due to harsh conditions such as low oxygen tension, reduced nutrients, and acidic pH to produce a niche for therapy-resistant stem-like cells and even cancer-promoting immune cells. This is particularly true of solid tumors that have grown to any significant size, as they will contain these regions owing to the limitations in vascular flow as well as oxygen diffusion within the tumor. Although many tumors trigger angiogenic factors within the tumor, these stimulants manifest as aberrant vasculature often with disorganized architecture. Moreover, larger tumors may have increased interstitial pressure that leads to further collapse of blood vessels, creating hypoxic regions and overt necrosis at times. Hypoxia is one of the most potent factors of radiation protection known since radiation relies on the production of oxygen free radicals (hypoxia generates 2- to 3-fold less radiation sensitivity).18 Therefore, drug therapies that mitigate this hypoxia can enhance radiation efficacy. There are four general chemotherapeutic approaches for accomplishing this. (1) Chemotherapy can shrink the tumor through cytotoxic action, thereby decreasing interstitial pressure. Moreover, since chemotherapy typically targets the fastest proliferating cells, those cells located next to blood vessels are removed, bringing the hypoxic regions into closer proximity with the oxygenated region. A good example of this process is demonstrated by taxanes such as paclitaxel.19 (2) Antiangiogenic therapies such as bevacizumab, an antibody targeting the vascular endothelial growth factor (VEGF), can potentially normalize vascular flow by eliminating the aberrant neovasculature of the tumor. Work by Batchelor et al.,20 Jain,21 and others22,23 provided early evidence of this phenomenon. (3) Hypoxic cell targeting agents, such as tirapazamine, can provide biological cooperation by eliminating the most radiationresistant cells. (4) Hypoxic cell radiation sensitizers can reverse the inherent radiation resistance of the hypoxic cells. Drugs such as

misonidazole, a nitroimidazole compound, can mimic the effects of oxygen within the hypoxic regions.24,25

Cell Death Pathway Effects All of the potential mechanisms of drug-radiation interaction discussed earlier display their efficacy through cytotoxicity. However, in recent years, it has become clear that there are several ways in which cytotoxicity is manifest. In 2018, the Nomenclature Committee on Cell Death (NCCD) updated their classification system to define and expand cell death subroutines that are broadly grouped into apoptotic versus necrotic morphologies with regulatory cell death modes. As such, 12 interconnected cell death processes have been defined: intrinsic and extrinsic apoptosis, mitochondrial permeability transition-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagydependent cell death, and immunogenic cell death.26 Although these are distinct forms of cell death, the stimuli and processes involved interrelate. Moreover, there is evidence that IR can manifest its cytotoxicity by several of these types of cell death. Therefore, as our understanding of these cell death pathways improves, novel therapeutics targeting these forms of cell death could enhance radiation efficacy. A few key cell death mechanisms related to radiation are briefly described here.

Apoptosis Apoptosis is the most clearly defined and studied mechanism of cell death. This “programmed cell death” involves characteristic morphological changes, including chromatin condensation (nuclear pyknosis) and nuclear fragmentation (karyorhexis). Apoptotic bodies ultimately form and the cell is removed through phagocytosis but without generating an inflammatory response. Apoptosis can occur with or without caspase activation27,28 and does not require DNA fragmentation,29 though this is a classic hallmark. Apoptosis is considered the major mechanism for chemotherapy-induced cell death. As a mechanism for radiation-induced cytotoxicity, apoptosis occurs readily in “liquid tumors” as opposed to most solid tumors, in which apoptosis is a minor component of cell death. As such, drugs targeting the apoptotic pathway may enhance radiation cytotoxicity in solid tumors.

Autophagy Whereas apoptosis is a clear self-destruct mechanism for the cell, the role of autophagy in cell death is more controversial. Autophagy, literally meaning “self-eating,” can provide a protective mechanism for a cell during times of stress (such as nutrient deprivation) because it allows recycling of cellular building blocks through a controlled breakdown of cytoplasmic components. However, autophagic cell death does occur that principally differs from apoptosis due to the lack of chromatin condensation.29

Necrosis Type 3 death, or necrosis, is a cell death mechanism in which the cell swells (oncosis), ruptures the plasma membrane, and releases its contents, resulting in a local inflammatory response.29 The best example of this type of cell death is ischemic injury. Large single-fraction radiation, or radio-ablative doses, can produce this type of cell death, as seen in stereotactic radiosurgery of brain lesions.

Mitotic Catastrophe Mitotic catastrophe is a unique form of cell death that involves failed mitotic events.29 Typically, this is manifest as micronucleation and multinucleation, suggesting that a series of mitotic divisions occurs without cytokinesis, which ultimately leads to cell death.

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CHAPTER 4

ANALYZING DRUG-RADIATION INTERACTION Several methodologies for determining the interaction between a drug and radiation have been detailed in the literature. Moreover, several definitions for the possible interactions have also been described. The concept of radiosensitization originated many years ago; classic radiosensitization has been defined as an increased amount of radiationinduced cell death that results from exposure to a second agent after correction for the cytotoxicity of this agent. Clonogenic survival assays, which measure all forms of cell death as well as prolonged or irreversible cell cycle arrest, is the most encompassing method of measuring radiation cytotoxicity in vitro (Fig. 4.1). Survival curves are generated by plating known quantities of cells on plates and treating them with various doses of radiation and/or chemotherapy and plotting the surviving fraction of colonies formed in a semi-logarithmic fashion. Normalization is performed by dividing the surviving fraction for treated groups by the plating efficiency, which relates to the percentage of untreated cells that form colonies. Modification in radiosensitization is demonstrated in clonogenic survival curve data in which a downward or leftward shift of the normalized surviving fraction implies a radiosensitizing interaction, while an upward or rightward shift implies a radioprotective shift. While survival curves can show interaction between chemotherapy and radiation, a better description of radiation modulation is necessary since both chemotherapy and radiation cytotoxicity do not typically follow a linear relationship. One of the early attempts at providing a more descriptive system was provided by Tyrrell,30 which may be a better starting point for describing various interactions among therapies: Antagonism: Used in all cases in which the action of two treatments is less than would be expected from the addition of the two treatments given independently. Zero interaction: Used when two treatments lead to the effect expected from the addition of the two treatments given independently. Positive interaction: Used in all cases in which the action of two treatments is greater than would be expected from the addition of the two treatments given independently. Synergism: A special case of a positive interaction; used strictly when kinetic data are available.

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Interaction of Chemotherapy and Radiation

These terms seem to have been supplanted by the “additivity” descriptors, including supra-additive, additive, and infra-additive. Once again, the classic paper by Steel and Peckham7 describes the construction of an “envelope of additivity” for evaluating the interaction of two treatments using isobologram analysis. This envelope of additivity is constructed from cytotoxicity data by calculating a mode 1 curve that assumes that both agents have completely independent mechanisms of action and a mode 2 curve that assumes that the two agents have exactly the same mechanism of action (additional information on isobologram construction can be found online). When plotting combination therapy data points on the isobologram, they can either fall between mode 1 and 2 (additive interaction—within the envelope), above mode 1 (infraadditive), or below mode 2 (supra-additive, or synergistic). An idealized isobologram is shown in Fig. 4.2. A step-by-step method for constructing an isobologram is presented in the online supplement for this chapter at ExpertConsult.com.

Median Dose Effect Principle A mathematical modeling system that has gained fairly widespread use for interactions of cytotoxic agents is the median effect principle of Chou and Talalay.31–33 This system was derived from Michaelis-Menten equations and basic mass-action law considerations. This system has been useful for describing competitive enzyme interactions and interactions of cytotoxic agents. The primary relationship of the median effect principle is described by the following equation: fa/fu = (D/Dm)m, in which D is dose, fa is the fraction affected, fu is the fraction unaffected, Dm is the dose required to produce the median effect (50%), and m is a Hill-type coefficient used to describe the sigmoid nature of the curve. For first-order Michaelis-Menten kinetics, m = 1. The following manipulation of this equation can be performed, with surviving fraction (SF) substituted for fraction unaffected in the last step: log(fa fu ) = log[(D Dm )m ] log(fa fu ) = mlog(D) − mlog(Dm ) log[(1 SF) − 1] = mlog(D) − mlog(Dm ) The general equation is y = mx + b

1.0

Infra-additive

lo pe

0.5

of

Radioprotection

ve

0.1

ad di

Dose A (RT)

0.75 En

Surviving fraction

1.0

tiv ity

0.25

Supra-additive

Radiosensitization 0.01 0

2

4

6

8

Gy Fig. 4.1 Graph of the concept of radiation modulation. The solid line indicates the control clonogenic survival assay plotted as surviving fraction relative to dose in Gy. A combined treatment that causes a rightward shift of the curve indicates a radioprotection effect; a leftward shift of the curve indicates a radiosensitization effect.

0.0 0.0

0.25

0.5

0.75

1.0

Dose B (drug) Fig. 4.2 Graph of an isobologram for examining the interaction of radiation (RT) and a drug. Isoeffective doses of A (RT) and B (drug) are indicated on the axes. This diagram shows regions of infra-additivity and supraadditivity as well as an envelope of additivity.

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CHAPTER 4

STEP-BY-STEP METHOD FOR CONSTRUCTING AN ISOBOLOGRAM The following is a step-by-step procedure for calculating isobolograms using Steel and Peckham’s method7,31 (see eFig. 4.1). Step 1. The investigator must choose to make the assessments at one level of cytotoxicity (e.g., construct an isobologram that represents the interaction of the agents for a cumulative cytotoxicity of 50%, 10%, or 1%). The example in eFig. 4.1 depicts the chosen level of cytotoxicity as horizontal line Z: 1% cytotoxicity (0.01 surviving fraction) in this case. Step 2. Plots are made of dose-response data for both agents. In eFig. 4.1, the dose-response data for the two agents are represented by curves A and B. Step 3. The extreme points of the envelope of additivity are determined. Initially, a separate Cartesian graph is created. The y-axis represents the dose of agent B and the x-axis the dose of agent A. The first extreme point of the envelope is placed on the y-axis at the dose of agent B alone that causes a specific level of cytotoxicity, as determined by the dose-response curve of agent B, at the intersection of line Z (see eFig. 4.1). The second extreme point of the envelope is placed on the x-axis at the dose of agent A alone that results in that level of cytotoxicity at the intersection of the dose-response curve with line Z (see eFig. 4.1).

Interaction of Chemotherapy and Radiation

Step 4. The mode 1 line is constructed assuming that the agents function independently. The individual dose-response curves are used for this construction. After exposure to dose X of agent A (XA), a level of cytotoxicity is obtained at a point on the dose-response curve that is above line Z. This level of cytotoxicity is identified as Y. Next, the dose of agent B (XB) that is required to produce cytotoxicity equal to the difference in cytotoxicity at line Z and point Y (identified as C) is determined. The Cartesian coordinate (XA, XB) is plotted and becomes a point on the mode 1 line. The entire mode 1 line is constructed in this manner by varying the dose of agent A (for a resulting level of cytotoxicity that falls above line Z) and subsequently calculating the appropriate complementary dose of agent B as described. Step 5. The mode 2 line is constructed assuming that the two agents have the same mechanism of action. As for mode 1 line construction, exposure to dose X of agent A (XA) results in a level of cytotoxicity identified as Y. The dose-response curve for agent B is then examined. The dose of agent B required for cytotoxicity equivalent to Y is determined and identified as YB. The change in dose of agent B that is required to increase cytotoxicity from YB to line Z is determined and labeled ΔB. The Cartesian coordinate (XA, ΔB) is plotted. Similar points are calculated for various initial doses of agent A, and the mode 2 line is formed. The mode 2 line varies in shape depending on whether agent A or agent B is selected first Points of the Envelope

A

B

Z

Step 1!2

log Surviving fraction

1

Step 3

Dose of A

Mode 1 Line

Mode 1 Line

C C A

0.01 Step 4

XA

B

Z

Point of envelope (steps) XB

Step 4

XB Dose

Mode 2 Line Y

Y

0.1 0.01

A

B

XA

∆B Dose

Point of envelope (step 3) XA Dose of A

Z

Experimental point (J,P) suggesting antagonism XB ∆B

Step 6

Step 5

First point mode 1 line (XA, XB)

Experimental Points Dose of B

log Surviving fraction

1

Dose of agent A required for Z cytotoxicity

Dose

Y 0.1

Dose of agent B required for Z cytotoxicity

Dose of B

0.01

Dose of B

log Surviving fraction

Dose-Response Studies for Agents A and B 1 0.1

65.e1

Mode 2

Mode 1

XA Dose of A

eFig. 4.1 Step-by-step construction of an isobologram to define an envelope of additivity for two cancer treatments. Isobologram analysis is used to evaluate the interaction of two treatments, and it requires the construction of an envelope of additivity that is bordered by mode 1 and mode 2 lines. The mode 1 line assumes that the two agents have completely independent mechanisms of action; the mode 2 line assumes that the two agents have the same mechanism of action.

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Scientific Foundations of Radiation Oncology

for step 5. Generally, the mode 2 line that results in the greatest separation from the mode 1 line is chosen for the envelope of additivity. Step 6. The two agents are given concomitantly, and a dose-response curve for concomitant treatment is obtained (typically by holding the dose of one agent constant while varying the dose of the other). The doses of the individual agents that result in combined cytotoxicity equivalent to the level represented by line Z are plotted (J, P). This procedure allows for characterization of experimental data. The experimental point (J, P) represents an antagonistic interaction if the point falls above the envelope of additivity. The effect of the combination treatment is less than would be expected if the agents had completely independent mechanisms of action. An experimental point that falls directly on the mode 1 line suggests that the agents have independent mechanisms of action and the interaction is additive. An experimental point that falls below the mode 2 line suggests a synergistic interaction between the two agents for the particular concomitant treatment used.

The most difficult result to interpret is an experimental point that falls within the envelope of additivity. In some respects, the envelope of additivity is a misnomer, because experimental points that fall in this range display an interaction that is greater than the additive effect that is achieved if the agents function by completely independent mechanisms. The interaction between the agents may be positive if the agents have independent mechanisms of action or may be negative if they have identical mechanisms of action. Although the isobologram analysis is useful, it is somewhat limited because interactions in each analysis are investigated at a single level of cytotoxicity. The investigation of interactions at several levels of cytotoxicity requires the construction of several envelopes of additivity. The ambiguity associated with experimental points that fall within the envelope can be disconcerting and may lead to erroneous conclusions, especially if several levels of cytotoxicity are not investigated. Other mathematical modeling systems have been developed to assess the interaction of agents that cause cytotoxicity. These assessments aim to account for the kinetics of cytotoxicity of the involved agents and to assess multiple levels of cytotoxicity.

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SECTION I

Scientific Foundations of Radiation Oncology Agent A Combination Agent B

log [(1/SF) – 1]

1 0.1 0.01

!1

0

1

2

log dose

3 Combination Index

66

2

Line of additivity Antagonistic

1 Synergistic 1

0.1

0.01

0.001

log SF

Point represents a contribution of doses A and B of the 2 agents given in a fixed ratio (e.g., 1:2) Fig. 4.3 The hypothetical graph (left) demonstrates the median effect principle analysis for agents A and B given alone or in combination. The combination treatments are given in a fixed ratio so that the individual contribution of each agent to the combined effect can be calculated. The combination index (right) is then calculated at various levels of cytotoxicity as measured by surviving fraction (SF). The areas of antagonism, additivity, and synergism are indicated.

A plot of log[(1/SF) – 1] on the y-axis and log(D) on the x-axis results in a line with a slope of m and a y-intercept of mlog(Dm). The survival curves for the individual agents and for the combination treatment (the individual agents given together in some fashion) can be fitted to the equation for a line by linear regression. If the interaction of two agents is assessed, three lines (i.e., median effect plots) are produced: one for each agent and one for the combination treatment. A graph of the median effect plots for mock individual agents A and B and for the combination of A and B is shown in Fig. 4.3. For the combination treatment, D is the sum of the doses of the two agents given concomitantly; it is helpful to perform the experiments with the two agents given together in a fixed ratio of doses (e.g., 1 : 2). By using various total doses (i.e., the sum), with the agents given in the same ratio, it is possible to determine the contribution of the individual agents to the combination treatment in a later calculation. This concept can be visualized in Fig. 4.3. For instance, in the case of log[(1/SF) – 1] = 0, where SF is surviving fraction, the corresponding log(D), D indicating the sum of the doses of the two agents, can be calculated from the median effect plot for the combination treatment. An example of an actual combination treatment that has been assessed in this manner is radiation followed by a 24-hour exposure to etoposide.31 In this example, a set of experiments was performed with the dose ratio fixed as 32 Gy to 1 μg/mL of etoposide. In this example, the dose D that resulted in log[(1/SF) – 1] equaling a given value was a combination of radiation and etoposide given in the ratio of 32 : 1. The radiation and etoposide components could be discerned from the median effect plot of the combination treatment by dividing the resulting dose into the appropriate components based on the ratio of delivery of the two agents. Definitions used in the median effect principle include the following: Mutually exclusive: The agents of interest have similar modes of action and do not act independently. Nonmutually exclusive: The agents of interest have different modes of action or act independently. Combination index (CI): The derivation of this index is beyond the scope of this chapter. Calculation of the CI allows characterization of an interaction as synergistic (CI < 1), antagonistic (CI > 1),

or a summation (CI = 1). Chou and Talalay33 provide a full description. The CI can be calculated for any surviving fraction and for mutually exclusive or mutually nonexclusive interactions. For a mutually exclusive interaction, CI = [D1 (Dx)1] + [D2 (Dx)2 ]. For a mutually nonexclusive interaction, CI = [D1 (Dx)1] + [D2 (Dx)2 ] + [D1D2 (Dx)1(Dx)2 ], in which (Dx)1 = Dm[(1/SF) – 1]1/m, solving the general equation for agent 1 given alone in a dose x. (Dx)2 = Dm[(1/SF) – 1]1/m, solving the general equation for agent 2 given alone in a dose x. (Dx)1,2 = Dm[(1/SF) – 1]1/m1,2, solving the general equation for the agents given in combination for dose x, which represents the sum of the doses of the agents given in a fixed combination. D1 = (Dx)1,2 × (fraction of the mixture that is agent 1). D2 = (Dx)1,2 × (fraction of the mixture that is agent 2). The CI represents the doses of the agents required for a given effect when they are given together divided by the doses required when the agents are given alone; in this way, a CI less than 1 represents a synergistic interaction. A diagram of a CI plot for various levels of surviving fraction is shown in Fig. 4.3. Despite the advent of these robust statistical tools for determining the additivity relationship between treatments, the applicability outside of in vitro models is limited based on time and expense necessary to complete dose-response experiments for both drugs and radiation. Therefore, preclinical in vivo experimentation typically involves the use of a single drug dose at a concentration that can be achieved clinically. Nevertheless, there continue to be calls for improved experimental design strategies for drug-radiation combination research.34

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CHAPTER 4

Interaction of Chemotherapy and Radiation

CHEMOTHERAPY AND RADIATION AND COMBINATIONS OF CYTOTOXIC AGENTS General Concepts From the Bench to the Clinic Occasionally, the process of quantifying interactions of chemotherapy and radiation has frustrated clinicians attempting to interpret in vitro and in vivo laboratory information, as exemplified by Charles Moertel (quoted by Tannock35) in his keynote speech at the first International Conference on Combined-Modality Therapy in 1978: Based on the results of various individual studies, I could conclude that it is most ideal to administer the nitrosourea 15 hours before irradiation, 2 hours before irradiation, simultaneously with irradiation, or 6 hours after irradiation. While we will continue to cheer our radiation biology colleagues on from the sidelines, I am afraid that we are not yet at the stage where we can comfortably incorporate their results into our clinical practice. This was not meant as disrespect for the radiobiology community but rather to point out that, at that time, the laboratory models were potentially quite different from the clinical setting. Because it has been difficult to extrapolate from laboratory results to clinical results, many clinicians have used combination treatments on a trial-and-error basis. However, the reverse order of study has occasionally been fruitful, and efficacious combinations of treatment demonstrated in clinical studies have inspired laboratory investigations that revealed interesting molecular bases of interaction.31,32 Translational research ideally occurs with a concept that arises from laboratory findings and subsequently is shown to have clinical efficacy. However, preclinical model systems have not always allowed investigators to take findings from the laboratory to the clinic, as indicated by the quotation of Moertel and by many of the early hypoxic cell sensitizer studies.

Therapeutic Benefits Tannock35 mentioned another problem with translating findings from the laboratory to the clinical setting, emphasizing that investigators must not merely explore combinations of therapeutic agents to find synergistic interactions but must also find interactions that will produce a therapeutic benefit (e.g., provide greater cytotoxicity in tumor cells than in normal cells). To categorize potentially exploitable differences, Tannock35 described three main categories of biological diversity between tumor cells and normal cells: tumor cells may display genetic instability compared with normal tissues; tumor cells and normal cells may be different with respect to cellular proliferation or proliferation that occurs after treatment; and environmental factors such as oxygenation and pH may affect tumor cells and normal cells differently. As findings are translated from the laboratory to the clinical setting, it is important to consider the effects of the host mechanisms on these three areas.

Chemotherapeutic Classes In the next section, several classes of systemic agents will be presented, followed by a brief review of clinical data describing combination treatment of these agents with radiation. There are a host of chemotherapeutic classes that are used in patients who will undergo radiation treatment. Although not all of these agents are used concurrently with radiation, it is helpful to understand their predominant mechanism of action. What follows is a brief description of several of the major classes of chemotherapeutics with some information regarding possible means of interaction with radiation. Fig. 4.4 summarizes the cell cycle phase specificity of these agents.

67

Cell cycle independent agents: alkylating agents Paclitaxel Etoposide Bleomycin Dactinomycin Vinca alkaloids

G2/M

G1

Dactinomycin 5-FU

S Gemcitabine Irinotecan 5-FU Topotecan Capecitabine Etoposide Methotrexate Camptothecin Adriamycin Vinca alkaloids Fig. 4.4 Diagram of the cell cycle with the cell cycle phase dependence of various chemotherapeutics. 5-FU, 5-Fluorouracil.

Antimetabolites The origin of antimetabolite chemotherapy dates back to the 1940s, when aminopterin was used to treat pediatric leukemia.36 Since then, a large number of antimetabolite chemotherapeutics have been developed with tremendous success. The targets for these drugs include folate metabolism and nucleoside analogs. The major antimetabolites associated with radiation are presented next. Fluoropyrimidines: fluorouracil, fluorodeoxyruridine, capecitabine, S-1. The fluoropyrimidines, as the name implies, are halogenated pyrimidines that function as antifolates by inhibiting thymidylate synthesis. As mentioned previously in historical perspectives, 5-FU is one of the most established drugs used in combination with radiation. It has been used in both a bolus infusion as well as a continuous venous infusion when combined with radiation and appears to target the radioresistant cells in S phase.17 The two delivery methods have some differences in terms of side effect profile, but both seem to have good efficacy. In a Phase III rectal cancer postoperative adjuvant chemoradiation trial, concurrent continuous infusion 5-FU during EBRT was more effective than the bolus delivery.37 Moreover, data shows that 5-FU plasma levels and intracellular metabolite levels are rather short-lived,38 also suggesting a need for continuous administration of the drug to be effective with radiation. Because of this, oral formulations have been developed, most notably capecitabine, a fluoropyrimidine carbamate prodrug of 5-FU, which must be converted through the action of thymidine phosphorylase. In addition to the improved patient comfort of taking an oral medication rather than having an infusion pump, another potential advantage of capecitabine in combination with radiation is that it appears that radiation increases thymidine phosphorylase levels in tumors, allowing potential bioaccumulation of active metabolite within the irradiated tumor.39,40 S-1 is a more recently introduced oral formulation that combines a different 5-FU prodrug (tegafur) with 5-FU metabolism modifiers (gimeracil and oteracil). S-1 is commonly used in Asia and Europe for many types of solid tumors and has been combined with radiation treatment but has not yet been approved by the US Food and Drug Administration (FDA).41 Deoxycytidine nucleoside analogs: gemcitabine, cytarabine. Gemcitabine is an analog of deoxycytidine that specifically functions during the S phase by preventing deoxyribonucleotide triphosphate (dNTP) production. There is both preclinical and clinical evidence demonstrating dramatic radiation-sensitizing properties to combined gemcitabine and radiation.42–45 In fact, a significant amount of toxicity has been

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demonstrated in clinical trials for pancreatic cancer,46 necessitating either decreased dose of gemcitabine or limited field size for radiation treatment ports. Cytarabine, also known as ara-C, is a deoxycytidine nucleoside analog that penetrates the central nervous system (CNS) and is used for hematological malignancies. Cytarabine has been used following whole-brain irradiation for CNS lymphoma47 but is being explored concurrently in leptomeningeal disease.48 Antifolates: methotrexate, trimetrexate, pemetrexed. The antifolate methotrexate tightly binds dihydrofolate reductase (DHFR), thereby inhibiting folate metabolism. Through this inhibition, thymidylate synthesis is blocked and, thus, purine biosynthesis. In addition, some amino acid synthesis is impaired through blockade of this enzyme, resulting in cytotoxicity.49 Pemetrexed is a pyrrolopyrimidine that functions as an antifolate that inhibits multiple enzymes, including thymidylate synthase, DHFR, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide formyl-transferase in a cell cycle–independent manner. Pemetrexed is effective against many solid tumors and has shown radiosensitizing properties in preclinical systems.50–52

Alkylating Agents Alkylating agents are composed of several classes of electrophilic compounds that share the antitumor characteristic that they form covalent bonds with (“alkylate”) DNA bases. Some alkylators interact with a single strand of DNA while others can cross-link two strands. The induced DNA damage leads to the cytotoxicity of these agents. The various classes of alkylators that are potentially used with irradiation are briefly presented here. Nitrogen mustard: chlorambucil, melphalan. The first of a long series of alkylating agents developed for clinical use, mustard gas was discovered based on clinical observations of people and animals exposed to mustard gas during World War I, particularly the effect on bone marrow.36,53 Later, nitrogen mustards were developed for lymphoma therapy as mechlorethamine or Mustargen, eventually used in the Mustargen, vincristine (Oncovin), procarbazine, and prednisone (MOPP) regimen for Hodgkin lymphoma. The most commonly used nitrogen mustards are chlorambucil and melphalan (L-phenylalanine mustard) and are principally used for the treatment of chronic lymphocytic leukemia and multiple myeloma, respectively. Because of the bone marrow effect of these drugs, caution should be used when irradiating large volumes of bone marrow. Oxazaphosporines: cyclophosphamide, ifosfamide. The oxazaphosphorines are nitrogen mustard–like compounds that include cyclophosphamide and its structural isomer, ifosfamide. These agents are used in combination with radiation in both pediatric and adult cancer treatments. Mitomycin C. Mitomycin C (MMC) is an antibiotic with alkylating characteristics derived from Streptomyces. This agent is an aziridine ring–containing compound that resembles nitrogen mustard as well. This drug blocks DNA synthesis but also causes cell cycle arrest during G2/M phase transition.54,55 MMC has also been shown to function well as a hypoxic cell radiosensitizer,56 which may help explain why MMCbased chemoradiation is so effective in anal cancer treatment,57,58 as discussed later in this chapter. Triazines: procarbazine, dacarbazine, temozolomide. Temozolomide has revolutionized the treatment of high-grade gliomas in combination with irradiation. It effectively crosses the blood-brain barrier (CSF can achieve 30% of plasma levels).59 Temozolomide generates DNA damage through methylation of DNA at the O-6 position of guanine. Interestingly, the O-6 methylguanine DNA-methyltransferase (MGMT) is a p53 DNA repair enzyme that can be regulated epigenetically and silenced by promoter methylation, which appears to predict for response to

temozolomide-based chemoradiation because of the inability of the cancer cell to remove the O-6 methylguanine causing cytotoxicity.60 Indeed, this DNA alkylation/methylation from temozolomide triggers the mismatch repair pathway with a G2/M phase arrest yielding apoptosis and radiosensitive cells.61 Ongoing clinical trials are examining the importance of MGMT status and combining temozolomide with other agents.60,62 Nitrosoureas: BCNU, methy-CCNU, CCNU, streptozotocin. Several members of the nitrosourea group of alkylating agents are capable of crossing the blood-brain barrier and cross-linking DNA. Bischloroethylnitrosourea (BCNU), or carmustine, has been used to treat brain tumors, predominantly gliomas, but has also been used for multiple myeloma and high-dose transplant regimens. Gliadel (BCNU-impregnated wafer) can be placed in a glioma resection cavity, which biodegrades slowly to release the chemotherapeutic. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), or lomustine, is a related compound with increased lipid solubility also used for brain tumors.63 CCNU, procarbazine, and vincristine—when combined with radiation—has been shown to improve overall survival in low-grade gliomas.64

Platinums: Cisplatin, Carboplatin, Oxaliplatin, Satraplatin Cisplatin (cis-diammine dichloroplatinum[II]), the prototypical and most widely studied member of the platinum family, has been used for decades as an anticancer treatment. Preclinical work in the late 1970s by Soloway et al. demonstrated radiosensitization in a murine model of transitional cell carcinoma.65 Since then, a host of both clinical and preclinical data suggests several mechanisms of interaction between cisplatin and radiation. Potential cooperation between the two modalities can occur at the level of DNA because radiation often causes repairable single-strand breaks (SSBs) in DNA, which can be converted to lethal double-strand breaks (DSBs) when they occur close to cisplatin-DNA adducts (intra- and interstrand cross-links). This may also be due to the ability of cisplatin to function as a free-electron scavenger that impairs the DNA repair mechanism, thus, “fixing” the radiation-induced DNA damage.66 Similarly, there is growing evidence that cisplatinmodified DNA is susceptible to hydrated electron damage (e-aq) produced by IR in water.67 In addition, radiation may enhance the uptake of cisplatin into the cell and help generate active platinum metabolites.1 The other family members—carboplatin, oxaliplatin, and the orally active satraplatin—appear to have similar mechanisms of action, although differences among the members may be due to the three-dimensional structure of the DNA adducts that each platinum generates, which influences binding to various polymerases and DNA repair enzymes.68 For these reasons, the platinums function independently of the cell cycle phase.

Microtubule Targeting Because microtubule polymerization and depolymerization are critical for spindle formation and chromosome segregation during mitosis, microtubule targeting agents have the ability to enhance radiation effect by creating a cell cycle blockade during M phase, which is a radiationsensitive phase of the cell cycle. Moreover, these agents promote apoptosis as well. The four predominant classes of microtubule targeting agents are discussed here. Estramustine. Estramustine is an interesting hybrid molecule that is derived from both nitrogen mustard and 17β-estradiol. Estramustine effectively blocks microtubules by binding β-tubulin and microtubuleassociated proteins, resulting in destabilization of microtubules. This targets the mitotic spindle and leads to cell cycle arrest during M phase, causing radiosensitization.69 This drug has been approved for hormonerefractory prostate cancer for over 3 decades.

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CHAPTER 4 Vinca alkaloids: vincristine, vinblastine, vinorelbine. The vinca alkaloids have been used as anticancer agents for well over 40 years and function by targeting microtubules. They are able to force depolymerization of microtubules and, thus, disrupt the mitotic spindle, resulting in an M-phase blockade.70 These drugs have been used for a wide variety of malignancies, both pediatric and adult. In terms of radiosensitization, vincristine, vinblastine, and vinorelbine impact cell cycle effects and DNA damage repair.9,70 Taxanes: paclitaxel, docetaxel, cabazitaxel, albumin-bound paclitaxel. As opposed to the vinca alkaloids, the taxanes stabilize microtubules and promote further tubulin polymerization, which inhibits centrosome mechanics during mitosis. In terms of enhancing radiation effect, the taxanes appear to manipulate several of the factors listed in Table 4.1. First, the taxanes will block the metaphase-anaphase cell cycle checkpoint, which could allow for accumulation of cells in the radiosensitive G2/M phase.70,71 Furthermore, taxanes can cause tumor shrinkage,72,73 thereby decreasing interstitial pressure and allowing for improved oxygenation.19 In addition, taxanes can manipulate signal transduction cascades involved in radiation response.74 One of the major challenges in using taxanes is the toxicity of the vehicle (e.g., cremophor for paclitaxel). Using cremophor-free formulations, such as albumin nanoparticle (nab-paclitaxel), greatly improves tolerability through reduction in hypersensitivity reactions and may even promote enhanced radiation sensitivity.75 Epothilones: epothilone B, aza-epothione B (ixabepilone). The epothilones are considered to be next-generation microtubule targeting agents that function similar to taxanes but are derived from myxobacterium. They are able to stabilize microtubules with high potency and halt mitosis, similar to taxanes.70 These drugs were developed to be independent of the p-glycoprotein efflux resistance mechanisms that target taxanes and vinca alkaloids.70,76 Despite some reports of radiation recall with ixabepilone,77 there remains some interest in combining epothilones with radiation.78

Topoisomerase Inhibitors Topoisomerases are critical enzymes in DNA replication of all cells because of their ability to unwind DNA. There are two major classes of topoisomerases in mammalian cells that are clinically relevant for oncology therapeutics: topoisomerases I and II. Topoisomerase I (TopI) is involved in DNA replication fork movement and unwinding supercoils during DNA transcription; topoisomerase II (TopII) is important for untangling DNA during transcription and remodeling chromatin.38,49 These classes are named based on how many DNA strand breaks are created during enzymatic action, an SSB for TopI and DSB for TopII.49 These breaks are required for TopI and TopII to unwind and disentangle DNA but are temporary, as the enzyme will reconnect the broken strands (religation). TopI/II inhibitors function by stabilizing/trapping the enzyme complexes and have cytotoxicity by disrupting the process and generating DNA DSBs. Topoisomerase I inhibitors: camptothecins—irinotecan, topotecan. Camptothecin is a naturally occurring alkaloid derived from the plant Camptotheca acuminata that was identified in an anticancer drug discovery screen in the 1960s.79 Camptothecin is believed to form a stable ternary complex that prevents normal DNA religation and a collision of the complex with the replication fork occurs, leading to a DNA DSB and cytotoxicity.80 The S-phase specificity of this drug class provides some of the rationale for radiosensitization. The drug was unsuccessful in the clinic owing to severe urinary complications, although camptothecin is still used as a research tool and positive control for cytotoxicity and apoptosis. However, derivatives of camptothecin— notably, irinotecan and topotecan—are used as chemotherapeutics. Irinotecan is FDA approved for colorectal cancer, and data related to

Interaction of Chemotherapy and Radiation

69

concomitant administration with radiation has been generated in rectal cancer,81,82 esophageal cancer,83 small-cell84–86 and non–small cell lung carcinoma patients.87,88 Topotecan is approved for ovarian, small-cell, and cervical cancer but has been combined with radiation in glioblastoma clinical trials.89,90 Liposomal forms of TopI inhibitors may further enhance the utility of this class of drug by itself or in combination with radiation.91,92 Topoisomerase II inhibitors Podophyllotoxins: etoposide, etoposide phosphate, teniposide. The plant extract podophyllotoxin has microtubule binding activity; yet, the clinically used derivatives do not function through microtubule action but actually are TopII poisons, although they do not intercalate DNA.93 These epipodophyllotoxins, most notably etoposide and teniposide, are glycoside derivatives that are used in both childhood and adult tumors.38 These drugs have also been used with radiation in both sequential and concomitant regimens.94–97 Anthracyclines: idarubicin, doxorubicin, epirubicin, daunorubicin, idarubicin. Anthracyclines are naturally occurring substances that intercalate into the DNA when they target TopII, leading to DNA DSBs.38,98 These drugs have a wide range of clinical indications, including both hematological and solid tumors. In terms of radiation sensitization, the interaction of doxorubicin and radiation are well known, such that concurrent administration is generally avoided. In fact, when doxorubicin is given after radiation, an inflammatory reaction known as “radiation recall” can occur.99,100 As with other chemotherapeutics, there is interest in alternative formulations. The polyethylene glycol(PEG)ylated liposomal form of doxorubicin was approved over 20 years ago with an improved toxicity profile.101 Others: mitoxantrone, dactinomycin. Mitoxantrone is an anthracenedione that was designed to function like an anthracycline but have less cardiotoxicity102 because it is less likely to form free radicals38 and may affect calcium release differently.103 Like anthracyclines, mitoxantrone can intercalate in DNA and poison TopII to form DNA DSBs. This drug is approved for hormone-refractory prostate cancer and acute myeloblastic leukemia. Dactinomycin is a Streptomyces-derived antibiotic that can intercalate in DNA, block TopII, and cause DNA DSBs.38 Dactinomycin is used in several pediatric malignancies, including rhabdomyosarcoma and Ewing sarcoma.

CHEMORADIATION CLINICAL EXAMPLES An all-encompassing review of the clinical examples of the use of chemoradiation is beyond the scope of this chapter. More comprehensive information regarding disease site–specific trials are included in the individual chapters devoted to each site. What follows is a brief account of some of the landmark trials that have demonstrated improved organ preservation, local control and overall survival in the modern era. Specifically, aerodigestive, genitourinary, gynecological, and CNS cancer examples are presented.

Gastrointestinal Cancers Anal Cancer

A classic example of the evolution of an efficacious interaction of chemotherapy and radiotherapy is combined-modality treatment for anal cancer. In the early 1970s, it was discovered that anal cancer could be treated successfully with a combination of 5-FU, MMC, and irradiation.58 In 1974, Nigro et al.58 reported on 3 patients who received variations of these 3 treatments, with excellent responses to the preoperative therapy (see eTable 4.1). This article became a classic in the oncology literature, and the regimen became prominent in the treatment of anal cancer. Because of this regimen, many patients were spared abdominal perineal resection.

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CHAPTER 4

Interaction of Chemotherapy and Radiation

eTABLE 4.1 Combined-Modality Treatment for Anal Cancer: A Study of Three Patients Patient

RT

Chemotherapy a

Results

1

34.7 Gy/5 wk

Concomitant 5-FU / porfiromycin (50 mg)

APR 9 wk after RT, NED

2

30.6 Gy/17 fx

Concomitant 5-FUa/ mitomycin (30 mg)

Clinically free of disease, patient refused APR

3

30 Gy/15 fx

None

APR 8 wk after RT, NED

a

Dose of 1500 mg of 5-fluorouracil in the form of a continuous 24-hour infusion for 5 days. APR, Abdominoperineal resection; 5-FU, 5-fluorouracil; fx, fractions; NED, no evidence of disease; RT, radiation therapy. Data from Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17:354–356.

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69.e1

70

SECTION I

TABLE 4.2

Scientific Foundations of Radiation Oncology

Concomitant Radiation and Chemotherapy for Anal Cancer

Study

Regimen

Outcome

Nigro et al. (1974), Wayne State University

RT (30 Gy/15 Fx) with CI 5-FU (1000 mg/m ) for 4 days × 2 cycles and MMC (15 mg/m2) on day 1

Of 104 patients, 31 required APR.

Sischy et al.106 (1989), RTOG/ECOG

RT (40 Gy/20 Fx) with CI 5-FU (1000 mg/m2) for 4 days × 2 cycles and MMC (10 mg/m2) on day 2

Of 79 patients, 8 required APR.

Flam et al.105 (1996), RTOG/ECOG

RT (45 Gy/25 Fx) with CI 5-FU during weeks 1 and 4, with randomization to MMC (10 mg/m2) on days 1 and 29 vs. no MMC

Colostomy-free survival improved with MMC, 71% vs. 59% (p = 0.014).

Bartelink et al.104 (1997), EORTC

RT (60–65 Gya) alone vs. RT plus 5-FU (750 mg/m2 on days 1–5, 29–33) and MMC (15 mg/m2) on day 1

Improved event-free survival with RT and chemo compared with RT alone (p = 0.03)

Ajani et al.57 (2008), Gunderson et al.107 (2012)

RT (55–59 Gy) with CI 5-FU (1000 mg/m2) and MMC (10 mg/m2) on days 1 and 29 vs. CI 5-FU (1000 mg/m2) + cisplatin (75 mg/m2 on days 1 and 29) with induction chemotherapy

(N = 682); Improved DFS and OS at 5 y (67.8% vs. 57.8%; p = 0.006 and 78.3% vs. 70.7%; p = 0.026, respectively) for MMC arm

58

2

a

Surgery 6 weeks after initial 45 Gy if no response. APR, Abdominoperineal resection; chemo, chemotherapy; CI, continuous infusion; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; 5-FU, 5-fluorouracil; Fx, fractions; GI INT, Gastrointestinal intergroup; MMC, mitomycin-C; N, total number of patients; OS, overall survival; RT, radiation therapy; RTOG, Radiation Therapy Oncology Group.

After the initial report of Nigro et al.,58 several other groups confirmed the efficacy of chemotherapy and irradiation (without surgery) as the standard treatment for primary anal cancer (Table 4.2).58,104–106 Subsequently, an intergroup effort was undertaken by the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) to determine whether MMC could be removed from the regimen, because its inclusion resulted in increased toxicity compared with that of 5-FU and radiation without MMC. With 5-FU alone, however, fewer patients were able to avoid colostomy (see Table 4.2). Additional attempts at replacing MMC with less toxic concurrent chemotherapy have been undertaken, most notably in the US GI Intergroup study (see Table 4.2) coordinated by the RTOG (RTOG 98-11). This trial compared an induction chemotherapy (5-FU and cisplatin) regimen followed by the same chemotherapy concurrently with radiation versus standard concurrent chemotherapy (5-FU and MMC) with radiation. The hypothesis was that the induction chemotherapy would decrease tumor bulk, making radiotherapy more effective and, thus, improving local control and that the additional cycles of induction chemotherapy may improve overall survival (OS) by decreasing distant metastases. However, these hypotheses were disproven, as the cisplatin arm not only failed to show a benefit in terms of local control, disease-free survival (DFS), and OS, but was clearly inferior to MMC in terms of colostomy-free survival (CFS).57 Long-term follow-up of the trial not only confirmed initial results but, more importantly, demonstrated a statistically significant superior DFS and OS with 5-FU and MMC compared to induction and concurrent 5-FU and cisplatin.107 Therefore, the combination of 5-FU, MMC, and irradiation remains the standard regimen for anal cancer. IMRT strategies combined with 5-FU/MMC-based chemoradiation have been investigated by multiple groups and demonstrate a reduction in normal tissue toxicities.108–110 A discussion of how the laboratory investigations followed the clinical data can be found in the online supplement for this chapter at ExpertConsult.com.

Esophagus/Esophagogastric Junction Esophageal/esophagogastric junction cancer remains a very challenging cancer to treat, primarily owing to the locally advanced stage that is typically found at diagnosis. For nonsurgical approaches to treatment, radiation alone has been shown to be quite limited in terms of controlling the disease. Chemoradiation has been clearly shown to be

the treatment of choice following several landmark trials comparing chemoradiation to radiation alone. The Intergroup trial coordinated by the RTOG (85-01) originally published by Herskovic et al.114 and later updated by Cooper et al.115 randomized patients to either 64 Gy radiation alone at 2 Gy/fraction or 50 Gy in 2 Gy/fraction concurrent with 5-FU (1000 mg/m2/day for days 1–4) and cisplatin (75 mg/m2 on day 1). In the concurrent arm, the chemotherapy was given every 28 days during radiation and then every 21 days thereafter for two additional cycles. This trial established that radiation alone was inferior to combinedmodality chemoradiation (5-year OS 0% vs. 26%, p = 0.0001).115 A meta-analysis by Wong and Malthaner116 confirmed that concurrent chemoradiation was beneficial in terms of survival (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.64–0.84; p < 0.0001). Sequential chemotherapy and radiation did not show a statistically significant benefit, however.116 The role of trimodality therapy with neoadjuvant chemoradiation followed by surgery has also been investigated. Tepper et al.117 published the results of the US GI Intergroup study (CALGB 9781) that randomized patients to neoadjuvant cisplatin/5-FU/EBRT (50.4 Gy) prior to esophagectomy versus esophagectomy alone. Although the trial was closed early due to poor accrual, the 56 patients enrolled were analyzed on an intent-to-treat analysis. This revealed a significant difference in median and 5-yr OS with trimodality treatment versus surgery alone (median, 54 vs. 21.6 months; 5-year OS, 39 vs. 16%; p = 0.002).117 More recently, the CROSS group completed a large randomized Phase III study of 366 analyzable patients comparing neoadjuvant carboplatin/ paclitaxel/EBRT (41.4 Gy) prior to esophagectomy versus esophagectomy alone.118 Results of this study revealed that preoperative chemoradiation improved OS (median, 48.6 vs. 24 months; 5-year OS, 47 vs. 33%; p = 0.003; HR, 0.68; 95% CI, 0.53–0.88) without significant increases in acute side effects or postoperative complications. Pathological complete response was noted in 29% of patients with neoadjuvant therapy. A complete resection of the tumor (R0 resection) was accomplished in 92% of patients who underwent neoadjuvant therapy compared to 69% in patients who had surgery alone.119

Gastric The US GI Intergroup 0116 Phase III trial, reported by McDonald et al., compared adjuvant postoperative chemoradiation to surgery alone for patients with resected high-risk gastric or gastroesophageal cancers.

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CHAPTER 4

LABORATORY INVESTIGATIONS IN ANAL CANCER The clinical finding of the efficacious combination of 5-FU, MCC, and radiation led to laboratory studies. Dobrowsky et al.111 performed a complex isobologram analysis using the same agents reported by Nigro et al.58 The assessment by Dobrowsky et al.,111 using an in vitro system of a squamous tumor cell line, illustrated some of the difficulties with the ideal progression of taking laboratory discoveries to the clinic. Two different endpoints were used: colony formation (cells plated after treatment and allowed to form colonies) and viable cells per flask (obtained by multiplying the cell number per flask at 96 hours by the surviving fraction, as stipulated by a standard colony formation assay). In an attempt to duplicate the clinical treatment of Nigro et al.,58 MMC was given as a 1-hour exposure and 5-FU as a 4-day exposure after initial radiation. The first experiments assessed the interaction of 5-FU and MMC without radiation. Initially, a single dose of MMC (0.5 μg/mL for 1 hour) was combined with various doses of 5-FU. Isobolograms were constructed for the colony formation endpoint at a surviving fraction of 0.04. Isobologram construction showed that the combination treatment resulted in an experimental point below the envelope of additivity at this level of cytotoxic assessment. Isobolograms also were constructed for the viable cells per flask endpoint at the 1% viability level; the experimental point for combined 5-FU and MMC was directly on the mode 2 line. This endpoint was included because it was believed to account for the cytotoxic and cytostatic effects of the treatment. Because the results of this synergy analysis varied with the endpoint used, the optimal endpoint, whether colony formation or viable cells per flask, is not known. That the use of these slightly different endpoints produced slightly different isobologram results illustrates some of the problems in interpreting in vitro data and in attempting to extrapolate this information to the clinical setting. In the future, it may be possible

Interaction of Chemotherapy and Radiation

70.e1

to assess which endpoints may be most useful for various cytotoxic agents and various tumors on the basis of the relative contribution of cytotoxic and cytostatic effects for a given situation. On the basis of the experiments without irradiation, specific concentrations of MMC (0.5 μg/mL) and 5-FU (0.15 μg/mL) were selected for subsequent experiments involving radiation.111 These concentrations resulted in 60% and 80% surviving fractions, respectively. With colony formation as the endpoint, it was discovered that the interaction of irradiation and 5-FU or irradiation and MMC (at the levels of cytotoxicity assessed) produced experimental points below the envelope of additivity. These results corroborated those reported previously by Byfield et al.,112 in which some level of 5-FU cytotoxicity was required for a positive interaction with irradiation. However, the results of radiation in conjunction with MMC were not entirely consistent with those of previous reports, which had suggested that a positive interaction of these agents did not exist.113 The previous example illustrates several important points. If the protocol of Nigro et al.58 had been designed on the basis of laboratory studies (if all of the just-mentioned studies had existed in 1974), it would have been difficult to assess where to begin. First, the investigator would need to decide which in vitro endpoint would be most relevant to anal cancer (viable cells per flask or colony formation); this decision would affect whether one believed that 5-FU and MMC interacted synergistically. Second, the investigator would need to decide which assessment of MMC and radiation was most relevant to the treatment of anal cancer, because authors disagreed about whether this interaction was synergistic. This example also illustrates the challenges that are faced when interpretations of in vitro or in vivo experimental data are used to guide the design of clinical trials. These challenges can be exciting as we learn more about the significance of various endpoints at the molecular level and how these molecular events may be manipulated in a particular tumor.

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CHAPTER 4 Bolus 5-FU/leucovorin was given prior to EBRT (one 5-day cycle) concurrently with EBRT (2 cycles: 4-day week 1, 3-day week 5), and after EBRT (2 additional 5-day cycles). A survival advantage of concurrent chemoradiation was shown (3-year OS, 50% vs. 41%, p = 0.005; 3-year relapse-free survival, 48 vs. 31%, p = 0.001),120 and this treatment has been the standard of care for gastric cancer in the United States. In the United Kingdom, the MAGIC trial established a nonradiation regimen that involves perioperative (neoadjuvant and adjuvant) epirubicin, cisplatin, and 5-FU (ECF) chemotherapy as an appropriate standard of care for resectable gastric cancer.121 The logical follow-up study was a postoperative adjuvant US GI Intergroup Phase III trial (CALGB 80101) that essentially married the INT-0116 and the MAGIC trial by investigating the role of chemoradiation in the setting of more modern ECF chemotherapy as the experimental arm versus the control arm of GI INT-0116. Although the experimental arm did not improve survival, the ECF regimen had a more favorable toxicity profile.122 Most recently, a Scandinavian study has been published comparing chemotherapy to chemoradiotherapy in the adjuvant setting. The CRITICS trial was a Phase III trial that randomized patients receiving preoperative ECF-type of chemotherapy to get either adjuvant ECF for 3 cycles versus 45 Gy concurrently with CF. The median overall survival was identical (HR, 1.01; 95% CI, 0.84–1.22) with very similar toxicity profiles.123 Therefore, current focus has shifted to preoperative regimens. The CRITICS-II trial is an ongoing randomized Phase II study looking at three experimental arms in the preoperative setting for resectable gastric cancer: (1) docetaxel, oxaliplatin, capecitabine (DOC) × 4 cycles; (2) DOC × 2 cycles followed by 45 Gy chemoradiation with paclitaxel and carboplatin; or (3) 45 Gy with paclitaxel and carboplatin.124

Rectal Although rectal cancer is a surgically managed disease, the addition of adjuvant therapy is well recognized as a vital component of therapy. Four randomized trials125–128 investigating the addition of chemotherapy to neoadjuvant EBRT in stage II and stage III rectal cancer are summarized in Table 4.3 (the Bujko trial did not use the same dose/duration of EBRT; thus, it is not a true comparison of EBRT ± concurrent chemotherapy). Furthermore, a meta-analysis analyzed these four trials.129 Although this analysis showed improved complete pathological response rate and local control with the addition of chemotherapy to preoperative radiation, no benefit was found in terms of sphincter preservation, DFS, or OS. Of note, preoperative chemoradiation was found to produce increased grade 3 and grade 4 toxicity versus preoperative EBRT alone.

TABLE 4.3

Rectal Cancer Study

Interaction of Chemotherapy and Radiation

71

The current standard of care approach, however, was defined in the Phase III German Rectal Trial.130 Preoperative chemoradiation was shown to be superior to postoperative chemoradiation in terms of local control, sphincter preservation rates, and toxicity.

Head and Neck Cancers Head and neck cancer management for locally advanced tumors was traditionally managed with surgery and postoperative radiation. However, over the past 2 decades, an explosion of chemoradiation trials shifted the management toward an organ preservation approach (summarized in Table 4.4). One of the most impressive results for a randomized trial in head and neck cancer was that of Intergroup 0099 (RTOG 8817) originally published by Al-Sarraf et al. in 1998.131 In this trial of nasopharyngeal cancer patients, radiation alone (70 Gy at 2 Gy/fx) versus radiation with concurrent cisplatin with adjuvant cisplatin/5-FU demonstrated a dramatic 67% versus 37% 5-year OS advantage in favor of the chemoradiation arm. Well over 100 randomized clinical trials have been performed examining chemoradiation in head and neck cancer.132 Several metaanalyses have been published showing an absolute survival benefit to chemoradiation. The most recent published update of the MACH-NC in 2009 analyzed over 17,000 patients in 93 randomized trials and showed an absolute OS benefit of 6.5% at 5 years.133 Although two large randomized trials of neoadjuvant chemotherapy followed by radiation have shown a benefit in terms of laryngeal organ preservation,134,135 subsequent studies—including RTOG 9111136,137 and the MACH-NC133— suggest that concurrent chemoradiation is more effective than sequential administration. An additional 15 trials have been added to the MACH-NC meta-analysis that continue to support the superiority of concurrent administration, although this has only been reported in abstract form.132 More recent meta-analyses have been focused more on weekly versus every-3-week platinum with radiation, although randomized data is limited.138–141 As mentioned earlier, RTOG 9111 was a landmark Intergroup trial for patients with what would currently be staged as T2 and T3 glottic and supraglottic squamous cell carcinomas.136 This trial randomized patients to induction versus concurrent chemoradiation versus radiation alone. OS was not statistically different between the groups; the DFS and locoregional control favored the concurrent chemoradiation arm.136,137 This benefit is not restricted to organ preservation studies. Two trials published in the same issue of the New England Journal of Medicine detailed the RTOG142 and EORTC143 trials randomizing patients to postoperative radiation with or without concurrent chemotherapy.

Randomized Trials of Neoadjuvant Concomitant Radiation and Chemotherapy for Regimen

Outcome

Preop RT (34.5 Gy at 2.3 Gy/fx) ± 5-FU 10 mg/kg/day days 1–4 followed by surgery

Trend toward improved 5-y OS (59% vs. 46%, p = 0.06)

Bosset et al.125 (2006)

4-arm study: preop RT (45 Gy) + S vs. preop CT-RT with 5-FU (325 mg/ m2/day)/LV (20 mg/m2/day) days 1–5, 28–32 + S vs. preop RT + S + adjuvant 5-FU/LV vs. preop CT-RT + S + adjuvant 5-FU/LV

5-y LR was worse in the RT-only arm (17.1% vs. 8.7%, 9.6%, and 7.6% in the CT-containing arms; p = 0.002)

Bujko et al.127 (2006)a

Preop RT (25 Gy at 5 Gy/fx) + S vs. Preop CT-RT (50.4 Gy at 1.8 Gy/fx with 5-FU (325 mg/m2/day)/LV (20 mg/m2/day) days 1–5, 28–32 + S

No difference in LC, OS, or late toxicity, but CT-RT had more early toxicity (8.2% vs. 3.2%; p < 0.001)

Gerard et al.128 (2006)

Preop RT (45 Gy at 1.8 Gy/fx) ± 5-FU (350 mg/m2/day days 1–5 + LV) followed by S + adjuvant 5-FU (350 mg/m2/day days 1–5 + LV)

Improved pCR (11.4% vs. 3.6%; p < 0.05) and less LR (8.1% vs. 16.5%; p < 0.05) with CT-RT

Boulis-Wassif et al. (1984)

126

a Not a true comparison of adjuvant EBRT ± concurrent chemo as markedly different adjuvant EBRT regimens were used. CT, Chemotherapy; CT-RT, concurrent chemoradiation; 5-FU, 5-fluorouracil; fx, fractions; LR, local recurrence; LV, leucovorin; OS, overall survival; pCR, pathologic complete response; RT, radiation therapy.

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72

SECTION I

Scientific Foundations of Radiation Oncology

Selected Concomitant Radiation and Chemotherapy for Head and Neck Cancer

TABLE 4.4 Study

Regimen

Outcomes

RT (70 Gy) vs. RT (70 Gy) + cisplatin (100 mg/m q3wk × 3) with adjuvant cisplatin (80 mg/m2)/5-FU (1 g/m2/day for 96h q4wk × 3)

At 5y update, PFS (58% vs. 29%), DFS (74% vs. 46%), and OS (67% vs. 37%) favors the CT-RT arm (p < 0.001)

Brizel et al. (1998)225

RT (75 Gy at 1.25 Gy BID) vs. RT (70 Gy at 1.25 Gy BID) with concurrent cisplatin (12 mg/m2/day) and 5-FU (600 mg/m2 days 1–5) on weeks 1 and 6.

3-y LRC favored CT-RT (70% vs. 44%, p = 0.01). 3-y OS trends in favor of CT-RT (55% vs. 34%, p = 0.07).

Forastiere et al. (2003)136

3-arm trial of glottic and supraglottic cancer patients: RT (70 Gy) vs. sequential chemo (cisplatin 100 mg/m2 + 5-FU g/ m2/day for 120h q3wk × 3) then RT (70 Gy) vs. concurrent chemoRT (cisplatin 100 mg/m2 q3wk × 3)

No difference in OS but concurrent arm had superior local control (2-y: 78% vs. 61% sequential vs. 56% RT alone; p ≤ 0.003) and highest organ preservation rate (88% vs. 75% vs. 70%; p ≤ 0.005)

Adelstein et al. (2003)226

3-arm trial: RT (70 Gy) vs. concurrent RT (70 Gy) + cisplatin (100 mg/m2 q3wk × 3) vs. split course RT (30 Gy with cycle 1 and 30–40 Gy with cycle 3) + concurrent 5-FU (1 g/m2/day for 96h) and cisplatin (75 mg/m2) q4wk

The concurrent nonsplit cisplatin/RT arm had superior 3-y OS (37% vs. 27% in split course CT-RT vs. 23% in RT alone; p = 0.014). Concurrent cisplatin/RT had highest rate of grade 3 + toxicity (89% vs. 77% vs. 52%; p < 0.0001)

Bernier et al. (2004)143

Postoperative RT (up to 66 Gy) vs. postoperative CT-RT (up to 66 Gy with cisplatin 100 mg/m2 q3wks × 3) for potential high-risk head and neck cancer patients (stage III/IV except T3N0 or T1-2N0-1 with + margins, + PNI, + ECE, + VSI, OC/ OP primary with + LNs at levels 4–5)

Improvement in 5-y OS (53% vs. 40%; p = 0.02), 5-y PFS (47% vs. 36%; p = 0.04), and 5-y LRC (82% vs. 69%; p = 0.007) with CT-RT; grade 3/4 mucositis was higher in CT-RT arm (41% vs. 21%; p = 0.001).

Cooper et al. (2004)142

Postoperative RT (up to 66 Gy) vs. postoperative CT-RT (up to 66 Gy with cisplatin 100 mg/m2 q3wk × 3) for potential high-risk head and neck cancer patients (2 or more + LNs, + ECE, + margins)

Improvement in 2-y DFS (54% vs. 44%; p = 0.04) and LRC (82% vs. 72%; p = 0.01) with trend toward better OS (63% vs. 57%, p = 0.19). Higher rate of grade 3 or greater acute toxicity in chemoRT arm (77% vs. 34%; p < 0.001).

Bonner et al. (2006)150 and (2010)151

Once-daily RT (70 Gy at 2 Gy/day), concomitant boost (72 Gy in 42 fx) or hyperfractionated (72–76.8 Gy at 1.2 Gy BID) ± cetuximab (given 1 wk prior to RT at 400 mg/m2 then given weekly at 250 mg/m2 × 7 wk)

Improvement in MS (49 vs. 29.3 mo) and 5-y OS (45.6% vs. 36.4%) in the cetuximab arm (HR, 0.73; 95% CI, 0.56–0.95; p = 0.018). No difference in grade 3 or 4 toxicity, including mucositis (except acneiform rash and infusion reaction).

Pignon et al. (2009)133

Meta-analysis of 93 randomized trials of CT in head and neck cancer, with 17,346 patients.

Concomitant CT-RT provides absolute 5-y OS benefit of 6.5% while induction chemo showed only 2.4% (HR, 0.81; 95% CI, 0.78–0.86; p 1.0). At higher Zs, the stability of nuclei tends toward neutron-rich nuclides. It has been observed that nuclei with 2, 8, 20, 28, 50, 82, or 126 nucleons (protons and neutrons combined) are stable. These stability “magic numbers” relate to the filling of nuclear energy levels, similar to the complete filling of electron shells. Pairing of like nucleons also results in increased nuclear stability. There are 165 stable nuclei with an even number of both protons and neutrons, 57 stable nuclei with an even number of protons and odd number of neutrons, 53 stable nuclei with an odd number of protons and even number of neutrons, but only 6 stable nuclei with an odd number of both protons and neutrons. Some nuclides are unstable and eventually transform to stable states by the emission of particles or energy. These nuclides are called

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CHAPTER 6

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Radiation Oncology Physics

TABLE 6.2

Physical Characteristics of Selected Atomic and Nuclear Particles

Name

Symbol

amu

MeV

me

Charge

Lifetime

Electron

e

−

0.000549

0.511

1

−1

Stable

Positron

e+

0.000549

0.511

1

+1

10−6 s

Proton

p

1.007276

938.256

1836.1

+1

Stable

Neutron

n

1.008665

939.550

1838.6

0

12 min

Neutrino

ν, ν

< 2.4 × 10

0

Considered Stable

Muon

μ

0.11320

105.659

206.4

−1

Unstable

Pion

±Π

0.14990

139.578

273.2

±1

Unstable

-9

< 2.2 × 10

< 4.3 × 10

-6

-6

amu, Atomic mass unit; me, rest mass of the electron; MeV, million electron volts.

Atomic Nomenclature

TABLE 6.3 Symbol

Item

Definition

Z

Atomic number

Number of protons in the nucleus and the amount of nuclear charge (+Z); also equal to the number of electrons in the neutral atom

N

Neutron number

Number of neutrons in the nucleus

A

Mass number

Total number of nucleons: A = Z + N

Class Isotopes

Z Same

N Different

A Different

Isotones

Different

Same

Different

8

Same

60

Same

99

Isobars

Different

Isomers

Same

Different Same

140

120

Is

++ +++ + ++ + ++ + + + + +++ ++ + + ++ + +++ + + ++ + + ++ + + ++ ++ + +++ ++ Isotones +++ + + + + + ++ + +++ ++ ++ ++ +++ + + ++ + + ++ ++ +++ +++ ++ ++ + +++ ++ ++ + +++ + +++ + +++ + ++ + + + +++ ++ ++ +++ + +++ ++ N=Z +++ + + ++ ++ + + + ++ + + + ++ + +++ + +++ + +++ + + +++ +++ +++ + +++ +++ + + + +++ + + ++ ++ + + ++ +++ ++ + + + + +++ + +++++ +++ + Stable nuclides + ++ + + + +++ + +++ + ++ + Naturally radioactive + + ++ +++ + + + +

ob

ar

Neutron number (N)

80

60

40

20

0

Isotopes

s

100

0

20

40 60 80 100 Atomic number (Z) Fig. 6.2 Distribution of stable and naturally radioactive nuclides. (Data from Bureau of Radiological Health. Radiological Health Handbook. Bethesda, MD: US Department of Health, Education, and Welfare; 1970.)

Examples H, 2H, 3H; 125I, 131I

1

He6, 9Li6; 137Cs82, 138Ba82 Ni, 60Co; 137La, 137Ba, 137Cs

Tc, 99mTc (Δ energy state)

radionuclides or radioactive species because a particle or energy is given off during the nuclear transition. Unstable nuclides lie off the line of stability and will have a neutron or proton excess relative to the stable nuclide. Modes of radioactive decay depend on the type of nucleon excess, whether neutron or proton, and are discussed later in more detail. Stable nuclides include 1H, 12C, 33P, 34S, and 59Co. Radioactive nuclides for these elements, some naturally occurring and others man-made, include 3H, 14C, 32P, 35S, and 60Co. Other radionuclides of interest to the medical field include 99mTc, 125I, 131I, 137Cs, and 226Ra.

Photons and Other Definitions Interactions of ionizing radiation occur at the atomic and nuclear levels, where binding energies range from 10s of eV to 10 MeV, relatively small compared with macroscopic realms. Electromagnetic radiation, or photons, are particles that have wavelike qualities with zero mass, which transfer energy from one location to another by propagation of an electromagnetic wave at the speed of light, c (c = 3 × 108 m/s). Photons are also the mediators of charged particle bonds. A photon has wavelength λ, frequency ν, speed c = λν, and energy E = hν; c is the speed of light, and h is Planck’s constant (h = 6.626 × 10−34 m2/kg/s). The electromagnetic spectrum consists of photons with wavelength, frequency, and energy ranges more than 10 orders of magnitude (the range is really infinite). From low to high energy, there are radar waves, microwaves, infrared, light (visible photons), ultraviolet, x-rays, and gamma rays. Photons are named by their wavelength (e.g., radar waves, microwaves), character (e.g., “purple”), and origins (e.g., x-rays from the atom, gamma rays from the nucleus; Table 6.4).

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TABLE 6.4

Scientific Foundations of Radiation Oncology

Physical Definitions

Item

Symbol

Definition

Atom

a

Smallest subunit of an element retaining the character of that element; composed of a nucleus of protons and neutrons and orbital electrons.

Electron

e−

Particle with a charge of −1 and mass of 0.511 MeV; used for radiation treatment when accelerated to energies capable of ionization.

Photon

hν, γ, x

Particle with zero charge and mass consisting of electromagnetic radiation; used for imaging and radiation treatment at energies capable of ionization.

Gamma ray

γ

Photon (electromagnetic radiation) originating from within the nucleus as a result of nuclear transformation.

X-ray

x

Photon (electromagnetic radiation) originating from within the atom as a result of atomic transformation.

Ionization

Removal of one or more electrons from an atomic shell, leaving the atom with a net positive charge. X−, X+

Ion

Atom of element X with an electron deficit, as is formed after ionization, or an electron excess.

Ionizing radiation

Radiation of sufficient energy to cause ionization on interaction.

Nonionizing radiation

Radiation of insufficient energy to cause ionization on interaction.

Electron volt

eV

The energy gained by 1 electron when it is accelerated through an electrical field potential of 1 V.

Kiloelectron volts

keV

1000 electron volts; used to denote the energy of a monoenergetic particle or photon, as in “100-keV photons” or “10-keV electrons.”

Million electron volts

MeV

1 million electron volts; used to denote the energy of a monoenergetic particle or photon, as in “1.17-MeV gamma rays” or “7-MeV electrons” (see Fig. 6.7).

Million volts

MV

Million volts; used to denote a spectrum of polyenergetic particles or photons with a maximum energy, as in “18-MV x-rays.” In this example, the x-rays have a maximum energy of 18 MeV and a continuous energy distribution of photons from 0 up to 18 MeV (see Fig. 6.7).

RADIATION PRODUCTION AND TREATMENT MACHINES External beam radiotherapy (EBRT) machines produce ionizing radiation by (1) radioactive decay of a nuclide or (2) electronically by the acceleration of electrons or other charged particles, such as protons. The basic purpose is to create an intense beam of ionizing radiation with known and predictable characteristics that can be aimed at a patient from a certain distance away (most commonly 100 cm). This beam of radiation with a source outside the patient is the “external beam.” The most commonly used radionuclide for EBRT has been 60Co. Although once quite common as the first widely used device for EBRT, 60Co treatment machines in the United States and other developed nations have been replaced over the past 20 to 30 years by linear accelerators (LINACs), which produce high-energy x-rays and electrons by electronic means. Basic components of all external beam treatment machines include a radiation source, a collimating system to form and direct a radiation beam, inherent or added shielding for radiation protection, a control system to turn the beam on and off and to monitor the amount of radiation being administered, a light field to delineate visibly the radiation field to be treated, a means to rotate the beam or otherwise change its direction, and a support assembly for the patient. These components are assembled for modern conventional treatment machines in an isocentric geometry (Fig. 6.3). The isocenter is a point in space at which the treatment machine rotational axes all intersect. Any mechanical rotation is about an axis that passes through the isocenter. With many common components, 60Co teletherapy units and LINACs differ primarily in the method of photon production: radioactive source emitting gamma rays versus electronic source emitting x-rays. In current configurations, LINACs also offer a wide range of sophisticated control systems for control and modulation of radiation beam shape, intensity, and trajectory (discussed later).

Radiation Production by Radioactive Decay Teletherapy is the use of radioactive material, such as 60Co, for production of an external beam of gamma rays for treatment at a distance from

Collimator (C)

Gantry (G) C G

Isocenter

T

Table (T) (patient support assembly) Fig. 6.3 Treatment machine geometry for gantry-based linear accelerator or teletherapy unit. Three rotational axes intersect at a point called the isocenter. The table surface can translate three directions for a total of 6 degrees of freedom.

the radioactive source (tele, meaning “at a distance”). The term is historical and is in contrast to brachytherapy, in which the radioactive source is placed in or on the treatment volume (brachy, meaning “close”). Gamma rays are emitted from a daughter nucleus formed after radioactive decay of an unstable parent nucleus. Each gamma ray has a unique energy that relates to the immediately preceding nuclear transformation; this unique energy can be used to identify the daughter (and, therefore, the parent). 226Ra, 137Cs, and most commonly 60Co have been used for teletherapy. While 226Ra was chemically separated from naturally occurring

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CHAPTER 6 ores, 137Cs and 60Co are manufactured and made available by neutron activation and as a by-product of fission after the invention of the nuclear reactor. Use of 60Co as a source of gamma rays for treatment was pioneered by H. E. Johns9 and represented a major step in obtaining high-energy photons above 1 MeV, termed “megavoltage” photons. At that time, electronic means of photon production from high-energy x-ray tubes was limited to 300 keV maximum because of electrical arcing at higher accelerating potentials. Specialized particle accelerators were required to produce potentials above 300 keV (e.g., betatrons10 and van de Graaff accelerators11). Although of historical interest for most readers, 60Co teletherapy units have lower cost and a relatively simple design with lower requirements for their operating environment compared with LINACs. For these reasons, 60Co teletherapy devices continue to be used worldwide in regions with limited resources for funding and operating infrastructure. One manufacturer (Best Theratronics, Ltd., Ottawa, Ontario, Canada) states that, as of 2010, there were 45,000 daily radiation treatments delivered worldwide using this conventional 60Co teletherapy device. In a conventional 60Co teletherapy unit (Fig. 6.4), a cylindrical sealed-source capsule about 3 cm in diameter and 5 cm high contains pellets of 60Co. In each transformation, a 60Co nucleus decays to 60Ni, with the prompt emission of two gamma rays at 1.17 and 1.33 MeV each (1.25 MeV average). Typical activity is 6000 to 9000 Ci (2.22-3.33 × 1014 Bq) for dose rates of approximately 2 to 3 Gy/min at 80 to 100 cm from the source. A disadvantage is the constantly decreasing dose rate as a result of the decay of the 60Co source and the requirement for eventual replacement of the source. The source decays with a half-life of 5.27 years and is replaced every 5 to 7 years when the dose rate becomes “too low”; treatment times may be excessive and radiobiological effect for treatment efficacy may be compromised below 1 Gy/min. In one of the most commonly available teletherapy unit configurations (Theratron Phoenix, Best Theratronics Ltd, Ottawa, Ontario, Canada), the source is stored in a shielded head of the machine, mounted on the end of a movable piston in a horizontal cylinder (see Fig. 6.4). On the initiation of treatment, the source is moved pneumatically to a position over an opening in the shield that allows a treatment beam to exit. A collimator consisting of interleaved bars of a high Z material is used to define the field size as the beam exits the shield port. Trimmer bars, additional collimator bars closer to the patient surface, can be used to reduce the beam penumbra, which is large because of the relatively large source diameter of approximately 3 cm. Maximum field size is 35 × 35 cm2 at 80 or 100 cm from the source. Irradiation time is measured

Radiation Oncology Physics

and controlled by two independent timers. An end effect caused by the mechanical movement of the source, for which the effective irradiation time is less than the timer setting, is inherent and can be measured. Cross-hairs and a field light are used to delineate the central ray and field dimensions. There is a source-to-surface indicator. Source movement is designed so that, in the event of treatment termination or device failure, the source is automatically returned to the shielded condition. An emergency push bar (T-bar) can be used to manually return the source to the shielded position, if necessary. The machine has a rotatable gantry allowing 360-degree rotation of the source and a nominal isocenter position of 80 cm from the source. Later models have a 100-cm isocenter and treatment distance. An additional degree of freedom is provided by a head swivel mechanism that allows the beam direction to be rotated away from the isocenter, if desired. A beam stopper may be used to intercept the beam for additional shielding of the exit beam, potentially reducing the amount of shielding needed in walls of the facility. The beam stop also acts as a counterweight for the head of the machine. There is a patient support assembly (treatment table) with vertical, longitudinal, lateral, and rotation motions. Beam modifiers include custom or standard field blocks, multivane collimation, and mechanical wedges for producing angled isodose distributions or tissue compensation. Other important currentday uses of gamma-ray beams from radioactive 60Co, discussed later, include gamma radiosurgery and gamma-magnetic resonance imaging (MRI) image-guided radiotherapy (IGRT).

Radiation Production by LINACs In a LINAC, electrons are accelerated to high energy and are allowed to exit the machine as an electron beam or are directed into a high Z target to produce x-rays by the bremsstrahlung interaction. The LINAC enables convenient production of megavoltage x-rays in a relatively small device; its existence is directly related to the invention of the magnetron and the klystron during the development of microwave radar in World War II. LINACs are quite versatile, with x-ray and electron modes, multiple energies, and computer controls. These capabilities have led to the replacement of most 60Co teletherapy machines in the United States with LINACs. The principle of operation for LINACs is to accelerate electrons through a waveguide by use of alternating microwave fields.12 Two basic waveguide designs exist: standing wave and traveling wave. Waveguide length is a function of the maximum acceleration energy (longer is higher energy) and the frequency of the microwave field.

Treatment head “Source Source On” Piston

“Source Off” Cylinder Collimators

γ rays

Field size

A

Gantry

97

Gantry stand

Axis of rotation

B Fig. 6.4 (A, B) In a typical 60Co unit, the source moves from the shielded position (Off) into an unshielded position (On) to produce a treatment beam. (B, Courtesy Best Theratronics, Ltd., Ottawa, Ontario, Canada).

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The most common frequency for gantry-based LINACs (Fig. 6.5B) is 2.998 GHz (S-band microwaves); however, specialized, shorter waveguides are possible at 9.3 GHz (X-band microwaves) that produce megavoltage energies above 6 MeV with acceptable dose rates for treatment. Major electronic components are described in Table 6.5 and are shown in Fig. 6.5 for C-arm gantry-based LINACs, the most common design. Major mechanical components are similar to those for teletherapy; two main designs are used for the mechanical support structures to implement C-arm geometries for the radiation beam. In the first design, a rigid, floor-mounted stand holds high-voltage microwave transport guides, cooling and control components, and supports the rotatable gantry holding the waveguide to allow 360-degree rotation of the source at an isocenter of 100 cm to enable multiple beam directions (see Fig. 6.5B). In a second design, the entire accelerator—including waveguide, high-voltage microwave transport guides, and other components—is contained within a large rigid cylinder. The cylindrical structure and all of its contents rotate on a horizontal axis about the isocenter (see Fig. 6.5C). A set of one or two pairs of high Z collimators (“jaws”), depending on the manufacturer’s design, provides at least 99.9% attenuation of the primary beam (0.1% transmission) and defines the length or width of the rectangular x-ray radiation field. A maximum field size of 40 × 40 cm2 at 100 cm (isocenter) is common, with 180- to 360-degree rotation of the entire collimator assembly about the isocenter (see Fig. 6.3). Collimator settings are continuously variable, and jaw pairs can be operated in coupled or independent modes to produce symmetrical and asymmetrical fields about the central axis. Cross-hairs and a field light are used to delineate the central ray and field dimensions, and there is a source-to-surface indicator. Electron gun

Although rarely used for LINACs, a beam stopper may be used to intercept the beam for additional shielding of the exit beam when facility shielding is limited. Otherwise, internal counterweights provide balance to the gantry to offset the weight of the accelerator waveguide and high-density shielding required around the x-ray target. There is an isocentric patient support assembly (treatment table) with vertical, longitudinal, lateral, and rotational motions. Fine tolerances for the rotational axes and isocentricity of the gantry, collimator, and table are important for accuracy in patient treatments. The combined variation in rotation and coincidence of the three axes is typically maintained within a 1-mm diameter sphere. The patient support assembly is usually the most difficult rotational axis to set for isocentricity because the table assembly is a separately added component to the rotating gantry structure. Accessories and beam modifiers for conventional geometry LINACs are important for customizing the external-beam field to an individual patient and include custom or standard shielding blocks to shape a patient’s treatment fields to minimize the amount of normal tissue treated or protect critical structures; electron applicators for defining electron fields at the patient surface; physical (made of steel) and “virtual” or “dynamic” wedges for producing angled isodose distributions; and compensators for shaping the dose distribution within a patient for desired dose uniformity. Custom block manufacturing for shaping of patient-specific fields was once common, using high Z alloy materials to provide primary x-ray beam attenuation of at least 97% (5 half-valve layers). The use of custom blocks has been almost totally replaced by a versatile collimator design called the multileaf collimator (MLC), which is now available from all LINAC manufacturers (Fig. 6.6). The MLC provides on-board, automated field-shaping capabilities, replacing standard manual or custom blocks by the use of a large number of 270-degree bending magnet

Accelerating waveguide

Injector Transmission waveguide Modulator

Microwave source: magnetron or klystron

Path of accelerated electrons

Target (x-rays) or scattering foils (electrons) Flattening filter (x-rays) Monitor chambers

A

Pulse-forming network

Collimators

X-rays

B

or

Electrons

C Fig. 6.5 Modern electron linear accelerator designs. (A) Electron linear accelerator schematic. Key components are shown that enable a beam of electrons to be accelerated to megavoltage energies, producing treatment beams of either electrons or x rays. (B) C-arm linear accelerator, with a rotating gantry pivoting on a rigid, floor-mounted stand located behind the gantry. (C) C-arm linear accelerator, with a rotating gantry supported by a large-diameter cylindrical structure located behind the gantry. Both types of linear accelerators have kV cone-beam CT imaging devices oriented orthogonal to the MV treatment beam to enable image-guided radiation treatment. (B, courtesy Varian Medical Systems; C, courtesy of Elekta AB and Wake Forest Baptist Medical Center.) Downloaded for [email protected] upr07 ([email protected]) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on April 23, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

CHAPTER 6

Radiation Oncology Physics

99

Major Electronic and Beamline Components of Linear Accelerators

TABLE 6.5 Componenta

Purpose

Electron gun

Source of electrons to be accelerated.

Microwave source

Provides accelerating potential and amplitude (power). Typically, magnetrons are used for ≤ 10 MV; klystrons are used for > 10 MV and for most dual-energy machines.

Pulse-forming network

Synchronizes electron bunches with microwave phase.

Transmission waveguide

Carries microwave power from its source to the accelerating waveguide.

Injector

Injects pulses of current to the electron gun (i.e., drives electron gun).

Accelerating waveguide

Location of electron acceleration through multiple coupled cavities in a linear geometry (i.e., the linear accelerator).

Bending magnet

Used in horizontally oriented accelerating waveguides to redirect the electron beam for electron energy selection and beam focusing.

Target (for x-rays)

Placed in electron beam for x-ray production on electron impact.

Scattering foils (for electrons)

Scatter electrons to produce a uniform beam of electrons for treatment.

Flattening filter (for x-rays)

Flattens the highly peaked x-ray beam exiting the target to produce a uniform beam of x-rays for treatment.

Monitor chambers

Ionization chambers that monitor the amount of radiation in the beam; count dose and turn machine off when set dose is reached; monitor beam flatness and symmetry.

Collimators (secondary)

Provide rectangular field shaping for x-rays and set field sizes for electrons.

Accessories and beam modifiersb Interlocksb

Define or modify beam shape or intensity. With other control systems, ensure proper operation of linear accelerator for dose assurance and safety.

A

Source

Multileaf collimator

a

Components are shown in Fig. 6.5. Components are not shown in Fig. 6.5.

b

adjustable high Z vanes, or leaves. The desired beam outline is shaped as a series of steps by positioning each leaf to approximate a continuous field edge (see Fig. 6.6B). Different manufacturers’ MLC designs include singly and doubly focused leaf ends, in which the leaf ends match beam divergence either across the direction of leaf travel (single) or both across and with the direction of leaf travel (double), and projected widths at the isocenter of 3, 4, 5, or 10 mm.13 MLCs also have capabilities for dynamic treatment, as required and discussed later for intensitymodulated radiotherapy (IMRT). LINACs and their supporting technologies have become computer controlled, enabling better-optimized dose distributions, rapid treatment setup, and in-room verification of target location through remote sensing and image-guided approaches. In particular, most modern LINACs are hybrid imaging treatment devices fitted with a gantry-mounted kV or MV x-ray imaging device that is coincident with the treatment isocenter. This imaging device provides “in-room” imaging to confirm patient and target position immediately before treatment in the process termed

Projected field

B Fig. 6.6 The multileaf collimator. (A) Installed 80-leaf device for a Varian 2100C linear accelerator. (B) Schematic of beam definition.

image-guided radiotherapy (IGRT). A wide range of IGRT designs is possible, as discussed later. Although LINACs typically have had an isocentric rotating C-arm gantry, there are other commercialized megavoltage accelerator designs that use the highly stable computed tomography (CT)-like ring gantry along with integrated image guidance for treatment. One precedentsetting design, called tomotherapy, uses a ring gantry around which an X-band LINAC rotates, always pointed toward the rotational center (an isocenter).14 A binary (“on” or “off ”) MLC intensity modulates a 6-MV x-ray fan beam as the accelerator waveguide is rotated. The treatment table is advanced in a stepwise or continuous motion for either

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slice-by-slice or helical-fan-beam treatment. Other ring gantry designs use a cone beam 6-MV x-ray beam with full or dual-layer MLCs, along with kV cone-beam CT (CBCT) imaging for image guidance. In one design, the entire ring-gantry unit is gimbaled to enable noncoplanar beam geometries relative to the transverse plane of the patient support (table). In general, ring and C-arm gantry designs using cone-beam x-rays can have high efficiency for treatment compared with fan-beam or pencil-beam designs depending on field size and intensity modulation because of the increased amount of solid angle that can be irradiated— and, thus, treatment volume—per unit time. Another unique LINAC geometry uses a nonisocentric format with an X-band LINAC fixed on the end of a high-precision robot that is computer controlled for a range of motions with multiple degrees of freedom.15 This device produces a relatively small-sized 6-MV x-ray beam that can be pointed at the target from various “nodes” in space— using a large collection of irradiation nodes from many directions generates the cumulative conformal dose distribution at the target. The x-ray beam can be shaped by circular collimators or a dynamic MLC for field sizes up to 6- to 10-cm widths. Three differences in radiation sources for teletherapy and LINAC devices are fundamental. First, a 60Co teletherapy source is always “on,” emitting radiation. Radioactive decay always occurs and cannot be interrupted; to initiate irradiation, the source must be moved from the shielded condition to an unshielded condition (see Fig. 6.4). With a LINAC, no source is present until the unit is energized; the irradiation is on or off with the flip of an electronic switch initiated by the operator with a key or button at the treatment console. Second, their photon spectra are different (Fig. 6.7). In a 60Co unit, two monoenergetic gamma rays are emitted with every decay to produce a discrete spectrum with peaks at 1.17 and 1.33 MeV. In contrast, a LINAC produces a continuous x-ray spectrum through the bremsstrahlung interaction. The spectrum has a maximum energy of Emax (i.e., accelerating potential) and all other photon energies down to zero. An average x-ray energy of approximately one-third Emax can be determined and is consistent with theoretical predictions for the continuous bremsstrahlung spectrum (see Fig. 6.7). Third, a LINAC can produce a treatment beam of electrons as well as photons. The accelerated electron beam is allowed to exit the machine under controlled conditions of scatter. Although 60Co gamma rays occur because of an immediately preceding beta decay, the beta particles (electrons) are stopped by the radiation source enclosure, a metallic Cobalt-60 gamma rays (discrete spectrum) Bremsstrahlung x-rays (10 MV) from linear accelerator (continuous spectrum)

No. photons per energy (dN/dE)

1.17 MeVγ 1.33 MeVγ

capsule that contains the radioactive material, and cannot be otherwise harnessed for treatment.

Radiation Production by Other Accelerators Other accelerator techniques have been used to produce a variety of high-energy particles such as electrons, protons, neutrons, and higher Z ions. These techniques have included the betatron,10 van de Graaff accelerators,11 cyclotrons,16 the racetrack microtron,17 and synchrotrons and synchrocyclotrons18 similar to those developed for high-energy physics experiments. Among high-energy charged particles, protons have become the most attractive for therapeutic uses, where proton energies of 220 to 250 MeV yield treatment depths of up to 30 to 40 cm. Although currently an expensive technology to build ($40-$200 million USD or higher) and maintain, the use of high-energy protons for treatment is increasing with approximately 80 operating proton facilities (28 in the United States, 52 sites in other nations, 11 with carbon ions), 45 sites under construction, and 25 in the planning stages worldwide.19 Typically, a large-scale proton facility has a single accelerator (e.g., cyclotron or synchrotron) with a beam line that is split to service two to four treatment rooms, each with either a fixed treatment beam or a movable gantry to aim the proton beam. An alternative design includes the use of a smaller (though still large) cyclotron combined with a short beam-line segment, all contained within a single treatment room (one cyclotron per treatment room). The in-room cyclotron is mounted on a large, double-legged gantry system that enables single-plane rotation about the patient, with a patient table that swivels to provide additional solid-angle coverage. Facility designs and technical aspects for proton therapy are available.20

INTERACTIONS OF IONIZING RADIATION WITH MATTER Photon Interactions Attenuation and Transmission When incident on matter, ionizing photon radiation undergoes interactions with atomic electrons or nuclei. Interacting photons are removed from the primary beam, an effect called attenuation. Photons that do not interact and instead exit the material are called transmitted photons. Attenuation and transmission are illustrated in Fig. 6.8. A number, N0, of monoenergetic x-rays or gamma rays is incident to a slab of material, and a smaller number, N, is transmitted. The attenuated photons, numerically equal to N0 − N, are absorbed in the material or scattered in other directions. In narrow-beam geometry, N-transmitted photons

Material Incident photons

Transmitted photons

Detector

Emax

2

4 6 8 10 Photon energy (MeV) Fig. 6.7 Discrete and continuous photon spectra. The discrete spectrum is characteristic of photons emitted by radioactive material. The continuous spectrum is characteristic of polyenergetic bremsstrahlung x-rays emitted by a linear accelerator. Emax, 10 MeV.

N (I or X)

N0, number (I0, intensity or X0, exposure) X

Thickness Fig. 6.8 Attenuation and transmission. A number, N0, of monoenergetic x-rays or gamma rays is incident to a slab of material, and a smaller number, N, is transmitted. The attenuated photons, N0 and N, are absorbed in the material or scattered in another direction.

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CHAPTER 6 Thickness, x (= ∑ ∆x)

Radiation Oncology Physics

101

1.00

Material 100 photons

90

81

N/N0

100

0.75

73 and so on...

∆x ∆x ∆x 100 x 0.10 90 x 0.10 81 x 0.10 = 8.1 = 10 =9 Fig. 6.9 Attenuation through successive slabs of material.

N(x) = N0e

N(x) or = e− µx N0

Eq. 2

I X = e− µx and X = X 0e− µx or = e− µx I0 X0

4.0 6.0 8.0 2.0 Absorber thickness, x (arbitrary units)

10.0

1.00

0.30

HVL N = –µx e N0

0.10 Slope = –µ 0.03

HVL

0.01 10.0 2.0 4.0 6.0 8.0 Absorber thickness, x (arbitrary units) Fig. 6.10 Graphic representation of attenuation. (A) Linear plot. (B) Semi-log plot. HVL, Half-value layer.

B

amount of attenuation for the same thickness traversed and attenuation curves that differ in their slopes (Fig. 6.11).

Beam Quality

In Eq. 2, N0 is the original number of incident photons, N(x) is the transmitted (unattenuated) number of photons, e is Euler’s constant (e ≈ 2.7), μ is the linear attenuation coefficient, and x is the thickness traversed by the photons. Exponential attenuation is valid for monoenergetic photons and all homogeneous materials in narrow beam geometry and applies to other radiation quantities such as intensity (I) and exposure (X): I = I0e− µx or

N = –µx e N0 HVL

A

N/N0

Eq. 1

In the equation, ΔN is the change in the number of photons as the result of attenuation, N is the number of incident photons, μ is a constant that represents the constant fractional attenuation per thickness, called the linear attenuation coefficient, with units of length−1 (cm−1), Δx is the thickness traversed by the photons for attenuation ΔN, and the minus sign indicates that the effect is negative, resulting in fewer photons—the attenuation process decreases the number of photons in a beam. Constant fractional attenuation per unit thickness compounds over successive thicknesses, illustrated in Fig. 6.9. This “fraction of a fraction” effect is nonlinear, and the integrated form of Eq. 1 yields an important relationship: attenuation in a continuous material is an exponential process: − µx

HVL

0.25

alone reach a detector as shown. In broad-beam geometry, scattered photons also reach the detector. Megavoltage photon interaction probabilities are less than 1, typically 2% to 4% per centimeter in tissue depending on the incident photon energy, atomic number of the interaction material, and interaction type. By physical law, the fractional number of unattenuated photons interacting per unit thickness of a material is constant, such that ∆N N ∆N = − µ or = − µ∆x. ∆x N

0.50

Eq. 3

The linear attenuation coefficient is unique for each photon energy and element or material but varies with absorber density. Attenuation coefficients are discussed more fully with radiation interactions. Eq. 2 can be graphed in linear or semi-log form (Fig. 6.10). In semi-log form, the attenuation curve is a straight line with a slope of −μ (Fig. 6.10B). A smaller attenuation coefficient results in less attenuation and a shallower attenuation curve. Different attenuation coefficients for different materials or different photon energies result in a different

Beam quality is a term used to describe the amount of penetration by a photon radiation beam. One indicator of quality is beam energy, defined by accelerating potential, effective energy, or gamma ray energy. Another indicator is the half-value layer (HVL). The HVL is the thickness of a material that reduces the transmitted intensity to one-half of the original intensity. When I I 0 = 1 2 , the thickness, x, is the HVL and the attenuation equation becomes I 1 = = e−µHVL. I0 2

Eq. 4

By taking the natural log (ln) of each side, and with ln(1/2) ≈ 0.693, two important relationships come from this equation: µ = 0.693 HVL and HVL = 0.693 µ . Thus, given the linear attenuation coefficient, the HVL can be computed and vice versa. For example, if μ = 0.10 cm−1, the HVL = 0.693/0.10 cm−1 = 6.93 cm, and if HVL = 10 cm, μ = 0.693/10 cm =

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e–µax e–µbx

0.75

N/N0

µ or µ/ρ

1.00

A

0.50

Depth

µa < µb; HVLa > HVLb

HVL1 = 1.2 cm – 0 cm = 1.2 cm HVL2 = 2.7 cm – 1.2 cm = 1.5 cm TVL = 4.5 cm – 0 cm = 4.5 cm

1.0 0.25

2.0 4.0 6.0 8.0 10.0 Absorber thickness, x (arbitrary units)

A

N/N0

Attenuation curve, polyenergetic photons 0.1

HVL1

Linear portion of curve (measure greatest HVL along this slope)

HVL2

1.00

0.01

4.0 6.0 8.0 10.0 Absorber thickness, x (cm) Fig. 6.12 Attenuation for polyenergetic photons. (A) Variation in attenuation coefficient as a function of depth for polyenergetic photons. (B) Attenuation curve for polyenergetic photons. HVL, Half-value layer; TVL, tenth-value layer.

N/N0

B

0.10

µ1 < µ2; HVL1 > HVL2

0.01 2.0 4.0 6.0 8.0 10.0 Absorber thickness, x (arbitrary units) Fig. 6.11 Attenuation for two different materials, indicated by the subscripts a and b. (A) Linear plot. (B) Semi-log plot. HVL, Half-value layer.

B

0.0693 cm−1. Note that the units for the HVL are the reciprocal of the units for μ. Because e − µHVL = 1 2 , and given a thickness of material in units of HVL (x = n HVL, n equals the number of HVLs), the amount of attenuation can be computed by n

I  1 =  . I0  2 

Eq. 5

In Eq. 5, I/I0 is the fractional transmission, intensity, or exposure and n is the thickness of the material, expressed as the number of HVLs. This equation is valid for positive integer and noninteger values of n (e.g., n = 1, 2, 5.9, 100.1). Similar to the HVL, the tenth-value layer (TVL) is the thickness required to reduce the number, intensity, or exposure by a factor of 10: m

I 1 I  1 = = e−µTVL and =   . I0 10 I0  10 

Eq. 6

In Eq. 6, m is the thickness of the material given in number of TVLs. The HVL can be found graphically from the attenuation curve, whether on a linear or log plot (see Fig. 6.10) and for monoenergetic

Attenuation curve, monoenergetic photons

TVL

–µ 1 –µ 2

2.0

photons can be determined anywhere along the curve because μ is constant; the ratio of the two intensities must be 1/2. For polyenergetic photons, μ is not constant but instead decreases with increasing depth (Fig. 6.12A). The low-energy component of the beam spectrum is attenuated preferentially compared with high-energy photons because of increased attenuation at low energies. As depth increases, the ratio of high-energy to low-energy photons increases, resulting in increased beam penetration, or “beam hardening.” After a large number of lowenergy photons are attenuated at depth, additional beam hardening is minimal and μ is essentially constant. The log attenuation curve begins steeply, has curvature, and then becomes linear at depth (see Fig. 6.12B). Because μ changes with depth, the HVL also changes, yielding different first and second HVLs, as defined in Fig. 6.12B. The monoenergetic case is shown for comparison. For a polyenergetic beam, HVL1 is always less than HVL2 because photons incident on HVL2 have a higher average energy, thus HVL1 is less than HVL2. The greatest HVL is found at maximum depth, on the linear portion of the attenuation curve where beam hardening is the greatest. For polyenergetic photon beams, an effective attenuation coefficient (μeff ) can be calculated by determining an effective HVL over a region of interest and then calculating the μeff: µ eff = 0.693 HVLeff. Characteristics of attenuation curves for monoenergetic and polyenergetic photons are summarized in Table 6.6.

Attenuation Coefficients The linear attenuation coefficient is one representation of photon interaction probabilities. Another form, the mass attenuation coefficient, μ/ρ, is the linear attenuation coefficient divided by the material’s density, ρ, and has units of cm2/g. It is independent of material density and is the form of attenuation coefficient commonly found in physics data

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CHAPTER 6

TABLE 6.6

Curves

103

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Characteristics of Attenuation

Electron Neutron

Monoenergetic

Polyenergetic

1. Exponential curve on linear scale

1. Complex exponential curve on linear scale.

2. Linear curve on semi-log scale

2. Curved on semi-log scale.

Proton

3. Constant μ

3. Varying μ/μeff can be determined.

4. Constant HVL

4. Varying HVL/HVL1, HVL2, TVL, and greatest HVL can be determined.

k l m

HVL, Half-value layer; TVL, tenth-value layer. See text for other terms.

tables, presented according to incident photon energy and the attenuating element (Z, atomic number) or material (effective atomic number). Its use in attenuation computations requires the density of the material according to µ

− ρx I =e ρ . I0

θ

Incident photon, hν Scattered photon, hν Fig. 6.13 Coherent scattering.

Eq. 7 Electron

Attenuation coefficients can also be expressed in other forms and can be converted from one form to another.21

Neutron Proton

Photon Interactions: X-Rays and Gamma Rays Attenuation of photon beams is the result of interactions in the intercepting material. There are five most common photon interactions: coherent scattering, photoelectric effect, Compton effect, pair production, and photodisintegration. Each interaction type has an independent interaction probability and contributes to the cumulative amount of attenuation. The total linear and mass attenuation coefficients are given by the sum of their components: µ TOT = µ COH + µPE + µ CE + µPP + µPD

k

l

Incident photon, hν Characteristic x-ray (or Auger electron)

m

Photoelectron (from K shell)

Characteristic x-ray (or Auger electron)

and µ ρ

TOT

= µ ρCOH + µ ρPE + µ ρCE + µ ρPP + µ ρPD.

In these equations, TOT signifies the total coefficient and COH, PE, CE, PP, and PD refer to the respective five interactions. The photoelectric and Compton effects are the most important interactions for imaging with kilovoltage photons. The photoelectric effect, Compton effect, and pair production are the most important interactions for megavoltage photons used for radiotherapy. Detailed presentations of these five interactions have been published.2,21,22 Coherent scattering. In coherent scattering, a photon is scattered off an outer orbital electron with a change in direction and no change in energy (Fig. 6.13). At very low energies (< 10 keV), the amount of coherent scattering can be large and attenuation can be high, even though there is no change in photon energy. The mass attenuation coefficient varies as (1/Eγ)2 and Z, and the amount of coherent scattering is 3% to 8% or less in the conventional x-ray imaging (~ 100 kV) and therapy (MeV) energy ranges compared with other principal interactions. Diagnostic and security imaging techniques are being developed using low-energy x-ray beams (~ 30 kV) based on the changes in coherent scatter that occur for soft-tissue surfaces and interfaces. Photoelectric effect. The following actions occur in the photoelectric effect (Fig. 6.14):

Fig. 6.14 Photoelectric effect.

1. An incident photon with energy, Eγ = hν, interacts with the inner orbital electron with binding energy EB (most tightly bound). The interaction can occur with other orbital electrons, but the most probable interaction is with the innermost electron. 2. The photon is completely absorbed and no longer exists. 3. The orbital electron, now called the photoelectron, is ejected with kinetic energy, Epe, equal to the photon energy minus the binding energy: Epe = Eγ − EB. If Eγ is less than EB, the interaction cannot occur, but the interaction may occur with another orbital electron with a binding energy less than Eγ. Depending on the incident photon energy and the orbital electron momentum at the time of interaction, the photoelectron can travel backwards toward the origin of the incident photon; however, the majority of ejected photoelectrons travel in the forward direction, especially as photon energy increases into the megavoltage range.

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103

Electron Neutron

Compton electron k m

l

φ θ

Incident photon, hν

Mass attenuation coefficient (cm2/g)

Proton 102

Lead Water

101 µ/ρPb 100 µ/ρw 10-1

Scattered photon, hν′ τ/ρw

Fig. 6.15 Compton effect.

σ/ρw

κ/ρw

10-2 10-2

4. Ejection of the orbital electron leaves a vacancy in the inner electron shell. This vacancy is filled by an electron from one of the outer orbitals, with the simultaneous emission of a characteristic x-ray with an energy of Ecx equal to the difference of the two electron binding energies (Fig. 6.15):

10-1

100

101

102

Photon energy (MeV) Fig. 6.16 Total mass attenuation coefficients for lead and water. Individual interaction coefficients for water (dashed lines) also are shown. (Data from Bureau of Radiological Health. Radiological Health Handbook. Bethesda, MD: US Department of Health, Education, and Welfare; 1970; and Evans RD. The Atomic Nucleus. Malabar, FL: Robert E. Krieger Publishing; 1955.)

ECX = EB1 − EB2. 5. This process leaves a new vacancy in an outer orbital shell, which is filled by an electron from an orbital beyond, with emission of a second characteristic x-ray of lower energy than the first. This cascade of vacancy creation, filling, and characteristic x-ray emission continues until the most outer orbital electron shell has a vacancy that is filled by a “free,” or unbound, electron. 6. A competing process to characteristic x-ray emission is the production of an Auger (pronounced “oh-jhay”) electron. In this process, the characteristic x-ray energy, EC X , is transferred to one of the nearby orbital electrons without x-ray emission, and the electron, called an Auger electron, is ejected with energy: EAU = ECX − EB2 = EB1 − 2EB2. Characteristic x-rays are so named because their energies are directly related to the unique energy levels of the electron orbits for an element. A material’s elemental composition can be determined by detecting its characteristic x-rays. Characteristic x-rays are named for the orbital electron transition that occurred. For instance, a Kα x-ray results in the L shell electron filling the K shell vacancy, an M → K transition yields a Kβ x-ray, and an M → L transition yields an Lα x-ray. For an atom with five electron orbitals, the possible electron transitions and their characteristic x-rays after a photoelectric interaction are L → K, M → L, N → M, O → N, M → K, N → K, O → K, N → L, O → L, and O → M. The most probable transitions are those between adjacent orbitals: L → K, M → L, N → M, and so forth. At the same time, Auger electron emission competes with the amount of characteristic x-ray emission, at a ratio given by w, the fluorescence coefficient. The photoelectric effect has a strong dependency on photon energy and atomic number of the material. The mass attenuation coefficient

varies as (1/Eγ)3 and Z3, respectively. Mathematically, this is shown as follows, where CPE is a proportionality constant: µ ρPE = CPEZ3 (Eγ )3.

Eq. 8

These dependencies for water are shown graphically in Fig. 6.16. In the photoelectric effect, no interaction is possible until the photon energy is greater than the electron binding energy. After the binding energy is barely exceeded, the probability for interaction increases greatly, leading to a sharp increase in μ/ρPE, with the graphical representation called an absorption edge. In Fig. 6.16, the K and L edges for lead are seen, corresponding to photoelectric interactions for the K and L shell electrons. No absorption edges are shown for water; the binding energies are less than 1 keV and do not show up on the graph. The dependence on Z and Eγ can be used to approximate the photoelectric contribution in a different material, using the following formula: µ ρPE,2 = µ ρPE,1 (Eγ ,1 Eγ ,2 )3 (Z2 Z1)3.

Eq. 9

If the material (Z) is constant but energy is changed, the approximate new photoelectric mass attenuation coefficient is found by µ ρPE ,2 = µ ρPE ,1 ( E γ 1 E γ 2 )3.

Eq. 10

If the photon energy (Eγ) is constant but the attenuating material is changed, the approximate new photoelectric mass attenuation coefficient is found by µ ρPE,2 = µ ρPE,1 (Z2 Z1)3.

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Eq. 11

CHAPTER 6 Compton effect. In the Compton effect (see Fig. 6.15), several events occur: 1. An incident photon with energy, Eγ = hν, interacts with a loosely bound, outer orbit electron. 2. The photon is scattered at some angle with reduced energy E′γ = hν′. 3. The orbital electron, now called the recoil or Compton electron, is ejected with kinetic energy, Ece, equal to the difference between the incident and scattered photon energies: Ece = Eγ − E′ γ . 4. Because the interaction is with the outer-shell electron, which has negligible binding energy, there are no characteristic x-rays or Auger electrons produced. The distribution of energies and scattering angles for the Compton photon and electron are coupled owing to conservation of momentum and energy and can be described mathematically. The scattered photon has energy E′γ = hν′ given by hν ′ =

hν = 1+ α(1− cos θ)

mo c2 . 1  1+  − cos θ α 

Eq. 12

In Eq. 12, α = hν/moc2 and represents the ratio of the incident photon energy to the rest mass of the electron, mo, and θ is the angle of photon scattering as defined in Fig. 6.15. The Compton electron has energy Ece given by the equation Ece = hν

α(1− cos θ) 1+ α(1− cos θ)

Eq. 13

and a scattering angle, ϕ, which depends on the incident photon’s energy and its scattering angle, θ: θ cos φ = (1+ α)tan . 2

Eq. 14

Selected scattering cases can be considered: 1. The minimum energy transfer occurs for a 0-degree photon scatter; there is no interaction, and the “scattered” photon has the same energy as the incident photon. The electron is scattered at 90 degrees (ϕ = 90 degrees) with zero energy. 2. The maximum energy transfer occurs for a direct hit with a backscattered photon (θ = 180 degrees) and yields a (minimum) scattered photon energy of hν′ =

hν . 1+ 2α

Eq. 15

The 180-degree backscattered Compton photon energy will always be less than and will approach a maximum of 0.25 MeV (which equals 1/2 moc2) even as the incident photon energy becomes very large. The electron has maximum energy of Ece = hν − hν′ = hν (2α/ [1 + 2α]) and travels in the forward direction. 3. A 90-degree Compton scattered photon has energy: hν′ =

hν . 1+ α

Eq. 16

The 90-degree scattered Compton photon energy will always be less than and will approach 0.511 MeV (which equals moc2) even as the

Radiation Oncology Physics

105

incident photon energy becomes very large. The electron has energy of Ece = hν − hν′ = hν (α/[1 + α]), and it travels in a direction that depends on the incident photon energy. For lower-energy incident photons, Compton electrons can scatter at most to 90 degrees from the forward direction—no backscatter greater than 90 degrees is possible—and they travel increasingly in the forward direction as incident photon energy increases. Their average energy also increases from about 10 keV to 7 MeV as incident photon energy increases from about 100 keV to 10 MeV.11 The forward-peaked distribution, also contributed to by photoelectrons in the forward direction, is responsible for the buildup region for megavoltage photon beams, as explained later. The Compton effect has a slight dependency on incident photon energy, decreasing as energy increases through the megavoltage range, but the interaction probability is essentially constant over most of the megavoltage energy range (see Fig. 6.16). Compton scattering is independent of atomic number and is dependent on the number of electrons available, or electron density (electrons per gram). The electron density for almost all materials is constant at approximately 3 × 1023 electrons per gram because the N/Z ratio is almost constant for most elements and materials. The exception is hydrogen, which, with one proton in the nucleus and no neutrons, has an electron density of around 6 × 1023 electrons per gram. Except for a small energy dependency and increased interaction probabilities for hydrogen-laden materials, the Compton mass attenuation coefficient is remarkably constant across energy and atomic number, especially for low Z biological materials such as tissues. Mathematically, this relationship is µ ρCE = CCE.

Eq. 17

In Eq. 17, CCE is almost a constant. With its relatively constant mass attenuation coefficient for a range of materials, the attenuation by the Compton effect reduces to the following expression: I I0

px

= e− CCE .

Eq. 18

CE

For unit thickness of a material, the transmitted amount depends primarily on material density, not atomic number and photon energy as with the photoelectric effect. Pair production. In pair production (Fig. 6.17), the following steps occur: 1. An incident photon with energy Eγ = hν and Eγ greater than 1.022 MeV passes near a heavy nucleus and spontaneously disappears, creating an electron, e−, and a positron, e+, in its place. These two particles are called an electron-positron pair. The total kinetic energy of the electron-positron pair, Eep, is equal to the photon energy minus the energy needed to create two electrons, or 1.022 MeV (the rest energy of an electron is 0.511 MeV): Eep = Eγ − 1.022 MeV. The electron and positron travel off in forward directions and do not have equal kinetic energies although their average (shared) energies are easily calculated. 2. The electron gradually slows down and is stopped in the material. 3. The positron, the antiparticle of an electron, slows down quickly and annihilates with a free electron, giving off two 0.511-MeV photons (called annihilation radiation) that travel in opposite directions (i.e., at 180 degrees).

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Annihilation radiation hν = 0.511 MeV Electron e-

Relative importance

100

PE

Pair 50

Water Z = 7.4

0.01

Incident photon hν ! 1.022 MeV

k

Free electron

l m

Positron e+ Electron Neutron

0.1

1.0 10 100 Energy (MeV) Fig. 6.19 Relative importance of photon interactions as a function of photon energy.

e-

Annihilation of electron-positron pair

Annihilation radiation hν = 0.511 MeV

Compton

Proton Fig. 6.17 Pair production.

Photoneutron

in treatment beams and facility shielding for photon beams of 15 MeV and greater.

Distribution of Secondary Electrons Electrons released by ionizing photon interactions can travel in many directions from the interaction point and, in general, have a complex probability for angular spread depending on incident photon energy and the interaction that occurs. The probability for forward directions increases with photon energy and is a likely direction for megavoltage photon interactions.2 As seen later, angular scattering of electrons is responsible for a number of characteristics for megavoltage photon beams, including surface dose, buildup region, depth of maximum dose, and penumbra region.

Total Attenuation Coefficient

Incident photon hν > 8–10 MeV

k l

Electron

m

Neutron Proton Fig. 6.18 Photodisintegration.

The mass attenuation coefficient for pair production varies linearly with atomic number and incident photon energy (when the photon energy is above the threshold of 1.022 MeV): µ ρpp = CppZ(Eγ − 1.022 MeV).

Eq. 19

Photodisintegration. Several steps occur in photodisintegration (Fig. 6.18): 1. An energetic photon of Eγ greater than 8 to 10 MeV interacts with the atomic nucleus. 2. The photon penetrates the nucleus and is absorbed. The energy deposition results in the emission of a nucleon—a neutron or proton. The nomenclature used is either (γ, p) or (γ, n) for a proton or neutron emitted from the nucleus, respectively. 3. Nucleon emission leaves a fragmented nucleus, prompting the name photodisintegration, which may also be unstable (i.e., radioactive). A photon energy of greater than 8 to 10 MeV is required because the nuclear binding energies for nucleons are 8 to 10 MeV for most materials. Photodisintegration is the interaction responsible for neutron production for photon energies at 10 MeV and greater. It can be an important radiation safety consideration for both neutron contamination

Each radiation interaction contributes its part to the total attenuation coefficient. Photons having the same energy can undergo any one of the five interactions when energetically possible. However, the probability for each interaction is different and in a particular energy range a particular interaction will dominate. In Fig. 6.16, the individual interaction and total mass attenuation coefficients are shown as a function of energy for lead and water. Notice the K edge in the curve for lead. It can be seen that different energy regions are dominated by particular interactions. For water, the photoelectric effect dominates for photon energies up to 60 keV, the Compton effect dominates from 60 keV to 10 MeV, and pair production dominates approximately above 10 MeV. For lead, the photoelectric effect dominates up to 700 keV, the Compton effect from 700 keV to 3 MeV, and pair production at 3 MeV and higher. An interaction’s region of dominance can be represented graphically to show relative importance as a function of energy (Fig. 6.19). Comparison of interaction dependencies shows why 30 to 100 kV energy photons give good contrast for diagnostic imaging: the photoelectric effect dominates and is quite sensitive to the atomic numbers of the materials being imaged. Materials with even slightly different Zs have good subject and image contrast because attenuation depends on the cube of the atomic numbers. Radiotherapy portal images with 6-MV photons, however, have poor contrast because the dominant interaction is the Compton effect. There is no dependence on atomic number, and the effect is constant for most biological materials (except for hydrogenous materials). Instead of imaging atomic number, the Compton effect images the density of a material, and subject contrast and image contrast are essentially representations of differences in material densities. A comparison of simulator and port images is given later (see Fig. 6.49).

Total Absorption Coefficient Radiation dose relates directly to the amount of energy absorbed at a point, not the amount attenuated, although the two are intimately related. This transfer of energy is done by secondary electrons

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CHAPTER 6 (photoelectrons, Compton electrons, and the electron-positron pair) that produce a large number of ionizations along their paths until their energy is expended. A portion of the photon energy that is attenuated may escape to other regions as a coherent or Compton scattered photon, an annihilation photon (0.511 MeV), or a bremsstrahlung photon after radiative energy loss of a secondary electron. The amount of energy absorbed from secondary electrons is less than the amount attenuated as photons, because not all of the incident photon energy is converted to secondary electrons, as described by Johns and Cunningham.21 In a similar fashion to the total mass attenuation coefficient, the total mass energy absorption coefficient, μen/ρ, or simply the mass absorption coefficient, describes the energy absorbed resulting from each interaction and is used for computing dose. The value of μen/ρ is nearly equal to μTOT/ρ in the photoelectric region (because all photon energy is transferred to the photoelectron except for a small amount needed to overcome the electron binding energy, EB), and then μen/ρ is less than μTOT/ρ in the region where the Compton effect dominates (because the Compton scattered photon carries energy away that does not contribute dose to the local region). At very high energies where pair production dominates, μen/ρ is less than μTOT/ρ by approximately a constant amount, based on the 1.022 MeV required to create the electron-positron pair. The two 0.511 MeV annihilation photons escape the system; thus, dose is essentially the kinetic energy carried by the electron-positron pair. Over the energy range used for radiotherapy, the amount of absorbed energy at a point in water (tissue) is about one-half the amount attenuated at the point. The mass absorption coefficient and dose are discussed more in the next section.

Summary of Photon Interactions 1. Coherent scattering occurs at very low photon energies (< 10 keV). 2. The photoelectric effect dominates up to 60 keV in water, with strong dependencies of Z3 and 1/E3γ for other materials. 3. The Compton effect dominates from 60 keV to about 10 MeV in water, with some dependence on energy or atomic number. Compton scattering depends only on the number of electrons per gram, which is almost constant for all materials (Ng ≈ 3.0 × 1023, except for hydrogen, for which Ng ≈ 6.0 × 1023). 4. Pair production occurs for photon energies only above 1.022 MeV, dominates above 10 MeV in water, and linearly depends on Z and photon energy. 5. Photodisintegration occurs at photon energies above 10 MeV and is responsible for the creation of neutrons in a LINAC facility. 6. At diagnostic photon energies, image contrast is determined primarily by differences in atomic numbers of materials being imaged because the photoelectric effect depends strongly on Z. Material thickness and density are secondary determinants. 7. At therapeutic photon energies, image contrast is provided by the densities of materials being imaged because the Compton effect depends on the number of electrons per gram, not the atomic number, of a material. 8. The total mass attenuation coefficient describes the amount of attenuation from all processes. A portion of the energy attenuated from the beam is deposited by secondary electrons as dose. The amount of energy absorbed as dose is described by the total mass absorption coefficient, which tracks the total mass attenuation coefficient and is numerically less.

Charged Particle Interactions Charged particles incident on matter undergo inelastic and elastic interactions with atomic electrons and nuclei, that is, other charged entities.2,12,13 Inelastic interactions include collisional and radiative processes and result in energy loss by the particle. In an elastic interaction,

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the particle is scattered by an atomic electron or nucleus, resulting in a change of direction for the particle but no energy loss. The interaction probability for charged particles is effectively 1; an incident charged particle interacts at every opportunity. The quotient dE/dx (units of million electron volts per centimeter) is called the stopping power; for charged particles, it describes the rate of energy loss, dE, that occurs over distance traveled, dx, for inelastic collisions. Stopping power is often expressed as the mass stopping power, dE/ρdx (units of million electron volts/g/cm2), which is independent of the absorber density. Because energy loss is almost continuous and a particle has a particular kinetic energy, EKE, the particle loses this amount of energy and then stops. The distance traveled is finite and is called the particle range; the particle can go no farther, and its kinetic energy is zero. For an absorber of density ρ, the particle range, r, can be calculated as follows: r = EkE

1 1 . dE ρ ρdx

Eq. 20

The energy lost through inelastic collisions depends on the particle mass, charge, and kinetic energy and on the mass and charge of the target atom, according to the formula dE 2πz2e4 = NZFQ. dx mo V 2

Eq. 21

In Eq. 21, z is the atomic number of the incident particle of mass M, V is its velocity, e is the electron charge, mo is the electron mass, NZ is the number of electrons per cubic centimeter in the absorber, and FQ is a complex function describing energy transfer per interaction. Collisional energy losses increase by the square of the particle’s atomic number and as the incident particle velocity (and energy) decreases. Increased atomic number results in a greater coulomb force and decreased velocity increases the amount of interaction time, both leading to increased dE/dx. The energy transfer function, FQ, is complex and varies with the type of interaction.2 It accounts for the atomic mass of the absorber, ionization potential, and relativistic effects as v approaches the speed of light.

Light Charged Particle Interactions: Electrons The electron mass is small compared with any atomic mass, and incident electrons undergo four types of particle interactions with a large amount of scattering.8 Collisional interactions result in energy loss of dECOL/dx, causing ionizations or excited states (higher electron orbits) (Fig. 6.20). Collisional losses increase as the electron velocity decreases, as stated previously, and decrease as the absorber atomic number increases. The decrease with absorber atomic number results from the decrease in the number of electrons per gram (NZ/ρ) as Z increases. For equivalent mass thicknesses (mass thickness is thickness divided by density, with units of cm2/g), electrons are stopped sooner in low Z than in high Z materials. Fig. 6.21 shows these relationships for water and lead. Radiative interactions of electrons result in x-ray emissions. The incident electron penetrates the electron cloud and interacts with the nucleus’s positive electrical field, undergoing an abrupt deceleration with energy loss dERAD/dx and a change in direction (see Fig. 6.20D). The energy change, dERAD/dx, is released in the form of x-rays, called bremsstrahlung (or braking) radiation. With an incident monoenergetic electron fluence, a continuous x-ray spectrum is emitted because the probability of any energy loss, large or small, is equal per interaction. Successive bremsstrahlung interactions may occur as the electron loses its energy; a bremsstrahlung x-ray spectrum has a maximum energy equal to the initial electron energy and all other x-ray energies below this

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Scientific Foundations of Radiation Oncology

A. Excitation

B. Ionization of outer shell

es Light

C. Ionization of inner shell

D. Bremsstrahlung production

Characteristic x-ray

es ei

Bremsstrahlung x-ray

es

ei

es

em

eo = Incident electron em = Excited electron es = Scattered electron ei = Ionized electron

eo

eo

eo

eo

Fig. 6.20 Electron interactions. (A) Excitation. (B) Ionization of outer shell. (C) Ionization of inner shell. (D) Bremsstrahlung production. (Adapted from Johns HE, Cunningham JR. The physics of radiology. 3rd ed. Springfield, IL: Charles C Thomas; 1978.)

Energy loss (MeV/g/cm2)

101

100 Lead collisional Water collisional Lead radiative Water radiative 10-1

10-2 100 101 102 Electron energy (MeV) Fig. 6.21 Collisional and radiative electron losses as a function of incident electron energy. (Adapted from Johns HE, Cunningham JR. The physics of radiology. 3rd ed. Springfield, IL: Charles C Thomas; 1978.) 10-2

10-1

maximum to zero (see Fig. 6.7). Radiative interactions are important; they are the mechanism by which bremsstrahlung x-rays are produced in diagnostic x-ray tubes and LINACs. Bremsstrahlung production increases with incident electron energy and the Z of the absorber (see Fig. 6.21). The probability for collisional and radiative interactions depends on electron energy and the atomic number of the incident material (see Fig. 6.21). At electron energies of 100 keV and for high Z absorbers (e.g., x-ray targets), 99% of the interactions are collisional and 1% are radiative (x-ray production), resulting ultimately in heat deposition. At electron energies of 10 MeV, bremsstrahlung is a much more efficient process; approximately 50% of the interactions are collisional and approximately 50% radiative. At 100 keV, x-ray production is inefficient, whereas at 10 MeV, x-ray production is efficient. Above 10 MeV, bremsstrahlung x-ray production exceeds collisional losses. It has been observed that dECOL/dx increases as electron kinetic energy decreases below 1 MeV

(see Fig. 6.21). As the electron slows down, it loses energy faster. Above 1 MeV, electrons lose about 2 MeV/cm traveling in water (dECOL/dx ≈ 2 MeV/cm). A 10-MeV electron has a range of about 5 cm in water (10 MeV ÷ 2 MeV/cm). Density scaling can be applied for materials different from unit density. For example, a 10-MeV electron travels approximately 3.3 cm in bone of density of 1.5 g/cm3 (10 MeV ÷ [2 MeV/ cm × 1.5]). These relationships use Eq. 20 as their basis.

Heavy Charged-Particle Interactions Heavy charged particles, such as protons and alpha particles, experience mainly inelastic collisions. The rate of energy loss is high, resulting in short ranges. Trajectories in water or tissue are in the forward direction with little scattering; the particle mass is similar to that of the interacting material, and few large-angle direction changes occur in contrast to the large amount of scattering experienced by electrons. Heavy charged particles exhibit rapidly increasing and large energy losses near the end of their ranges because of the dependency on Z2 and 1/v2 discussed previously (see Eq. 21). This increase in energy loss results in a dramatic increase in ionization at the tail of the particle track length after a length of relatively constant loss, a phenomenon called the Bragg peak.2,12,13 Bragg peaks are observable for protons (Fig. 6.22) and alpha particles. All charged particles exhibit a Bragg peak, including electrons; however, electrons are light enough such that multiple scatters occur and ionization paths are randomly oriented, blurring any observable effect. The proton finite range can be modulated through a physical attenuator or other means to decrease the range from the maximum. This process is essentially modulating the incident proton beam energy. If range modulation is done continuously while the beam is on, the Bragg peak will be swept over a range called the Spread Out Bragg Peak (SOBP) and will produce a high-dose plateau (see Fig. 6.22). The width of the SOBP dose plateau can be designed to match a tumor size at a certain depth and demonstrates the attractiveness of protons for radiotherapy.

Heavy Uncharged-Particle Interactions: Neutron Neutrons have no charge and do not undergo coulomb interactions like charged particles. Instead, neutrons interact by inelastic and elastic

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CHAPTER 6

100.0

Relative ionization

80.0

60.0

40.0

250 MeV protons 250 MeV protons (modulated) Neutrons

20.0

0.0 20.0 30.0 40.0 Depth in water (cm) Fig. 6.22 Ionization curves for heavy particles. Protons are charged and exhibit a Bragg peak at the end of their range. Neutrons are uncharged and are exponentially attenuated. (Data for protons from Miller DW. Update on proton radiotherapy. In: Mackie TR, Palta JR, eds. Teletherapy: Present and Future. Madison, WI: Advanced Medical Publishing; 1996.) 0.0

10.0

collisions with nuclei through the strong force. Commonly for lower and middle Z materials, a neutron penetrates the nucleus and is absorbed, followed by the ejection of a proton (the [n, p] reaction). The new nucleus may be radioactive, a process called neutron activation. Neutrons may also cause nuclear disintegrations, similar to photodisintegration. For very heavy nuclei, neutrons may cause fission, a reaction harnessed for power production in nuclear reactors. Elastic scattering of neutrons is also common. The type of collision, inelastic or elastic, that a neutron experiences depends on the neutron energy and absorber atomic number with complex reaction probabilities.18,21 Neutrons lack charge; thus, for higher-energy (nonthermal) neutrons, their interactions with nuclei are exponential in nature, like photons (see Fig. 6.22). Their range can be stated as a mean path length equal to the inverse of the neutron attenuation coefficient.

Summary of Particle Interactions 1. Particles with kinetic energy have inelastic and elastic interactions with an absorbing material. Inelastic collisions result in loss of energy, whereas elastic collisions do not. 2. Electrons experience inelastic collisions through coulomb interactions with the atomic electrons or nucleus. Collisional interactions with the atomic electrons result in excitation or ionization and, thus, radiation dose. Interactions with the nucleus result in production of bremsstrahlung x-rays. 3. For electrons, collisional energy losses dominate at lower energies, whereas radiative losses dominate at higher energies. Interestingly, collisional energy losses are greater per gram of low-Z material than for high-Z material. The material of choice for electron shielding is a low-Z material because the stopping power per gram is higher and bremsstrahlung production is minimized. 4. In water or tissue, megavoltage electrons lose about 2 MeV/cm traveled. The electron range is finite, and its length in centimeters is found by dividing the energy (in MeV) by 2. 5. Electron interactions result in a large amount of scattering, caused by the light mass of the electron relative to the nuclear mass of any absorber.

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6. Charged heavy particles undergo inelastic collisions mainly through coulomb interactions with the atomic electrons, resulting in excitation or ionization and, thus, radiation dose. Nuclear interactions occur only at very high energies and do not include bremsstrahlung production. 7. Charged heavy particles have a finite range and experience a rapid increase in energy loss near the end of their track, dumping much of their remaining energy quickly and producing an ionization curve with a Bragg peak. This is of greatest interest for the use of protons for treatment, using range modulation to create an SOBP that covers a target at depth. 8. Neutrons experience inelastic and elastic collisions with nuclei, resulting in nuclear rearrangements that are followed by ionization events. Neutrons do not have a finite range.

RADIATION QUANTITIES AND MEASUREMENT Ionization and Its Fate Ionizing radiation is quantified by measuring the amount of ionization produced. The number of ions is directly proportional to the amount of energy imparted to a material. An average of 33.97 eV is required to produce one ion pair (ip) in air.23 This number is called the W value (W = 33.97 eV/ip for air), and it is almost independent of the radiation energy. W for other gases is similar to that of air, and its uniformity from material to material relates to atomic energy levels and capabilities for transfer of excitation energy.2 Note that several values for the W value have been determined over time; these variations are small and are responsible for the slight differences in the coefficients used for conversion of exposure to dose, as reviewed later.22,23 In four of the five photon interactions, energy is transferred from incident photons to produce ionization or secondary processes. This energy transfer results in radiation dose. For each interaction, it has origins as follows: 1. In coherent scattering, there is no ionization. However, the scattered photon is removed from the primary beam and might be able to undergo an ionizing interaction. 2. In the photoelectric effect, the inner shell electrons are ionized. The photoelectron is ejected and loses its energy by excitation and ionizations. Characteristic x-rays and Auger electrons are energetic enough to cause ionizations. 3. In the Compton effect, the outer shell electrons are ionized. The scattered photons and the Compton (recoil) electrons may be energetic enough to cause ionizations. 4. In pair production, there is no direct ionization of the atom. However, the electron and positron each have enough energy to cause ionizations, and annihilation radiation is energetic enough to cause ionizations. 5. In photodisintegration, there is no direct ionization of the atom. However, the remaining atom (with one fewer neutron or proton) may be unstable and decay by emission of ionizing particles. An ejected neutron may cause activation of other atoms, resulting in nuclear decay and ionizations, and an ejected proton will directly deliver dose. If all of the created ions are collected and measured, the amount of energy deposited can be determined. This measurement of ionization is the basis for the determination of radiation dose.

Radiation Quantities and Units Ionizing radiation is quantified using two important quantities: exposure and dose. A third quantity, kerma, is an important concept that relates to exposure and dose.

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110

SECTION I

Ionization in (or energy in)

Scientific Foundations of Radiation Oncology

Ionization out (or energy out)

Measurement point or volume Fig. 6.23 Ionization lost downstream from a volume of interest is replaced by an equal amount from upstream, producing electronic equilibrium and an accurate ionization measurement.

Exposure, X, is the measurement of the amount of ionization produced by photon interactions per mass of air (charge per mass of air). Exposure has historical significance as the first quantitative definition of ionizing radiation quantity. The SI unit for exposure is a charge of 1 coulomb (C) per mass of 1 kilogram (kg): X = C/kg. The original unit of exposure, X, essentially as the first quantitative definition of radiation dose (circa 1933), is the roentgen (R), named after the discoverer of x-rays, Wilhelm Conrad Roentgen:

a

X 2. Convert exposure to dose to air X

Exposure

a

X

1. Measure exposure (roentgens)

a

Da

3. Convert dose to air to dose to medium Da

m

Da

Dm

m m

Dm

Fig. 6.24 The dose measurement process. Exposure to a small mass of air is converted to the dose to medium.

1R = 2.58 × 10−4 C kg of air (= 1 esu cm3 in air). In the previous expression, C (coulomb) is a unit of charge (or ionization) such that 1 ip = 1.6 × 10−19 C. The original definition of charge per volume, 1 R = 1 esu/cm3, was based on the electrostatic unit and is responsible for the odd units of the roentgen as now defined. Use of the roentgen as a radiation quantity remains quite common, particularly within the radiation protection field. Several important concepts characterize exposure, X: 1. It is defined for all ionizations, primary and secondary, when produced and measured in air. 2. It is defined only for ionizing photons (x-rays and gamma rays), not electrons or other particles. 3. It is properly measured only under conditions of electronic equilibrium, and it is difficult to measure for photon energies higher than 3 MeV. Above this energy, the electron range in air becomes too large for electronic equilibrium to be achieved practically. Electronic equilibrium. With electronic equilibrium, ionization lost downstream from a volume of interest is replaced by an equal amount from upstream, producing an equilibrium and an accurate ionization measurement within the volume of interest. The concept is illustrated in Fig. 6.23. After interaction, ionization—made up of photoelectrons, Compton electrons, and pair production electrons—travels away from the interaction point in the direction of the incident photons and a portion actually leaves the volume of interest. To accurately measure the amount of ionization produced in the volume, the lost kinetic energy of the escaping electrons must be replaced by an equal amount that enters the volume from upstream (see Fig. 6.23). This equilibrium of energy flow is called electronic equilibrium or charged-particle equilibrium and is a required condition for measurement of exposure.

Dose Dose, D, is the measurement of the amount of energy imparted per mass of material (energy per mass).11 The unit of dose is the gray (Gy): 1 Gy = 1 J/kg. An earlier dose unit is the rad (rad): 1 rad = 100 erg/g = 0.01 Gy; 1 Gy = 100 rad. Although not an official unit, cGy is often used because of its numerical equivalency to the rad: 1 cGy = 1/100 Gy = 1 rad. Thus, 100 cGy = 1 Gy. Dose does not have the restrictions of exposure. Therefore, the following two statements apply: 1. Dose is valid for any ionizing radiation at any energy (e.g., x-rays, gamma rays, e−, e+, n, p, α, Π). 2. Dose is valid for any material and phase: solid, liquid, or gas.

In practice, dose to a medium is determined by measuring exposure and converting it to dose using the W value and the mass energy absorption coefficient, μen/ρ. The mass energy absorption coefficient is similar to the mass attenuation coefficient, except that it describes energy absorbed, not attenuated. The process is illustrated in Fig. 6.24 for the following steps, using the original definition of exposure, the roentgen, and with the assumption of electronic equilibrium: 1. Exposure, X, of 1 R is given to a small air-filled cavity contained in a material, m: X = 1R. 2. Dose to air in the cavity is computed using the W value and the definition of the roentgen, converting energy units as needed: Da = WX = 33.97 eV ip × 1R (converting units) = (33.97 eV ip)(1ip 1.6 × 10−19 coul) × (2.58 × 10−4 C kg 1R) × (1.6 × 10−12 erg eV) × (1kg 1000 g)

(converting to Gy) = (87.6 erg g R)(0.01Gy 100 erg g) , thus, Da = 0.00876 Gy R for an exposure of 1R.

Eq. 22

The coefficient of 0.00876 Gy/R is called the roentgen-to-gray conversion coefficient and is commonly expressed as the roentgento-centigray coefficient of 0.876 cGy/R. The important concept is that an exposure of 1 R, by definition, results in the energy release in air of 0.00876 Gy: 1 R → 0.00876 Gy (in air). This representation of exposure is called “air kerma”; it is the kinetic energies of charged particles released in air. Kerma and the Gray as a unit of dose are discussed later in greater detail. For X number of roentgens, the dose to air is calculated as follows: Da = 0.00876 Gy R X(R).

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Eq. 23

CHAPTER 6

Radiation Oncology Physics

5.0

3. Dose to the material is calculated by converting dose to air, Da, to Dm. Conceptually, this step replaces the air cavity with an identical volume of the material. It can be shown21,24 that

Air (f = 0.875) Water

4.0

Compact bone Muscle

m

Dm = Da

µ en , ρ a

111

Eq. 24 3.0

µ en ρ

m

a

is the mass energy absorption coefficient for the material, m,

f Factor (cGy/R)

in which

2.0

µ en ρ m divided by 1.0

µ en ρ

0.8

a

the mass energy absorption coefficient for air, a. Combining Eqs. 23 and 24 yields the following expressions: Dm =

µ en ρ

m

0.876 cGy RX(R)

Eq. 25

a

10-2

10-1

100

101

Photon energy (MeV) Fig. 6.25 The f factor varies as a function of the material and the photon energy. (Data from Bureau of Radiological Health. Radiological Health Handbook. Bethesda, MD: US Department of Health, Education, and Welfare; 1970.)

and Dm = fX(R),

Eq. 26

in which the f factor, f, is calculated as follows: f=

µ en ρ

m

0.876 cGy R.

Eq. 27

a

For any exposure, X(R), measured in air, the dose to a material substituted at that point can be found by multiplying the f factor by the exposure. In practice, the air-filled cavity is an ionization chamber that is inserted into the radiation beam and the ionization collected in the chamber is converted to dose using exposure-to-dose calibration factors in a prescribed procedure that accounts for the properties of the ionization chamber and particular radiation beam energy and irradiation geometry. The f factor is an important parameter, which varies as a function of the material and the photon energy, as shown for water, muscle, and bone in Fig. 6.25. By its definition, the f factor for air is always 0.876 cGy/R. Water, muscle, and air have similar f factors because their effective atomic numbers are similar. Bone has a higher atomic number (by a factor of 2) and receives up to 4 times the dose that soft tissue would receive in the photoelectric region. This effect is responsible for high bone doses received during orthovoltage treatment as well as the contrast seen in diagnostic x-ray images. Note the decrease in f factor for fat in the photoelectric region because of its lower Z as a result of its high hydrogen content. For treatment with ionizing radiation, the amount of energy deposited is quite small per fraction of dose. It takes about 1 million cGy to raise the temperature of 1 cm3 of water by 1° C. Conversely, for a daily treatment dose of 2 Gy (200 cGy), the increase in temperature per gram is only 0.0002° C. Thermal effects are nonexistent for fractionated and radiosurgical radiation treatment.

Kerma When photon radiation interacts with a material, energy is transferred to secondary electrons (the photoelectron, Compton electron, pair production electrons) and results in their kinetic energy. This transferred energy is called kerma (kinetic energy released in medium). Kerma, K, is expressed as the amount of energy released per mass of irradiated material and has the same unit as for dose, the Gray (J/kg). For example, and as reviewed previously, the amount of ionization produced (released) in air for 1 R of exposure is also the “air kerma,” with conversion ratios of 1 R = 0.00876 Gy (air kerma) and 1 Gy (air kerma) = 114.3 R. Kerma differs from dose in that kerma is the energy released per mass and dose is the energy absorbed per mass. These two quantities may be numerically quite similar, but there are three important aspects to their relationship: 1. The kerma at a point travels (primarily) in the forward direction for megavoltage photons. Secondary particles released at the point deliver their dose downstream from the point, not at the point. Kerma at an interaction point may result in a numerically equal dose at a downstream point of interest. 2. Even if at the same point of interest, kerma will be greater than dose, because secondary electrons may lose some of their energy by the bremsstrahlung process. The bremsstrahlung x-rays carry energy away from the point of interest. D = K(1 − g), in which g is the fraction of energy lost to bremsstrahlung. 3. If electronic equilibrium is satisfied and bremsstrahlung is negligible (g < 1), dose equals kerma at the point of interaction. Thus, dose equals kerma, provided that there is electronic equilibrium; this concept is key to radiation dose measurements. Thorough explanations of exposure, dose, kerma, and their relationships are available.12-14 Much has been studied and written about these and other dosimetric concepts to establish meaningful and consistent definitions. A summary is presented in Table 6.7.

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112

SECTION I

Scientific Foundations of Radiation Oncology

Radiation Detection and Measurement

Solid-State Detectors

There are different types of radiation detection and measurement instruments with particular characteristics that enable measurements of a certain kind to be performed. General classes of instruments are gas-filled detectors, scintillation detectors, other solid-state detectors, absolute dosimeters, and personnel dosimeters.

Thermoluminescent dosimeters. In a simple model, crystalline solids have two electron energy levels, called the valence and conduction bands. The valence band holds bound electrons, whereas the conduction band consists of free electrons. Energy states between these two bands are forbidden. When ionized, a bound electron may gain sufficient energy to jump to the conduction band, leaving a positive “hole” in the valence band. The conduction band electron and the hole can move through the lattice and eventually recombine, with the emission of light on recombination. Because of impurities in the lattice, some crystalline materials have the property of having long-lived “traps” that can hold an electron-hole pair in an excited (or unfilled) state. The electron-hole pair is created and excited into the trap by the absorption of ionizing radiation, which provides the energy to push the pair into the trap (Fig. 6.28). Heating the crystal enables the electron-hole pair to leave the trap and return to the de-excited state. With this transition, an amount of

Gas-filled detectors operate on the basic principle of measuring exposure, that is, collecting ionization in air or a substitute gas. A gas-filled volume is defined as one that contains two oppositely charged plates or wires to collect the charge resulting from ionization in the gas. The reading is in units of charge (coulombs), exposure, or exposure rate. Fig. 6.26A shows a simple parallel plate gas-filled detector and its components. As the voltage applied to the electrodes is increased from zero, the amount of charge collected increases (see Fig. 6.26B). The distinct voltage regions are expanded in Table 6.8. In general, gas-filled detectors require calibration before making radiation measurements. Ionization chambers. Ionization chambers operate in region II (see Fig. 6.26B) and are an important type of radiation dosimeter as the principal device used for calibration of radiotherapy beams. The design most commonly used for photon beams is the thimble chamber, also called a Farmer chamber, which has a cylindrical geometry with central linear and outer cylindrical electrodes (Fig. 6.27A). An active volume of 0.6 mL is convention, although chambers with smaller or larger volumes are available for specialized purposes such as small field dosimetry or low-dose-rate measurements. Parallel-plate chambers are also used and are the recommended chamber geometry for electron beam dosimetry (see Fig. 6.27B). In general, ionization chambers require calibration before use. Ionization currents produced by radiation beams are very small, on the order of 10−9 amperes (A), and require a highprecision device called an electrometer for accurate measurement. An ionization chamber and electrometer require calibration before use and with a triaxial connecting cable are required tools for radiation beam calibration. Conditions for radiation beam calibrations are set by national protocols such as the Task Group (TG)-51 from the American Association of Physicists in Medicine15 and by national or state regulatory bodies. A requirement for operation of all ionization chambers is that the chamber be operated under conditions of electronic equilibrium. In disequilibrium conditions, the amount of ionization measured is incorrect, as will be the exposure or dose calculation.

TABLE 6.7

Ion chamber

+ e–

Voltage

–

Photons

A

Meter V III

Ionization

Gas-Filled Detectors

IV

II I

B

Applied voltage Fig. 6.26 Response of a gas-filled detector. (A) A gas-filled detector collects ionizations from an irradiated volume. (B) Variation of collected ionization as bias voltage is increased. Regions are explained in Table 6.8.

Radiologic Units

Quantity

What Is Measured

Unit (Symbol)

Value

Exposure

Ionization in air

Roentgen (R)

2.58 × 104 C/kg|air

Dose

Energy absorbed in matter

rad (rad)

100 erg/g

Dose (SI)

Energy absorbed in matter

Gray (Gy)

1 J/kg

Kerma

Kinetic energy released in matter

Gray (Gy)

1 J/kg

Dose equivalent

Biological effect of energy absorbed

rem (rem)

QF × 100 erg/g

Dose equivalent (SI)

Biological effect of energy absorbed

Sievert (Sv)

QF × 1 J/kg

Activity

Disintegrations per time

Curie (Ci)

3.7 × 1010 d/s

Activity (SI)

Disintegrations per time

Becquerel (Bq)

1 d/s

Exposure rate constant

Exposure rate per activity

Gamma (Γ)

Exposure rate constant (SI) Air kerma strength

Exposure rate per activity Air kerma in free space

μ

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−1

−1

2

Gamma (Γ) Sk

−1

2

2

−1 −1

CHAPTER 6

TABLE 6.8

Detectors

Add heat

Description

I

The recombination region. The voltage is not high enough to separate the ion pairs and recombination occurs.

II

The saturation region. The voltage is high enough to collect almost 100% of the ionization (hence, “saturation”). Also called the ionization region.

Ionizing radiation

III

The proportional, or gas amplification, region. The voltage is high enough to accelerate the ionized electrons to an energy that causes additional ionization, amplifying the actual amount of initial ionization by a factor M.

IV

The Geiger-Muller, or GM, region. The voltage is high enough that amplification by accelerated ions proceeds so that the entire gas in the detector is ionized each time a photon hits the detector. Whether low or high energy, the amount of ionization that occurs is the same. Thus, a GM counter emits a “click” for each photon seen and is really a photon counting device. The continuous discharge region. The voltage is high enough to spontaneously ionize the detector gas. Once started, the ionization continues without interruption, independent of the absence or presence of ionizing radiation. The detector is not useful at this applied voltage.

Direction of ionizing radiation

Buildup cap

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Excited state

Voltage Regions of Gas-Filled

Region

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Radiation Oncology Physics

+

– Active volume

A Direction of ionizing radiation Active – volume +

B Fig. 6.27 Ionization chamber designs. (A) Thimble chamber. (B) Parallelplate chamber. A buildup cap may be added to either chamber to ensure electronic equilibrium depending on the measurement being performed.

light is emitted that is proportional to the amount of radiation dose. Dose is measured by measuring the amount of light emitted. The two most common types of thermoluminescent dosimeter (TLD) are lithium fluoride (LiF, almost tissue equivalent) and calcium fluoride (CaF, not tissue equivalent) in the form of rods or chips with spatial dimensions of 1 to 3 mm. A calibration factor must be obtained before use as a dosimeter. TLD is used for in vivo patient dose monitoring during treatment and for personnel monitoring for radiation safety purposes.

Light

Trap

Electron Ground state Fig. 6.28 Thermoluminescence. Ionizing radiation raises an electron-hole pair to an excited but trapped state. Addition of heat allows de-excitation, which occurs with the emission of light.

Optical density

A

log (Dose) Diagnostic energy range

Optical density

B

Dose Therapy energy range

Fig. 6.29 Film radiation response varies with film type, photon energy, and dose. (A) Diagnostic photon energy response. (B) Therapeutic photon energy response.

Optically stimulated luminescent dosimeters. As a replacement to TLD, an optically stimulated luminescent dosimeter (OSLD) has been developed that uses the crystalline material of carbon-doped aluminum oxide (Al2O3:C). This crystalline dosimeter has similar behavior to the TLD, with energy levels (conduction and valence bands) and long-lived traps that can store electron-hole pairs after exposure to ionizing radiation. However, different from the TLD, the OSLD uses light, instead of heat, to stimulate the trapped electron-hole pairs to return to the deexcited state, emitting light of a lower energy (higher wavelength) than the stimulating light used for de-excitation. As with the TLD, because the large number of traps is induced by exposure to ionizing radiation, the radiation dose received (measured) is proportional to the amount of light emitted. Individual disks of the OSLD are small disks (~ 5 mm diameter) of composite plastic and Al2O3:C. The Al2O3:C material is not tissue equivalent and each OSLD requires calibration for the type of ionizing radiation being used. The OSLD is widely used for both personnel monitoring, as discussed more later, and in vivo patient dosimetry. Film. Film is a solid-state detector and historically has referred to silver-halide films that are sensitive to both light and ionizing radiation. The amount of optical density is proportional to the dose. The response is energy sensitive because film is relatively high Z (the silver content). Response curves are shown in Fig. 6.29. Film is used to obtain relative dose distributions (i.e., isodose distributions) for treatment machine quality assurance tests for flatness, symmetry, radiation/light field congruence, and imaging.16,25 A dose-response curve must be carefully measured, including constant processor control, to enable film to be used to measure actual (not relative) doses. Because of electronic image receptors for digital photography and medical imaging with kV and MV photons (e.g., diagnosis and treatment verification), relatively high cost, and the chemical development process required after exposure, medical uses of silver-halide radiographic film are almost nonexistent, except for specialized imaging applications such as mammography. For physics quality assurance and dosimetry purposes, a new type of

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tissue-equivalent film, called radiochromic film, has become a powerful tool. Radiochromic film uses opacity changes from radiation-induced polymerization to indicate dose.26 This film does not require developing but does have an optimal wavelength of light for reading. A digital flatbed three-channel (color) scanner can be used to read the radiochromic film opacity and, through a calibration procedure, one- and two-dimensional dose distributions can be obtained. Uses include small- and large-animal radiation research and therapy beam quality assurance and dosimetry, such as small-beam dosimetry, patient treatment plan verification (i.e., IMRT quality assurance), large-field size confirmation, and LINAC mechanical and radiological confirmations. Radiochromic film is tissue equivalent and can be used over the full range of x-ray energies. Radiochromic film types are also available for different dose ranges, from 1 up to 50 Gy. Radiochromic film is typically not used for medical imaging because of its cost and lack of imaging contrast. Metal oxide-silicon semiconductor field effect transistor detectors. A semiconductor device called the metal oxide-silicon semiconductor field effect transistor, or MOSFET, can be used as a radiation detector for in vivo dosimetry and physics quality assurance. The p-type device generates electron-hole pairs during irradiation proportional to the dose delivered, and the number of holes, corresponding to dose, can later be read using an appropriate metering device. Advantages include very small size, which enables small-field—or “point”—dose measurements and the capability for being incorporated into both implantable dosimeters and surface-placed dosimeters for in vivo patient dosimetry.27 MOSFET dosimeters are primarily used for EBRT with photons and require calibration for the photon energy in use. Surface applications require an understanding of the buildup effect for proper assessment of surface dose. Real-time monitoring of brachytherapy dose delivery is also possible. Scintillation detectors. Scintillation (light) detectors detect radiation by measuring the amount of light produced in special crystalline materials by the ionizing radiation. The most common material used is sodium iodine (NaI). The NaI crystal is coupled to a photomultiplier tube that amplifies the detection signal coming from the crystal (Fig. 6.30A). NaI detectors are extremely sensitive and detect background radiation easily. They are used to detect low-energy or low-activity (dose rate) sources, for instance, in an isotope laboratory within the radiotherapy clinic or a research laboratory using liquid radioactive tracers. These detectors are used in uncalibrated form; a pulse indicates that a photon has been detected. NaI crystal Light Ionizing photons

ns

tro

c Ele

Signal out

Photomultiplier tube

A

Photocathode

PMT

PMT PC LS

B

PC Light-proof enclosure

Fig. 6.30 Scintillation detectors. Ionizing radiation creates light photons that are converted to electrons and amplified. (A) Sodium iodine crystal and photomultiplier tube. (B) Liquid scintillation detection.

Scintillation materials can also be made in liquid form. With this technique, a radiation source (i.e., a sample of radioactive material) is put in direct contact with a liquid scintillator by immersion (see Fig. 6.30B). This intimate contact enables extremely small activities to be detected. Detection limits are in the microcurie and picocurie ranges. This method is used most for detection of very-low-energy beta particles for radioisotope tracer studies, environmental sampling, and isotope analysis of waste or other materials. The liquid scintillator is called a cocktail, which includes a solvent and the scintillation material. Liquid scintillation detectors require calibration before use, including determination of background count rates. Semiconductor detectors: germanium and silicon. Germanium (GeLi) and silicon (SiLi) detectors are semiconductor materials that can be used to detect the energies of photons. These detectors are useful only at very low dose rates (i.e., small sample activities or low fluence rates) and are used to measure the photon energy spectrum, not dose.

Absolute Dosimeters Most dosimeters require calibration in the form of the dose or exposure per reading. Absolute dosimeters do not require calibration and instead measure the amount of dose directly. Calorimetry. All radiation dose, which is energy imparted per mass, eventually becomes heat. If the change in temperature is measured, the amount of dose is known. Temperature changes per Gray are quite small, as previously stated; thus, a sensitive device called a calorimeter is used. Standard-setting bodies, such as the National Institute of Science and Technology, have calorimeters to set the exact calibration factors for radiation beams and instrumentation, and calorimeters are not part of the routine dosimetry instruments used in the radiotherapy clinic. Chemical or Fricke dosimeter. The Fricke dosimeter measures chemical changes that are catalyzed by ionizing radiation. The chemical yield of the new product is directly proportional to the radiation dose. The most common reaction used is ferric to ferrous sulfide, such that the amount of Fe3+ produced is proportional to the dose delivered. The yield per Gray is small, and Fricke dosimeters are typically used in unique geometries and for high dose rates.

Personnel Dosimetry Monitoring of dose for radiation safety purposes is required for workers who are occupationally exposed to ionizing radiation. Although the TLD and film have been used previously, the OSLD is now the primary dosimeter material. The aluminum oxide dosimeter wafer is assembled with other components into a radiation “badge” that is worn at the waist or collar during work. Filters that overlay the dosimeter enable discrimination between electrons or low-energy photons and high-energy photons. Dose readout is accomplished in a light-tight reader that provides the optical stimulation and the conversion of light emission to radiation dose. Besides personnel dosimeters that must be interrogated with a specialized reader, for high-dose-rate environments there are direct-read dosimeters that can be used for instant readout. Such dosimeters are important for instances of emergency response. Personnel dosimeters are made in holders to enable whole-body and extremity monitoring based on the work activities being conducted by the user. References on radiation instrumentation and measurement are available that give detailed theory, design parameters, and operational characteristics for different classes of detectors.21,22,28

BUILDUP PHENOMENON Megavoltage photon beams used for radiotherapy exhibit a phenomenon in which the dose in an absorber is relatively low at the surface but rapidly increases to a maximum during the next few millimeters or

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CHAPTER 6 tens of millimeters. This region of rapidly increasing dose is called the buildup region and is explained as follows. The secondary electrons— photoelectrons, Compton electrons, and pair production electrons— produced by megavoltage photon interactions travel primarily in the forward direction from the interaction point. The direction and range are represented by the groups of arrows in Fig. 6.31. The surface is the first point of interaction; the dose from these interactions is delivered in the forward direction (point A). Because there are no interaction points upstream from the surface to produce secondary electrons, the surface dose is low. Ignoring attenuation and other small changes to the photon fluence with depth, interactions occur in the next layer of material beneath the surface, with a similar forward dose distribution. These electron tracks overlap (sum) with those from the surface. Additional layers at depth have similar interactions and resulting secondary electron distributions that sum with previous ones. The amount of dose increases rapidly and nonlinearly as successive electron tracks overlap (point B). Given an average, finite secondary electron range, a point is eventually reached where full electron overlap occurs (point D). At this point, the number of summed electron tracks is constant because the electrons being produced match those being lost. A maximum dose, Dm, is reached at a depth called dm (see Fig. 6.31); dm indicates the average secondary electron range and is the point at which electronic equilibrium is obtained. Because photon attenuation occurs, the number of interactions and resulting secondary electrons decreases with depth from the surface. Attenuation competes with the buildup process; however, buildup is more rapid than attenuation, resulting in a net gain of dose. The presence and steepness of a buildup region depend on incident photon energy that governs the type of interaction and the range and distribution of secondary electrons. At higher photon energies,

D

Dm

B

the dm is larger because the average secondary electron range is greater. Beyond the dm, photon attenuation results in transient electronic equilibrium (i.e., energy in is slightly greater than energy out) and a decrease in dose with depth (shown in Fig. 6.31 as the dotted line; the difference is exaggerated).

DOSE RELATIONSHIPS FOR EXTERNAL BEAMS Three mathematical functions that remain important both conceptually and in practice are used to describe the dose characteristics for external radiation beams: percent depth dose (PDD), tissue-air ratio (TAR), and tissue-phantom ratio (TPR).12,13 These dose functions relate the dose at any point to the dose at a reference point. The irradiation geometry shown in Fig. 6.32 illustrates the measurement conditions for the following discussions.29

Percent Depth Dose The PDD is the ratio of the dose at depth, Dd, to the maximum dose, Dm, measured along the central axis of the beam and expressed as a percent. Points X and Y are the locations at depth, Dd and Dm, respectively, in Fig. 6.32B. PDD is dependent on the depth, d; reference depth, dm (the point of maximum dose); beam quality (or energy), E; source-to-surface distance, SSD; and field size at the surface, w. Mathematically, PDD(d, dm, E, SSD, w) =

Dd D × 100% = X × 100%. Eq. 28 Dm DY

PDD is often expressed as a fraction rather than as a percentage. PDD was the dose function first measured for diagnostic and therapy radiation beams because of the simplicity of measurement; it remains a basic dose measurement for beam characterization. Inherent in a PDD measurement are the effects of attenuation by the material and the inverse square effect as the distance from the source is changed. PDD is used for photon and electron beams and is often used in tabular form for monitor unit calculations. S

Relative dose

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S

S

Attenuation SPD

SSD

A

SSD″

Electron track sums Point A: 5 tracks Point B: 15 tracks Point D: 25 tracks Beyond point D: 25 tracks, but attenuated

w

Y′

Y

d

A

dm d′′

wd X Water

wd X′ Air

dm

Depth Fig. 6.31 Radiation dose buildup. With secondary electrons primarily in the downstream direction, successive electron tracts overlap to produce a rapidly increasing region of dose, called buildup. A maximum dose, Dm, reached at a depth called dm, indicates the average secondary electron range and is the point at which electronic equilibrium is obtained. Because photon attenuation occurs, the number of interactions (dotted line) and resulting secondary electrons decreases with the depth from the surface. Attenuation competes with the buildup process, but because buildup occurs more rapidly than attenuation, a net gain of dose results.

w

B

X′′

wd Water

C

Fig. 6.32 Reference irradiation geometries used for measurement of percent depth dose, tissue-air ratio, and tissue-phantom ratio. (A) In-air geometry for tissue-air ratio. (B) In-phantom geometry for percent depth dose, tissue-air ratio, and tissue-phantom ratio. (C) In-phantom geometry for tissue-phantom ratio. (Adapted from ICRU Report 24: Determination of absorbed dose in a patient irradiated by beams of x and gamma rays in radiotherapy procedures, Washington, DC: International Commission on Radiation Units and Measurements; 1976.)

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Tissue-Air Ratio Given a fixed irradiation point in space, the ratio of the dose in phantom, Dx, to the dose in air, Dx′, at the same point is called the TAR (see Fig. 6.32A and B). TAR indicates how the dose in air is affected when the air is replaced by tissue. The field size at the point and source-to-point distance are constant; the only variable is the depth in phantom: TAR(d, w d, E) =

DX (d, w d, E) . D′ X (w d, E)

Eq. 29

The TAR is essentially independent of SSD because scatter contributions are almost constant for fixed-field sizes regardless of SSD. This independence enables the use of the TAR over a wide range of clinically used SSDs without correction. The TAR is used for photon beams only and is not valid for electron beams. A special case of the TAR, called the backscatter factor (BSF), exists when the point of interest is the depth of maximum dose (when d = dm). In this case, the TAR has a maximum value, and BSF(w dm , E) = TAR(dm, w dm , E) =

DY . DY ′

Eq. 30

The BSF takes its name for historical reasons, from a time when low-energy photons were used and the point of maximum dose was on the surface. Any dose scattered to the surface from the phantom or patient was truly backscattered dose. To determine the TAR and BSF, dose data are acquired at sampled points in phantom and air across and along the radiation beam central axis for the range of field sizes, depths, and SSDs or source-to-axis distances (SADs) clinically relevant.

Tissue-Phantom Ratio The TPR must be used for photon energies above about 4 MV, when in-air measurements required for the TAR are impractical. As with the PDD and TAR, the TPR is the ratio of two doses; however, both doses are made in phantom. The TPR is the ratio of dose Dx, measured at depth d, to dose Dx″, measured at a reference depth d″ (see Fig. 6.32B and C): TPR(d, w d, E, d′′) =

DX (d, w d, E) . DX′′ (d′′, w d′′, E)

Eq. 31

Both measurement points are fixed in space such that the sourceto-point distance and field size are the same at each point. The depth of point X is varied to generate TPRs over a range of depths for a particular field size. The TPR is essentially independent of the SSD because scatter contributions are almost constant for fixed field sizes regardless of SSD. This independence enables the use of the TPR over a wide range of clinically used SSDs without correction. The TPR is used for photon beams only and is not valid for electron beams. When d″ is the depth of maximum dose, the TPR is called the tissue-maximum ratio (TMR). The TPR and TMR are used in the same manner as the TAR in dose calculations. The TMR is the most common data format used for photon monitor unit calculations in second-check computer programs used to confirm monitor unit results from threedimensional (3D) radiation treatment planning systems and manual (by hand) calculations.

Primary and Scatter Dose: the Scatter-Air Ratio Mayneord first proposed that PDD could be separated into primary and secondary (or scatter) components12 and later, Clarkson30 proposed

sector integration of scatter components in calculating the PDD at any point inside or outside an irregular field. This concept was later applied by Gupta and Cunningham to the TAR.31 The concept states that dose at a point is the sum of primary and scatter components. The primary dose results from photons that have interactions at the point of interest. The secondary dose results from photons and electrons that scatter to the point of interest from other interaction points. With this concept, TAR is given by the following expression: TAR = TAR0 + SAR.

Eq. 32

In the equation, TAR0 is the TAR for zero field size, representing primary dose, and SAR is the scatter-air ratio (SAR), representing secondary dose. TAR0 is found by extrapolation of circular field TARs to zero field size. The SAR is calculated as the difference between the TAR and the TAR0. For an irregular field, an effective TAR can be found that is the sum of the TAR0 and an effective SAR for the irregular field: TARirreg (d, Wd, E) = TAR0 (d, E) + SARirreg (d, Wd, E). Eq. 33 The irregular field SAR is found by sector integration: SARirreg (d, Wd, E) =

1 ∑ SARi(d, Wd,E) × ∆θ, 2π

Eq. 34

in which Δθ is the angular increment in radians for each sector. Separation of primary and secondary dose can be applied to any of the dose functions in a similar fashion. For instance, the TMR can be represented as TMR = TMR0 + SMR. The TAR/SAR and TMR/SMR functions are more commonly used than PDD in broad-beam dose computation algorithms because fewer inverse square corrections are needed. The TAR and TMR are easily found for isocentric treatment geometries, in which the size of the treatment field at the isocenter is equal to the treatment field size at the center of the target volume, which simplifies manual (noncomputer) calculations. Although PDD can be measured with an ionization chamber beyond dm over the wide range of clinically used photon energies, the TAR cannot be measured when the photon energy exceeds about 3 MV because the range of secondary electrons exceeds the thickness of the buildup cap for the ionization chamber—electronic equilibrium is difficult to obtain. At these energies, PDD is measured and converted to TPR and TMR by well-known relationships.21,22 PDD remains the most important and fundamental dose function and performance specification to be measured for almost all physics quality assurance procedures for all external-beam treatment devices.

CHARACTERISTICS OF RADIOTHERAPY PHOTON BEAMS Dose Characteristics Photon beams used in radiotherapy have dose characteristics that vary primarily as a function of beam energy and treatment machine design. In the standard irradiation geometry (see Fig. 6.32B and C), PDD measurements are obtained in water along the central axis, beginning at the surface and proceeding to depth. A typical PDD curve shown in Fig. 6.33 for megavoltage beams has the characteristics listed in Table 6.9. Other important descriptors include an effective attenuation coefficient for depths beyond the maximum depth (dmax) and the HVL. The 10-cm PDD in water is most used as an indicator of beam quality in place of the HVL, because the 10-cm PDD has clinical relevance and the HVL is a better indicator for shielding purposes.

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CHAPTER 6 Dmax Percent depth dose

Central axis Flatness

Shoulder % Dose

Buildup region PDD at 10 cm

Surface dose

100% 80% 50%

90% depth

Field

50% depth

5

15 10 Depth (cm) Fig. 6.33 A typical photon percent depth dose (PDD) curve is characterized by surface dose, a buildup region, a point of maximum dose, and an exponentially attenuated region. Standard PDD measurements are obtained along the central axis (dotted lines), beginning at the surface and proceeding to depth. d max

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width

Penumbra region Penumbra 20%

Toe

Fig. 6.34 The dose profiles of a typical photon beam are characterized by shoulder and toe regions, with definitions for field width, flatness, and penumbra as indicated.

Characteristics of a Typical Percent Depth Dose Curve for Megavoltage Beams

TABLE 6.10 Characteristic

Definition

Characteristic

Definition

Field size

Surface dose

Nonzero dose at the incident surface.

Buildup region

Region between the incident surface and dmax where the dose rapidly increases.

Distance from field edge to opposite edge at the 50% dose level, with normalization to 100% on the central axis—basically, full width at half maximum (FWHM).

Dmax

Maximum dose along the central axis; often used as a reference dose.

Flatness

Deviation in dose level across the width of the field.

Symmetry

dmax

Depth of maximum dose; often used as a reference point.

Deviation in dose level for points symmetrical about the central axis.

Penumbra

Percent depth dose

Dose along the central axis of the beam as a percentage of the dmax dose.

Dose gradient regions from high to low dose at the beam edge.

90% dose depth

Depth from the surface where the dose in the buildup region reaches 90% of Dmax.

50% dose depth

Depth from the surface beyond dmax, where the dose falls to 50% of Dmax.

10-cm percent dose

The percent depth dose at 10 cm from the surface, a value often quoted as an indicator of beam penetration.

TABLE 6.9

Field size, flatness, symmetry, and sharpness of the beam edge can be measured with a dose profile (Fig. 6.34), which is a scanned dose measurement perpendicular to the central axis, across a beam (at a fixed depth, occurring along the horizontal line wd in Fig. 6.32B and C). These and PDD measurements are most commonly obtained using a large water phantom with a three-axis scanning system to move a water-immersible ionization chamber or diode detector (Fig. 6.35). Dose profiles are normally made at several depths of interest (e.g., dm, 5 cm, 10 cm, and 25 cm). Beam characteristics from a dose profile are listed in Table 6.10. The flattening filter and beam steering determine flatness and symmetry in a LINAC. Flatness is defined at a reference depth, for instance, at a 10-cm depth at the isocenter (SSD = 90 cm). A typical specification is for no more than 3% dose variation across the useful 80% of the field width (see Fig. 6.34). A radiation beam does not have a perfectly sharp edge across the defined beam edge but instead has a gradient from high to low dose with a rounded “shoulder” and “toe.” This penumbra region (“penumbra” means “partial shadow”) is the result of both the finite source size, “geometric penumbra,” and the scattered

Dose Profile

Beam Characteristics From a

photons and secondary electrons that cross the beam edge from within the field, the “radiological penumbra.” A geometric penumbra can be large because of shadowing of part of the source, as is the case for 60Co teletherapy beams, as a result of a very large (2-cm) physical source size. However, the penumbra region for LINAC beams is mostly a radiological penumbra because of secondary scatter from within the field and from the collimators. This scattered radiation degrades the beam edge; the dose from the shoulder region scatters outside the beam edge to form the toe. Penumbra for radiation fields is defined as the distance over which the dose falls from 80% to 20% of the central axis dose at the same depth or at the width of the 90% to 10% dose gradient (see Fig. 6.34). Various methods exist to measure a radiation beam along lines of equal dose, called isodose lines. In a three-axis water phantom scanner, after determining PDD along the central axis, a certain isodose level is identified in the standard geometry and then tracked to obtain a digital representation of the dosimetric shape of the beam. Fig. 6.35 shows sample isodose curves for a plane containing the central ray of a beam and a plane perpendicular to the central ray. The modern water phantom scanning device is computer controlled and has robust software tools for two-dimensional (2D) and 3D renderings and analysis of acquired dose distribution data.

Effect of Energy Photon beam characteristics change with beam energy. Representative beam data are presented in Table 6.11, PDDs in Fig. 6.36, and isodose curves in Fig. 6.37. Several key observations should be considered:

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Incident beam direction

Plane with central ray

Surface

A

Central ray

Orthogonal plane

Source Field edge Radiation field

Isodose lines

Water phantom

Central ray

B Fig. 6.35 Irradiation geometries for isodose measurements. (A) Beam orientation with phantom. (B) Planes orthogonal to the central axis and isodose curves. (A, Courtesy IBA Dosimetry, Schwartzenbruck, Germany.)

TABLE 6.11

Photon Beam Characteristics in Water

Beam Energy

Surface Dose (%)

90% Buildup Depth (cm)

dmax (cm)

50% Dose Depth (cm)

10 cm PDD

HVL and Material

60 kVp

100

None

0.0

2

10

1.9 mm Al

120 kVp

100

None

0.0

4

21

5.0 mm Al

None

0.0

7

35

3.17 mm Cu

60

300 kVp

40-90

0.4

0.5

12

55

11.9 mm Pb

4-MV x-rays

20-40

0.3-0.6

1.2

15

63

14.8 mm Pb

6-MV x-rays

10-30

0.4-0.7

1.5

15

67

15.4 mm Pb

10-MV x-rays

6-30

0.7-1.0

2.5

19

74

16.9 mm Pb

18-MV x-rays

6-30

1.0-1.5

3.2

22

80

16.2 mm Pb

Co

100

dmax, Depth of maximum dose; HVL, half-value layer; PDD, percent depth dose.

by the depth of the 50% dose or the PDD at 10 cm and is consistent with the change in the effective attenuation coefficient. more forwardly directed, away from the surface, as energy increases, reducing the dose contribution at the surface. The breakthrough in achieving megavoltage energies is that surface dose decreased from 100% and dm moved away from the surface, providing “sparing” of skin and superficial tissues. Dm. Most therapy beams have reached at least 90% of their Dm within 1 cm of the surface.

dm is at or near the surface for low-energy beams and increases in depth as energy increases. As incident photon energy increases, the effective electron range (photoelectrons and Compton electrons) increases and the scatter component (secondary electrons and Compton scattered photons) is more forwardly directed. The dm value is directly related to the average energy of secondary electrons produced in photoelectric and Compton interactions; the dm increases with energy. Dm is defined as a point, but as energy increases, the PDD curve becomes very broad because of a broader spectrum for the scattered electrons. Strictly speaking, Dm is the one point where electronic equilibrium occurs.

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CHAPTER 6

70 kVp 120 kVp 3 mm Cu Cobalt-60 6 MV 10 MV 18 MV

100.0

Percent depth dose

80.0

Radiation Oncology Physics

exponential fall-off in dose with depth. peak energy is increased until about 6 MV, and it then falls slightly (see Table 6.11). The HVL decreases because an increased amount of pair production increases the attenuation coefficient for photon energies above 6 MV (see Fig. 6.16). In tissue or water, the attenuation coefficient decreases monotonically and the minimum is reached at very high energies, to the far right in Fig. 6.16. mately one-third of the accelerating potential. For example, an 18-MV photon beam (polyenergetic, bremsstrahlung spectrum) has an effective energy approximately equivalent to that of 6-MeV monoenergetic photons.

60.0

40.0

20.0

0.0 0.0

10.0 20.0 Depth in water (cm) Fig. 6.36 Photon percent depth dose curves. (Data courtesy Wake Forest Baptist Medical Center, Winston-Salem, NC; and the Bureau of Radiological Health. Radiological Health Handbook. Bethesda, MD: US Department of Health, Education, and Welfare; 1970.)

portion of a megavoltage beam from a LINAC is “harder” (more penetrating) than the off-axis region because the flattening filter is thicker in the central ray than off-axis (see Fig. 6.5). Because the flattening filter is designed to produce a flat field at a depth of 10 cm, not dm, and the off-axis beam is softer than the central axis, a greater beam intensity off-axis is allowed at the depth of dm to compensate for the increased attenuation of the off-axis beam component. This greater intensity is exhibited as “horns” in the isodose distribution for off-axis regions near dm (see Fig. 6.37A). This beam-profile effect

Isocenterof10x10

Isocenterof10x10 100 95

100

90 5

5

95

80

90 70 80

10

10

60 70 50 95

60 40 20

20

C

70 90 20 50 10

50

30

40

20

30

10 90 95 70 20 50

20

A

B

119

D

10

Fig. 6.37 Photon isodose curves, 10 × 10 cm2 fields. (A) 6 MV, cross plane. (B) 18 MV, cross plane. (C) 6 MV, orthogonal plane. (D) 18 MV, orthogonal plane. (Data courtesy Wake Forest Baptist Medical Center, Winston-Salem, NC.)

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is greater for lower-energy megavoltage photons than for higher energies.

Effect of Field Size Field size determines the amount of scatter present in the beam, with the following observations: a differential increase in scatter such that points at depth receive a greater relative amount of scatter than does dm, leading to an increase in PDD. The increased scatter at depth comes from interactions that occur in the increased irradiation volume. of scattered radiation from the collimator faces is increased. This scattered radiation includes secondary electrons and scattered photons of lower energy. (Fig. 6.38). Output increases because there is increased scatter at dm from the collimator faces as well as from interactions that occur in the increased volume of irradiated material. Fig. 6.38 also illustrates the separation of dose into primary and secondary components. dm decreases as the field size increases because of the presence of an increased amount of lower-energy photon and electron scatter.

Penumbra Beam edge sharpness, or penumbra, is typically 7 to 12 mm in width and varies with the amount and energy of secondary electrons and scattered photons. As the amount of scatter increases, the penumbra does likewise: scatter from the larger irradiated volume upstream; thus, the penumbra is wider. from the increased volume of irradiated material and because there is a slight increase in beam divergence (a geometric effect). 60

Co has a wide penumbra because the source size is large and the geometric penumbra is large. However, some units have “trimmer” bars that greatly reduce the geometric penumbra component, yielding penumbrae comparable to those of linear accelerations. that have a higher effective energy have a corresponding higher lateral range of scatter outside the beam edge. This effect is seen as a degradation of the profile (more pronounced shoulder and toe). This comparison is shown in Fig. 6.37A and B.

1.00 Percent depth dose (or TAR, TPR, TMR) PDD0 (or TAR0, TPR0, TMR0)

Scatter Extrapolation to zero field size Primary

30 10 20 40 Square field size (length of side, cm) Fig. 6.38 Relative dose as a function of photon field size. TAR, Tissue-air ratio; TMR, tissue-maximum ratio; TPR, tissue-phantom ratio.

Beam Modifiers Various devices can be put into a photon beam to modify the shape of the beam and its dose distribution. MLCs or perhaps custom blocks are used to shape the field, as previously discussed. Their dosimetric effect is to change the irradiated volume and, therefore, the amount of scatter. Physical wedges produce skewed isodose lines at fixed angles across the central ray (Fig. 6.39) to compensate for beam angle of incidence, tissue shape, or the trajectory of other treatment beams. Historically, wedge angles of 15, 30, 45, and 60 degrees have been available using physical wedges made of steel or lead. Isodoses show that the wedge angle is measured from a perpendicular to the central ray, typically at a depth of 10 cm. A physical wedge produces an attenuated beam that is decreased in absolute dose rate and slightly more penetrating, resulting from both attenuation and beam hardening by the thickness of the metal wedge in the beam. A commonly available alternative wedging system uses no physical wedge and produces angled isodose lines by scanning one of the independent collimator jaws across the field while the beam is on. This dynamic method does not result in hardening or attenuation of the beam and is called a dynamic, virtual, or soft wedge. Another method to produce an angled beam intensity is to use one physical wedge with the maximum wedge angle of 60 degrees that is left in the beam for various fractions of time to produce wedge angles from 0 (no time in beam) to 60 (full time in beam) degrees. The single 60-degree physical wedge, with its dwell time in the beam varied to produce desired wedge angles, and the dynamic wedge, using moving collimators across the beam, are the principal automated techniques used by two major vendors to produce angled isodoses for flat photon beams. These two approaches have essentially replaced the use of manually placed, individual physical wedges. Compensators attenuate the beam in desired locations to provide dosimetric shaping. A variety of methods exist that include simple and complex approaches.13 Compensators have an important role in dose optimization schemes that include static applications as an alternative to dynamic techniques, including IMRT32 and, for uniformity of largefield irradiation, geometries such as whole-body irradiations for bone marrow transplantation.

CHARACTERISTICS OF RADIOTHERAPY ELECTRON BEAMS Dose Characteristics Electrons differ from photons in that electrons have a finite range; electrons travel a certain distance and then stop, and their kinetic energy is zero. PDD measurements are obtained along the central axis in the standard irradiation geometry as for photons (see Fig. 6.32). The one difference in the geometry is that an electron cone is used that requires fixed collimator positions in length and width. A typical PDD curve for megavoltage electrons (Fig. 6.40) has many of the same characteristics as do photons, including surface dose, a “buildup region,” Dm, and dm. An electron PDD curve also has the characteristics listed in Table 6.12. Table 6.13 gives several characteristics for megavoltage electron beams as a function of energy. Although electron beams have some of the same features as photon beams, their finite range and the presence of bremsstrahlung contamination are unique. Field size, flatness and symmetry, and sharpness of the beam edge for electrons can be measured similarly as for photon beams (see Fig. 6.34). However, the measurement depth is typically at dm or at the 95% dose level beyond dm. Beam steering, scattering foils, monitor chambers, collimator length and width, and electron applicator design all determine flatness and symmetry for electron beams.33 These design parameters

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CHAPTER 6

Isocenterof10x10

90

5

100 95 90

5

80

Isocenterof10x10

100

5

5

95 90

80

70

10

Isocenterof10x10

Isocenterof10x10

100 95

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100

80

70 10

10

60

10

70

60

80 70

60 50

95 90

50

60

50 20

40

20

20

20

40

50

40 40

30

30 30 30 20

20 20

10

A

B

10

10

C

D

Fig. 6.39 Isodose curves with physical wedges, 6-MV photons, and a 10 × 10 cm2 field. (A) A 15-degree wedge. (B) A 30-degree wedge. (C) A 45-degree wedge. (D) A 60-degree wedge. (Data courtesy Wake Forest Baptist Medical Center, Winston-Salem, NC.) Dmax

TABLE 6.12

PDD Curve

Percent depth dose

Surface dose Dose fall-off

Bremsstrahlung background

dmax d80 Rp Depth (cm) Fig. 6.40 A typical electron percent depth dose (PDD) curve is characterized by surface dose, a region of buildup, a point of maximum dose, a rapid dose fall-off, and a tail resulting from bremsstrahlung background radiation. Dmax, Maximum depth.

are important for controlling the distribution and amount of electron scatter. A penumbra is the result mainly of electron scattering from within the defined beam and is defined similarly as for photons.

Characteristics of an Electron

Characteristic

Definition

Dose fall-off

Region beyond where the dose falls steeply and almost linearly.

d90

Depth of the 90% dose beyond dmax—a clinically relevant point beyond which dose is not therapeutic.

d80

Depth of the 80% dose beyond dmax.

d50

Depth of the 50% dose beyond dmax.

Rp

Practical range: the maximum depth to which electrons penetrate; determined by the intersection of the linear part of the dose fall-off curve and the bremsstrahlung background.

Bremsstrahlung background

Contamination of the electron beam by bremsstrahlung x-rays created by collisions of the electrons with parts of the machine and with the patient; prevents the dose from going to zero at depth.

dmax, Depth of maximum dose; PDD, percent depth dose.

Effect of Energy

with energy. The values for d90, d80, and Rp (see Table 6.12) all increase with energy.

Electron beam characteristics change with beam energy. Representative beam data are presented in Table 6.13, central axis PDD in Fig. 6.41, and isodose curves in Fig. 6.42. Several key observations apply:

Table 6.13), and it increases as energy increases (an opposite effect from photon beams) because of changes in the

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Electron Beam Characteristics in Water

Beam Energy (MeV)

Surface Dose (%)

dmax (cm)

d90 (cm)

d80 (cm)

Rp (cm)

6

78-79

1.2

1.55-1.59

1.74-1.78

2.8

9

83-86

1.5

2.25-2.58

2.59-2.87

4.4

12

84-88

2.0

3.05-3.44

3.50-3.82

5.7

16

89-91

2.0

3.84-4.89

4.53-5.49

8.0

20

91-95

2.0

4.28-5.86

5.15-6.68

9.9

d, Depth; d90, d80, depth of the 90% or 80% dose beyond dmax; max, maximum; MeV, million electron volts; Rp, practical range.

100.0

6 MeV 9 MeV 12 MeV 16 MeV 20 MeV

80.0 Percent depth dose

Field Size, 15 " 15 cm2

60 5 80

!5 100

40 90

20 10

60.0 5

A 40.0

Field Size, 15 " 15 cm2

20.0

5

!5 0.0 15.0 5.0 10.0 Depth in water (cm) Fig. 6.41 Electron beam percent depth dose curves: 6, 9, 12, 16, and 20 MeV. (Data courtesy Wake Forest Baptist Medical Center, WinstonSalem, NC.) 0.0

amount of lateral electron scattering and its dose contribution at dm. dm starts at shallow depths and increases as energy increases because the electron range increases with energy. Dm becomes quite broad. In this case, dm is defined at a selected point. energy. Increased scattering occurs, and a wider energy spectrum is created with a distribution of electron ranges. The originally monoenergetic electron beam is degraded into a wide spectrum beam with a varied practical range. because the probability for radiative interaction increases with electron energy. Bremsstrahlung contamination can be minimized but not eliminated totally. Structures lying beyond the electron range still receive dose from bremsstrahlung x-rays. d90 (depth to the 90% isodose line in centimeters) in tissue beyond dm can be found by dividing the nominal electron energy (in million electron volts) by 4. The d90 of a 9-MeV electron beam is 9/4 (cm), or about 2.3 cm. This number can be useful for indicating the largest therapeutic depth to the deep side of a target. d80 (depth to the 80% isodose line in centimeters) in tissue beyond dm can be found by dividing the nominal electron energy (in million electron volts) by 3. The d80 of a 9-MeV electron beam is 9/3 (cm), or about 3 cm. This number can be useful for indicating the

100 80

90 60

40 20 10

B

10

Fig. 6.42 Electron beam isodose curves for a field size of 15 × 15 cm2. (A) 6 MeV. (B) 20 MeV. (Data from Hogstrom KR, Steadham RE. Electron beam dose computation. In: Mackie TR, Palta JR, eds. Teletherapy: Present and Future. Madison, WI: Advanced Medical Publishing; 1996:137-174.)

largest therapeutic depth, although many clinicians consider the d90 as the maximum effective depth for an electron beam.

Effect of Field Size Electron field sizes are changed by using fixed-size applicators to produce square field sizes from approximately 6 × 6 cm up to 35 × 35 cm. Custom cutouts can be used that are inserted into an applicator to provide a shaped field to match a target outline. have a finite range that is much less than Rp; therefore, for increasing field sizes above 10 × 10 cm or greater, the contribution to the central axis is small. This effect is different from photon beams, in which scattered photons still have a relatively large mean path length. amount of scattered electrons from the beam path is increased. dm decreases as field size increases because the amount of lateral electron scatter increases near the surface.

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CHAPTER 6 dm, usually increases as field size increases but can decrease depending on collimator design.

Penumbra Beam edge sharpness for electron beams varies with measurement depth because of the nature of electron scattering.22 On interaction at a point, an elementary line of electrons produces a scattering envelope that is teardrop shaped in the forward direction of the beam (Fig. 6.43). Electron scattering angles, which initially are primarily in the forward direction, become more randomly oriented at depth. have a higher effective energy and a corresponding increased range. This effect is seen as a degradation of the profile (enhanced shoulder and toe). shape of electron scattering (see Fig. 6.43). dm, but the shape of the isodose curves changes with increased depth. This effect should be considered during treatment planning. from the increased volume of irradiated material. the applicator to the surface. An increased gap allows electrons to scatter laterally before reaching the surface, degrading the field edge.

Other Effects Electrons scatter easily, and regions of bone and air greatly change the dose distribution. Density scaling can be applied to approximate the electron range in non–unit density materials (see Eq. 20), because mass stopping power is somewhat constant for low Z materials. Rm, the approximate electron range for a material of density pm, is given by the following equation, in which Rw is the range in water and ρW is the density of water (1 g/ cm2). For instance, the electron range for a material with a density of 2 g/cm3 is 0.5 times the range in water. Rm = Rw ×

ρw ρm

Eq. 35

distance is not the actual source location (i.e., the scattering foil) but instead a virtual source point that is located along the beam path. This distance is called the effective source-to-skin distance (effective SSD) and is usually less than the SAD, for example, 85 cm for a 100-cm SAD LINAC. Effective SSD is measured for each energy and applicator and occurs because of multiple electron scatterings along the beam path. and changes output, penumbra, the position of dmax, and field

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homogeneity. These effects are most pronounced when the cutout size is less than one-fourth of the applicator dimension or on the order of the electron range.22 Individual calibration of a cutout or other procedures are required to establish the cutout’s dosimetric character when these poor geometric conditions exist.

RADIATION TREATMENT SIMULATION Purpose In the early years of radiation treatment, patients were taken to the treatment machine and fields were chosen based on the clinician’s general anatomic knowledge and the patient’s disease. Diagnostic radiographs were available to help localization. This process is called clinical setup because the treatment machine is used with various aids to decide on the beam geometry. Simple fields and manual blocking may be used. Currently, clinical setup alone is not commonly done and is typically reserved as a desired approach for certain electron beam and emergent or single-fraction palliative treatments. Instead of using a treatment machine, radiation treatment simulation is performed on a dedicated x-ray unit, called a simulator—either a conventional simulator or a CT simulator. Radiation treatment simulators, whether conventional (radiographic/ fluoroscopic unit) or CT based (CT unit plus software tools), have been developed to enable imaging of the patient in the treatment position and determination of radiation treatment parameters prior to radiation treatment. Use of a radiation treatment simulator has the following advantages: 1. Treatment simulation on a dedicated simulator does not compete with valuable treatment time on the radiation treatment machine. 2. Simulators are dedicated to the simulation process. The patient can be immobilized in the treatment position and different treatment geometries can be explored without the pressure to turn the room back over for treatment. 3. Simulators are diagnostic x-ray units that have either radiographic and fluoroscopic capabilities or CT. Images are of diagnostic quality with high contrast and spatial resolution compared with poorer image quality of megavoltage portal images. 4. Either through device geometry or software tools, the dedicated simulator unit can simulate different treatment machine geometries with regard to SSD, SAD, field shape, and field size. 5. Simulators can be versatile and can be used to localize and verify brachytherapy implants within the confines of the radiation oncology department (no exposure to outside individuals) and under controlled conditions.

Treatment Setup There are two basic methods for patient setup: SSD and SAD (Fig. 6.44). While the SAD technique is most commonly used with today’s isocentric treatment devices, the SSD technique remains extremely useful for extended distance and large-field treatments.

SSD Treatment Elementary electron beam

Surface Average dose distribution

Medium

Fig. 6.43 Elementary electron scattering kernel. (Adapted from Khan F. The Physics of Radiation Therapy. 2nd ed. Baltimore, MD: Williams & Wilkins; 1994.)

If a treatment technique is set up as an SSD treatment, the distance to the patient’s skin is recorded in the chart and used as a reference distance for each treatment. The SSD is measured and set to the same point on the patient’s surface each time the field is treated. When a different field is treated, the new SSD is set as required before the patient is treated. Each field is independently set and treated. The SSD is standardized to equal the SAD for isocentric machines; thus, a normal SSD treatment is at 100 cm (80 cm on older treatment machines). The standard SSD is also the distance used for machine calibration. Occasionally, alternative SSDs are used to allow larger field sizes to be used.

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SSD setup

SAD

SSD

SAD (isocentric) setup

90 degrees

Field size is measured as shown by the arrows Fig. 6.44 Treatment geometries: source-to-skin distance (SSD) and source-to-axis distance (SAD) approaches.

Compared with SAD treatments, SSD treatments place the target farther away from the source. Because the inverse square effect is less, PDDs are greater and larger field sizes may be possible, as when a single field is desired to be used to cover a larger region, such as an extremity, the entire spinal cord, or the hemibody or whole body. If multiple fields are to be used, then the disadvantage is that each treatment field has to be individually set, requiring movements of the treatment couch and patient between successive fields.

SAD Treatment An alternative to setting the SSD is to set the target volume at the SAD (the isocenter of rotation of the machine). This isocenter is a point in space in the treatment room about which the gantry, collimator, and table all rotate (see Fig. 6.3). In this case, the SSD is always less than the SAD (SSD < 100 cm). In SAD treatments, the target volume always intercepts the beam regardless of gantry, table, or collimator angles. An advantage is that after one field is set properly, the target is at the isocenter and subsequent treatment fields can be set up rapidly without having to set multiple SSDs. Therefore, treatment of a multifield plan is more quickly done because of less setup time, and the target cannot be missed. The disadvantage is that field sizes may occasionally be limited, and there is slightly more inverse square effect. The advantages of rapid setup and targeting for SAD treatment outweigh those of larger field size and increased PDD for SSD treatments in most cases; thus, SAD treatments are performed for most patients. This has been especially true because isocenters changed from 80 to 100 cm, providing larger field sizes and less PDD effect, and also because image-guided treatment devices, either orthogonal to or coincident with the central axis of the treatment beam, are designed for rotations around the isocenter, which is most consistent with the SAD treatment technique. Also, rotational treatments using gantry arcs, such as rotational IMRT or arc radiosurgery, essentially require the use of SAD since the gantry rotation point is indeed the isocenter.

Conventional Radiographic/Fluoroscopic Simulator Description and Components A conventional radiographic/fluoroscopic (R/F) C-arm simulator unit was originally designed to replicate all of the mechanical and patient

positioning aspects of the radiation treatment unit and has the following components in the geometry shown in Fig. 6.3: 1. A fixed gantry stand or base supports the gantry structure that holds the x-ray tube and collimator at one end and the image receptor, such as a flat panel imaging device, on the other. The gantry is mounted isocentrically, and the x-ray tube can be positioned to a wide range of SADs or SSDs. 2. The x-ray tube is a diagnostic energy x-ray tube that rides at the top of the gantry. Kilovoltage ranges from 60 to 120 kV(p), and tube current is as much as 1000 mA. 3. The collimator is an assembly that defines the radiographic (image) field size at a given SAD (usually 100 cm). The collimator is isocentric and has field size and rotation capabilities comparable to those of the treatment machines. 4. Two pairs of field-defining wires or digital indicators, one positioned in the x direction and one in the y direction, indicate the size of the treatment field as would be defined by the collimator jaws on the treatment machine. A simulator radiograph shows two radiation fields. The larger field is the actual field imaged as defined by the x-ray unit collimator, to provide anatomical context. The smaller field is the treatment field, indicated by images of the delineator wires. Thus, a simulator image shows the treatment field and nearby contextual region. 5. The simulator table is isocentric and has vertical, lateral, longitudinal, and rotational motions. It can be remotely operated from the console to move the patient during fluoroscopy. 6. Hand and console controls allow operation of all of the machine motions from a hand-control unit or the table pedestal in the room; some of these are duplicated at the control console. All radiographic technique settings are done at the console.

Conventional Simulation Procedures and Immobilization While less commonly used, conventional simulation is of value where CT simulation is not available and for simulations for brachytherapy procedures or other unique geometries. These conventional simulation procedures remain relevant and can be executed on a treatment machine for palliative or clinical setups. A patient to be simulated is placed on the conventional simulator table in the treatment position. The supine position is most common, but prone positioning and other geometries are also used. Immobilization devices of various functions and rigidity may be used to maintain patient position, including head holders, thermoplastic face masks, foam molds, cushions and pillows, bite blocks, reflective stereoscopic markers, and vacuum bags. The patient is moved in the treatment position to align the target region or other reference anatomy with the simulator’s isocenter. This location is chosen based on available information on the target volume and nearby structures (from planar images, CT, MRI, positron emission tomography [PET], clinical examination, surgical reports) or in anticipation of imaging studies for treatment planning. Fluoroscopic imaging or static images are used to determine the location of the isocenter or other reference point in the patient coordinate system. An SSD or SAD setup is chosen, and orthogonal planar images are usually taken to record the patient’s position. All geometric information (gantry angle, collimator angle, table position, field size, SSD, SAD) is recorded for each image. Marks are placed on the patient’s skin or the immobilization device to indicate the reference field axes. In conventional simulation, individual treatment field geometries may be determined at the time of simulation. All field data are recorded, and simulator images are taken for each field as a record of the intended treatment and for use in designing field shapes. Target and other data are often drawn or annotated on each acquired image. Images with added contrast agents show certain structures (bladder, rectum). Other

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CHAPTER 6 data are the clinical examination, surgical reports, surgical clips, markers placed during simulation, and manually transferred contours from CT or MRI images. After the desired data are annotated on the image, a treatment field is drawn that will later be transferred to the shape of the MLC (or custom blocks) for definition of the treatment field aperture on the treatment machine. Additional geometric information on the patient is needed if treatment planning is to be performed, such as an external contour and the locations of important internal anatomy, including the target, landmarks, and critical structures. For simple 2D planning, at least one transverse contour is obtained; however, sagittal and coronal slices (or obliques) can also be obtained. Sources for patient contours include mechanical methods (e.g., solder wire, tracer device), optical methods (e.g., laser grid, light grid, stereo-shift camera), and CT or ultrasound acquisition.22 As stated earlier, conventional simulation is used in many practices for patients who will be treated palliatively because treatment complexity is low (for instance, one pair of parallel-opposed fields) and patient setup and data acquisition can be done quickly, followed by simple dose calculations, without the need for full 3D representations of the patient anatomy for higher-level dose computations. Thus, institutions with CT simulation capabilities may often retain the “old” conventional simulator for simple cases or for imaging of brachytherapy cases. However, conventional simulation devices are decreasing in number because of the ready availability and maturity of CT simulation, which enables the rapid identification of structures and incorporation of other 3D digital image datasets.

Computed Tomographic Simulation CT simulation, also called virtual simulation34 or computer-aided simulation, is state-of-the-art technology that uses a CT volumetric image of the patient in treatment position and computer software to perform patient simulation without a conventional simulator. CT simulation is performed on the patient’s CT image set, not the patient, hence the name virtual simulation. Workflow may vary depending on clinic preferences for patient flow. However, general principles are to immobilize the patient in the treatment position, obtain CT scout views to verify positioning and to delineate the range of CT scanning, and then acquire the desired CT image sets, which may include noncontrast and postcontrast images. With the patient still in the treatment position in the CT scanner, the CT simulation process then takes place within the computer where the proposed treatment geometry is designed and viewed on screen. Software tools are used to identify and segment anatomic information within the image set (external contour and volumes such as lung, kidney, cord, and tumor) and determine an isocenter for treatment or other identifying reference point. This information is displayed and the treatment beam geometry is reviewed. Once the isocenter has been selected and marked within the CT image set, the isocenter location (or other reference point) is transferred to the actual patient or the patient’s immobilization device, still on the CT scanner, for permanent marking on the patient or immobilization device. Mechanical or laser light technologies exist for a three-point marking that can be replicated on the treatment machine. Importantly, in most software implementations, the CT simulation procedure includes virtual simulation only of the proposed treatment geometry and does not include dose calculations. Dedicated CT simulators, comprised of a CT scanner and simulation software tools, are commercially available and in regular clinical use.35,36 Large aperture CT simulators offer a greatly improved aperture size from a standard 70 cm up to 85 or 90 cm depending on the vendor. This increased size greatly improves the image field of view (FOV), allowing bariatric and off-center patients to be CT simulated, and enables access for relatively wide or tall immobilization devices.37 Other readily

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available CT simulator improvements include multislice and cone-beam CT scanning for rapid acquisition, and four-dimensional (4D) CTfluoroscopy techniques for assessment of target motion resulting from physiological processes such as respiration.38,39 Moving simulation to the digital CT simulation approach has allowed a variety of image processing tools to be applied to the process, such as autosegmentation algorithms and 3D renderings, and has enabled the incorporation of registered multimodality images from MRI, PET, and other modalities. As briefly reviewed later, radiation simulation technologies continue to evolve, with dedicated PET-CT, and especially MRI, simulators in active development. MRI-based simulation has the advantage of no radiation dose to the patient compared with x-ray-based simulators. The use of 4D imaging for simulation and treatment, which is important for moving targets in the thorax, is briefly reviewed later with image-guided treatment. Treatment planning techniques, the next important process after simulation, are discussed in the next section.

EXTERNAL BEAM TREATMENT PLANNING AND DOSIMETRY Purpose and Procedures After conventional or CT simulation, the simulator images (if any); CT, MRI, and other digital images; beam geometries; and other patient data are transferred to dosimetry for further treatment planning. During treatment planning, possible beam geometries and combinations are investigated. Simulated beams may be fine-tuned or deleted, or new beams may be created; the beam weights may be adjusted, wedges added, beam energy changed, field sizes adjusted, different normalizations used, and compensation checked. The intent is to produce a treatment plan in the form of a 3D isodose distribution overlaid on the reference CT treatment planning images that can be evaluated by the physician and approved or modified. Treatment plans describe the following characteristics about the patient’s treatment, as illustrated in two dimensions for simplicity for the static four-field plan shown in Fig. 6.45: 1. Prescription isodose (i.e., the 97% line, or % prescription dose to a % target volume) or depth (at the isocenter or at 3 cm deep) gives the location where the prescribed dose is to be given. 2. Various tumor, target, and normal-tissue volumes as specified according to the International Commission on Radiation Units and Measurement Reports 50 and 62 (ICRU 50 and ICRU 62) recommendations for volumes of interest. This information must be represented in some manner to enable plan evaluation (see later discussion). These volumes may be 3D contours or isodose lines or surfaces. 3. Beam weights indicate the relative dose delivered to the prescription or normalization point by each beam. 4. The presence of beam modifiers (i.e., wedge, custom block, compensation filter, dynamic field shaping, or intensity modulation) is specified. 5. The size and shape of each field (i.e., collimator settings) is specified. If the MLC is used for a shaped field or intensity modulation, each MLC leaf has a specified position as a function of the number of monitor units elapsed and for rotational fields as a function of gantry angle. 6. The SSD is specified for each field. 7. “Inhomogeneities” are identified. These are volumes that are not water or soft tissue equivalents (e.g., lung, bone, metal prosthesis) for which dose may need to be corrected. In a CT image set, each voxel intensity relates to the average electron density for that voxel and most modern-day treatment planning systems are configured to compute the dose distribution based on the voxel-by-voxel electron density information carried in the CT image. 8. The number of monitor units, or amount of beam-on time, must be set on the machine for each beam.

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Femoral head

Dose Specification Components of a dose prescription for a patient treatment course include the patient’s name, clinic identification number, treatment site, radiation energy and modality (photons or electrons), prescription point location, dose per fraction, number of fractions, and total dose. These components are recognized standards40 and are required by most regulatory bodies.41 The point of prescription defines the location within the patient where dose is to be delivered and, therefore, defines the geometric point for dose computation. Prescription point selection and additional recommendations for prescribing, recording, and reporting volumes of interest and dosimetric parameters for photon beam treatment are specified by ICRU 50 and ICRU 62.42,43

Tumor

A 1 Skin contour

80

3

50

100

Isodose lines

40 20

2

Beam data 1. AP:18MV x rays, SSD = 92.5 cm, weight = 1.0, field size = 8!10, G:0 C:0 T:0 2. PA:18MV x rays, SSD = 90.5 cm, weight = 1.0, field size = 8!10, G:180 C:0 T:0 3. RLAT:18MV x rays, SSD = 87.5 cm, weight = 1.2, field size = 8!8, G:270 C:0 T:0 4. LLAT:18MV x rays, SSD = 87.5 cm, weight = 1.2, field size = 8!8, G:90 C:0 T:0

Fig. 6.45 Typical treatment plan information. (A) The patient contour and segmented regions of interest. (B) A treatment plan with superimposed isodose lines. Beam data are shown. AP, Anterior-posterior; LLAT, left lateral; PA, posterior-anterior; RLAT, right lateral; SSD, source-to-skin distance.

ICRU 50 defines five volumes of interest related to treatment. The following definitions are illustrated in Fig. 6.46 for an idealized case: Gross tumor volume (GTV): The GTV is the volume that contains the gross palpable or visible extent and location of malignant growth. The GTV may be identified on a simple contour, radiograph, or sectional images. Clinical target volume (CTV): The CTV is the volume that contains the GTV and any suspected microscopic disease. The CTV is the volume that must receive the prescribed dose to effect cure or palliation. Planning target volume (PTV): The PTV is a volume that contains the GTV and CTV and that is defined to account for the irradiation geometry and all uncertainties in treatment, such as organ and patient motions and setup errors. The PTV is a volume that, when covered by the prescription dose, will ensure the delivery of the prescription dose to the CTV. The PTV includes a margin for motion and setup error but not for microscopic disease. The PTV is a function of treatment geometry because the number of beams and their orientations may impose limitations on the PTV’s shape or scope.

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B Fig. 6.46 (A) The International Commission on Radiation Units and Measurement Report 50 (ICRU 50) defines five volumes of interest related to treatment. (B) Schematic representations of the relations between the different volumes (GTV, CTV, PTV, and PRV) in different clinical scenarios. (A, From ICRU Report 50—Prescribing, recording, and reporting photon beam therapy. Washington, DC: International Commission on Radiation Units and Measurements; 1993. B, From ICRU Report 62, Supplement to ICRU Report 50, Washington, DC: International Commission on Radiation Units and Measurements; 1999.)

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CHAPTER 6 Treated volume (TV): The TV is the volume enclosed by a selected (prescribed) isodose surface and is a function of the treatment geometry required for planning the PTV. For an acceptable plan, the TV is greater than the PTV, although an ideal TV/PTV ratio would be 1.0, indicating perfect conformation (assuming that the locations of the volumes were identical). Irradiated volume (IV): The IV is a volume that receives a significant dose; significance is determined by morbidity or other measures. ICRU 50 considered radiation target volumes only and did not specify normal-tissue volumes that might be relevant for morbidity and avoidance. ICRU 62 addressed this deficiency by specifying organs at risk (OARs) and the planning organs-at-risk values (PRVs).43 In ICRU 62, the GTV, CTV, and PTV remain and new defined volumes are the following: Internal target volume (ITV): The ITV is an expansion of the CTV to account for motion of the CTV, for instance, as caused by respiratory or digestion motions. Motion may be in a preferential direction such that the expansion of the CTV through internal margins (IMs) may not be isotropic and can be nonuniform. Organ at risk (OAR): The OAR is a nearby normal tissue or critical structure at risk for radiation-induced morbidity based on the recognition that normal-tissue response is radiation treatment limiting. Thus, relevant OARs are to be identified for purposes of morbidity assessment and assignment of dose constraints. Tissue physiological organization of OARs as serial or parallel units, or combinations of the two, are considered to aid risk assessment. Planning organ at risk volume (PRV): The PRV is an expansion of the OAR as a result of possible motion. However, incorporating motion into the OAR can be a challenging process.

Dose Recording and Reporting The ICRU recommendations for dosing include a point for dose computation and indicators of dose homogeneity. The reference point is a point within the PTV at which dose is specified. There are several criteria for selecting the reference point: in the PTV.

Radiation Oncology Physics

With these criteria, suitable point locations include the center of the PTV, near the central axis, or where tumor cell density is a maximum. In many cases, the isocenter has these characteristics and serves as the reference point, because for static fields the isocenter is most commonly placed within the target. However, the isocenter may not properly serve as the reference point for IMRT plans because dose constraints for nontarget volumes determine the dose distribution and may result in a nonhomogeneous dose distribution in the target, including a dose gradient through the isocenter.44 Dose homogeneity is also to be reported and is represented by the maximum and minimum doses in the PTV. Together, the reference, maximum, and minimum point doses represent the dose to the PTV as well as the variation in that dose.

Dose Reporting for Different Techniques ICRU 50 demonstrates its recommendations for three levels of complexity: single-plane plans, multiple planes, and 3D volume studies. In each case, the reference point dose is computed and the maximum and minimum point doses are estimated or computed. Isodose distributions are computed if a contour plane or multiple planes are acquired. In the highest complexity, dose evaluation tools such as dose-volume histograms are recommended. Together, the ICRU 50/62 recommendations create a standardized, consistent set of definitions for target and normal-tissue volumes to enable the comparison of treatment plans across institutional and international boundaries. Institutions use the ICRU 50/62 recommendations, which have been adopted by national protocol groups.

Beam Nomenclature When using complex field arrangements, it can be difficult to describe the precise beam orientation. A system has been developed to allow this description to be done simply.45,46 The suggested nomenclature defines a coordinate system that corresponds to the patient’s anatomic position (Fig. 6.47). The axes are labeled A, L, and S (for anterior, left, and superior) and P, R, and I (for posterior, right, and inferior). A beam name begins with the closest cardinal axis and then gives the angle of rotation from that axis to the beam central axis. Simple beams with no off-axis rotation are named after their anatomic positions. Examples include A, P, R, and L for the beam orientations commonly called AP,

30°

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Fig. 6.47 Three-dimensional beam nomenclature. Beams are named in reference to the patient coordinate system. (A) The A30S beam is 30 degrees superior from the anterior axis. (B) The A60L30S beam is 60 degrees left from the anterior axis and 30 degrees superior. (C) The P20R40I beam is 20 degrees right from the posterior axis and 40 degrees inferior.

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Scientific Foundations of Radiation Oncology

Three-Dimensional Treatment Planning With 3D treatment planning, radiation beam geometries are not constrained to lie in an image plane. Instead, beam trajectories are possible over all solid angles, greatly increasing the number of potential beam paths (see Fig. 6.47). Software tools enable target and volume of interest localization/segmentation, image reconstructions, automatic and beam’s eye view field designs, 3D dose calculations, and visualization techniques and metrics for plan evaluation. Advantages of 3D treatment include better target localization resulting from image-based planning, more accurate field delineation to include the target and exclude critical and normal structures, and improved dose calculation models that consider the 3D shape of the patient and composition.49-52

Dose Computation Algorithms

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Photon dose calculation methods can be classified as one of four types: (1) empirical or semi-empirical models (e.g., broad-beam methods based on the TMR and SMR), (2) analytic models based on first principles, (3) convolution models that use dose kernels and pencil beams, and (4) random sampling or Monte Carlo models that directly calculate the dose. Broad-beam methods have been reviewed,48 and work continues on higher-fidelity models.49,50,53-55 A clinically implemented electron calculation model with acceptable accuracy has been published and further developed.56 Advances include convolution pencil beams and full Monte Carlo methods, which account for the 3D electron density distribution of the irradiated volume, radiation transport, and the spectral components of megavoltage photon and electron beams.57 Convolution models for photon beams are well studied and implemented in every commercial treatment planning system. They compute dose based on the electron densities of the individual CT voxels traversed, using “density scaling” across non–unit density voxels. Thus, tissue inhomogeneity or other “corrections” are not needed, as they are for broad-beam models, to compensate for inadequacies in the computation model. Physics requirements for dose calculation systems include calibration of the CT scanner intensity values (CT numbers) and proper commissioning of the treatment planning system using measured beam data to confirm dose computation accuracy over the range of irradiation geometries and electron densities clinically encountered. Photon and electron dose distributions, including optimization of IMRT plans and robust 3D image presentation techniques, can be computed and displayed rapidly using graphics processing units (GPUs) or other

se

Treatment plans such as those shown in Fig. 6.45 are the results of 2D treatment planning. The patient contour, whether manually obtained at the time of simulation or obtained from a particular CT slice, must contain the central ray and one collimator axis of the beam; the beam must be coplanar with the contour plane. Beam orientations with central rays outside the contour plane are not permitted. Uses and limitations of 2D treatment planning have been thoroughly discussed47,48 and very few 2D-only treatment systems are now in use.

Evaluation of a treatment plan to determine clinical acceptability is a process that depends on patient geometry, target dose coverage, protection of normal structures, and other clinical criteria. A treatment planner (dosimetrist) can provide several “reasonable” plans under physician guidance, but acceptability is a clinical decision made by the radiation oncologist. One tool that aids quantitative plan evaluation is the dose-volume histogram (DVH).60 A DVH represents a treatment plan by graphically indicating the fractional amount of a volume of interest that receives a specified dose (or more). Two histograms are possible: the differential DVH (dDVH) shows the fractional volume receiving a specified dose whereas the cumulative DVH (cDVH) is the integral form and shows the fractional volume receiving a specified dose or more. Both forms are shown in Fig. 6.48 for hypothetical target and normal tissue volumes. The cDVH is the form most commonly used. Although DVHs show dose coverage of a volume, a disadvantage is that spatial information of the dose distribution is lost. For instance, inadequate coverage of a target volume may be indicated by the shape of the DVH but the location of the poorly covered region is not indicated; the treatment plan must be viewed to determine the location. Optimization of treatment plans depends on quantification of optimization criteria and may include dosimetrics (dose constraints at points or regions), permitted and prohibitive beam geometries, DVH indices, and approximations to biological response functions, such as tumor control probability (TCP) and normal tissue complication probability (NTCP) or other indices.53,54 Mathematical optimization does not necessarily equate with clinical acceptability; optimization

or

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fast hardware. The greatest accuracy possible uses Monte Carlo algorithms that account for all unique aspects of the patient dataset; these algorithms are commercially available for both photon and electron computations.58,59

r

PA, right lateral, and left lateral, respectively. Beams with off-axis rotations include the angle of rotation. For instance, A30S indicates an anterior beam that is angled 30 degrees to the superior and A60L30S indicates an anterior beam that is angled 60 degrees to the left then angled 30 degrees superior (see Fig. 6.47). This nomenclature is in clinical use in several institutions, and its use removes ambiguities in beam identification. An advantage over naming conventions based on machine coordinates (e.g., the GTC system, for gantry, table, and collimator) is that beam names are reported in the patient coordinate system and can be readily interpreted with respect to the patient position.

tte

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Fig. 6.48 Dose-volume histograms (DVHs). (A) Cumulative DVH for the target. (B) Cumulative DVH for normal tissue. (C) Differential DVH for the target. (D) Differential DVH for normal tissue. Ideal DVHs are shown by the dashed lines. Indications for better or worse DVHs are shown.

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CHAPTER 6 criteria may be improperly selected or otherwise limited. Similarly, rank-ordered, mathematically optimized plans may yield numerous clinically equivalent plans. Continuing work in treatment planning, research, and development requires clinical trials to show efficacy of the techniques.

Monitor Unit Calculations Treatment planning data include beam parameters and weights that indicate the dose contribution of each beam to the prescription point. The setting on the treatment machine that controls dose delivery, either monitor units (MUs) or timer setting, must be computed so that the proper dose for each beam will be delivered. Typically, the MU or timer setting is calculated by the treatment planning system, particularly so for 3D treatment planning systems and for IMRT plans. As an independent check of the planning system and for simple irradiation geometries, the MU or timer setting is validated by performing a second-check calculation using treatment machine data tables of PDD, TMR, and other parameters—a TMR-based algorithm using measured data for each beam is an almost universal practice. Generally, this calculation is based on a broad-beam model with homogeneous media (water, based on acquisition of beam data in a 3D water phantom) or the water-equivalent path length for heterogeneous media; thus calculations may give poor agreement (outside of ±5%) for complex irradiation geometries with heterogeneous media, strong surface or interface perturbations or small beams. This simple model is not appropriate for an independent check for IMRT fields without having a model that accounts for the contribution of each beamlet to the prescription point. In a second-check MU calculation system and for applicable irradiation geometries the MU or timer setting can be calculated with the basic equation: Setting =

Dose D = ! Dose rate D

Eq. 36

in which the dose, D, is the desired dose (in centigrays) to the prescription point from the beam (target dose), and the dose rate, , is the dose per MU (centigrays per MU) or dose per time (centigrays per minute) that the beam delivers to the prescription point. Dose rate is relative to 0, the calibrated dose rate of the treatment unit, which is obtained for a reference geometry (depth = dmax, 10 × 10 cm2 field size at 100 cm SAD) and material (water) using a national consensus protocol (in the United States, TG-51, American Association of Physicists in Medicine). Eq. 37 is used for calculation of monitor units (for LINACs): D(cGy) MU = ! . D(cGy MU)

Eq. 37

Eq. 38 is used for timer calculations (for teletherapy devices): D(cGy) . T(min) = ! D(cGy min)

Eq. 38

The real work comes in determining the dose rate at the prescription point, , for the particular treatment geometry being calculated. (Gy/MU or Gy/min) can be found from the reference dose rate, 0, by the following equation: ! =D ! × PDD(or TMR or TAR) × OF. D 0

Eq. 39

The term OF represents other factors, including attenuation factors for beam modifiers, such as field shapes (use of MLC or custom blocks), wedges, and compensators; output factors for field sizes; off-axis dose

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rate factors; an inverse square term if needed; transmission and buildup factors for immobilization devices (molded sponges, thermal plastic masks, arm or breast boards, stereotactic frames); and any other devices or parameters that must be considered. As stated previously, in most cases, the beam weight and are computed by the treatment planning system, yielding a completed MU calculation for treatment. As explained here, the simple MU calculation is performed as an independent second check for confirming the treatment planning dose computation. Any MU calculation system must be thoroughly understood and defined to ensure its appropriate application to computation of the correct dose to the patient. MU calculations have been formalized in consensus documents in the United States61 with similar formats in other countries.

EXTERNAL BEAM TREATMENT VERIFICATION Treatment Portal Imaging External beam treatments are verified by validating setup data such as beam geometries, including SSD measurements, and through comparison of simulator and treatment portal images. The use of portal images (originally performed with film) has been shown to have a positive impact on treatment.62 Common practice is to obtain portal images at the beginning of treatment and for each week thereafter. The image quality of megavoltage portal images is poorer than the quality for companion x-ray radiographic images or kV-equivalent digitally reconstructed radiographs (Fig. 6.49) because of poor subject contrast63 caused by the dominance of the Compton effect. However, improvements to portal image quality have included many approaches to addressing the deficiencies of film (e.g., design of more sensitive films, enhancement of film image capture, combined diagnostic and therapy imaging, and image enhancement of digitized portal films), especially simply, digital acquisition of the portal image with a high spatial and contrast resolution image receptor, which is the current state-of-the-art.63-65 Digital portal imaging systems, referred to as electronic portal imaging devices (EPIDs) were originally designed with at least five types of EPIDs,63 depicted schematically in Fig. 6.50: mirror-based video systems, fiberoptic video systems, liquid ionization chamber systems, scanning ionization chamber systems, and static solid-state systems—the flat-panel image receptor. This last design, using primarily amorphous silicon (aSi) as the detector element, has become the industry standard and is used by all LINAC manufacturers (see Fig. 6.5). The use of EPIDs in clinical practice includes simple replacement of film, treatment verification by manual comparison with digital reference films, image enhancement by digital techniques such as adaptive histogram equalization for improved structure recognition, automatic determination of patient positioning to permit or prohibit treatment, dynamic monitoring of conventional treatment, dynamic monitoring of dynamic treatment (e.g., IMRT), and real-time verification of treatment dose delivery.64 These applications depend on the design and operational characteristics of the devices, such as image sampling and refresh rates (as needed for real-time assessment), signal-to-noise ratio, detector resolution, detector radiation sensitivity, size of the active imaging area, software for image processing, physical size, and ease of use.

In Vivo Dosimetry Dosimetric verification of treatment may be required for unique patient geometries, protection of normal anatomy or critical situations such as total-body irradiation. Techniques for in vivo dose measurements include the following: 1. OSLDs or TLDs can be packaged in capsules or protective bags and placed in cavities, directly on the skin surface, and under extremities or bolus. Evaluation of results can be challenging for geometries

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A

B

Fig. 6.49 Imaging with diagnostic and high-energy photons. (A) Simulator film of a brain tumor patient, with a block indicated by the outline. (B) Port film of the patient in (A) shows the blocked area and context around the treatment region. Contrast is much higher in (A) because of increased amount of photoelectric effect. Contrast is poorer and of more limited range in (B) because of dominance of the Compton effect.

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E Fig. 6.50 Five methods for electronic portal imaging. (A) Fluorescent screen, mirror, and camera. (B) Fluorescent screen and light pipe carrier. (C) Direct irradiation of the matrix array of liquid ionization chambers. (D) Direct irradiation of the linear array of solid-state detectors, with scanning. (E) Direct irradiation of the matrix array of solid-state detectors.

7.

where buildup is not complete. The OSLD has replaced the TLD as a commonly used method for in vivo dosimetry, although the TLD remains a quite valid method. Diode or MOSFET detectors with integral buildup may be placed superficially or intracavitarily. Diode and MOSFET systems can be set up rapidly and results are immediately available. They have gained popularity because of their ease of use compared with the TLD. Designs exist with direct electronic connection to an in-room readout device or detectors alone that after irradiation are inserted into a readout device. Remote-reporting MOSFET detectors are now available, with primary use in the breast or prostate. These solid-state detectors can be interstitially implanted and interrogated remotely to measure dose in situ. Such devices are biocompatible, relatively small, and can be visualized with kilovoltage imaging. Radiochromic film can be used in a patient-equivalent phantom in the replicated patient treatment geometry. Film density is read with a calibrated digital scanner and, with a film dose-response curve, enables the readout and evaluation of isodose lines to yield a qualitative indicator of the relative dose distribution delivered. Ionization chambers rarely are used for in vivo dosimetry but may be placed with a protective sleeve in vivo superficially or in intracavitary locations, such as for monitoring a high-dose-rate brachytherapy procedure. A patient-equivalent phantom is tissue equivalent and includes internal structures such as bone, lung, and airways. Some phantoms are sectioned into transverse slabs and can accept radiochromic film, an OSLD, TLD, or even ionization chambers at a particular anatomic level. Anatomic phantoms differ in shape or anatomy from the real patient but are useful for studying treatment geometries. EPIDs can be used for transmission dosimetry for integrated or real-time measurement of dose when the patient geometry is known. Developing uses include real-time dosimetry for static fields and IMRT.

EXTERNAL BEAM TREATMENTS: GENERAL TECHNIQUES Target depth, size, anatomic site, and proximity of critical structures all influence the choice of treatment modality (photons or electrons) and the technique to be used. Technique includes the number of beams;

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CHAPTER 6 beam energy; beam weight (the relative amount of dose delivered by a beam); field shape; irradiation geometry; and use of bolus, wedges, compensators, or other special devices. Treatment planning techniques have been well studied and presented.66,67 General practice is that photons are almost always used in a combination of two or more fields (i.e., parallel opposed, wedged pair, three field, four field, more field, or arc) and electrons are used as single en face fields (perhaps junctioned with other electron fields to cover a larger area). Example photon plans demonstrate these principles for the parallel-opposed, wedged-pair, three-field, four-field, and arc techniques in Figs. 6.51 to 6.56. As the number of fields increases, there are two observations: The high-dose region becomes more conformal to the target, and the peripheral dose decreases but the volume of tissue covered by peripheral dose increases.21 Current-day radiotherapy uses from one field (as delivered in a simple unidirectional treatment) up to effectively several hundreds or thousands, as delivered with IMRT or dynamic arc treatment. Even now, electron treatment planning is less mature than photon planning and 3D planning may not be performed at all, although pencil beam and even Monte Carlo calculation algorithms are available with accuracies that are clinically acceptable.56,57 Commonly enough, electron treatment plans are based on graphic or tabulated measured data as previously shown (see Figs. 6.42 and 6.43).

Radiation Oncology Physics

plan with a dose distribution that “conforms” to the target volume (Fig. 6.57). For many clinical sites, conformal radiation treatment is the state-of-the-art through the use multiple static, shaped fields, static or dynamic IMRT, or other computer-controlled approaches. Conformal radiation treatment is reviewed in Chapter 21. Conformal radiotherapy plans are realized by using a large number of beams of various weights, sizes or shapes, and orientations to hit the target. If enough beams of the proper kind are used, a dose distribution can be created with a shape that conforms to the target volume. This technique was recognized early21 and is the reason that multiple fields are used. In this regard, all radiotherapy treatment plans are conformal; however, the degree of conformation greatly varies based on the irradiation technique. Conformal delivery techniques include a variety of approaches. Multiple static fields for 3D conformal radiotherapy (3D CRT) can be shaped by custom blocks, MLCs, miniature MLCs,68 and custom stereotactic collimators.69 Dynamic fields using arcs of gantry motion can be delivered using fixed field shapes70 or variable field shapes71 for each arc path. IMRT has several delivery approaches and can be delivered using static fields with 3D compensators32 or by dynamic techniques using a binary collimator13,72 or MLCs.73,74 Some of these approaches are used for single-fraction radiosurgery techniques and others for fractionated treatment. IMRT has become an important treatment approach over the past 15 years for curative treatment as well as for challenging irradiation geometries.75-77 In IMRT, the shaped outline of the radiation beam at a particular gantry angle is subdivided into a large number of beamlets, with the intensity of each beamlet set during an optimization procedure to give a particular dose. Beamlet width is set by the projected width of an individual MLC leaf. With a nonbinary MLC, the length of each beamlet is variable and depends on the required dose, dose gradient needed, and the technical specifications of the MLC device. The reconstruction of a conformal dose distribution for IMRT is the same process as CT image reconstruction from transmission profiles.75 If an optimized plan is one that is conformal, solving the inverse radon

THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY The goal of delivering dose to the target volume and minimal dose elsewhere was not easily approached with the limitations of early treatment technologies, because volumetric images (CT, MRI), beam shaping/ modulation techniques, and computerized treatment planning were not available or were primitive. The 3D problem was understood, but tools did not exist to allow a solution. Development and maturation of 3D treatment planning tools have rapidly enabled clinicians to consider the search for an “optimal” treatment plan, reasonably thought of as a

15-degree wedge

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Fig. 6.51 Parallel-opposed plan for treatment of a target in the head or neck.

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CHAPTER 6

Radiation Oncology Physics

Beam 1

Anterior

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9588 70 90

60 50 200

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Fig. 6.54 Three-field plan for treatment of a target in the pelvis.

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Posterior Beam 2 Fig. 6.55 Four-field plan for treatment of a target in the pelvis.

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30 20 Posterior Beam stop, 360 degrees

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Fig. 6.56 Arc plan for treatment of a target in the pelvis.

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Fig. 6.57 The conformal problem. A conventional plan (A) treats the target quite well but also treats a nearby critical structure. A conformal plan (B) treats the target well and spares part of the critical structure. Is the conformal plan better than the conventional plan?

transform will provide a solution that is optimal. However, it can be shown that a solution cannot be found that will give an exactly conforming distribution because negative beam weights (use of negative energy) are required but are not possible. Thus, the approach is to find an approximate solution to the inverse radon transform through iterative techniques. Also, importantly, dose constraints are set for both target (minimum dose to a point or volume) and normal or critical structures (maximum dose to a point or volume); these constraints drive the automated dose optimization process. A thorough review of the conformal problem and its solutions is available,54 and the field continues to develop with new approaches, faster optimization algorithms, and integrated plan evaluation tools. In a newer technique, rotational IMRT is delivered, using the conventional C-arm LINAC design, with

simultaneous motions of the MLC leaves and gantry (arc movements). This technique is called intensity-modulated arc therapy (IMAT) or volumetric-modulated arc therapy (VMAT).78 An intensity-modulated conformal plan is shown in Fig. 6.58, and Chapter 21 gives additional information.

IMAGING IN RADIOTHERAPY Radiotherapy procedures have become image based. Image-guided interventions—whether for surgery, lesion ablations, embolization of vascular defects, radiotherapy, or other therapies—are increasing in number.56-58,77,78 The contributions of advanced imaging for radiotherapy include two primary areas: imaging for verification of treatment delivery

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CHAPTER 6

Critical

Target 100 95 90

80 60

70 Critical

50

Fig. 6.58 Example of a conformal plan. Intensity-modulated plan for a target located between two critical structures. (Adapted from Oldham M, Webb S. A 9-field static tomotherapy planning and delivery study. In: Leavitt DD, Starkschall G. Proceedings of the XIIth International Conference on the Use of Computers in Radiation Therapy, Salt Lake City, Utah. Madison, WI, Medical Physics Publishing; 1997.)

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with that corresponding phase. A “playback” of the images over time yields a coherent set of dynamic images on which target motion can be observed and measured as a function of time. This technique is possible for 4D CT and PET imaging modes,84 with 4D MRI under investigation. At the time of treatment planning and treatment, any observed target motion can be accommodated by one of several techniques: using a larger treatment field, gating the treatment to match a particular phase of the respiratory cycle, real-time tracking of the target using a surrogate fiducial marker detected by optical means or rapid radiological imaging, or optical patient surface tracking.82,84 Motion assessment and compensation techniques continue to be developed. Techniques that use optical and remote monitoring show promise for being fast in detecting motion and changes in patient position. Although optical methods tend to be limited to detection of visible surfaces, in one technique, real-time remote monitoring of target position is performed before and during treatment using interstitially implanted, glass-encapsulated transponders and an in-room remote readout device.85 At least three transponders are implanted into the target and their relative positions are determined from the treatment planning CT scan and the remote readout unit, with geometric reference to the isocenter position. Each day, patient position is set based on the planning CT scan and then monitored in real time to ensure treatment delivery to the correct location.85,86 Accuracy is high and transponder migration is typically small, although possible. Imaging modalities should be considered for the best information flow with minimal image artifact.86,87

Biological Imaging and imaging for better understanding of the biology of cancers and normal tissues.

Image-Guided Radiotherapy Image-guided interventions have been developed for a multitude of medical procedures, including radiotherapy.79,80 The main justification has been the development and use of highly conformal radiotherapy plans, which carry risk for their implementation—in general, 3D CRT and IMRT plans use small fields that, if delivered with geometric miss to the wrong location, increase the likelihood of CTV underdoses. Thus, use of highly conformal radiotherapy techniques has heightened the need for image-based verification of treatment delivery on a more frequent basis than just the weekly portal images. This need has led to IGRT, in which daily in-room imaging is performed immediately before each radiation treatment fraction. IGRT approaches that use in-room imaging include isocentric ultrasound imaging, CT-on-rails, radiographic and fluoroscopic projection imaging, kV cone beam CT, MV cone beam CT, and MV fan beam CT.81,82 These devices are integrated with the MV treatment device to form a hybrid imaging-treatment unit. Implementation issues include image quality, imaging dose, image interpretation, manual versus automated comparison of daily and reference images, revisions to treatment plans based on observed daily variations of position and anatomy compared to a reference treatment plan, and image archival and retrieval.81-83 Imaging for treatment simulation and IGRT techniques have made possible the study of target motion to assess if a target moves outside the radiation field such that a geometric miss might occur.84 Target motion is primarily because of the respiratory cycle; however, bladder and bowel filling or emptying or other noncyclic motions may also cause target motion. The main approach is to perform a motion study of the target, using (typically) CT and possibly PET, using a variety of 4D image acquisition and reconstruction techniques. A common method is to acquire images at the same time that the respiratory cycle is tracked over a time period of several respiratory cycles. Each image is correlated with the respiratory phase at the time of acquisition and then rebinned

Biological imaging is imaging of physiological, metabolic, and functional processes to noninvasively measure the biological character of tumors or normal tissues. Important biological aspects of tumors to be imaged include metabolite content, presence of hypoxia, and cell proliferation. Methods with biological imaging potential include PET and PET/CT with novel radionuclides and ligands for specific receptor targeting, MR spectroscopy, functional MRI (fMRI), MR diffusion and perfusion imaging, ultrasonography, and optical methods for targeted receptors.80 Biological and molecular imaging techniques have increased tremendously over the past 10 years, and their applications include preclinical basic science research, the use of imaging as a biomarker, and studies of clinical responses to radiotherapy. Molecular imaging applications in radiation oncology are in active development.88 As a biomolecular imaging example, brain tumors have been studied using magnetic resonance spectroscopy (MRS) to measure the spatial distribution of metabolites that correlate with tumor grade.59,60,84,85 Choline, creatine, N-acetyl-aspartate (NAA), lactate, and other metabolites relevant to the type of tumor (in this case, brain tumors) are determined by MRS. The ratio of choline to NAA is determined by spectroscopic peak height analysis and mapped on a contrast-enhanced MR image (Fig. 6.59B). One observation is that the spatial distribution of metabolite values and ratios for brain tumors differ in size and shape from that of (conventional) contrast-enhanced MRI.89,90 Fig. 6.59 shows the problem for targeting with radiation: metabolite ratios or other tumor-specific information from biological imaging modes will redefine how oncological targets are determined. Anatomic methods that image endogenous contrast or contrast-enhanced regions will be complemented with advanced biologically based imaging techniques. These multimodality images will be used for targeting. The information is greater than having two different imaging modalities such as CT and MRI; it is the addition of patient-specific imaging to determine tumor character and environment. The validation of these new imaging techniques is important to ensure the understanding of the image information content, that is, the meaning of an intensity value for a voxel and how the image should be used as part of the radiation planning process.89,91

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MRI-enhanced volume MRSI volume Other biologic volume Functional volume to avoid

Midline External contour

B

A

Fig. 6.59 Biological target volumes. (A) Schematic shows the possible arrangement of three representations of a brain tumor: contrast-enhanced magnetic resonance imaging (MRI, green), magnetic resonance spectroscopic image (MRSI, purple), and other biological volume (violet), such as proliferation and receptor density. A region of avoidance (blue) is represented as may be obtained by functional MRI. (B) From inner to outer shells, successive iso-ratio lines for choline-N-acetyl-aspartate (NAA) metabolite ratios (cho/NAA) of 6 (dotted line), 4 (dotted line), and 2 (solid line). Distribution of the metabolite map crosses the midline and differs in size and shape from the (conventional) contrast-enhanced region. (A, From Bourland JD, Shaw EG. The evolving role of biological imaging in stereotactic radiosurgery. Tech Cancer Treat Res. 2003;2:135-140. B, From Pirzkall A, McKnight TR, Graves EE, et al. MR-spectroscopy guided target delineation for high-grade gliomas. Int J Radiat Oncol Biol. Phys. 2001;50:915-928.)

Biological imaging and methods for IGRT will continue to mature over the next decade. Biological imaging will contribute especially to the understanding of cancer and normal-tissue biology. Costs, technological aspects of implementation, and clinical benefits of multimodality imaging remain to be solved for biological imaging and its uses in radiation treatment planning and the evaluation of patient response to treatment.79,92 For instance, dedicated PET/CT and MR simulators have been implemented to facilitate the uses of these advanced imaging modalities for radiation oncology patients.93 Also, the development of hybrid imaging-treatment devices for IGRT continues with MR-LINAC and MR-gamma teletherapy designs now being brought into clinical use.94,95

than conventional dose-fractionation regimens, an approach called hypofractionation. SRT techniques include noninvasive and replaceable patient fixation,108 extracranial treatment,109,110 static or shaped fields,69,111 intensity-modulated treatment with large- or small-width collimators, treatment with robot-controlled x-ray units,14,112 shape-based planning,113 and other optimization algorithms. In particular, stereotactic body radiotherapy (SBRT), which uses a relatively large number (e.g., 7, 9, or 11) of shaped, static fields or arc IMRT (IMAT/VMAT) and hypofractionated dose regimens, has become quite common for small lung targets, and metastases in the liver, bone, and elsewhere, possibly including 4D motion accommodation and always using IGRT.109,110,114,115 Gamma radiosurgery, LINAC radiosurgery, and SBRT are covered in detail in Chapters 7, 27, and 28.

STEREOTACTIC RADIOSURGERY AND RADIOTHERAPY

TOTAL-BODY PROCEDURES

High accuracy and precision radiotherapy can be performed using stereotactic image-guidance and rigid immobilization or remote monitoring and positioning systems. The stereotactic component of these techniques refers to immobilization or fixation of the patient with a rigid or otherwise stable system coupled with same-day imaging to establish a patient-specific, image-based coordinate system for the entire treatment process. Stereotactic radiosurgery (SRS) refers to the use of single-fraction, small-field, high-dose (12- to 24-Gy margin dose), focal radiation for treatment of relatively small intracranial or extracranial tumors.96 By two available SRS techniques, a gamma radiosurgery unit97-102 or specially designed LINAC systems,68-70,103-107 a large number of small circular or shaped radiation fields are aimed accurately from multiple directions to intersect a common point at which a target is positioned. In contrast, stereotactic radiotherapy (SRT) refers to the use of more than one fraction, typically two to five fractions, using similar techniques with small fields and higher dose per fraction

Total-body irradiation (TBI) is an irradiation procedure performed as part of bone marrow transplantation and requires special physics measurements for implementation of treatment.116 The patient is irradiated in the anterior-posterior/posterior-anterior or lateral-opposed directions at an extended distance from the treatment machine using large photon fields to encompass the whole body (Fig. 6.60). The goal is to provide dose homogeneity within ±10% of the prescription dose at the patient’s midline. Dose compensation for narrow-width regions of the body and protection of the lungs with shielding blocks is required depending on the technique used. Radiation beam data—such as beam profiles, depth dose or tissue-maximum ratios, and reference dose rates—must be obtained at the extended distance used. Data obtained for conventional treatment at the isocenter may not apply to large fields at extended distances because of changes in scattering conditions. Higher beam energies are used for lateral techniques, matching the increase in patient thickness compared with anteroposterior geometries.

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CHAPTER 6

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137

BRACHYTHERAPY

A

B

C

D

E Fig. 6.60 Irradiation geometries for total-body irradiation. (A) Movingsource technique, with the patient on the floor. (B) Large-field irradiation, with the patient on the floor. (C) Single, large, lateral field, with the patient erect. (D) Opposed, large, anterior and posterior fields, with the patient erect. (E) Opposed, large, lateral fields, with patient erect. (A to C, From AAPM RTC Task Group 29, Report 17: The physical aspects of total and half body photon irradiation. College Park, MD: American Association of Physicists in Medicine; 1986.)

Total-skin electron treatment (TSET) is similar to TBI except that electrons are used instead of photons. Considerations for this technique, which is used for skin cancers such as mycosis fungoides, have been delineated and include measurement of beam data (e.g., beam profiles, depth dose, and reference dose rate), measurement and any required reduction of bremsstrahlung contamination, and methods for ensuring relatively homogeneous irradiation of the patient surface. In particular, the irradiation geometry must avoid overdoses to thin anatomic regions such as the hands and fingers and prevent underdoses to anatomic regions that might be shielded by skin folds or extremities.117 Typically, a six-field approach with six different patient positions is recommended. The setup techniques are described in more detail in Chapter 23.

Brachytherapy is a term that comes from brachy (“short”), combined with therapy, meaning short-distance therapy. The contrast is teletherapy, meaning therapy at a distance, as with external beam treatments using 60 Co or LINAC devices, where the radiation source is 80 to 100 cm from the patient. In brachytherapy, radioactive sources of small physical size are placed very close to or in the tumor for surface, interstitial, or intracavitary treatment. Several terms relevant to brachytherapy are defined here: 1. Surface mold: Sources are fixed to an applicator, or mold, that conforms to the patient surface. The surface applicator positions the sources in the desired geometry and is placed on the skin surface to irradiate a superficial target. This technique is not commonly performed except for purposes of treatment of ocular melanoma. 2. Interstitial treatment: Sources are implanted in tissues directly or within catheters that are first implanted within the target volume. 3. Intracavitary or intraluminal treatment: Sources are inserted into body cavities by means of applicator devices. Sites include the oral, rectal, vaginal, and uterine cavities and the tracheal and bronchial lumina. Brachytherapy has several advantages compared with external beam treatment: 1. The inverse square law dominates the decrease in dose rate and dose as the distance from a source increases. The dose fall-off is steep so that the dose delivered near a source is quite high (thousands of centigrays), whereas a few centimeters away, the dose is low (tens of centigrays). The steep dose gradient confines the high-dose region to a small volume. 2. The photons emitted by brachytherapy sources have relatively low energies and greater attenuation in tissue compared with photons used for external beam treatment. This increased attenuation concentrates dose near the source and minimizes dose at a distance. 3. In conventional brachytherapy, dose rates are relatively low, about 0.40 Gy/h up to 0.80 Gy/h, and it takes several days to deliver the prescribed dose. This approach may allow treatment of all cells in each phase of the cell cycle for a radiobiological advantage. 4. In high-dose-rate (HDR) brachytherapy using a remote afterloading device, dose rates are very high, approximately 2 Gy/min at the prescription point, comparable to external beam dose rate. The prescribed dose is delivered in 5 to 10 minutes. HDR approaches are quite common for a variety of treatment sites and are the preferred technique for both intracavitary and interstitial brachytherapy.

Radioactive Decay The atomic nucleus contains protons and neutrons that prefer certain configurations for stability, as discussed previously. Those configurations that are not stable undergo spontaneous transformation to another nuclear species that may or may not be stable. This spontaneous transformation is called radioactive decay. The mode of radioactive decay, meaning the type of transformation and emitted particles, depends on the parent species’ nuclear composition. For a particular parent nuclide, a decay mode is allowed or prohibited, and it is one of the following types2,12,13 (nomenclature is as defined previously, and particles are defined in Table 6.2): 1. In alpha decay (Fig. 6.61A), the nucleus gives off an alpha particle, 4 2+ α (2 protons and 2 neutrons—a helium nucleus), resulting in a daughter nucleus of mass A-4 and atomic number Z-2. Alpha

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particles are monoenergetic and tend to have 4 to 8 MeV in kinetic energy: A Z

X→

A−4 Z −2

Y + 4 α 2+ + Q;

2n + 2p → 4 α 2+ + Q.

Secondary processes after alpha decay include gamma ray emission (or internal conversion, yielding characteristic x-rays or Auger electrons), which may occur after alpha decay as the daughter deexcites to the ground state. Radionuclides undergoing alpha decay tend to have high Zs and include 216Ra, 222Rn, 218Po, 235U, 239Pu, and 241 Am. 2. For beta decay, a single nucleon (neutron or proton) transforms from one type to the other in the nucleus. The nucleus gives off an electron, called a β particle because of its nuclear origin, and a neutrino. There are two types of β particles, one with a negative charge, β−, which is a “regular” electron, also called a negatron, and one with a positive charge, β+, the antiparticle to the electron, also called a positron. Radioactive decay modes with emission of a β− or β+ are possible. a. For β− decay (i.e., negatron decay; see Fig. 6.61B), a neutron transforms into a proton in the nucleus. The nucleus gives off a β− particle and an antineutrino. The resulting daughter nucleus has the same mass A and increased atomic number of Z + 1. The β− particles have a distribution of energies less than or equal to Q (the antineutrino carries off the remainder). The average β− energy is about one-third Q: A Z

X→

Y + β − + v + Q;

A Z +1

n → p + β − + v + Q.

Secondary processes after β− decay include gamma ray emission (or internal conversion, yielding characteristic x-rays or Auger electrons), which may occur after β− decay as the daughter deexcites to the ground state. The β− decay occurs for neutron-rich nuclides over all Zs. Example nuclides include 3H, 14C, 32P, 60Co, 89 Sr, 99Mo, 131I, 137Cs, and 198Au.

A X Z

α1

A X Z

γ

A–4 Y Z–2

A

A Y Z+1

B

Alpha decay

Beta minus decay

A X Z β1 β2

γ A Y Z–1

A X Z

2moc2

EC1 EC2

γ

A Z

A Y Z–1

C Beta plus decay D Electron capture Fig. 6.61 Modes of radioactive decay. (A) α Decay. (B) β− Decay. (C) β+ Decay. (D) Electron capture.

X→

Y + β + + v + Q;

A Z −1

p → n + β + + v + Q.

Secondary processes occur after β+ decay. The positron, β+, has a short lifetime before annihilation. There is a small chance that the β+ will hit an electron and annihilate in flight. The greater probability is that the β+ slows down (through coulomb interactions) and combines with a free electron. The combined β+/e− (or e+/e−) species is called positronium. Positronium exists for about 10−10 seconds before annihilation and the creation of two 0.511-MeV photons (i.e., one photon for each electron mass). A longer-lived state of positronium (10−7 seconds) yields three simultaneous annihilation photons. Gamma ray emission (or internal conversion, yielding characteristic x-rays or Auger electrons) may also occur after β+ decay as the daughter de-excites to the ground state. The β+ decay occurs for proton-rich nuclides over lower and intermediate Zs. Example nuclides include 11C, 15 O (used in PET), and 22Na. 3. In electron capture (see Fig. 6.61D), the nucleus captures an orbiting electron, increasing the nuclear mass by 0.511 MeV and transforming a proton into a neutron. Electron capture is similar to β+ decay because the daughter has mass Z-1 and a neutrino is emitted. Most often, the K shell electron is captured. Electron capture occurs for proton-rich nuclides over lower and intermediate Zs when there is not sufficient energy (2 moc2, or 1.022 MeV) for β+ decay to occur: A Z

β1 β2

α2

γ

b. For β+ decay (i.e., positron decay; see Fig. 6.61C), a proton transforms into a neutron in the nucleus. The nucleus gives off a β+ particle and a neutrino. The resulting daughter nucleus has the same mass A and decreased atomic number of Z − 1. The β+ decay requires that 2 moc2, or 1.022 MeV, be available between the parent and initial daughter energy states to be possible. If this energy difference is not available, β+ decay is prohibited and electron capture may occur. The β+ particles have a distribution of energies less than or equal to Q (the neutrino carries off the remainder). The average β+ energy is about one-third Q but is higher than the average β− energy for the same Q because of repulsion by the nucleus:

X + e− →

Y + v + Q;

A Z −1

p + e− → n + v + Q.

Secondary processes occur after electron capture. Because an orbital electron is captured, subsequent filling of the electron shell results in the emission of characteristic x-rays after an electron capture event. Gamma ray emission (or internal conversion, yielding characteristic x-rays or Auger electrons) may occur after electron capture as the daughter de-excites to the ground state. Nuclides decaying by electron capture include 22Na, 40K, 51Cr, 57Co, and 192Ir (also with β−). The term Q in each decay equation represents the total energy given off as kinetic energy of the ejected particles (α, β−, β+, ν , ν), the remaining nucleus, or both. The neutrino, with a mass of almost zero, was first postulated for existence because of the observed continuous energy distribution for β− and β+ energies in beta decay. Without a third reaction product, the β− or β+ energies would be monoenergetic and almost equal to Q, reflecting the discrete energy levels in the nucleus.

Secondary Decay Processes Each of the primary decay modes can leave the daughter nucleus or atom in the ground state or excited state. If an excited state exists, the additional energy is given off in various ways to yield a ground-state daughter. 1. Isomeric transition by fast gamma emission: With an excited daughter nucleus, the excitation energy may be given off by photons called

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CHAPTER 6 gamma rays. The gamma ray energy is equal to the difference between the initial and next energy state of the nucleus. Because energy states are fixed for particular nuclei, gamma emissions are fixed and unique for a particular nucleus. Gamma rays identify their nucleus of origin in the same way that characteristic x-rays identify their atom. Gamma emission may result in a ground state nucleus by a single gamma emission or by successive gamma emissions through several energy states. The release of energy by gamma emission is fast—the excited state exists for a very short time, no longer than 10−6 seconds or even less—thus, gamma emission is immediate after α, β−, β+, or electron capture decay. Although the phrases “60Co gamma rays” and “137Cs gamma rays” are used, these gamma rays are really from the daughter nuclei. Gamma rays from 60Co are really 60Ni gamma rays and gamma rays from 137Cs are really 137Ba gamma rays. However, the terminology is based on the parent nuclide’s name. 2. Isomeric transition from a metastable state: When an excited nuclear state exists for greater than 10−6 seconds before gamma emission, the state is called a metastable state. Metastable states for certain isotopes exist long enough to enable the chemical separation of the metastable species from the parent, as is the case for 99mTc, with a half-life of 6 hours. The “m” refers to metastable. 99mTc decays to 99 Tc (an isomeric transition) in a principal pathway by the emission of two gamma rays in succession. 3. Internal conversion: An excited nucleus can de-excite without gamma emission by the process of internal conversion. Instead of a gamma ray, the excitation energy is used to eject an orbital electron, usually from the K shell. The ejected electron is called a conversion electron and has energy equal to the gamma energy minus the electron binding energy. The usual cascade of characteristic x-rays and Auger electrons follows. Internal conversion competes more with gamma emission as Z increases. The pathways of gamma emission and internal conversion are parallel to the competing processes of characteristic x-ray and Auger electron emission; a photon carries off the excitation energy, or the energy is transferred to an electron that is then ejected. Radioactive decay is characterized by the following observations: Z = 82 are radioactive. Z = 82, some are naturally radioactive (e.g., 14C 40 and K). Z nuclei tend to undergo alpha decay; their nuclei have an abundance of protons and neutrons that may be emitted as coupled pairs (i.e., an alpha particle). Z nuclei tend to undergo β− (i.e., negatron) decay. Z nuclei tend to undergo β+ (i.e., positron) decay. particles are energetic. particles are low energy.

Radioactive Decay Mathematics Radioactive decay occurs spontaneously but also with a distinct probability for each radioactive nuclide. The number of transformations occurring per unit time, A(t), is called activity and is given by the equation A(t) = λN(t),

Eq. 40

in which N(t) is the number of atoms of the radioactive species at time t and λ is a proportionality constant called the decay constant. The SI unit for activity is the becquerel, equal to one transformation per second. The original unit of activity is the curie, which is 3.7 × 1010 transformations per second (3.7 × 1010 s−1), an amount equal to the number of disintegrations occurring in 1 g of 226Ra. λ is called the decay constant,

Radiation Oncology Physics

139

which is unique for a nuclide and is equal to ln(2) divided by the half-life, t 1 2 : λ=

ln(2) 0.693 = , t1 t1 2

Eq. 41

2

in which t 1 2 is the amount of time required for the activity or the number of nuclei to decay to one-half of the original value. The relationship between λ and t looks like the relationship between HVL and λ. The half-life—and, hence, the decay constant—is constant and unique for a particular radionuclide, and its measurement can be a means for identifying a species. Depending on the species, the half-life can be large or small and governs the lifetime over which decay occurs. The equation that radioactive decay obeys is N(t) = N0e− λt or A(t) = A 0e− λt,

Eq. 42

where N(t) and No are the number of nuclei at time t and t = 0, respectively, and A(t) and A0 are the activities (in becquerels or curies) at time t and t = 0, respectively. Decay is exponential and can be represented in linear or semi-log form (Fig. 6.62).

Properties and Applications of Isotopes Table 6.14 lists isotopes, their properties, their physical forms, and their therapeutic applications. As discussed earlier, brachytherapy sources may be constructed as sealed sources in the forms of needles, tubes, or seeds. The solid radioactive material—in a metallic, stable inorganic or organic chemical form, adsorbed onto a material, or possibly as a liquid or gas—is sealed into a metal source capsule by welds or other means that prevent leakage of the material. Most radioactive sources are beta emitters, and the useful radiations for treatment are the gamma rays or characteristic x-rays emitted after beta decay. Besides containment of the source material, the metal encapsulation stops all beta (or alpha) emissions and allows only the gamma or x-rays to be transmitted. Sources can also be used for their beta emissions when encapsulated in a thin-wall enclosure (i.e., 90Sr) or in unsealed (liquid) form for both beta and alpha emitters. Dose distributions from sealed sources have a shape that reflects the rapid fall-off with dose because of the inverse square law, source energy, distribution and amount of activity within the source, and source encapsulation. Source encapsulation in particular affects the apparent activity, active length, and shape of the dose distribution through attenuation by the source capsule walls and ends. Sealed-source dose distributions are anisotropic, not uniform, because of increased encapsulation thickness and self-absorption along the length of the source (Fig. 6.63). Investigators have performed measurements and applied Monte Carlo techniques and other models to determine brachytherapy source dose characteristics.118,119 Radioactive decay and its energetics are represented by decay schematics (see Fig. 6.61). Horizontal lines represent the relative nuclear energy levels of the parent and daughters. Branches from the parent to the daughter represent the type of decay, whereas the horizontal spacing of each species represents the atomic number, Z. A branch to the left indicates a transition in which Z decreases (α, β+, or electron capture; see Fig. 6.61A-D). A branch to the right indicates a transition in which Z increases (β− decay; see Fig. 6.61B). Elevated horizontal lines above the ground state indicate excited nuclear levels. Vertical arrows from one excited level to a lower one or the ground state indicate gamma emission. Fractional or percentage amount of time in which a transition occurs is indicated, as are the absolute energies of levels, particles, and photons. Decay schemes for the medical isotopes listed in Table 6.14

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CHAPTER 6

T1/2 ! 5 yr

T1/2 = 74 days .161 MeV .058 MeV 0 MeV

1.2 MeV

Radiation Oncology Physics

1.453 MeV

192 Ir 77

1.379 MeV 1.358 MeV

β1(.1%) β2(4.5%) β3(42%) β4(49%)

EC (!4.4%)

1.201 MeV

.916 MeV

β5#7(!.01%)

.785 MeV .608 MeV

.690 MeV .580 MeV .489 MeV

.317 MeV β"(!10#5)

.206 MeV 0 MeV

0 MeV 192 Os 76

192 Pt 78

Method of production: 191Ir(n,γ) 192Ir

Emitted radiation

Energy (MeV)

Mean number per disintegration

γ ray (Nickel-192 γ rays)

0.296

0.290

γ ray (Nickel-192 γ rays)

0.308

0.298

γ ray (Nickel-192 γ rays)

0.317

0.810

γ ray (Nickel-192 γ rays)

0.468

0.490

γ ray (Nickel-192 γ rays)

0.589

0.040

γ ray (Nickel-192 γ rays)

0.604

0.090

γ ray (Nickel-192 γ rays)

0.612

0.060

γ ray (Nickel-192 γ rays)

Average of !0.370

Average of !2.2

eFig. 6.1 A 192Ir decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.)

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139.e1

139.e2

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Scientific Foundations of Radiation Oncology

226 Ra 88

222 Rn 86

α

T1/2 = 3.82 days T1/2 = 3.05 min

γ 218 Po 84

214 Pb 82

T1/2 = 1620 yr 4.60 MeV (5%) 4.78 MeV (95%) 0.19 MeV (4% ! IC)

α 5.49 MeV (100%) α 6.00 MeV (100%)

T1/2 = 26.8 min

T1/2 = 19.7 min

0.69 MeV (47%) β 0.74 MeV (44%) 1.03 MeV (6%) 0.05 MeV (1% ! IC) γ 0.24 MeV (4%) 0.29 MeV (19%) 0.35 MeV (36%)

214 Bi 83

Method of production: Naturally occurring

206 Pb 82

γ

0.61 MeV (47%) 0.77 MeV (5%) 0.93 MeV (3%) 1.12 MeV (17%) 1.24 MeV (6%) 1.38 MeV (5%) 1.76 MeV (17%) 2.20 MeV (5%) 2.44 MeV (2%)

214 Po 84

T1/2 = 5.01 days

{

"2.00 MeV (!76%) 3.26 MeV (!19%)

T1/2 = 164 µsec

210 Pb 82

β 0.01 MeV (81%) 0.06 MeV (19%)

β

α 7.69 MeV (100%) γ 0.05 MeV (4% ! IC)

210 Bi 83

β 1.16 MeV (100%) T1/2 = 138.4 days

α 5.31 MeV (100%)

210 Po 84

Emitted radiation

Energy (MeV)

Mean number per disintegration

γ ray (Radon-222 γ rays) γ ray (Bismuth-214 γ rays)

0.186 0.053

0.040 0.020

γ ray (Bismuth-214 γ rays)

0.242

0.075

γ ray (Bismuth-214 γ rays) γ ray (Bismuth-214 γ rays)

0.295 0.352

0.210 0.380

γ ray (Polonium-214 γ rays)

0.609

0.470

γ ray (Polonium-214 γ rays)

0.769

0.053

γ ray (Polonium-214 γ rays)

0.935

0.033

γ ray (Polonium-214 γ rays)

1.120

0.160

γ ray (Polonium-214 γ rays)

1.238

0.060

γ ray (Polonium-214 γ rays)

1.379

0.048

γ ray (Polonium-214 γ rays)

1.400

0.040

γ ray (Polonium-214 γ rays)

1.728

0.032

γ ray (Polonium-214 γ rays)

1.764

0.170

γ ray (Polonium-214 γ rays)

2.204

0.060

γ ray (Polonium-214 γ rays)

2.435

0.020

eFig. 6.2 A Ra decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.) 226

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Scientific Foundations of Radiation Oncology

A(t) = e–λt A0

1.00

A(t) = e–λt A0

1.00

A(t) = e–λ2t A0

A/A0 (or N/N0)

A/A0 (or N/N0)

0.50

t1/

2

0.30

0.75

t1/

2

λ2 < λ, t2, 1/2 > t2 0.25

A(t) = e–λ2t A0 t2,1/

Slope = –λ2

2

λ2 < λ, t2, 1/2 > t2 0.10

0.03

t1/

t1/

Slope = –λ

2

2

0.01 2.0

A

4.0 6.0 Time, t (arbitrary units)

8.0

10.0

2.0

4.0

6.0

8.0

10.0

B Time, t (arbitrary units) Fig. 6.62 Graphic representation of radioactive decay. (A) Linear plot. (B) Semi-log plot.

TABLE 6.14

Properties and Applications of Isotopes

Nuclide

Half-Life

Decay Mode

Decay Productsa

Physical Form

60

5.263 y

β

β, γ

SSS tubes

90

64 h

β, IT

β, γ

LQ-MS

103

17 d

EC

1.48

0.008

IS, prostate

30.2 y

β

γ, 0.021 x β, 0.662 γ

SSS seeds

137

SSS tubes

3.26

5.5

IC, RA, gyn, H/N

125

60.2 d

EC

0.027 x

SSS seeds

1.46

0.025

IS, prostate, H/N, pancreas, sarcoma

192

74.2 d

EC, β

β, γ, 0.38 γ

SSS, seeds, wire

4.69

2.5

IC, IS, RA, gyn, H/N, breast, sarcoma

226

1602 y

α

α, β, γ, 0.83 γ

SSS tubes, needles

8.25

8.0

IC, IS, gyn, H/N, breast

2.2

2.5

OR, thyroid and mets

2.38

2.5

IC (peritoneal), IS

10.15

8.0

IS, breast

Co Y Pd Cs I Ir Ra

Other Isotopes 32 P 14.28 d

β

β

LQ

131

8.05 d

β

β, γ

LQ

198

2.7 d

β

β, γ

LQ, seeds

222

3.83 d

α

α, β, γ

GSS, seeds

I Au Ra

Γ

mCi−1

2

13.07 –

−1

)

HVL (mm Pb) 11.9 –

Clinical Application RA, gyn, H/N RE, mets

IC (peritoneal)

Where a number is given, the units are in million electron volts. An overlined particle, γ or x , indicates that the energy given is an average energy. α, Alpha decay; β, beta decay; EC, electron capture; γ, gamma emission; GSS, glass-sealed source; gyn, gynecological; H/N, head and neck; HVL, half-value layer; IC, intracavitary; IS, interstitial; LQ, liquid pharmaceutical; LQ-MS, liquid microspheres; mets, metastatic; OR, taken orally; RA, remote afterloading; RE, radioembolization; SSS, solid-sealed source. a

are presented in Figs. 6.64 to 6.71 and web-only eFigs. 6.1 and 6.2, available on the Expert Consult website. It is observed that the nuclear configurations and transitions for these isotopes are simple for some and complex for others. For instance, 60Co decays by β− decay to 60Ni, which de-excites by the emission of two gamma rays, one at 1.17 MeV and one at 1.33 MeV (see Fig. 6.64). 125I decays by electron capture to 125 Te, with the emission of one gamma ray (35 keV) and two characteristic x-rays (27.3 keV, 31.4 keV; see Fig. 6.67). After decay, the resulting daughter nucleus itself may be radioactive, resulting in an additional decay or decays. The decay chain for 226Ra has nine decays (and daughters) until stable 206Pb is reached (see eFig. 6.2).

Source Strength Source strength, that is, the amount of radiation or dose given off per unit time, is an important physical and clinical parameter because dose rate must be known to enable a prescribed dose to be delivered. Source strength has been specified as the amount of milligrams of 226Ra (mg-Ra), the equivalent amount of milligrams of 226Ra (mg-Ra eq, for 226Ra substitutes such as 137Cs or 192Ir), the actual activity encapsulated, the apparent activity, and the exposure rate at a distance. These historical representations of activity have been replaced by the current day recommended source strength specification of air kerma strength120 (SK) with

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CHAPTER 6 100 80 60 40 20

100 80 60 40 20

141

Radiation Oncology Physics

103 Pd 46

0.093 MeV

20 40 60 80100

20 40 60 80100

T1/2 = 17 days

EC

10%

90%

0.040 MeV IC

Method of production: 103Pd

102Pd(n,γ)

A

B

103 Rh 45

0 MeV

100 80 60 40 20

100 80 60 40 20 20 40 60 80100

20 40 60 80100

Emitted radiation

Energy (MeV)

Mean number per disintegration

γ ray (Rhenium-103 γ rays)

0.0397

0.001

γ ray (Rhenium-103 γ rays)

0.357

0.001

x-ray, Kα (EC and IC)

0.201

0.656

x-ray, Kβ (EC and IC)

0.230

0.125

Fig. 6.65 A Pd decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.) 103

C

D

Fig. 6.63 Brachytherapy source anisotropy. (A) Relative dose rate using a 2-cm radius, 226Ra tube, and 1.35 active length. (B) Relative in-air fluence for 192Ir seed. (C) Relative in-air fluence for 125I seed, model 6711. (D) Relative in-air fluence for 103Pd. (A, Data from Johns HE, Cunningham JR. The Physics of Radiology. 3rd ed. Springfield, IL: Charles C Thomas; 1978. B to D, Data from Interstitial Collaborative Working Group. Interstitial Brachytherapy: Physical, Biological, and Clinical Considerations. New York, NY: Raven Press; 1990.)

137 Cs 55

T1/2 = 30 yr 1.18 MeV β2(93.5%) 0.66 MeV

Method of production: Fission byproduct

β1(6.5%) γ 137 Ba 56

T1/2 = 5.26 yrs

60 Co 27

β1

(99!%)

β2(.013%) 0 MeV

γ

1

2.16 MeV

γ

β3(.12%)

Method of production: 59Co(n,γ) 60Co

2.82 MeV 2.51 MeV 3

γ

2

1.33 MeV γ

4

60 Ni 28

Emitted radiation

Energy (MeV)

Mean number per disintegration

γ ray (Barium-137 γ rays)

0.662

0.85

Fig. 6.66 A Cs decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.) 137

0 MeV

Emitted radiation

Energy (MeV)

Mean number per disintegration

γ ray (Nickel-60 γ rays)

1.173

0.998

γ ray (Nickel-60 γ rays)

1.332

1.0

Fig. 6.64 A Co decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.) 60

units of μGy/m2/h. SK is based on the air kerma rate in free space, K1, which gives the kerma rate in air in micrograys per hour at a fixed distance from the source, measured radially from a point source or along the perpendicular bisector for a linear source. Kerma equals dose with less than 1% difference for brachytherapy photon energies; thus, K1 essentially gives the dose rate in air at the reference distance. Although air kerma strength is adopted as a standard, multiple specifications for source strength are still in use by source manufacturers and treatment planning systems. The same convention of source strength must be

0 MeV

125 I 53

T1/2 = 60.2 days

EC 0.035 MeV

γ

0 MeV

Method of production: 125 Te 52

124Xe(n,γ)

125Xe

EC

125I

Mean number per disintegration

Emitted radiation

Energy (MeV)

x-ray, Kα (EC and IC)

0.0273

x-ray, Kβ (EC and IC)

0.0314

1.126 (0.576 ! 0.540) 0.240 (0.124 ! 0.116)

γ ray (Tellurium-125 γ rays)

0.0355

0.068

γ ray (Tellurium-125 γ rays)

Average of !0.0285 (28.5 keV)

Average of !1.47

Fig. 6.67 A 125I decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.)

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142

SECTION I

0.546 MeV

90 Sr 38

Scientific Foundations of Radiation Oncology

131 I 53

T1/2 = 28.1 yr β

0 MeV

90 Y 39

T1/2 = 64hr

2.27 MeV

0 MeV

Emitted radiation

Energy (MeV)

β! (Strontium-90 βs)

0.546 max

1.0

2.268 max, 0.90 average

1.0

Fig. 6.68 A 90Sr decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.)

1.71 MeV

32 P 15

T1/2 =14.3 days β 32 S 16

0 MeV

Energy (MeV)

5 11 8

0.637 MeV

7 3

0.405 MeV 0.364 MeV 0.341 MeV 0.164 MeV 0.080 MeV

6

Method of production: Fission byproduct

β5(.8%)

4

9

2

12 10 1

0 MeV

131 Xe 54

Emitted radiation

Energy (MeV)

Mean number per disintegration

γ rays (Xenon-131 γ rays)

0.080

0.026

γ rays (Xenon-131 γ rays)

0.284

0.054

γ rays (Xenon-131 γ rays)

0.364

0.820

γ rays (Xenon-131 γ rays)

0.637

0.068

γ rays (Xenon-131 γ rays)

0.732

0.016

Fig. 6.70 A I decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.) 131

Method of production: 31P(n,γ) 32P 31S(n,p) 32P

Emitted radiation

0.667 MeV

13 14

β4(89.8%)

Mean number per disintegration

β! (Yttrium-90 βs)

β3(6.64%)

γ 90 Zr 40

0.723 MeV

β2(.67%) 1.75 MeV

β1(99.8%)

0.970 MeV

β1(2%)

β2(0.02%) Method of production: Fission byproduct

T1/2 = 8.06 days

Mean number per disintegration

β!(Phosphorus-32 βs) 1.710 max, 0.70 average

198 Au 79

T1/2 = 2.7 days

1.0

1.3710 MeV

β1(!1%)

Fig. 6.69 A 32P decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.)

1.0875 MeV β2(!99%)

γ

γ

3

Method of production: 197Au(n,γ) 198Au

β3

(!.025%)

2

γ

0.4117 MeV 198 Hg 79

used for the radiation source and the planning system to ensure correct computations of dose rate and dose. Additional guidance is available on source strength specification and other brachytherapy planning issues.120-122

Emitted radiation

Energy (MeV)

Brachytherapy Applicators and Afterloading

β! (Gold-198 βs)

0.962 max, 0.30 average

1.0

0.4117

0.95

When first used in the early 1900s, brachytherapy sources were directly implanted into the patient for interstitial or intracavitary treatment. To reduce personnel doses and allow greater flexibility in determining source configurations without having to handle “hot” sources, a technique called afterloading was developed in the 1950s, first for intracavitary treatments and later for interstitial applications. With afterloading, the source configuration is determined using nonradioactive “dummy” sources and the actual sources are efficiently loaded at a later time. Afterloading techniques require the use of specialized source applicators to position the dummy sources and allow accurate (re)placement of actual sources. A variety of applicators and techniques have been developed to facilitate implantation of the isotopes shown in Table 6.14. These are reviewed in a later chapter and elsewhere.123,124 Preplanning can be used in brachytherapy to optimize the source locations and activities. For implantation, physical templates may help

1

γ ray (Mercury-198 γ rays)

0 MeV

Mean number per disintegration

Fig. 6.71 A Au decay scheme. (Data from Lederer CM, Hollander JM, Perlman I. Table of Isotopes. 6th ed. New York, NY: Wiley & Sons; 1967.) 198

maintain the intended source geometry and are recommended when possible. Once the applicators are in place, adjustments to the implant geometry are limited to number of sources per applicator, spacing, and activity. Dummy sources are loaded, and each source location is determined by obtaining orthogonal images. These images are best obtained for an applicator(s) that matches the imaging device. Applicators exist that are compatible with either a conventional radiographic/

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CHAPTER 6 fluoroscopic simulator, a CT simulator, or (more recently) an MR simulator. A magnification indicator may be needed depending on the imaging method. On the images, each source location and anatomic and dosimetry points of interest are identified and digitized. Planning determines the position, activity, and insertion time for each source based on the chosen point of prescription. A plan is represented by isodose distributions that show dose rate (typically, Gy/h).

Brachytherapy Treatment Planning Planning for brachytherapy treatments initially was nonexistent. Beginning in the 1920s, various systems were developed that provided rules and guidelines for implantation geometries and specifications for prescription. Initially, 226Ra was the only radionuclide used for brachytherapy because of its natural abundance; systems were developed that were specific to 226Ra source configurations of needles and tubes. Other radionuclides for brachytherapy became available in the 1950s through neutron activation in a nuclear reactor or as by-product material. The radium systems were modified for the physical characteristics of these nuclear-age radionuclides.

Gynecological Implants Three systems using different applicators, source strengths, and treatment times were developed for intracavitary implants of the cervix and uterus.123 The first two, the Paris and Swedish systems, were modified and became known as the Manchester system, the most widely used brachytherapy system. Four points of interest of the Manchester system are anatomically defined here (Fig. 6.72): 1. Point A is 2 cm superior to the external cervical os and 2 cm lateral to midline. Point A is specified on the right and left and indicates the location where nominally the uterine vessels and ureters cross. 2. Point B is 2 cm superior to the external cervical os and 5 cm lateral to midline. Point B is specified on the right and left and indicates the presumed location of the obturator lymph nodes. 3. A radiographically defined point indicates the dose of relevance to the bladder. 4. A radiographically defined point indicates the dose of relevance to the rectum. The Manchester system prescribes dose to point A using a dose rate of 55.5 R/h, delivering 8000 R in 144 hours in two 3-day sessions over 2 weeks. Point B gives an indication of peripheral dose at the obturator nodes, and the bladder and rectum points indicate the dose at these dose-limiting structures. The classic gynecological implant uses three 2-cm sources in a line, or tandem, in the uterus and two 2-cm sources, one on either side of the cervix, as shown in Fig. 6.73. With activities

Radiation Oncology Physics

of 15, 10, and 10 mg (of 226Ra, or mg-Ra eq of 137Cs) in tandem and 15 mg each in the lateral vaginal fornices, for a total of 65 mg-Ra eq, a well-known pear-shaped dose distribution results (Fig. 6.73). Variations to the Manchester system are readily apparent. Implant duration and dose, number of sources, source activity (dose rate), source geometry, applicator design, number of implants, and primary versus boost treatment can all be varied. Gynecological implant approaches have been reviewed and Points A and B remain relevant anatomic locations for gynecological implants, even when now performed almost exclusively with HDR (see later discussion).123-125

Interstitial Implants Classic approaches to interstitial implants developed particular geometries for placement of radioactive needles, based on target shape and size, which would result in clinically acceptable dose distributions. The Manchester system of implantation rules and dose prescription, also called the Paterson-Parker system after its authors,126,127 formed the basis for interstitial implant approaches and was originally developed for 226Ra needles. This system specifies source distribution rules for planar and volume implants. The system is based on the concept of using a relatively uniform distribution of sources having differing linear activities to deliver a dose distribution with a homogeneity of ±10%

15 mg

10 mg

40

60

80 10 mg

20

5 cm

A

5 cm 10 mg

10 mg 2 cm 2 cm

AR

15 mg

15 mg

Anterior view

Uterus

BR

143

AL

15 mg 80

BL

15 mg

60 40

B

Vaginal fornix Cervical os Fig. 6.72 Gynecological Anatomy and Definitions for Points A and B.

20 Fig. 6.73 Typical gynecological implant. (A) Coronal plane. (B) Sagittal plane. Source arrangement coincides with anatomy shown in Fig. 6.72. Isodose values are in units of centigrays per hour.

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of prescription. Rules include the distribution of activity, that is, the percentage of activity to load in the implant center versus the periphery; for planar targets; and cylindrical, spherical, and cubical implant volumes. A fixed source spacing of 1 cm is specified. The Quimby system was developed in the United States based on the concept of using a uniform distribution of sources of the same linear activity throughout the implant volume (226Ra needles were available in the United States with constant linear activity). Source spacing is uniform, with 1- to 2-cm source intervals. The modern Paris system is based on the use of 192Ir wire. Sources are arranged in parallel fashion in planes, the linear activity is constant for all sources, and source spacing is uniform.128 Target coverage is specified as an isodose surface that encompasses the target volume relative to a reference point at the implant center. An example of a single-plane implant is shown in Fig. 6.74. Combinations of implant planes enable an entire target volume to be treated to a particular dose surface. Table 6.15 summarizes some of the rules for the Manchester,

30

20 40

60

60 40 30 20

A

High-Dose-Rate Remote Afterloading HDR remote afterloading devices use a single, large activity (10 Ci, 192Ir) source that is stored in a shielded container within the base of the unit and then inserted into implanted applicators or catheters under remote control from outside the treatment room130-132 (Fig. 6.75). The source position is known continuously and can be moved to various locations within an implanted applicator to build a desired dose distribution. The amount of dwell time in one location determines the amount of dose delivered. Multiple catheters or applicator connections are possible to enable an entire implant volume to be treated with a single source in step-by-step fashion. Almost all intracavitary and interstitial implants just described have been replicated using HDR techniques. Primary implant sites are breast, gynecological, and prostate130-132 (Fig. 6.76). In a novel technique, local, partial breast irradiation is delivered to the breast, using a balloon catheter that positions the HDR source in one or more dwell positions within the postlumpectomy surgical cavity (see Fig. 6.76A). HDR advantages include shorter overall treatment times, opportunities for fractionated treatment, advanced imaging techniques for improved treatment planning, improved treatment planning by customization of the 192Ir source dwell times, and reduced radiation exposure to the implant team. Radiation safety considerations are important for HDR treatment because of the HDR of the source. Pre- and post-HDR radiation room surveys must be conducted to ensure proper source storage and radiation-safe conditions for both the patient and personnel.130-132 Computerized systems now provide customized planning for all brachytherapy treatments, including image-based planning, tools for automated source localization, and fast optimization of the dose distribution. HDR planning systems, in particular, provide optimization schemes to determine source dwell times to provide a desired 3D dose distribution. A planning system must use the source strength convention for the source being applied (i.e., apparent activity or air kerma strength) and must account for radial and axial anisotropies in the dose distribution,133 such as the anisotropies shown previously (see Fig. 6.63).

Dose Specification

B

Fig. 6.74 Single-plane interstitial implant. (A) Source plane. (B) Plane orthogonal to the source plane. Isodose values are in centigrays per hour. (Data from Interstitial Collaborative Working Group. Interstitial Brachytherapy: Physical, Biological, and Clinical Considerations. New York, NY: Raven Press; 1990.)

TABLE 6.15

Quimby, and Paris systems. More complete reviews are available and required for complete details for each system.128,129

An implant system specifies dose or dose rate at a point or points (e.g., point A) or possibly to a plane or volume of interest that contains the implant. The ICRU has recommended that dose be reported to a reference volume and points of interest for gynecological implants and for mean central and peripheral dose for interstitial implants.134,135 The

Classic Brachytherapy Approaches: The Manchester, Quimby, and Paris Systems System

Parameter

Manchester

Quimby

Paris

Dose

6000-8000 R

5000-6000 R

6000-7000 R

Dose rate

40-60 R/h

60-70 R/h

25-90 cGy/h

Prescription point

10% above absolute minimum

On bisector (planar) or periphery (volume)

85% of minimum central dose

Linear activity

Variable

Constant

Constant

Activity Distribution Single plane

Varies with area

Uniform

Uniform Multiple, uniform planes

Volume implant

Varies with shape

Uniform

Source spacing

Constant at 1 cm

Constant, 1-2 cm

Constant, 0.5-2.0 cm

Crossing needles

Yes

Yes

No

Adapted from Glasgow GP, Perez CA: Physics of brachytherapy. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 2nd ed. Philadelphia, PA: J. B. Lippincott; 1987:213-251.

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CHAPTER 6

Radiation Oncology Physics

145

B

A

Fig. 6.75 High-dose-rate (HDR) remote afterloading. (A) Multiport 192Ir remote afterloading device with integrated source shield and head for source path selection. (B) Integrated HDR brachytherapy procedures suite. (Courtesy Nucletron, an Elekta Company, Elekta AB, Stockholm, Sweden.)

A

B

C

D

Fig. 6.76 Brachytherapy applicators. (A) Breast high-dose-rate (HDR) balloon catheter, postlumpectomy. (B) HDR tandem and ovoids. (C) Kuske interstitial breast template. (D) HDR prostate. (Courtesy Nucletron, an Elekta Company, Elekta AB, Stockholm, Sweden.)

recommendations are similar to the ICRU’s specification of volumes for use in external beam therapy in ICRU 50 and ICRU 62,42,43 and it is recommended that ICRU’s nomenclature be used in clinical practice.136

Other Brachytherapy Techniques Brachytherapy applications also include episcleral plaques for ocular melanoma using 125I seeds, biliary stent implantation with 192Ir, ultrasound-guided prostate brachytherapy using 103Pd or 125I, and once-popular procedures such as endovascular brachytherapy (90Sr, 192Ir, and other nuclides), and treatment of pterygium (90Sr).122,137 Development of new radionuclides for specific applications continues, particularly for liquid forms of radionuclides, such as colloidal 90Y in glass or resin microspheres for treatment of liver metastases via radioembolization. Another example of novel isotope development is the use of alpha emitters with unique ligands carried to particular cellular locations by targeted molecules such as monoclonal antibodies (-mabs) or small molecule inhibitors (-ibs).

RADIATION PROTECTION Radiation protection practices are important in the radiation oncology clinic to safeguard the patient, radiation oncology personnel, ancillary staff, and the general public. Recommendations by international bodies are enacted into law and serve as dose limits for occupationally exposed individuals and the general public.138 The dose-related quantity of interest for radiation protection purposes is called the dose equivalent, H: H = D × QF.

Eq. 43

In the equation, H is the dose equivalent (in sieverts [Sv], with units of J/kg), D is the dose received (in Grays, with units of J/kg), and QF is the quality factor (unitless) of the exposing radiation. The quality factor indicates the biological effect of the radiation type, relative to x-rays, and varies with linear energy transfer. High

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Scientific Foundations of Radiation Oncology

linear energy transfer radiations, such as particle radiations, have a high-quality factor (Table 6.16). The units of the sievert are still joules per kilogram, as for the Gray; however, the meaning of the sievert is different than that of the Gray. Given photon and fast neutron exposures of 1 Gy each, the dose equivalent (meaning the biological effect) for each is different: the photons deliver 1 Sv; the fast neutrons deliver 20 Sv. Exposure limits for occupational exposure and the general public are given in Table 6.17. A safety factor of 10 is applied to the general public limits compared with the occupational limits for whole-body exposures. However, for annual whole-body exposures, the general public is limited to 1/20 the occupational limit if exposure is frequent. This lower limit (0.1 rem or 0.001 Sv) is the regulatory limit for exposure of the general public in the United States. Exposure limits for occupational radiation protection are based on laboratory studies and observed effects for irradiated human populations and are believed to give equivalent risk as in other safe occupations. Radiation protection principles are based on three factors: time, distance, and shielding. To reduce any dose, minimize the time of exposure, maximize the distance away from the sources, and maximize the shielding between the sources and the point of exposure. The degree to which each of these principles is exercised for a particular exposure scenario depends on the type of radiation source; its physical properties, such as energy, intensity, collimation, and beam orientation; the presence of barriers; distances to points of interest; potential time of exposure; and category of individual exposed (occupational or general public). Common protection practices in radiation oncology include the use of heavily shielded vaults for protection of LINAC operators and the public, administrative controls that limit access to radiation sources, physical barriers to room entry during exposure, interlocks that prevent irradiation during unsafe conditions, use of long-handled tools when

TABLE 6.16

Protection

Quality Factors for Radiation

Radiation

Quality Factor

X-rays, gamma rays, and electrons Thermal neutrons

5

Neutrons and heavy particles

TABLE 6.17

1 20

handling brachytherapy sources, afterloading equipment such as source applicators and dummy sources to negate the need to load sources “hot,” remote afterloading devices operated under remote control, the use of lead aprons and shielded control consoles during radiographic or fluoroscopic procedures, and assessment of fetal dose for patients or occupationally exposed personnel. A body of literature addresses specific situations that may be encountered.138-140 Even though radiation protection exposure limits exist, in general, radiation protection philosophy incorporates the ALARA principle: as low as readily achievable. This philosophy holds that although dose rates may be within the legal (acceptable) limits given previously, all exposures should be reduced as much as possible given practical constraints of money, time, and human and material resources. Examples of ALARA in practice might be the relocation of clerical personnel away from a radiation source storage area, developing a more efficient method for source handling in a busy brachytherapy practice, or the addition of another HVL of shielding to a LINAC room ceiling during a time of renovations to further reduce doses to an upstairs pediatric playroom. Ownership, use, receipt, and transfer of radiation sources are governed by national or state laws and are authorized or licensed under the supervision of institutional committees and state and national regulatory agencies. The Nuclear Regulatory Commission (NRC) regulates radioactive materials only (e.g., 60Co, 137Cs), and its laws are published in the Code of Federal Register and in regulatory guidance documents.141,142 These rules apply to all states and US territories. However, the NRC does not regulate electronically produced radiation sources (x-ray tubes and LINACs). Some states have agreed to implement the NRC rules as part of their state radiation control program; these states are called agreement states. Radiation users in agreement states are inspected by the state, not the NRC. Radiation users in nonagreement states are inspected directly by the NRC for their radioactive materials. Nonagreement states may have their own state radiation control programs for electronically produced radiation sources. About 75% of US states are agreement states; the remaining 25% are nonagreement states. Other regulatory agencies with radiation-related regulations include the US Department of Transportation, the US Environmental Protection Agency, and possibly other state or local agencies. General provisions for radiation sources are specified in a license that is granted to an individual or institution by the appropriate regulatory authority. Radiation source licenses cover a variety of classes of sources and generally require adequate administrative controls by the

Exposure Limits for Radiation Protection

Exposed Region or Site Annual Exposure Limits Whole body; head and trunk; active blood-forming organs; lens of eyes; gonads

Occupational (mSv) 50

General Public (mSv) 1 (frequent exposure) 5 (infrequent exposure)

Hands and forearms; feet and ankles

750

75

Skin of whole body

300

30

Additional Exposure Limits Nonoccupational areas: < 0.02 mSv/h (0.02 mSv/h ≈ 50 mSv/y if exposed year round) < 1 mSv/wk (≈ 0.006 mSv/h for continuous exposure) Fetal dose: < 5 mSv during the gestation period Mortality Risk Population risk from exposure: risk is approximately 2.5 × 10−2 deaths/person/Sv or 2.5 × 10−4 deaths/person/cSv. There are approximately 2.5 deaths if 10,000 people receive 0.01 Sv (1 cSv) each.

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CHAPTER 6 user. For instance, academic institutions with medical and research uses of radiation sources must have a radiation safety program that specifies items such as educational and experience requirements for users, radiation control procedures, and the administrative chain. Institutional radiation safety programs include a radiation safety committee for oversight and a radiation safety officer for implementation of policy. Recent events in the United States in which patients were injured or died as a result of overdoses from both radiological imaging and treatment procedures143 have highlighted the need for continued vigilance for radiation safety for patients. The issues relate to the computercontrolled automation of imaging and treatment procedures and the understanding of operators and radiological professionals regarding radiation dose and other performance aspects for the equipment being used. In unfortunate incidents, the imaging or treatment devices were operated with unknown and incorrect parameters or with a partial malfunction that still enabled radiation delivery. In the United States, additional state and national laws or recommendations have been formulated for required quality assurance procedures, operator training, and other aspects. Importantly, besides errors in radiological procedures, the National Council on Radiation Protection and Measurements has expressed great concern (NCRP Report 160)144 about the average collective effective dose in the United States. There has been approximately a twofold increase in the average yearly collective effective dose, from 3.6 to 6.2 mSv over about a 15-year period from 1982 to 2006, owing to a large increase in the amount of dose from radiological medical imaging, mainly CT, and followed by nuclear medicine imaging. Clearly, the radiological community must be cognizant of the ionizing radiation dose being delivered by both imaging and treatment procedures to ensure that no dose is given without an intended benefit.

QUALITY ASSURANCE Radiation machines and sources, beam modifiers, measurement instrumentation, and treatment planning computers must be regularly verified for proper operation and characteristics to ensure quality and consistency of dose. A basic quality assurance program for dose-related items entails daily, weekly, monthly, and annual tests with satisfactory results within specified tolerances. Recommendations and standards for quality assurance exist for machines, sources, instrumentation, and treatment planning computers.40,145-147 References also are available on the general quality assurance process.148-150 An important consensus report was recently published by the American Association of Physicists in Medicine on a risk analysis approach to ensuring quality assurance for radiation treatment. The report gives recommendations on assessing the magnitude and probability of errors that could occur for radiation treatment.151 STOP Dose verification by an independent, accredited radiological physics center is a desirable service and is required for participation in many cooperative protocol groups. The age of computerized and automated radiation treatment planning, delivery, and verification presents new challenges for quality assurance of treatment. Treatment processes may now be wholly contained within commercially provided “black boxes” of computer software and automated, hybrid image-guided treatment machines such that important quality assurance tests must be appropriately designed and performed to provide meaningful results that are readily interpreted. The radiation imaging and treatment errors mentioned previously are examples of the “black box” syndrome and failed quality assurance procedures, with a majority attributed to human error and not device or software failures. The implication is that high-technology approaches to quality assurance are also needed with redundant methods for ensuring and proving the correct delivery of treatment. Quality assurance and safety in hightechnology radiotherapy remain high priorities for those individuals

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who are prescribing, delivering, and ensuring quality for the benefit of radiation treatment patients.

CRITICAL REFERENCES 12. Karzmark CJ, Morton RJ. A Primer on Theory and Operation of Linear Accelerators in Radiation Therapy. 2nd ed. Madison, WI: Medical Physics Publishing; 1998. 14. Mackie TR. History of tomotherapy. Phys Med Biol. 2006;51:R427–R453. 20. Smith AR. Vision 20/20: proton therapy. Med Phys. 2009;36:556–568. 21. Johns HE, Cunningham JR. The Physics of Radiology. 3rd ed. Springfield, IL: Charles C Thomas; 1978. 22. Khan F. The Physics of Radiation Therapy. 3rd ed. Baltimore: Williams & Wilkins; 2003. 24. Almond PR, Biggs PJ, Coursey BM, et al. AAPM’s TG-51 protocol for clinical reference dosimetry of high-energy photon and electron beams. Med Phys. 1999;26:1847. 34. Sherouse GW, Bourland JD, Reynolds K, et al. Virtual simulation in the clinical setting. Some practical considerations. Int J Radiat Oncol Biol Phys. 1990;19:1059. 38. Keall P. 4-Dimensional computed tomography imaging and treatment planning. Semin Radiat Oncol. 2004;14:81–90. 42. ICRU. Report 50: Prescribing, Recording, and Reporting Photon Beam Therapy. Washington, DC: International Commission on Radiation Units and Measurements; 1993. 43. ICRU. Report 62: Prescribing, Recording, and Reporting Photon Beam Therapy (Supplement to ICRU 50). Washington, DC: International Commission on Radiation Units and Measurements; 1999. 54. Webb S. The Physics of Three-Dimensional Radiation Therapy: Conformal Radiotherapy, Radiosurgery and Treatment Planning, Medical Science Series. Bristol, UK: IOP Publishing; 1993. 55. Mackie TR, Liu HH, McCullough EC. Treatment planning algorithms: Model-based photon dose calculation algorithms. In: Khan FM, Potish RA, eds. Treatment Planning in Radiation Oncology. Baltimore: Williams & Wilkins; 1998:90–112. 56. Hogstrom KR, Steadham RE. Electron beam dose computation. In: Mackie TR, Palta JR, eds. Teletherapy: Present and Future. Madison, WI: Advanced Medical Publishing; 1996:137–174. 57. Chetty I, Curran B, Cygler JA, et al. Report of the AAPM Task Group No. 105. Issues associated with clinical implementation of Monte Carlo–based photon and electron external beam treatment planning. Med Phys. 2007;34(12):4818–4853. 60. Drzymala RE, Mohan R, Brewster L, et al. Dose-volume histograms. Int J Radiat Oncol Biol Phys. 1991;21:71. 64. Herman MG, Balter JM, Jaffray DA, et al. Clinical use of electronic portal imaging. Report of AAPM Radiation Therapy Committee Task Group 58. Med Phys. 2001;28:712–737. 67. Orton CG, Bortfeld TR, Niemierko A, et al. The role of medical physicists and the AAPM in the development of treatment planning and optimization. Med Phys. 2008;35:4911–4923. 69. Bourland JD, McCollough KP. Static field conformal stereotactic radiosurgery. Physical techniques. Int J Radiat Oncol Biol Phys. 1994;28:471. 72. Carol MP. PEACOCK. A system for planning and rotational delivery of intensity-modulated fields. Int J Imag Syst Tech. 1995;6:56. 75. Yu CX, Amies CJ, Svatos M. Planning and delivery of intensity-modulated radiation therapy. Med Phys. 2008;35:5233–5241. 76. Ezzell GA, Galvin JM, Low D, et al. Guidance document on delivery, treatment planning, and clinical implementation of IMRT. Report of the IMRT subcommittee of the AAPM radiation therapy committee. Med Phys. 2003;30:2089–2115. 77. Ezzell GA, Burmeister JW, Dogan N, et al. IMRT commissioning. Multiple institution planning and dosimetry comparisons. A report from AAPM Task Group 119. Med Phys. 2009;36:5359–5373. 79. Hendee WR, Bourland JD. Image-guided intervention. Acad Radiol. 2003;10:896. 81. Dawson LA, Jaffray DA. Advances in image-guided radiation therapy. J Clin Oncol. 2007;25:938–946.

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148

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82. Bourland JD. Image-guided radiation treatment. In: Wolbarst AB, Mossman KL, Hendee WR, eds. Advances in Medical Physics—2008. Madison, WI: Medical Physics Publishing; 2008:179–192. 83. Murphy MJ, Balter J, Balter S, et al. The management of imaging dose during image-guided radiotherapy. Report of the AAPM Task Group 75. Med Phys. 2007;34:4041–4063. 84. Keall PJ, Mageras GS, Balter JM, et al. The management of respiratory motion in radiation oncology. Report of AAPM Task Group 76. Med Phys. 2006;33:3874–3900. 88. Munley MT, McGee KP, Kirov AS, et al. An introduction to molecular imaging in radiation oncology: a report by the AAPM Working Group on Molecular Imaging in Radiation Oncology (WGMIR). Med Phys. 2013;40(10):101501. 89. Pirzkall A, McKnight TR, Graves EE, et al. MR-spectroscopy guided target delineation for high-grade gliomas. Int J Radiat Oncol Biol Phys. 2001;50:915. 92. Pan T, Mawlawi O. PET/CT in radiation oncology. Med Phys. 2008;35:4955–4966. 94. Fallone BG, Murray B, Rathee S, et al. First MR images obtained during megavoltage photon irradiation from a prototype integrated linac-MR system. Med Phys. 2009;36:2084–2088. 99. Goetsch SJ. Stereotactic radiosurgery using the Gamma Knife. In: Mackie TR, Palta JR, eds. Teletherapy: Present and Future. Madison, WI: Advanced Medical Publishing; 1996:611–642. 100. Lindquist C, Paddick I. The Leksell Gamma Knife Perfexion and comparisons with its predecessors. Neurosurgery. 2007;61(3 suppl):130–140, discussion 140–141. 102. American Association of Physicists in Medicine Task Group 178. Gamma stereotactic radiosurgery dosimetry and quality assurance. 2008–present. 103. Lutz W, Winston KR, Maleki N. A system for stereotactic radiosurgery with a linear accelerator. Int J Radiat Oncol Biol Phys. 1988;14:373. 104. AAPM RTC Task Group 42. Report 54: Stereotactic Radiosurgery. College Park, MD: American Association of Physicists in Medicine; 1995. 106. Podgorsak EB, Pike GB, Olivier A, et al. Radiosurgery with high-energy photon beams. A comparison among techniques. Int J Radiat Oncol Biol Phys. 1989;16:857. 109. Chang BK, Timmerman RD. Stereotactic body radiation therapy. A comprehensive review. Am J Clin Oncol. 2007;30:637–644. 110. Benedict SH, Bova FJ, Clark B, et al. The role of medical physicists in developing stereotactic radiosurgery. Med Phys. 2008;35:4262–4277. 112. Adler JR, Cox RS. Preliminary clinical experience with the cyberknife: Image-guided stereotactic radiosurgery. In: Kondzi-olka D, ed. Radiosurgery—1995. Basel: Karger; 1996:316–326.

114. Timmerman RD, Forster KM, Chinsoo Cho L. Extracranial stereotactic radiation delivery. Semin Radiat Oncol. 2005;15:202–207. 121. Hanson WF. Brachytherapy source strength: quantities, units, and standards. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:71–85. 132. Kubo HD, Glasgow GP, Pethel TD, et al. High dose-rate brachytherapy treatment delivery. Report of the AAPM Radiation Therapy Committee Task Group No. 59. Med Phys. 1998;25:375–403. 135. ICRU. Report 58: Dose and Volume Specification for Reporting Interstitial Therapy. Washington, DC: International Commission on Radiation Units and Measurements; 1997. 139. NCRP. Report 147: Structural Shielding Design for Medical X-Ray Imaging Facilities. Bethesda, MD: National Council on Radiation Protection and Measurements; 2004. 140. NCRP. Report 151: Structural Shielding Design and Evaluation for Megavoltage X- and Gamma-Ray Radiotherapy Facilities. Bethesda, MD: National Council on Radiation Protection and Measurements; 2005. 143. Bogdanich W. The radiation boom—radiation offers new cures, and ways to do harm, The New York Times, 2010. 144. NCRP. Report 160: Ionizing Radiation Exposure of the Population of the United States. Bethesda, MD: National Council on Radiation Protection and Measurements; 2009. 146. Klein EE, Hanley J, Bayouth J, et al. Task Group 142 Report: Quality Assurance of Medical Accelerators. College Park, MD: American Association of Physicists in Medicine; 2009. 147. Mutic S, Palta JR, Butker EK, et al. AAPM Radiation Therapy Committee Task Group No. 66. Quality assurance for computed-tomography simulators and the computed-tomography-simulation process. Med Phys. 2003;30:2762–2792. 150. Williamson JF, Dunscombe PB, Sharpe MB, et al. Quality assurance needs for modern image-based radiotherapy. Recommendations from 2007 interorganizational symposium on quality assurance of radiation therapy: challenges of advanced technology. Int J Radiat Oncol Biol Phys. 2008;71(1 suppl):S2–S12. 151. Huq MS, Fraass BA, Dunscombe PB, et al. The report of Task Group 100 of the AAPM: application of risk analysis methods to radiation therapy quality management. Med Phys. 2016;43(7):4209. doi:10.1118/1.4947547.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 6

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148.e2

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57. Chetty I, Curran B, Cygler JA, et al. Report of the AAPM Task Group No. 105. Issues associated with clinical implementation of Monte Carlo–based photon and electron external beam treatment planning. Med Phys. 2007;34(12):4818–4853. 58. Gu X, Choi D, Men C, et al. GPU-based ultra-fast dose calculation using a finite size pencil beam model. Phys Med Biol. 2009;54:6287–6297. 59. Jia X, Gu X, Sempau J, et al. Development of a GPU-based Monte Carlo dose calculation code for coupled electron-photon transport. Phys Med Biol. 2010;55:3077–3086. 60. Drzymala RE, Mohan R, Brewster L, et al. Dose-volume histograms. Int J Radiat Oncol Biol Phys. 1991;21:71. 61. Gibbons JP, Antolak JA, Followill DS, et al. Monitor unit calculations for external photon and electron beams: report of the AAPM Therapy Physics Committee Task Group No. 71. Med Phys. 2014;41(3):031501. doi:10.1118/1.4864244. 62. Marks JD, Haus AG, Sutton GH. Localization error in the radiotherapy of Hodgkin’s disease and malignant lymphoma with extended mantle fields. Cancer. 1974;34:83. 63. Boyer A, Antonuk L, Fenster A, et al. A review of electronic portal imaging devices (EPIDs). Med Phys. 1992;19:1. 64. Herman MG, Balter JM, Jaffray DA, et al. Clinical use of electronic portal imaging. Report of AAPM Radiation Therapy Committee Task Group 58. Med Phys. 2001;28:712–737. 65. Hazle JD, Boyer AL, eds. Imaging in Radiation Therapy, American Association of Physicists in Medicine: Monograph No. 24. Madison, Wisconsin: Medical Physics Publishing; 1998. 66. Khan FM, Potish RA, eds. Treatment Planning in Radiation Oncology. Baltimore: Williams & Wilkins; 1998. 67. Orton CG, Bortfeld TR, Niemierko A, et al. The role of medical physicists and the AAPM in the development of treatment planning and optimization. Med Phys. 2008;35:4911–4923. 68. Schlegel W, Pastyr O, Bortfeld T, et al. Computer systems and mechanical tools for stereotactically guided conformation therapy with linear accelerator. Int J Radiat Oncol Biol Phys. 1992;24:781. 69. Bourland JD, McCollough KP. Static field conformal stereotactic radiosurgery. Physical techniques. Int J Radiat Oncol Biol Phys. 1994;28:471. 70. Serago CF, Lewin AA, Houdek PV, et al. Improved linac dose distributions for radiosurgery with elliptically shaped fields. Int J Radiat Oncol Biol Phys. 1991;21:1321. 71. Yu CX, Symons MJ, Du MN, et al. A method for implementing dynamic photon beam intensity modulation using independent jaws and a multileaf collimator. Phys Med Biol. 1995;40(5):769–787. 72. Carol MP. PEACOCK. A system for planning and rotational delivery of intensity-modulated fields. Int J Imag Syst Tech. 1995;6:56. 73. Spirou S, Chui C. Generation of arbitrary intensity profiles by dynamic jaws or multileaf collimators. Med Phys. 1994;21:1031. 74. Bortfeld T, Kahler D, Waldron T, et al. X-ray field compensation with multileaf collimators. Int J Radiat Oncol Biol Phys. 1994;28:723. 75. Yu CX, Amies CJ, Svatos M. Planning and delivery of intensitymodulated radiation therapy. Med Phys. 2008;35:5233–5241. 76. Ezzell GA, Galvin JM, Low D, et al. Guidance document on delivery, treatment planning, and clinical implementation of IMRT. Report of the IMRT subcommittee of the AAPM radiation therapy committee. Med Phys. 2003;30:2089–2115. 77. Ezzell GA, Burmeister JW, Dogan N, et al. IMRT commissioning. Multiple institution planning and dosimetry comparisons. A report from AAPM Task Group 119. Med Phys. 2009;36:5359–5373. 78. Yu CX, Tang G. Intensity-modulated arc therapy: principles, technologies, and clinical implementation. Phys Med Biol. 2011;56(5):R31–R34. 79. Hendee WR, Bourland JD. Image-guided intervention. Acad Radiol. 2003;10:896. 80. Carson PL, Giger M, Welch MJ, et al. Biomedical imaging research opportunities workshop. Report and recommendations. Radiology. 2003;229:328. 81. Dawson LA, Jaffray DA. Advances in image-guided radiation therapy. J Clin Oncol. 2007;25:938–946.

82. Bourland JD. Image-guided radiation treatment. In: Wolbarst AB, Mossman KL, Hendee WR, eds. Advances in Medical Physics—2008. Madison, WI: Medical Physics Publishing; 2008:179–192. 83. Murphy MJ, Balter J, Balter S, et al. The management of imaging dose during image-guided radiotherapy. Report of the AAPM Task Group 75. Med Phys. 2007;34:4041–4063. 84. Keall PJ, Mageras GS, Balter JM, et al. The management of respiratory motion in radiation oncology. Report of AAPM Task Group 76. Med Phys. 2006;33:3874–3900. 85. Balter JM, Wright JN, Newell LJ, et al. Accuracy of a wireless localization system for radiotherapy. Int J Radiat Oncol Biol Phys. 2005;61:933–937. 86. Litzenberg DW, Willoughby TR, Balter JM, et al. Positional stability of electromagnetic transponders used for prostate localization and continuous, real-time tracking. Int J Radiat Oncol Biol Phys. 2007;68:1199–1206. 87. Zhu X, Bourland JD, Yuan Y, et al. Tradeoffs of integrating real-time tracking into IGRT for prostate cancer treatment. Phys Med Biol. 2009;54:N393–N401. 88. Munley MT, McGee KP, Kirov AS, et al. An introduction to molecular imaging in radiation oncology: a report by the AAPM Working Group on Molecular Imaging in Radiation Oncology (WGMIR). Med Phys. 2013;40(10):101501. 89. Pirzkall A, McKnight TR, Graves EE, et al. MR-spectroscopy guided target delineation for high-grade gliomas. Int J Radiat Oncol Biol Phys. 2001;50:915. 90. Pirzkall A, Nelson SJ, McKnight TR, et al. Metabolic imaging of low grade gliomas with three dimensional magnetic resonance spectroscopy. Int J Radiat Oncol Biol Phys. 2002;53:1254. 91. Bourland JD, Shaw EG. The evolving role of biological imaging in stereotactic radiosurgery. Technol Cancer Res Treat. 2003;2:135. 92. Pan T, Mawlawi O. PET/CT in radiation oncology. Med Phys. 2008;35:4955–4966. 93. Bourland JD, Flowers KI, Huey KH, et al. Dedicated PET-CT and MR-simulators in a state-of-the-art radiation treatment facility [abstract]. Med Phys. 2006;33:2165. 94. Fallone BG, Murray B, Rathee S, et al. First MR images obtained during megavoltage photon irradiation from a prototype integrated linac-MR system. Med Phys. 2009;36:2084–2088. 95. Kirkby C, Stanescu T, Rathee S, et al. Patient dosimetry for hybrid MRI-radiotherapy systems. Med Phys. 2008;35:1019–1027. Erratum: Med Phys. 2009;36:1042. 96. Radiation Therapy Oncology Group. RTOG Protocol 90-05. Phase I Study of Small-Field Stereotactic External Beam Irradiation for the Treatment of Recurrent Primary Brain Tumors and CNS Metastases. Philadelphia: Radiation Therapy Oncology Group; 1990. 97. Leksell L. Stereotaxis and Radiosurgery: An Operative System. Springfield, IL: Charles C Thomas; 1971. 98. Walton L, Bomford CK, Ramsden D. The Sheffield stereotactic radiosurgery unit. Physical characteristics and principles of operation. Br J Radiol. 1987;60:897–906. 99. Goetsch SJ. Stereotactic radiosurgery using the Gamma Knife. In: Mackie TR, Palta JR, eds. Teletherapy: Present and Future. Madison, WI: Advanced Medical Publishing; 1996:611–642. 100. Lindquist C, Paddick I. The Leksell Gamma Knife Perfexion and comparisons with its predecessors. Neurosurgery. 2007;61(3 suppl):130– 140, discussion 140–141. 101. Goetsch SJ, Murphy BD, Schmidt R, et al. Physics of rotating gamma systems for stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 1999;43(3):689–696. 102. American Association of Physicists in Medicine Task Group 178. Gamma stereotactic radiosurgery dosimetry and quality assurance. 2008–present. 103. Lutz W, Winston KR, Maleki N. A system for stereotactic radiosurgery with a linear accelerator. Int J Radiat Oncol Biol Phys. 1988;14:373. 104. AAPM RTC Task Group 42. Report 54: Stereotactic Radiosurgery. College Park, MD: American Association of Physicists in Medicine; 1995. 105. Friedman WA, Bova FJ. The University of Florida radiosurgery system. Surg Neurol. 1989;32:334. 106. Podgorsak EB, Pike GB, Olivier A, et al. Radiosurgery with high-energy photon beams. A comparison among techniques. Int J Radiat Oncol Biol Phys. 1989;16:857.

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CHAPTER 6 107. Graham JD, Nahum AE, Brada M. A comparison of techniques for stereotactic radiotherapy by linear accelerator based on 3-dimensional dose distributions. Radiother Oncol. 1991;22:29. 108. Ruschin M, Nayebi N, Carlsson P, et al. Performance of a novel repositioning head frame for gamma knife Perfexion and image-guided linac-based intracranial stereotactic radiotherapy. Int J Radiat Oncol Biol Phys. 2010;78:306–313. 109. Chang BK, Timmerman RD. Stereotactic body radiation therapy. A comprehensive review. Am J Clin Oncol. 2007;30:637–644. 110. Benedict SH, Bova FJ, Clark B, et al. The role of medical physicists in developing stereotactic radiosurgery. Med Phys. 2008;35:4262–4277. 111. Jin JY, Yin FF, Tenn SE, et al. Use of the BrainLAB ExacTrac X-Ray 6D system in image-guided radiotherapy. Med Dosim. 2008;33:124–134. 112. Adler JR, Cox RS. Preliminary clinical experience with the cyberknife: Image-guided stereotactic radiosurgery. In: Kondzi-olka D, ed. Radiosurgery—1995. Basel: Karger; 1996:316–326. 113. Wu QJ, Bourland JD. Morphology-guided radiosurgery treatment planning and optimization for multiple isocenters. Med Phys. 1999;26:2151. 114. Timmerman RD, Forster KM, Chinsoo Cho L. Extracranial stereotactic radiation delivery. Semin Radiat Oncol. 2005;15:202–207. 115. Yin FF, Wang Z, Yoo S, et al. Integration of cone-beam CT in stereotactic body radiation therapy. Technol Cancer Res Treat. 2008;7(2):133–139. 116. AAPM RTC Task Group 29. Report 17: The Physical Aspects of Total and Half Body Photon Irradiation. College Park, MD: American Association of Physicists in Medicine; 1986. 117. AAPM RTC Task Group 30. Report 23: Total Skin Electron Therapy: Technique and Dosimetry. College Park, MD: American Association of Physicists in Medicine; 1987. 118. Williamson JF, Meigooni AS. Quantitative dosimetry methods in brachytherapy. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:87–133. 119. Weaver K. Dose calculation models in brachytherapy. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:135–147. 120. AAPM RTC Task Group 32. Report 21: Specification of Brachytherapy Source Strength. College Park, MD: American Association of Physicists in Medicine; 1987. 121. Hanson WF. Brachytherapy source strength: quantities, units, and standards. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:71–85. 122. Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995. 123. Glasgow GP, Perez CA. Physics of brachytherapy. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 2nd ed. Philadelphia: JB Lippincott; 1987:213–251. 124. Perez CA, Glasgow GP. Clinical applications of brachytherapy. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 2nd ed. Philadelphia: JB Lippincott; 1987:252–290. 125. Fletcher GH. Textbook of Radiotherapy. Philadelphia: Lea & Febiger; 1973. 126. Paterson R, Parker AM. A dosage system for gamma ray therapy. Br J Radiol. 1934;7:592. 127. Paterson R, Parker AM. A dosage system for interstitial radium therapy. Br J Radiol. 1938;11:252, 313. 128. Gillin MT, Albano KS, Erickson B. Classical systems II for planar and volume temporary interstitial implants: the Paris and other systems. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:323–342. 129. Anderson LL, Presser JL. Classical systems I for temporary interstitial implants: Manchester Quimby systems. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:301–321. 130. Glasgow GP, Bourland JD, Grigbsy PW, et al. American Association of Physicists in Medicine Report No. 41: Remote Afterloading Technology. New York: American Institute of Physics; 1993.

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131. Glasgow GP. Principles of remote afterloading devices. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:485–502. 132. Kubo HD, Glasgow GP, Pethel TD, et al. High dose-rate brachytherapy treatment delivery. Report of the AAPM Radiation Therapy Committee Task Group No. 59. Med Phys. 1998;25:375–403. 133. Meigooni AS, Williamson JF, Nath R. Single-source dosimetry for interstitial brachytherapy. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:209–233. 134. ICRU. Report 38: Dose and Volume Specification for Reporting Intracavitary Therapy in Gynecology. Washington, DC: International Commission on Radiation Units and Measurements; 1985. 135. ICRU. Report 58: Dose and Volume Specification for Reporting Interstitial Therapy. Washington, DC: International Commission on Radiation Units and Measurements; 1997. 136. Hanson WF, Graves M. ICRU recommendations on dose specification for brachytherapy. In: Williamson JF, Thomadsen BR, Nath R, eds. Brachytherapy Physics. Madison, WI: Medical Physics Publishing; 1995:361–378. 137. Interstitial Collaborative Working Group. Interstitial Brachytherapy: Physical, Biological, and Clinical Considerations. New York: Raven Press; 1990. 138. NCRP. Report 116: Limitation of Exposure to Ionizing Radiation. Bethesda, MD: National Council on Radiation Protection; 1993. 139. NCRP. Report 147: Structural Shielding Design for Medical X-Ray Imaging Facilities. Bethesda, MD: National Council on Radiation Protection and Measurements; 2004. 140. NCRP. Report 151: Structural Shielding Design and Evaluation for Megavoltage X- and Gamma-Ray Radiotherapy Facilities. Bethesda, MD: National Council on Radiation Protection and Measurements; 2005. 141. United States Nuclear Regulatory Commission. The Code of Federal Regulations, Title 10, Part 20 (10 CFR-20). Washington, DC: U.S. Nuclear Regulatory Commission; 1991 and subsequent updates. 142. United States Nuclear Regulatory Commission. Consolidated guidance about materials licenses—Program-Specific guidance about medical use licenses: Final report, NUREG 1556, vol 9, rev 2, 2008. 143. Bogdanich W. The radiation boom—radiation offers new cures, and ways to do harm, The New York Times, 2010. 144. NCRP. Report 160: Ionizing Radiation Exposure of the Population of the United States. Bethesda, MD: National Council on Radiation Protection and Measurements; 2009. 145. AAPM RTC Task Group 40. Report 46: Comprehensive Quality Assurance for Radiation Oncology. College Park, MD: American Association of Physicists in Medicine; 1994. 146. Klein EE, Hanley J, Bayouth J, et al. Task Group 142 Report: Quality Assurance of Medical Accelerators. College Park, MD: American Association of Physicists in Medicine; 2009. 147. Mutic S, Palta JR, Butker EK, et al. AAPM Radiation Therapy Committee Task Group No. 66. Quality assurance for computed-tomography simulators and the computed-tomography-simulation process. Med Phys. 2003;30:2762–2792. 148. JCAHO. Comprehensive Accreditation Manual for Hospitals. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 1996. 149. Starkschall G, Horton JL, eds. Quality Assurance in Radiotherapy Physics. Madison, WI: Medical Physics Publishing; 1991. 150. Williamson JF, Dunscombe PB, Sharpe MB, et al. Quality assurance needs for modern image-based radiotherapy. Recommendations from 2007 interorganizational symposium on quality assurance of radiation therapy: challenges of advanced technology. Int J Radiat Oncol Biol Phys. 2008;71(1 suppl):S2–S12. 151. Huq MS, Fraass BA, Dunscombe PB, et al. The report of Task Group 100 of the AAPM: application of risk analysis methods to radiation therapy quality management. Med Phys. 2016;43(7):4209. doi:10.1118/1.4947547.

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7 Radiation Physics: Stereotactic Timothy D. Solberg, Paul M. Medin, and Brian A. Hrycushko

The field of stereotactic radiosurgery (SRS) is now over 60 years old. The intervening decades have seen numerous technical developments, facilitating clinical success in numerous disease sites throughout the brain and body. Yet the fundamental principles remain largely unchanged: from conventional fractionation; many directions to create a conformal and compact dose distribution, effectively minimizing damage to intervening tissue; the use of a stereotactic frame or, more recently, through image guidance; and

demands on beam measurement, commissioning, and quality assurance. The chapter covers the principles of stereotactic localization, the physics associated with small photon beams, selection of appropriate detectors, and the processes for commissioning SRS systems. The History of Stereotactic Irradiation section is presented in the online supplement for this chapter.

PRINCIPLES OF STEREOTACTIC IRRADIATION There are several key principles that make SRS distinct from conventional radiotherapy. First, the procedure involves the delivery of an ablative dose of radiation that overwhelms the capacity of the irradiated cells to survive. The biological processes associated with high-dose delivery are quite different from those occurring at ~ 2 Gy per fraction; an increasing number of investigators have alluded to these threshold effects.37 The ablative intent implies that the approach is meant to treat gross disease exclusively and not microscopic extension. The accompanying need for tight margins places demands on both physical and dosimetric accuracy. The superior contrast resolution provided by magnetic resonance (MR) necessitates its use in most cranial indications, albeit with careful consideration of potential spatial distortions.38–41 Second, the accuracy and precision of both spatial and dosimetric localization are essential. Prior to the advent of computed tomography (CT), stereotactic localization was performed using a pair of projection radiographs. Fiducials located on the entrance and exit surfaces of the localization device facilitated calculation of both target location and magnification from a pair of radiographs (Fig. 7.1). Studies have demonstrated that the target point can be determined to within 0.3 mm over a large range of source-to-target and source-to-image distance

and projection angles using such a technique.42,43 The obvious shortcoming of the approach is that it cannot adequately reconstruct a target volume. The principle of stereotactic localization based on tomographic images is illustrated in Fig. 7.2. The superior-inferior dimension (z) is defined by measuring the in-plane distance between diverging fiducials (y) and applying simple geometry: zi = yi tanθ

(1)

With modern imaging and head frames, localization accuracy on the order of 1 to 2 mm is achievable.44–47 There are numerous sources of geometric uncertainty, including mechanical and radiation device isocentricity, imaging resolution, target delineation, and the stereotactic frame itself. The report of American Association of Physicists in Medicine (AAPM) Task Group 42 specifies an overall localization uncertainty of 2.4 mm (1 σ), provided that the planning images use a sufficiently thin-slice thickness.48 Dosimetric localization requires the delivery of many beams from many directions, overlapping only at the target of interest. Ideally, the intensity of any individual beam is sufficiently low that little damage occurs along the beam path, except at the point that all beams intersect. Conformality of the high dose and target volumes is essential, as is compactness of the overall dose distribution. Because the intermediate dose volume increases rapidly as a function of target size, single-fraction cranial applications are largely limited to lesions smaller than 4 cm.49

DOSIMETRY OF RADIOSURGERY BEAMS radiosurgery. Dosimetric integrity begins with the accurate measurement of photon beam characteristics.50 In general, SRS planning systems require the measurement of depth dose characteristics (percent depth dose [PDD] or tissue maximum ratio [TMR]), off-axis profiles, and relative output factors. For systems equipped with a micro-MLC, measurement of leaf transmission and dynamic leaf gap is also required. For commissioning Monte Carlo (MC) algorithms, additional beam measurements, including central and off-axis profiles and output factors in air, are often required.51,52 In-air scans require a brass build-up cap suitable for the beam energy used.

Considerations in Small-Field Dosimetry The measurement of beam characteristics (relative output factors, PDDs, and profiles) in small fields is challenging owing to their inherent

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CHAPTER 7

HISTORY OF STEREOTACTIC IRRADIATION The field of stereotactic irradiation owes its origins to parallel development in two disparate medical disciplines dating back over a century: those of stereotactic surgery and external beam radiation. In the late 1800s, surgeons and anatomists began exploring quantitative methods for studying the structure and function of the brain. The methodology known as stereotaxis relies on external fiducials to define a threedimensional frame of reference in which targeting can be performed. Historically, the fiducials consisted of a head frame that was rigidly attached to the skull. Because the skull and cranial structures remained fixed with respect to the frame, the external fiducials served as an appropriate surrogate for intracranial localization. The stereotactic method was pioneered by Horsley and Clarke, who devised an instrument for producing lesions at exact locations within the brains of nonhuman subjects.1,2 Other early efforts included those of Mussen and Kirschner.3,4 Routine clinical application of stereotactic surgery in humans is credited to the team of Speigel and Wycis.5 Lars Leksell subsequently developed a frame based on polar rather than Cartesian coordinates, providing maximum flexibility in choosing entry point and trajectory.6 The commercial Leksell frame (Elekta AB, Stockholm, Sweden) remains identical in function to the 1949 device. Other developments in stereotactic frames include the efforts of Talairach, Narabayashi, Riechert, and Mundinger, and Brown, Roberts, Todd, and Wells.7–14 Brown’s

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modifications to the original Wells-Todd device resulted in the BrownRoberts-Wells (BRW) coordinate system that is available commercially from Integra Radionics (Burlington, MA) and Brainlab (Feldkirchen, Germany).12,14 Examples of commercial stereotactic localization devices are shown in eFig. 7.1. In the era of image guidance, the skull serves as its own set of fiducials, and head frames are no longer required.15–18 The discovery of x-rays by Wilhelm Roentgen in late 1895 is well known. Throughout subsequent decades, efforts to increase the penetration ability of x-rays produced with conventional tubes met with modest success, with tube potentials limited to approximately 200 kV. In the early 1950s, Leksell realized that external forms of energy, such as ultrasound and ionizing radiation, could be coupled to a stereotactic frame. In 1951, Leksell proposed the term stereotactic radiosurgery to refer to the delivery of a single high dose of radiation accurately directed to an intracranial target. The principles of dose localization require irradiation “through a large number of small portals…which all meet and cross in the structure in question.”19 Leksell also appreciated the limitations imposed by low-energy x-rays; his subsequent efforts, as well as those of groups located in Boston, Massachusetts, and Berkeley, California, utilized beams of protons and other light ions.20–25 In the mid-1960s, Leksell’s colleagues at the Karolinska Institute in Stockholm, Sweden, began efforts on what would become the first dedicated radiosurgery device. The initial Gamma Knife, installed in Sofiahemmet Hospital in 1967, used 179 rectangular-collimated 60Co sources;

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Leksell CT

Leksell MR

eFig. 7.1 Commercial localization devices for defining stereotactic coordinates.

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subsequent commercial versions were implemented with 201 circularcollimated sources.26,27 The Perfexion unit, consisting of 192 cobalt sources arranged in eight independent sectors, was introduced by Elekta in 2007. Each sector can move to one of 4 locations to choose between blocked, 4-, 8-, and 16-mm circular collimation.28 eFig. 7.2 shows the evolution of the commercial Gamma Knife, from the Model U to the present Perfexion and Icon. The development of technology for linear accelerator-based radiosurgery began in the early 1980s, with the first radiosurgery patient treated on a modified medical linear accelerator (LINAC) in 1982.29 All early LINAC systems used hardware modifications designed to facilitate stereotactic frames and improve targeting accuracy to overcome shortcomings with the treatment couch.29–31 Subsequent improvement

A

in LINAC couches allowed the stereotactic frame to be affixed directly to the couch top. Subsequent developments included LINACs dedicated for radiosurgery, including the CyberKnife (Accuray, Sunnyvale, CA), 600SR (Varian Medical Systems, Palo Alto, CA), Novalis (BrainLAB AG, Heimstetten, Germany), and C-arm multi-rotation-axis LINAC (Mitsubishi Electric Ltd., Tokyo, Japan).32–36 Modern LINACs, such as the TrueBeam STx and EDGE (Varian Medical Systems, Palo Alto, CA), and Axesse and Versa HD (Elekta AB, Stockholm, Sweden) have localization and dosimetric characteristics that make them very well suited for radiosurgery applications. eFig. 7.3 shows the evolution of the radiosurgery LINACs, including the original Betti device, an early floor stand, the original CyberKnife, the original Novalis, and current offerings from Varian and Elekta.

C

B

D

E

eFig. 7.2 Several generations of the Leksell Gamma Knife: (A) Gamma Knife Model U; (B) Gamma Knife Model B; (C) Gamma Knife Model 4C; (D) Gamma Knife Perfexion; (E) Gamma Knife Icon.

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D

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C

E

F

eFig. 7.3 Evolution of linear accelerator technology for radiosurgery: (A) Betti system29; (B) Philips SRS200 floor stand system, circa 1990; (C) original CyberKnife32; (D) Novalis, circa 1997; (E) Elekta Versa HD; (F) Varian Edge.

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Fig. 7.1 Principles of stereotactic localization using biplanar radiography.

steep dose gradients. A misunderstanding of detector requirements or misinterpretation of measured beam data can lead to injurious or even life-threatening consequences.53,54 There is no accepted criterion defining a “small field,” but, in general, a small field can be labeled so depending on the electron range in the irradiated medium, the detector dimensions, and/or partial obstruction of the radiation source through collimation.55 Lateral electronic equilibrium becomes compromised when the beam radius is comparable in size to the maximum electron range. The maximum electron range depends on the photon beam energy and the irradiated medium composition (i.e., density and atomic number). At this point, electrons leaving the central portion of the field are insufficiently replaced by electrons scattered from the surrounding medium. Output factors for small fields are difficult to measure in these conditions owing to spectral differences causing stopping power ratios and correction factors to be unclear. AAPM Task Group 65 recommends a general rule-of-thumb for the lateral electron range being about one-third of the forward range, and in a 6-MV x-ray beam, electron disequilibrium has been shown to occur for radii 1 cm), increased in number, with homogeneous density. Typically, the paratracheal and anterior mediastinal lymph nodes are involved (Fig. 11.5). Lymphoma can also present as a soft-tissue mass within the anterior mediastinum that conforms to surrounding structures. Low-density or cystic areas can be seen within the mass (Fig. 11.6A). Imaging may show associated pleural or pericardial effusions and chest wall invasion (Fig. 11.6B). Pulmonary involvement of lymphoma is rare; however, it can manifest as pulmonary nodules or masses with or without cavitation, ground-glass opacities, or endobronchial masses. NHL and HL can also be seen in patients with posttransplant lymphoproliferative disorder (PTLD). PTLD can be divided into subgroups based on the presence of the Epstein-Barr virus. Imaging manifestations of PTLD include solid pulmonary nodules or masses, consolidation, ground glass, or interstitial disease.

Fig. 11.5 Imaging of a 22-year-old with a mediastinal mass. Axial contrast-enhanced computed tomography demonstrates extensive lymphadenopathy within the mediastinum (white circle) consistent with the patient’s tissue-proven diagnosis of Hodgkin lymphoma.

CT and PET/CT play a key role in imaging of lymphoma. CT can be employed for initial diagnosis and subsequent follow-up imaging to assess location and size of enlarged lymph nodes or soft-tissue masses. PET/CT provides the added benefit of evaluating metabolic response to treatment based on changes in FDG uptake within the nodal soft tissue.24 Furthermore, PET/CT is beneficial when evaluating extranodal tissue, such as occult bone marrow lesions. PET/CT has been fully incorporated into staging and response assessment of FDG-avid lymphoma.25 In instances in which FDG uptake is low, CT remains the mainstay for follow-up evaluation of lymphoma.

Thoracic Metastatic Disease Contrast-enhanced CT imaging is the modality of choice when initially staging metastatic disease within the chest and for following response to therapy. Many malignancies secondarily involve the lungs and present with a myriad of findings, including—but not limited to—pulmonary nodules, malignant pleural or pericardial effusions, lymphadenopathy, and osseous lesions. Evaluation of response to treatment generally is based on decrease in size and number of lesions. The most common primary tumors to metastasize to the lungs are breast cancer, colorectal cancer, renal cell carcinoma, uterine leiomyosarcoma, and head and neck squamous cell carcinoma (eFig. 11.4). Patients with known chest metastases are typically followed with routine CT imaging of the chest.

IMAGING OF THE GASTROINTESTINAL TRACT Esophagus Esophageal malignancies are the third most common in the gastrointestinal tract and primarily consistent of squamous cell carcinoma in the proximal two-thirds of the esophagus and adenocarcinoma in the distal third of the esophagus.26 Although esophageal cancer can be suspected on the basis of mass-like thickening on CT, diagnosis is typically made via endoscopy by biopsy. The esophagus lacks a serosal layer, allowing for direct spread of tumor into the neck or mediastinum. Tumor may also

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CHAPTER 11

Imaging in Oncology

eFig. 11.4 Imaging of a 63-year-old man with renal cell carcinoma and pulmonary nodules. Axial contrast-enhanced computed tomography demonstrates innumerable pulmonary nodules (arrows) seen throughout the lungs. Given his history of renal cell carcinoma, these findings were highly suspicious for widespread pulmonary metastatic disease. Tissue diagnosis demonstrated pathology consistent with metastatic renal cell carcinoma.

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CHAPTER 11 spread via lymphatics to mediastinal, gastrohepatic, and celiac lymph nodes and/or hematogenously to the lungs, liver, and bones. The primary role of CT at the time of diagnosis is for initial staging (eFig. 11.5). Endoscopic US more reliably distinguishes early T stages, but T3 disease is characterized on CT by definite wall thickening or a mass.27 Invasive T4 disease can generally be distinguished by loss of the fat plane and direct extension of tumor involving the pleura, pericardium, tracheobronchial tree, or spine. CT and PET/CT are both used in the assessment of lymph nodal involvement and distant metastatic disease. Both will also guide the initial and subsequent treatment strategy.

Stomach Gastric adenocarcinoma is the second most common gastrointestinal tract malignancy. The diagnosis is usually made via endoscopy, with endoscopic US performed to assess the depth of invasion for T staging. Patients may present initially with abdominal pain and undergo CT as the first evaluation, with tumor manifesting as mass-like ulceration or wall thickening without submucosal edema.28 CT is helpful in staging T4 disease with extragastric extension of tumor through the serosa or invasion of adjacent structures and is used in conjunction with PET/CT for staging of lymph nodes or distant metastases (Fig. 11.7). Proximal gastric tumors in the cardia or fundus will drain to the gastrohepatic and periaortic lymph nodes, with distal cancers in the body or antrum draining along the lesser curvature of the stomach.29 Distant metastases most commonly involve the peritoneum and liver. Rarely, distant metastases can involve the ovaries (Krukenburg tumor). Other malignant tumors of the stomach include lymphoma (eFig. 11.6) or metastatic disease, particularly from the breast, or lung cancer, which often present with diffuse infiltration and thickening of the stomach.30 Gastrointestinal stromal tumor (GIST) occurs most frequently in the stomach, manifests typically as a rounded, submucosal mass that may exhibit endoluminal or exophytic growth, and may be benign or malignant.

Small Bowel Small bowel tumors are uncommon within the gastrointestinal tract, occurring more frequently in the duodenum than in the jejunum or

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ileum.31 Neuroendocrine tumors such as carcinoid are the most common primary small bowel tumor, more typically arise from the distal ileum, are hyperenhancing on arterial phase CT or MRI, and may present with desmoplastic mesenteric lymph node metastases and/or liver metastases (eFig. 11.7). Adenocarcinoma is the second most common primary neoplasm of the small bowel, occurs most frequently in the duodenum near the ampulla, and manifests on CT or MRI as an ulcerated, eccentric, or concentric mass constricting the bowel lumen and potentially infiltrating the adjacent mesenteric fact32 (Fig. 11.8). Small bowel lymphoma often appears as a mass markedly thickening the small bowel wall with aneurysmal dilation of the lumen rather than obstruction.33 GIST in the small bowel has a similar appearance as it does in the stomach. CT and MRI evaluation of the small bowel are typically performed with an enterography protocol that includes oral contrast material to optimally distend small bowel loops and administration of an antiperistaltic agent in the case of MR enterography to minimize bowel motion during the examination. Staging is performed in the same examination to carefully evaluate mesenteric lymph nodes, the liver, and peritoneum. Metastatic cancers infrequently involve the small bowel and are usually due to disseminated peritoneal disease in the setting of gynecological or gastrointestinal malignancies resulting in serosal deposits that can result in malignant bowel obstruction. CT is more typically employed for imaging in this setting to assess the presence and cause of bowel obstruction.

Colon, Rectum, and Appendix Primary colonic adenocarcinoma is most commonly diagnosed at colonoscopy but is not infrequently diagnosed on conventional CT, either incidentally as focal wall thickening or as an obstructing mass.34 CT colonography is also being increasingly performed either for primary screening or for patients who have failed optical colonoscopy. CT is primarily employed for staging of disease, including local invasion of the peritoneum, regional lymph node metastases, or hematogenous spread to the liver or lungs35 (Fig. 11.9). Rectal tumors in particular are best assessed with high-resolution pelvic MRI, which is used in conjunction with endoscopic US for local staging. Invasion of tumor

B Fig. 11.6 Imaging of a 25-year-old man with an anterior mediastinal mass. (A) Contrast-enhanced chest computed tomography demonstrates a large anterior mediastinal mass with low attenuation cystic spaces (arrow). This mass was biopsied and demonstrated pathology consistent with classic Hodgkin lymphoma. (B) Note the associated pericardial effusion (black arrow).

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B eFig. 11.5 Imaging of a 55-year-old woman with newly diagnosed esophageal cancer referred for staging computed tomography (CT). (A) Contrast-enhanced axial CT demonstrates an enhancing solid mass in the proximal thoracic esophagus (arrow). (B) Additional axial CT image from the same study demonstrates gastrohepatic ligament lymphadenopathy (arrow) consistent with lymphatic spread of disease.

eFig. 11.6 Imaging of an 82-year-old woman with a gastric mass. Contrast-enhanced axial coronal computed tomography demonstrates circumferential thickening and soft-tissue attenuation infiltration of the wall of the stomach. Endoscopic biopsy demonstrates large B-cell lymphoma.

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B eFig. 11.7 Imaging of a 47-year-old woman with small bowel carcinoid. (A) Contrast-enhanced axial computed tomography (CT) demonstrates a speculated, enhancing mesenteric mass (arrow), representing metastatic lymphadenopathy. (B) Contrast-enhanced axial CT demonstrates the primary enhancing small bowel carcinoid tumor (arrow).

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Fig. 11.7 Imaging of a 60-year-old man with newly diagnosed gastric cancer. (A) Contrast-enhanced coronal computed tomography (CT) demonstrates circumferential thickening and soft-tissue attenuation of the gastric antrum (arrows). (B) Contrast-enhanced axial CT images demonstrate gastrohepatic ligament lymphadenopathy (solid arrow) and (C) peritoneal metastases (dashed arrows).

C

Fig. 11.8 Imaging of a 66-year-old woman with Lynch syndrome and gastrointestinal bleeding. Contrast-enhanced axial computed tomography demonstrates an annular constricting jejunal mass (arrows) consistent with small bowel adenocarcinoma.

Fig. 11.9 Imaging of a 63-year-old woman with melena. Contrast-enhanced axial computed tomography demonstrates cecal wall thickening (solid arrow) with regional lymphadenopathy in the cecal mesentery (dashed arrows) consistent with colon cancer.

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CHAPTER 11 into the mesorectal fat and involvement of the circumferential resection margin or direct extension into adjacent organs will affect treatment planning and can be accurately assessed with rectal MRI36 (Fig. 11.10). Lymphatic spread of tumor in the inferior mesenteric chain can be evaluated simultaneously. Liver metastases from colorectal cancer are best assessed with gadoxetate disodium contrast-enhanced liver MRI in the hepatobiliary phase, where they will appear hypointense to normal liver.37 Careful attention to performing and optimizing the correct MRI protocol is key in the imaging evaluation of these patients. Appendiceal neoplasms may be suggested prospectively on CT or MRI with thickening or dilation of the appendix out of proportion to the degree expected with appendicitis or the presence of an obstructing mass38 (eFig. 11.8). Neuroendocrine tumors of the appendix have a similar appearance as those in the small bowel. Mucinous appendiceal neoplasms occur along the spectrum from adenoma to adenocarcinoma,

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and rupture can result in pseudomyxoma peritonei or gelatinous mucinous deposits within the peritoneum.

IMAGING OF THE ABDOMEN Primary Liver Tumors Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. HCC occurs most frequently in patients with risk factors such as cirrhosis or chronic liver disease. Many at-risk patients are serially screened with US, which may reveal a hypoechoic or hyperechoic liver nodule. Multiphase CT or MRI can be used to definitively diagnose HCC by imaging without the need for tissue sampling according to the Liver Imaging Reporting and Data System (LI-RADS) 2017 guidelines, which specify a combination of arterial phase hyperenhancement, delayed phase washout, and an enhancing capsule as the requisite features39

B

Fig. 11.10 Imaging of a 76-year-old man with newly diagnosed rectal cancer. Axial (A) and coronal (B) high-resolution small field of view T2-weighted magnetic resonance images (MRIs) demonstrate extrarectal extension (arrows) of a midrectal mass beyond the serosal margin of the rectum, consistent with a T3a tumor. Sagittal high-resolution small field T2-weighted MRI (C) demonstrates that the mass does not involve the peritoneal reflection (arrow).

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B eFig. 11.8 Imaging of a 72-year-old man with abdominal pain. Axial contrast-enhanced CT demonstrates a cystic right lower quadrant mass (arrow) with slightly thickened wall. Coronal contrast-enhanced CT (B) confirms the appendiceal origin (arrow) of this mass.

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(Fig. 11.11). Ancillary imaging features include the presence of fat or hemorrhage within a lesion, best assessed on MRI. HCC may be focal or diffuse; assessment of the portal and hepatic veins and inferior vena cava for tumor thrombus and portal lymph nodes for lymphatic spread are performed as part of primary imaging evaluation. The lungs and bones are other common sites of metastatic disease from HCC. Intrahepatic cholangiocarcinoma (ICC) occurs less frequently than HCC but in a similar at-risk population. The LI-RADS guidelines can also be applied in assessment of these tumors on liver CT or MRI, as the imaging features will often be distinct compared with HCC, with a targetoid pattern of enhancement, washout, or diffusion restriction40 (Fig. 11.12). Concern for a non-HCC malignancy when assessing a liver

A

lesion using LI-RADS will frequently prompt tissue sampling for definitive diagnosis, as the management of these patients can differ substantially from patients with HCC.

Metastatic Liver Disease CT is most commonly used in detection of liver metastases from other primary malignancies. The appearance of metastases will vary substantially based on the primary tumor.41 Hypervascular lesions such as neuroendocrine tumors, renal cell carcinoma, melanoma, or breast cancer will enhance avidly on the arterial phase of contrast. Hypovascular metastases are more common, particularly with adenocarcinomas, and will frequently demonstrate a peripheral rim of enhancement. Metastases

B Fig. 11.11 Imaging of a 71-year-old woman with hepatic mass. (A) Axial T1-weighted, fat-suppressed, arterialphase magnetic resonance image (MRI) demonstrates diffuse hyperenhancement of a liver mass (arrow). (B) Axial T1-weighted fat-suppressed delayed-phase MRI demonstrates an enhancing capsule (arrow) and washout of the mass relative to normal liver (asterisk), consistent with hepatocellular carcinoma.

A

B Fig. 11.12 Imaging of a 62-year-old woman with an intrahepatic cholangiocarcinoma. (A) Axial T1-weighted, fat-suppressed, arterial-phase magnetic resonance image (MRI) demonstrates a peripherally enhancing dominant liver mass (solid arrow) and satellite metastases (dashed arrow). (B) Axial T1-weighted, fat-suppressed, delayed-phase MRI demonstrates central enhancement of the dominant (solid arrow) and satellite (dashed arrow) lesions.

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B Fig. 11.13 Imaging of a 37-year-old man with metastatic rectal cancer. (A) T1-weighted, fat-suppressed, arterial-phase magnetic resonance image demonstrates numerous hypoenhancing liver metastases (arrows). (B) The hepatobiliary phase image provides greater contrast and sensitivity for detection of small or equivocal lesions.

may appear cystic, particularly with mucinous primary tumors from the ovary or colon. MRI is more sensitive to identify metastases, particularly from colorectal cancer (Fig. 11.13) and can be used to identify hemorrhagic metastases such as melanoma, which appear intrinsically T1 hyperintense. MRI is helpful in assessing indeterminate lesions on single-phase CT, as benign lesions can frequently be diagnosed with greater confidence on MRI.

Gallbladder Primary gallbladder cancer is the most common gallbladder malignancy. It can manifest either as a polypoid mass, gallbladder wall thickening, or extraluminal mass.42 The lack of a muscularis mucosa or submucosa results in frequent direct extension into the adjacent liver. Metastatic lymphadenopathy and peritoneal disease are frequently present at the time of diagnosis. US is frequently employed as the initial imaging modality in identifying an abnormality, with CT and MRI performed to confirm the presence of a mass and stage local invasion and the presence of liver, lung, lymph node, or peritioneal metastases (eFig. 11.9).

Bile Duct Ductal biliary tumors can occur anywhere along the bile duct, from the liver hilum to the ampulla. They frequently come to clinical attention owing to biliary obstruction and resulting jaundice. Ductal thickening and enhancement are key diagnostic imaging features42 (Fig. 11.14). Multiphasic CT, MR cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP) are used in combination to assess involvement of adjacent vasculature, such as the hepatic arteries and portal veins, and extent of disease within the bile ducts, both of which affect resectability and prognosis. Diagnosis is typically obtained by endoscopic biopsy, but obtaining a definitive tissue diagnosis is notoriously challenging for ductal cholangiocarcinoma.

Pancreas Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy. Occurring most commonly in the pancreatic head, PDAC may obstruct the pancreatic duct, common bile duct, or

both. Multiphasic CT or MRCP can be used for initial diagnosis and local staging. PDAC is an infiltrative tumor that is best detected in the arterial phase as a hypoenhancing mass relative to normal pancreas43 (Fig. 11.15). The advantage of CT is better spatial resolution to detect subtle vascular involvement of the portal vein and hepatic arteries, superior mesenteric vein and artery, and splenic vein and artery. MRCP can detect smaller or subtle lesions and is more accurate for detection of liver metastases. PET/CT is helpful in staging pancreatic cancer, particularly in detecting lymph node metastases. Neuroendocrine tumors are the second most common solid pancreatic malignancy, presenting as hypervascular masses (eFig. 11.10) in distinction to PDAC, less likely to cause pancreatic ductal obstruction.44 Multiphasic CT and MR are standard diagnostic imaging methods, but gallium-68 dotatate PET/CT is gaining acceptance as a valuable tool in diagnosis and staging.45

Adrenal Metastases to the adrenal gland are the most common form of adrenal malignancy. Distinguishing metastases from nonfunctional adenomas, the most common adrenal lesion, is crucial in accurate staging of many malignancies, particularly lung cancer.46 Adrenal adenomas can be confidently diagnosed on unenhanced CT when measuring less than 10 Hounsfield units. Incidentally detected adrenal nodules on contrastenhanced CT (Fig. 11.16) can be further assessed with either adrenal washout CT or MRI. Compared with MRI, adrenal washout CT is more accurate overall, particularly when the adrenal lesion measures more than 20 to 30 Hounsfield units on unenhanced CT. Chemical shift MRI can be used to detect subtle fat within adrenal adenomas without the need for intravenous contrast administration. Primary tumors of the adrenal gland include adrenocortical carcinoma (ACC; eFig. 11.11) and pheochromocytoma (Fig. 11.17), both of which are rare.47 ACC is typically large at the time of diagnosis (> 5 cm) and frequently invades the inferior vena cava. Pheochromocytoma is often suspected clinically based on episodic hypertension and can be localized with MRI, where its T2 hyperintensity and hypervascularity distinguishes it from adenomas.

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D eFig. 11.9 Imaging of a 73-year-old woman with epigastric pain. (A) Axial contrast-enhanced computed tomography (CT) demonstrates a polypoid intraluminal gallbladder lesion (arrows). (B) Gallbladder ultrasound performed for further evaluation demonstrates a polypoid gallbladder mass (arrow). Coronal T2-weighted fat suppressed (C) and coronal T1-weighted fat-suppressed, postcontrast magnetic resonance image (D) demonstrate a primary gallbladder wall cancer with a polypoid component (arrows).

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eFig. 11.10 Imaging of a 60-year-old man with pancreatic neuroendocrine tumor. Coronal contrast-enhanced computed tomography demonstrates a hyperenhancing mass in the uncinate process of the pancreas (arrow), consistent with pancreatic neuroendocrine tumor.

A

B eFig. 11.11 Imaging of a 67-year-old man with a primary right adrenocortical carcinoma. (A) Axial T2-weighted magnetic resonance image (MRI) demonstrates a large, heterogenous right adrenal mass (asterisk) invading the inferior vena cava (solid arrow). (B) Coronal T1-weighted, fat-suppressed, postcontrast MRI demonstrates the same findings and a right pulmonary metastasis (dashed arrow).

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Fig. 11.14 Imaging of a 67-year-old man with painless jaundice. (A) Coronal magnetic resonance (MR) cholangiopancreatography demonstrates focal cut-off of dilated intrahepatic ducts at the hilum (circle). (B) Axial T2-weighted MR demonstrates the site of stricture in the hepatic hilum (circle). (C) Axial T1-weighted, fat-suppressed, postcontrast MR demonstrates a hypoenhancing ductal mass (circle) corresponding to the ductal hilar cholangiocarcinoma.

C

Kidney Renal cell carcinoma (RCC) is more frequently being diagnosed as an incidental finding on CT imaging being performed for other indications. RCC is typically a solid, enhancing mass that may be confirmed with multiphasic CT or MRI.48 Subtypes of RCC, such as clear cell RCC and papillary RCC, can be suggested by particular MR features, including T2-weighted signal intensity and dynamic enhancement pattern.49 While enhancing renal masses were classically viewed as surgical lesions, smaller lesions are now more frequently being biopsied, particularly in patients with borderline or impaired renal function, to avoid unnecessary resection of potentially benign lesions such as renal oncocytomas or lipid-poor angiomyolipomas.50 Staging with CT or MRI includes local staging of renal

vein or adjacent organ invasion, evaluation for regional lymphadenopathy, and assessment of distant organ metastases (Fig. 11.18).

Retroperitoneum Primary malignant masses of the retroperitoneum are frequently sarcomas.51 Tissues of origin include the inferior vena cava, renal capsule, fat, or muscle. CT is most commonly used for diagnosis and staging (Fig. 11.19), but MRI can be helpful to assess for vascular, organ, or body wall invasion. CT may be more helpful for assessing bowel involvement. MRI can detect subtle amounts of fat to suggest a liposarcoma when gross fat is not evident on CT. Lung and liver metastases are common.

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B Fig. 11.15 Imaging of a 73-year-old man with weight loss. (A) Axial contrast-enhanced computed tomography (CT) demonstrates distal pancreatic ductal dilation (arrow) and atrophy. (B) Coronal contrast-enhanced CT demonstrates a hypoenhancing mass in the pancreatic head, consistent with a pancreatic ductal adenocarcinoma.

defect, with nephrographic phase images to confirm the presence of enhancement.

IMAGING OF THE PELVIS Bladder While most bladder cancer is urothelial in origin, squamous cell carcinomas can occur (especially with chronic schistosomiasis or recurrent urinary tract infections).53 Adenocarcinoma occurs most frequently in urachal remnants. Cystoscopy is the primary method to diagnose bladder cancer. MRI can be used to more precisely assess tumor extension into or through the wall of the bladder compared with CT urography54 (Fig. 11.20). CT urography can investigate the presence of synchronous tumors in the upper tract.

Prostate

Fig. 11.16 Imaging of a 64-year-old man following a left radical nephrectomy for renal cell carcinoma with enlarging left adrenal nodule. Axial contrast-enhanced CT demonstrates a left adrenal nodule (arrow). Biopsy subsequently confirmed metastatic renal cell carcinoma.

Urinary Tract Urothelial carcinomas occur most commonly in the bladder but can also develop in the renal pelvis and anywhere within the ureter. Primary or synchronous urothelial carcinoma is typically initially assessed with CT urography, using delayed-phase excretory imaging to obtain highresolution images of the upper tract and bladder52 (eFig. 11.12). MR urography is an alternative in younger patients or in those with mild renal impairment. When the collecting system is adequately opacified with contrast, urothelial carcinoma can be detected as a filling

The diagnostic paradigm for prostate cancer has rapidly evolved in recent years with the advent of multiparametric prostate MRI.55 Performed preferentially on a 3.0 T MR scanner with or without an endorectal coil, prostate MRI gives high-resolution, T2- and diffusionweighted images combined with dynamic contrast enhancement to detect prostate cancers as T2 hypointense lesions with corresponding diffusion restriction and early enhancement (Fig. 11.21). Increasingly, MRI is performed in patients with suspected prostate cancer based on an elevated prostate-specific antigen level prior to initial biopsy or after a negative biopsy.56 Lesions detected on MRI can be used to guide transrectal ultrasound-guided prostate biopsy using software fusion techniques. MRI can preoperatively stage extraprostatic tumor extension into the periprostatic fat, seminal vesicles, or bladder and assess for neurovascular bundle involvement in high-risk patients. MRI plays a role in detection of suspected recurrence after treatment with prostatectomy, hormonal therapy, or radiotherapy. Multiple PET imaging agents for prostate cancer are being developed or introduced,57 promising to continue rapid changes in the prostate imaging landscape.

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B eFig. 11.12 Imaging of a 70-year-old man with microscopic hematuria. (A) Coronal contrast-enhanced excretoryphase computed tomography (CT) demonstrates a filling defect in a lower pole calyx of the right kidney (arrow). (B) Axial contrast-enhanced excretory-phase CT confirms enhancement of the mass (arrows) consistent with transitional cell carcinoma in contradistinction to nonenhancing lesions in the left kidney (asterisk), which represent peripelvic cysts.

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Fig. 11.17 Imaging of a 59-year-old man with a right adrenal mass and elevated catecholamine levels. Axial contrast-enhanced computed tomography (A) demonstrates an indeterminate right adrenal mass (arrow). Axial fat-suppressed, T2-weighted magnetic resonance image (B) demonstrates T2 hyperintensity within the mass. Axial I123metaiodobenzylguanidine imaging (C) demonstrates increased activity within the right adrenal mass, consistent with a pheochromocytoma.

B Fig. 11.18 Imaging of a 77-year-old woman with left renal lesion on ultrasound. (A) Axial T2-weighted magnetic resonance image (MRI) and T1-weighted, fat-suppressed, postcontrast MRI (B) demonstrate a T2 hyperintense, enhancing left renal mass (asterisks) invading the left renal vein (arrow) consistent with renal cell carcinoma.

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B Fig. 11.19 Imaging of a 76-year-old man with abdominal distension. Axial (A) and coronal (B) contrast-enhanced computed tomography scans demonstrate a large right-sided fatty retroperitoneal mass (asterisks) with scattered soft-tissue attenuation components (arrows) consistent with retroperitoneal liposarcoma.

A

B Fig. 11.20 Imaging of a 64-year-old woman with a muscle-invading bladder cancer. (A) Coronal T2-weighted magnetic resonance image (MRI) and axial T1-weighted, fat-suppressed, contrast-enhanced MRI (B) demonstrate an endophytic, T2-intermediate, intensity-enhancing bladder mass (arrows).

Testicle Ultrasound is the primary modality for imaging of testicular cancer.58 MRI, although highly accurate, is used only in atypical or challenging cases and to distinguish testicular from extratesticular tumors. Testicular masses are usually hypoechoic with varying degrees of vascularity depending on tumor subtype (eFig. 11.13). CT imaging of the abdomen and pelvis is performed to assess for retroperitoneal lymphadenopathy following the lymphatic drainage pathway of the gonadal veins. Chest CT is recommended if retroperitoneal or pelvic adenopathy is present.

Determining treatment response of enlarged lymph nodes after chemotherapy may be challenging if the lymph nodes do not decrease in size. PET/CT can be useful in this circumstance to assess for residual metabolic activity.

Cervix Cervical cancer is the most common gynecological malignancy worldwide and is staged according to the revised International Federation of Gynecology and Obstetrics (FIGO) system, which recommends use of CT or MRI

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eFig. 11.13 Imaging of a 34-year-old man with a painless right scrotal mass. Ultrasound demonstrates a bilobed right testicle hypoechoic, solid mass (arrow) with internal color Doppler flow consistent with testicular cancer. Orchiectomy confirmed a nonseminomatous germ cell tumor.

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D Fig. 11.21 Imaging of a 63-year-old man with elevated prostate-specific antigen level and two prior negative biopsies. (A) Axial T2-weighted magnetic resonance image (MRI) demonstrates a T2-hypointense in the right medial peripheral zone (circle). Axial diffusion-weighted MRI (B) and apparent diffusion coefficient (ADC) map (C) demonstrate corresponding diffusion hyperintensity and ADC hypointensity of the lesion (circles). Axial dynamic contrast enhancement MRI (D) demonstrates early enhancement (circle) of this lesion, which biopsied demonstrated was a Gleason 4+5 prostate cancer.

if available.59 CT is more readily available but is less accurate than MRI for assessing tumor size; parametrial extension; and invasion of the bladder, rectum, or pelvic sidewall. Both CT and MRI are effective methods for detecting ureteral involvement and hydroureter. Cervical cancers on MRI present as T2 intermediate intensity masses that enhance less-than-normal cervical tissue and restrict diffusion. High-resolution multiplanar T2-weighted imaging is most helpful for looking for preservation of the low-intensity cervical stromal ring to exclude parametrial invasion (Fig. 11.22). Staging of pelvic lymph nodes with CT and MRI is limited by the use of size criteria and morphology. PET/CT is particularly helpful in

assessment of nodes and distant metastases.60 Hybrid PET/MR systems allow the simultaneous acquisition of metabolic and anatomic imaging to comprehensively stage cervical cancer in a single examination.61

Uterus Endometrial cancer frequently comes to clinical attention in a postmenopausal woman with vaginal bleeding. Pelvic ultrasound is used as a first-line imaging modality to assess endometrial thickness, which should typically not exceed 4 to 5 mm.62 MRI is more accurate than CT for diagnosis and staging and can assess depth of myometrial or serosal invasion, involvement

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Fig. 11.22 Imaging of a 36-year-old woman with intermenstrual vaginal bleeding from a cervical cancer. Sagittal (A) and axial (B) T2-weighted magnetic resonance images (MRIs) demonstrate a T2 intermediate intensity mass confined to the cervix (arrows) without parametrial extension. Sagittal T1-weighted, fat-suppressed, postcontrast MRI (C) demonstrates similar confinement of the mass (arrow) to the cervix without extension into the upper vagina.

of adjacent organs and structures, and pelvic lymphadenopathy using a combination of multiplanar T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging63 (Fig. 11.23). PET/CT is useful for assessment of lymph nodes and distant metastatic disease.

Ovary Ovarian masses may be cystic, solid, or mixed in composition and are most frequently initially evaluated or incidentally detected on ultrasound.64 MRI is helpful in further characterization of an ovarian mass as likely benign, indeterminate, or likely malignant. It is particularly

C

useful for detecting small solid components within large cystic tumors (eFig. 11.14); assessing for fat, hemorrhage, or fibrosis; and for identifying pelvic lymphadenopathy.65 CT is helpful in staging and posttreatment follow-up of ovarian cancer, particularly in assessment of peritoneal or omental carcinomatosis.66

IMAGING OF THE BRAIN Neuroimaging plays an essential role in the diagnosis, staging, treatment planning, and posttreatment surveillance of patients with brain tumors.

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C eFig. 11.14 Imaging of a 59-year-old woman with cystic left adnexal mass. Axial (A) and sagittal (B) T2-weighted magnetic resonance images (MRIs) demonstrate a cystic left ovarian mass with mural nodule (arrow). Axial T1-weighted, fat-suppressed, contrast-enhanced MRI (C) confirms enhancement of the mural nodule (arrow). Pathology demonstrated a low-grade serous carcinoma.

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Fig. 11.23 Imaging of a 60-year-old woman with pelvic pain. Axial (A) and coronal (B) T2-weighted magnetic resonance image (MRI) and axial T1-weighted, fat-suppressed, postcontrast MRI (C) demonstrate an intermediate T2-intensity endometrial carcinoma (arrows) extending greater than 50% through the myometrium within 5 mm of the uterine serosa. A uterine fibroid (asterisk) is also present.

C

CT may be performed as an initial test in a patient with a focal neurological deficit or in the emergency setting to evaluate for life-threatening conditions. CT is also useful in the detection of tumoral calcification in tumors such as oligodendrogliomas or meningiomas.67–69 MRI, however, is the preferred modality in brain tumor imaging given its superior soft-tissue contrast and structural characterization.70,71 MRI allows for accurate tumor localization, assessment of tumor extent, evaluation of tumor relationship with adjacent structures, and development of a differential diagnosis. Standard structural MRI sequences include T2-weighted fluidattenuated inversion recovery (FLAIR) and pre- and postcontrast T1-weighted images.67 FLAIR images nicely demonstrate peritumoral edema as T2/FLAIR hyperintense signal surrounding the tumor. This increased signal may represent purely vasogenic edema as seen in brain metastases versus edema containing infiltrative tumor cells (infiltrative edema) as seen with gliomas (Fig. 11.24A).67,72–74 Contrast enhancement is an important finding in many brain tumors and reflects disruption of the blood-brain barrier. In regard to gliomas, contrast enhancement

generally indicates a higher-grade tumor (Fig. 11.24B). However, lower-grade gliomas, such as pilocytic astrocytomas and pleomorphic xanthoastrocytomas, generally enhance.67,75,76 T2- weighted sequencing, such as susceptibility-weighted imaging, is also routinely performed to detect tumoral hemorrhage and calcification.77 Advanced MRI techniques—including diffusion weighted imaging (DWI), perfusion imaging (PI; Fig. 11.24C), diffusion tensor imaging (DTI), functional MRI (fMRI), and MR spectroscopy (MRS)—are used to better assess tumor grade and tumor composition and to generate physiological information.78 Brain tumors may be classified as intra-axial or extra-axial in location. Depending on location and size, extra-axial tumors—such as meningiomas, schwannomas, and dural-based metastases—are often easily distinguished from intra-axial tumors with structural imaging (Fig. 11.25). Radiographic features that suggest an extra-axial location include a cleft of cerebrospinal fluid (CSF) between the tumor and adjacent brain; expansion of the subarachnoid space; intervening cortex between the tumor and white matter; associated dural thickening; and

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Fig. 11.24 Imaging of a patient with a left parietal glioblastoma. (A) Axial T2-weighted, fluid-attenuated inversion recovery (FLAIR) magnetic resonance image (MRI) demonstrates abnormal FLAIR signal within the left occipital lobe, peritrigonal white matter, and splenium of the corpus callosum (arrows) consistent with infiltrative edema. (B) Axial postcontrast T1-weighted MRI demonstrates a ring-enhancing left parietal lobe glioblastoma (arrow). (C) Axial relative cerebral blood volume (rCBV) perfusion MRI reveals increased rCBV corresponding to the areas of tumoral enhancement (arrow).

erosion, invasion, or hyperostosis of the adjacent calvaria.79 Extra-axial tumors arise from the meninges and may involve the pachymeninges as well as the leptomeninges (eFig. 11.15). Nonneoplastic meningeal-based disease processes—such as sarcoidosis, immunoglobulin G4 (IgG4)-related disease, and meningitis—may serve as mimics of extra-axial tumor. Generating a differential diagnosis for intra-axial tumors is largely based on patient age, a history of underlying malignancy, and the tumor’s appearance on imaging.67,80,81 Multiplicity of lesions is suggestive of metastatic disease (eFig. 11.16).82 Metastases, however, can be solitary, and primary brain tumors can be multifocal. Additionally,

C

many nonneoplastic diseases, such as brain abscesses and demyelinating disease, can be multifocal and mimic tumor. Features such as location at the gray-white matter interface and within the cerebellum as well as the presence of significant surrounding vasogenic edema support a diagnosis of metastatic disease. Additional imaging findings that may help distinguish intra-axial tumors (Fig. 11.26A) include tumoral necrosis and hemorrhage (often seen in higher-grade tumors), the presence of calcification (seen in tumors such as oligodendrogliomas and pineal tumors), and the presence of a cyst with a mural nodule (seen in entities such as pilocytic astrocytoma and pleomorphic xanthoastrocytoma).67,68,83,84

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eFig. 11.15 Imaging of a patient with metastatic melanoma. Axial postcontrast, T1-weighted magnetic resonance image demonstrates marked, diffuse leptomeningeal enhancement (arrows) consistent with leptomeningeal carcinomatosis.

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eFig. 11.16 Imaging of a patient with headache. Axial postcontrast, T1-weighted magnetic resonance image demonstrates multiple intra-axial, enhancing lesions (arrows). A metastatic workup revealed squamous cell carcinoma of the lung.

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Scientific Foundations of Radiation Oncology MRS can be helpful in the characterization of brain tumors. MRS provides information regarding the biochemical profile of tissue. The most relevant peaks in brain tumor imaging include choline (Cho), which is a marker of cellular turnover; creatine (Cr), which reflects normal metabolism; and N-acetylaspartate (NAA), which is a marker for neuronal viability.70 Brain tumor spectra reflect loss of neuronal viability and rapid cell turnover. Higher-grade gliomas, therefore, are associated with an elevated Cho/NAA ratio.90 Similarly, elevated Cho/ NAA and Cho/Cr ratios may be helpful in differentiating infiltrative edema from vasogenic edema.91 By assessing tumor vascularity, perfusion imaging also helps characterize tumors. Several MR perfusion techniques are currently used to derive parameters such as relative cerebral blood volume (rCBV)—a parameter that is elevated in tumors due to angiogenesis. An association between elevated rCBV and higher-grade gliomas has been described; however, rCBV may also be elevated in lower-grade tumors, such as oligodendrogliomas.92,93 Perfusion imaging is also useful in distinguishing recurrent or residual viable tumor from posttreatment-related phenomena such as pseudoprogression and radiation necrosis with rCBV elevated in tumor but not in pseudoprogression or radiation necrosis.94,95

Fig. 11.25 Imaging of a patient with an extra-axial mass. Coronal postcontrast T1-weighted magnetic resonance image demonstrates a left-parafalcine extra-axial tumor (asterisk) that exerts mass effect on the underlying brain with an adjacent dural tail (arrow). This tumor was resected and found to be a grade 2 meningioma.

DWI evaluates the diffusivity of water molecules in tissues, a valuable tool in the assessment of brain tumors. Apparent diffusion coefficient (ADC) maps are derived from the diffusion-weighted images. The ADC value is inversely proportional to cellular density.78 The ADC may therefore be used to assess tumor cellularity with low values suggesting highly cellular tumors such as lymphoma and medulloblastoma (Fig. 11.26B).70 ADC values may also direct biopsy sampling, predict treatment response, and assess perioperative injury.70,85 DWI is very helpful in differentiating tumor from tumor mimics, such as demyelinating lesions and cerebral abscesses. DTI is similar to DWI but provides information on the threedimensional diffusivity of water along white matter tracts. Using DTI data, tractography can be performed that delineates white matter tracts such as the corticospinal tract, arcuate fasciculus (Fig. 11.26C), and optic radiation. Preoperatively, the relationship of a tumor with these tracts can be assessed, determining whether there is tumor invasion or displacement.86,87 The location of tumor in relation to adjacent white matter tracts may also be important in planning a surgical approach. Similar to DTI, fMRI is employed for pretreatment planning. fMRI identifies areas of neuronal activity by detecting changes in blood flow based on the premise that blood flow and neuronal activation are coupled. Changes in blood flow are detected with blood oxygen level–dependent (BOLD) signals using the ratio of deoxyhemoglobin to oxyhemoglobin. fMRI can be used preoperatively to map areas of activation corresponding to sensorimotor activity, language, and vision (Fig. 11.26D).88 fMRI can be performed using a task-based approach that requires patient participation, having the patient alternate between a passive resting state and a task-related activity. Alternatively, resting state fMRI (rs-fMRI) can be performed without patient participation. Rs-fMRI detects spontaneous fluctuations in BOLD signals to detect resting-state networks.89

IMAGING OF THE HEAD AND NECK Imaging plays an essential role in the diagnosis, staging, and follow-up of head and neck cancer.96 The goals of initial imaging are to detect a primary head and neck tumor and to define a tumor’s size and anatomic location. Imaging also establishes a tumor’s relationship with adjacent structures; reveals locoregional spread, including perineural spread; and identifies nodal metastatic disease. CT and MRI are the mainstays of head and neck imaging. Both modalities have strengths and weaknesses that should be considered when selecting the appropriate modality for initial imaging and follow-up.97 CT of the neck is fast and widely available. It is therefore often the initial imaging modality used when a patient presents with signs or symptoms of head and neck cancer. Intravenous contrast should be administered, as it greatly improves lesion conspicuity.98 CT offers superior bone detail and is the preferred modality for imaging tumors of the oral cavity, pharynx, and larynx owing to rapid image acquisition that reduces artifacts from swallowing and breathing (Fig. 11.27).99 The disadvantages of CT include exposure to ionizing radiation, need for iodinated contrast, and limited ability to detect superficial mucosal lesions. It also has inferior soft-tissue contrast, is susceptible to artifacts from dental restorations, and has limited ability to detect perineural spread and dural invasion. When compared with CT, MRI provides excellent soft-tissue contrast and is the preferred modality for sinonasal, nasopharyngeal, and salivary gland tumors given its superb ability to delineate tumor extent (Fig. 11.28A).99 MRI is also the preferred modality in the evaluation of perineural spread (Fig. 11.28B), skull base invasion, and marrow replacement. T1-weighted images display anatomic relationships and are useful in detection of lesions embedded in fat, such as lesions within the fat-containing parotid gland or bone marrow replacement.97 Fatsuppressed T2-weighted images are useful in tumor characterization, with many head and neck tumors demonstrating T2 hyperintensity.97 However, highly cellular tumors—such as small, round blue cell tumors—often demonstrate relative T2 hypointensity. Lymph nodes, cystic lesions, and certain T2-hyperintense masses such as pleomorphic adenomas are also well defined on T2-weighted images. Fat-suppressed gadolinium-enhanced T1-weighted images improve lesion conspicuity and define tumoral extent.97,98 Similar to CT, the normal enhancement of the aerodigestive mucosa make the detection of superficial mucosal lesions difficult.99

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B

A

C

D Fig. 11.26 Imaging of a patient with primary central nervous system lymphoma. (A) Axial postcontrast T1-weighted magnetic resonance image (MRI) reveals a large, avidly enhancing intra-axial tumor (oval) within the left temporal lobe that extends into the temporal horn of the left lateral ventricle. Of note, the patient also had an extra-axial focus of lymphoma within along the pituitary infundibulum in the suprasellar cistern (arrow). (B) The apparent diffusion coefficient map demonstrates a decreased signal (arrow), a feature common to lymphoma due to high cellularity. (C) Three-dimensional image demonstrates normal corticospinal tracts (red and green), arcuate fasciculi (orange and blue) as well as areas of sensorimotor (purple) and language (yellow) activation. (D) Axial postcontrast T1-weighted MRI with superimposed diffusion tensor imaging tractography and resting state functional MRI demonstrates that the inferior limb of the left arcuate fasciculus (arrow) as well as an area of language activation that represents the putative Wernicke area lie immediately lateral to the enhancing tumor.

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Fig. 11.27 Imaging of a patient with head and neck cancer. Axial postcontrast computed tomography scan demonstrates a large, enhancing mass centered within the right palatine tonsil (asterisk) that invades the tongue and floor of mouth with right jugulodigastric nodal metastases (arrow).

PET/CT is especially useful in detecting occult primary head and neck tumors, has greater sensitivity to detect small nodal metastases versus CT alone, and identifies distant metastases.100 It is also useful for the detection of tumor recurrence.96 PET/MRI has recently been introduced as an alternative to PET/CT in imaging head and neck cancer. A direct comparison of PET/CT and PET/MRI demonstrates increased tumoral conspicuity and characterization with PET/MRI.101

IMAGING OF THE SPINE Metastases to the spine can involve the osseous vertebrae, spinal cord, leptomeninges (Fig. 11.29), and epidural space. The spine is overall the third most common site of metastatic disease and the most common site for osseous metastases.102–104 Nuclear bone scans most commonly identify metastases to the spine. MRI is the preferred modality for assessing details of spinal osseous metastatic disease, allowing the early detection of marrowreplacing lesions. Standard sequences include precontrast T1-weighted images, fat-suppressed postcontrast T1-weighted images, short tau inversion recovery (STIR) images, and fast spin echo T2-weighted images. Not only can MRI detect osseous lesions early but, due to its superb softtissue contrast, it allows detection of epidural tumor spread, spinal canal stenosis, and cord compression (Fig. 11.30). MRI is the preferred modality for assessment of leptomeningeal and intramedullary metastases. In addition to MRI, CT is an important modality in the detection of osseous metastatic disease given its ability to delineate osseous detail and detect cortical destruction. Lesions confined to the bone marrow without cortical destruction may be difficult to identify on CT. The sensitivity of CT to identify spinal osseous metastases is around 66%, far lower than MRI (98.5%).105 CT is inferior in the evaluation of epidural, leptomeningeal, or intramedullary metastases.

B Fig. 11.28 (A) Axial postcontrast, T1-weighted magnetic resonance image (MRI) of the face reveals a large enhancing mass (oval) centered within the left nasal cavity that extends into the left maxillary sinus. It extends through the posterior wall of the left maxillary sinus into the left pterygopalatine fossa and into the left masticator space (arrow). (B) Coronal postcontrast, T1-weighted MRI demonstrates perineural spread of tumor from the left masticator space up the V3 segment of the left trigeminal nerve through the foramen ovale (arrow).

Although more rare than metastatic disease, primary tumors also affect the spine and spinal cord. While CT is the preferred modality to assess the bony details of a primary vertebral body tumor, including its internal matrix, MRI easily allows a primary spine tumor to be classified as extra- or intradural and extra- or intramedullary.106 Intradural tumors are rare, with the majority being extramedullary in location. The most common intradural extramedullary primary tumors include meningiomas and nerve sheath tumors.106 The most common intramedullary tumors include astrocytomas and ependymomas.

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Fig. 11.29 Fat-saturated, postcontrast, T1-weighted magnetic resonance image (MRI) through the lumbar spine in a patient with widely metastatic lung cancer demonstrates enhancement along the surface of the conus (solid arrow) plus multiple nodular foci of enhancement along the cauda equina and within the lower thecal sac (dashed arrow) consistent with leptomeningeal carcinomatosis.

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Fig. 11.30 Fat-saturated, postcontrast, T1-weighted magnetic resonance image (MRI) through the thoracic spine in a woman with metastatic breast cancer reveals an enhancing lesion within a midthoracic vertebral body resulting in pathological compression (asterisk) as well as a large lesion within the posterior epidural space (arrow) causing severe spinal canal stenosis and cord compression.

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48. Sasaguri K, Takahashi N. CT and MR imaging for solid renal mass characterization. Eur J Radiol. 2018;99:40–54. 49. Lopes Vendrami C, Parada Villavicencio C, DeJulio TJ, et al. Differentiation of solid renal tumors with multiparametric MR imaging. Radiographics. 2017;37:2026–2042. 50. Almassi N, Gill BC, Rini B, et al. Management of the small renal mass. Transl Androl Urol. 2017;6:923–930. 51. Messiou C, Moskovic E, Vanel D, et al. Primary retroperitoneal soft tissue sarcoma: imaging appearances, pitfalls and diagnostic algorithm. Eur J Surg Oncol. 2017;7:1191–1198. 52. Froemming A, Potretzke T, Takahashi N, et al. Upper tract urothelial cancer. Eur J Radiol. 2018;98:50–60. 53. Hartman R, Kawashima A. Lower tract neoplasm: update of imaging evaluation. Eur J Radiol. 2017;97:119–130. 54. Huang L, Kong Q, Liu Z, et al. The diagnostic value of MR imaging in differentiating T staging of bladder cancer: a meta-analysis. Radiology. 2018;286:502–511. 55. Furlan A, Borhani AA, Westphalen AC. Multiparametric MR imaging of the prostate: interpretation including Prostate Imaging Reporting and Data System version 2. Radiol Clin North Am. 2018;56:223–238. 56. Shaish H, Taneja SS, Rosenkrantz AB. Prostate MR imaging: an update. Radiol Clin North Am. 2017;55:303–320. 57. Cuccurullo V, Di Stasio GD, Mansi L. Nuclear medicine in prostate cancer: a new era for radiotracers. World J Nucl Med. 2018;17:70–78. 58. Coursey Moreno C, Small WC, Camacho JC, et al. Testicular tumors: what radiologists need to know–differential diagnosis, staging, and management. Radiographics. 2015;35:400–415. 59. Rauch GM, Kaur H, Choi H, et al. Optimization of MR imaging for pretreatment evaluation of patients with endometrial and cervical cancer. Radiographics. 2014;34:1082–1098. 60. Akin EA, Kuhl ES, Zeman RK. The role of FDG-PET/CT in gynecologic imaging: an updated guide to interpretation and challenges. Abdom Radiol (NY). 2018;doi:10.1007/s00261-017-1441-8. Epub ahead of print. 61. Ohliger A, Hope TA, Chapman JS, et al. PET/MR imaging in gynecologic oncology. Magn Reson Imaging Clin N Am. 2017;25:667–684. 62. Sadro CT. Imaging the endometrium: a pictorial essay. Can Assoc Radiol J. 2016;67:254–262. 63. Nougaret S, Lakhman Y, Vargas HA, et al. From staging to prognostication: achievements and challenges of MR imaging in the assessment of endometrial cancer. Magn Reson Imaging Clin N Am. 2017;25:611–633. 64. Javadi S, Ganeshan DM, Qayyum A, et al. Ovarian cancer, the revised FIGO staging system, and the role of imaging. AJR Am J Roentgenol. 2016;206:1351–1360. 65. Stein EB, Wasnik AP, Sciallis AP, et al. MR imaging-pathologic correlation in ovarian cancer. Magn Reson Imaging Clin N Am. 2017;25:545–562. 66. Diop AD, Fontarensky M, Montoriol PF. CT imaging of peritoneal carcinomatosis and its mimics. Diagn Interv Imaging. 2014;95:861–872. 67. Mabray MC, Barajas RF Jr, Cha S. Modern brain tumor imaging. Brain Tumor Res Treat. 2015;3(1):8–23. 68. Lee YY, Van Tassel P. Intracranial oligodendrogliomas: imaging findings in 35 untreated cases. AJR Am J Roentgenol. 1989;152(2):361–369. 69. Eskandary H, Sabba M, Khajehpour F, Eskandari M. Incidental findings in brain computed tomography scans of 3000 head trauma patients. Surg Neurol. 2005;63(6):550–553, discussion 553. 70. Villanueva-Meyer JE, Mabray MC, Cha S. Current clinical brain tumor imaging. Neurosurgery. 2017;81(3):397–415. 71. Brindle KM, Izquierdo-Garcia JL, Lewis DY, et al. Brain tumor imaging. J Clin Oncol. 2017;35(21):2432–2438. 72. Klatzo I. Presidental address. Neuropathological aspects of brain edema. J Neuropathol Exp Neurol. 1967;26(1):1–14. 73. Lu S, Ahn D, Johnson G, Cha S. Peritumoral diffusion tensor imaging of high-grade gliomas and metastatic brain tumors. AJNR Am J Neuroradiol. 2003;24(5):937–941. 74. Law M, Cha S, Knopp EA, et al. High-grade gliomas and solitary metastases: differentiation by using perfusion and proton spectroscopic MR imaging. Radiology. 2002;222(3):715–721.

75. Ginsberg LE, Fuller GN, Hashmi M, et al. The significance of lack of MR contrast enhancement of supratentorial brain tumors in adults: histopathological evaluation of a series. Surg Neurol. 1998;49(4): 436–440. 76. Koeller KK, Rushing EJ. From the archives of the AFIP: pilocytic astrocytoma: radiologic-pathologic correlation. Radiographics. 2004;24(6):1693–1708. 77. Haacke EM. Susceptibility weighted imaging (SWI). Z Med Phys. 2006;16(4):237. 78. Al-Okaili RN, Krejza J, Wang S, et al. Advanced MR imaging techniques in the diagnosis of intraaxial brain tumors in adults. Radiographics. 2006;26(suppl 1):S173–S189. 79. Curnes JT. MR imaging of peripheral intracranial neoplasms: extraaxial vs intraaxial masses. J Comput Assist Tomogr. 1987;11(6):932–937. 80. Borja MJ, Plaza MJ, Altman N, Saigal G. Conventional and advanced MRI features of pediatric intracranial tumors: supratentorial tumors. AJR Am J Roentgenol. 2013;200(5):W483–W503. 81. Sze G, Milano E, Johnson C, Heier L. Detection of brain metastases: comparison of contrast-enhanced MR with unenhanced MR and enhanced CT. AJNR Am J Neuroradiol. 1990;11(4):785–791. 82. Cha S, Lupo JM, Chen MH, et al. Differentiation of glioblastoma multiforme and single brain metastasis by peak height and percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AJNR Am J Neuroradiol. 2007;28(6):1078–1084. 83. Raz E, Zagzag D, Saba L, et al. Cyst with a mural nodule tumor of the brain. Cancer Imaging. 2012;12:237–244. 84. Kondziolka D, Bernstein M, Resch L, et al. Significance of hemorrhage into brain tumors: clinicopathological study. J Neurosurg. 1987;67(6):852–857. 85. Ellingson BM, Sahebjam S, Kim HJ, et al. Pretreatment ADC histogram analysis is a predictive imaging biomarker for bevacizumab treatment but not chemotherapy in recurrent glioblastoma. AJNR Am J Neuroradiol. 2014;35(4):673–679. 86. Shahar T, Rozovski U, Marko NF, et al. Preoperative imaging to predict intraoperative changes in tumor-to-corticospinal tract distance: an analysis of 45 cases using high-field intraoperative magnetic resonance imaging. Neurosurgery. 2014;75(1):23–30. 87. Coenen VA, Krings T, Mayfrank L, et al. Three-dimensional visualization of the pyramidal tract in a neuronavigation system during brain tumor surgery: first experiences and technical note. Neurosurgery. 2001;49(1):86–92, discussion 92–93. 88. Nadkarni TN, Andreoli MJ, Nair VA, et al. Usage of fMRI for presurgical planning in brain tumor and vascular lesion patients: task and statistical threshold effects on language lateralization. Neuroimage Clin. 2015;7:415–423. 89. Lee MH, Smyser CD, Shimony JS. Resting-state fMRI: a review of methods and clinical applications. AJNR Am J Neuroradiol. 2013;34(10):1866–1872. 90. Bulik M, Jancalek R, Vanicek J, et al. Potential of MR spectroscopy for assessment of glioma grading. Clin Neurol Neurosurg. 2013;115(2):146–153. 91. Horska A, Barker PB. Imaging of brain tumors: MR spectroscopy and metabolic imaging. Neuroimaging Clin N Am. 2010;20(3):293–310. 92. Aronen HJ, Gazit IE, Louis DN, et al. Cerebral blood volume maps of gliomas: comparison with tumor grade and histologic findings. Radiology. 1994;191(1):41–51. 93. Cha S, Tihan T, Crawford F, et al. Differentiation of low-grade oligodendrogliomas from low-grade astrocytomas by using quantitative blood-volume measurements derived from dynamic susceptibility contrast-enhanced MR imaging. AJNR Am J Neuroradiol. 2005;26(2):266–273. 94. Hu LS, Baxter LC, Smith KA, et al. Relative cerebral blood volume values to differentiate high-grade glioma recurrence from posttreatment radiation effect: direct correlation between image-guided tissue histopathology and localized dynamic susceptibility-weighted contrastenhanced perfusion MR imaging measurements. AJNR Am J Neuroradiol. 2009;30(3):552–558.

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CHAPTER 11 95. Barajas RF, Chang JS, Sneed PK, et al. Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrastenhanced perfusion MR imaging. AJNR Am J Neuroradiol. 2009;30(2):367–372. 96. Escott EJ. Role of positron emission tomography/computed tomography (PET/CT) in head and neck cancer. Radiol Clin North Am. 2013;51(5):881–893. 97. Wippold FJ 2nd. Head and neck imaging: the role of CT and MRI. J Magn Reson Imaging. 2007;25(3):453–465. 98. Cummings CW. Cummings Otolaryngology Head & Neck Surgery. 4th ed. Philadelphia, Pa.: Elsevier Mosby; 2005. 99. Abraham J. Imaging for head and neck cancer. Surg Oncol Clin N Am. 2015;24(3):455–471. 100. Veit-Haibach P, Luczak C, Wanke I, et al. TNM staging with FDG-PET/ CT in patients with primary head and neck cancer. Eur J Nucl Med Mol Imaging. 2007;34(12):1953–1962.

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101. Kuhn FP, Hullner M, Mader CE, et al. Contrast-enhanced PET/MR imaging versus contrast-enhanced PET/CT in head and neck cancer: how much MR information is needed? J Nucl Med. 2014;55(4):551–558. 102. Shah LM, Salzman KL. Imaging of spinal metastatic disease. Int J Surg Oncol. 2011;2011:769753. 103. Witham TF, Khavkin YA, Gallia GL, et al. Surgery insight: current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol. 2006;2(2):87–94, quiz 116. 104. Klimo P Jr, Schmidt MH. Surgical management of spinal metastases. Oncologist. 2004;9(2):188–196. 105. Buhmann Kirchhoff S, Becker C, Duerr HR, et al. Detection of osseous metastases of the spine: comparison of high resolution multidetector-CT with MRI. Eur J Radiol. 2009;69(3):567–573. 106. Van Goethem JW, van den Hauwe L, Ozsarlak O, et al. Spinal tumors. Eur J Radiol. 2004;50(2):159–176.

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12 Nuclear Medicine Terence Z. Wong, Amir H. Khandani, and Arif Sheikh

Molecular imaging techniques such as nuclear medicine and functional magnetic resonance imaging (MRI) are playing an increasingly important role in oncology. Hybrid functional/anatomic imaging modalities, such as positron emission tomography/computed tomography (PET/CT) and single photon-emission computed tomography/computed tomography (SPECT/CT), can provide more accurate initial staging and follow-up in oncology patients. More recently, combined PET/MRI has also become available. Since metabolic changes to therapy almost always precede anatomic changes, functional imaging can be useful to assess early response to therapy. Over the past half-century, a variety of nuclear medicine probes have been used to evaluate disease processes at the cellular level. Nuclear medicine is the only clinical discipline using intracellular contrast agents in imaging; therefore, it is more sensitive than anatomic modalities in detecting disease processes. The concentration of tracer needed (picomolar levels) for PET imaging is many orders of magnitude less than needed to measure enhancement using MR or CT contrast agents (millimolar levels). On the other hand, nuclear medicine imaging techniques have generally suffered from low specificity and low spatial resolution, the latter being associated with the physics of single-photonemitting radiotracers. Hybrid imaging (SPECT/CT, PET/CT, and PET/ MRI) affords the opportunity to combine the strengths of both anatomic and functional imaging. Because CT is used routinely for radiation treatment planning, adding the metabolic information provided by PET or SPECT tracers provides a natural opportunity for selectively targeting tumor subpopulations. Adaptive treatment plans based on PET imaging are currently being investigated.

PET is a nuclear medicine modality that uses positron emitters such as 18F, 15O, 13N, 11C, and 68Ga. The fact that these nuclides are components of common biological molecules makes PET particularly suitable for probing a wide range of biological pathways. With the exception of 18F, most positron-emitting radionuclides have a relatively short half-life and generally require an on-site cyclotron or a generator for availability. The longer half-life (110 minutes) of 18F has enabled 18F PET tracers to be produced commercially at centralized cyclotron facilities and distributed widely for PET imaging. Currently, the most widely used PET tracer is the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose (fluorodeoxyglucose [FDG]). FDG-PET has proven efficacy as a general-purpose tracer for staging and restaging a variety of malignancies. FDG-PET can be used to evaluate early response to therapy and is routinely used to guide therapy for some malignancies, most notably lymphoma. While FDG will likely remain a “workhorse” oncology tracer in the foreseeable future, additional PET tracers are available and have recently been approved by the US Food and Drug Administration (FDA) in the United States for imaging of prostate cancer and neuroendocrine tumors. Additional PET biomarkers for hypoxia and receptor imaging are also under investigation. PET imaging with FDG and other tracers can also provide information about tumor heterogeneity, which can be intratumoral or intralesional. For example, in patients presenting with adenopathy, PET may help define the biopsy target most likely to be diagnostic. In the future, PET imaging with specific target probes can be used as predictive biomarkers prior to targeted therapy.

SINGLE-PHOTON EMISSION TOMOGRAPHY

BASIC PHYSICS OF POSITRON EMISSION TOMOGRAPHY

SPECT images are produced by rotation of the gamma camera(s) around the patient to obtain and reconstruct three-dimensional data. By using appropriate collimators and energy windows, SPECT cameras can be employed to image a variety of lower- and higher-energy radionuclides. SPECT scanners can be equipped with CT imaging capability. The CT technology can vary widely—some SPECT/CT scanners have CT detectors built into the rotating gamma camera so that acquisition is slow, and CT images are subject to respiratory motion artifact. Newer SPECT/ CT scanners incorporate full multidetector CT technology (similar to PET/CT), enabling faster and higher-quality CT scans to be obtained as part of SPECT/CT imaging. The data obtained from the CT images can be used for attenuation correction of the SPECT images, which enables quantification of the tracer activity. The most recent SPECT technology includes solid-state detectors replacing the previous photomultiplier tubes.

The radioisotope portion of the molecule used in PET imaging emits a positron (i.e., positively charged electron), which travels a distance of a few millimeters in tissue before it collides with a negatively charged electron. This collision annihilates the entire mass of the positron and electron, generating two photons with energy of 511 keV each. These two photons travel at the speed of light in exactly opposite directions (i.e., 180 degrees apart). Coincident detection of these two photons by two oppositely positioned detectors in the PET scanner results in images with a much higher resolution compared with the conventional, singlephoton nuclear medicine studies. More recently, with time-of-flight PET imaging, the detectors have fast time resolution to enable localization along each line of response between the coincidence detectors, further improving quality of the PET images. PET/CT allows metabolic information from PET to be combined with the anatomic information from CT. PET/CT increases the diagnostic

POSITRON EMISSION TOMOGRAPHY

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Fig. 12.1 Computed tomography (A) provides diagnostic information (morphology), anatomic localization (D), and photon attenuation data to equalize the intensity of uptake between deeper and superficial structures on the positron emission tomography (PET) scans. (B,C) In this example, the metastatic liver lesion (arrow) is better appreciated on the attenuation-corrected PET image (C) than on the nonattenuation-corrected PET image (B).

accuracy compared with stand-alone PET. In PET/CT, the patient undergoes a CT scan, followed by a PET scan, without changing the patient’s position. PET for most oncological indications is acquired from the base of the skull through the upper thighs. In some instances, such as in melanoma patients, PET is acquired from the vertex of the skull through the toes. The CT portion of PET/CT is acquired within seconds, whereas the PET acquisition time for each bed position (about 15 cm) is several minutes; the total PET acquisition time in newer machines is 15 to 25 minutes. In addition to delivering anatomic information, the CT portion of PET/CT is used to measure the attenuation of the x-ray photons traveling through the patient to produce the so-called attenuation map and correct the PET data for tissue attenuation. During PET acquisition, photons from structures deep in the abdomen or pelvis are more strongly attenuated than those from superficial structures and the chest. The intensity of uptake in deeper structures is underestimated on nonattenuation-corrected PET images; the intensity of uptake in the deeper structures is normalized to the intensity of uptake in the superficial structures on the attenuation-corrected PET images (Fig. 12.1). Attenuation correction of the PET data is also a prerequisite for quantification of radiotracer uptake in PET/CT scans. Spatial alignment between the PET and CT scans is crucial both for correct anatomic localization and accurate quantification. Misalignment may be caused by the changed position of a body part (e.g., neck, legs) or physiological changes in the position of an organ (e.g., respiratory movement, bladder filling, bowel peristalsis) between the CT scan and PET scan. The most commonly encountered problem occurs at the lung bases because CT is obtained over a short time interval and PET images are acquired with the patient quietly breathing. This respiratory misregistration can be minimized by acquiring the CT scan with respiration suspended in quiet end expiration. Because the degree of

misalignment and resulting mislocalization can be significant, the radiologist must be cautious when interpreting or quantifying the attenuation-corrected PET/CT images or using PET/CT images for radiation therapy planning. The magnitude of this misalignment can be assessed by using the fusion display of the nonattenuation-corrected PET images with CT. In the case of significant misalignment, the nonattenuation-corrected PET images should be reviewed without fusion with CT, and the metabolic findings on PET should be correlated side by side with the anatomic findings on CT (Fig. 12.2). Current PET/CT scanners are equipped with multidetector CT (MDCT) and have full diagnostic CT capabilities that are equivalent to stand-alone CT scanners. This enables comprehensive PET/CT examinations to be performed that combine PET with fully diagnostic contrast-enhanced CT.1 MDCT allows reconstruction to be performed using isotropic voxels, enabling multiplanar display of CT images with full spatial resolution. This provides optimal definition of target lesions as well as morphological characterization and, therefore, can maximize the diagnostic capabilities of combined PET/CT imaging. PET-MR has been introduced clinically relatively recently, which offers the ability of obtaining PET images with MRI and fusion of that information. MRI provides superior soft-tissue contrast compared with CT. In addition, advanced imaging sequences—such as diffusion-weighted imaging (DWI) and dynamic contrast enhancement (DCE-MRI) permit quantitative physiological information to complement the PET radiotracer information. MRI is also used to calculate attenuation correction for the PET images. Because MRI is limited in its ability to visualize bone and does not use photons, quantification of uptake on PET images may be less accurate compared with PET/CT. However, MRI has diagnostic advantages over CT in evaluating the brain, head and neck, and pelvis; clinical applications for PET/MRI are currently being developed. Another advantage of MRI is that there is no associated

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Fig. 12.2 Respiratory misregistration. The patient took a full inspiratory breath during the computed tomography (CT) scan (A), while fluorodeoxyglucose–positron emission tomography (FDG-PET) imaging (NAC = without attenuation correction) was obtained with the patient quietly breathing (D). Consequently, the lung nodule on CT (blue arrowhead) does not correlate with the hypermetabolic focus (blue arrow) on PET, as illustrated on the fused PET/CT image (C). On the attenuation-corrected (AC) PET images (B), a photopenic rim is noted at the lung base reflecting diaphragmatic misregistration (red arrows). Because the CT scan is used for attenuation correction of the PET images, standardized uptake value (SUV) measurements made on misregistered lesions may not be accurate.

ionizing radiation; thus, PET/MRI may have additional applications in the pediatric population.

GENERAL ASPECTS OF TUMOR VISUALIZATION ON FDG-PET FDG is currently the most widely used radiotracer in clinical PET imaging. Tumor imaging with FDG is based on the principle of increased glucose metabolism of cancer cells, which are more dependent on anaerobic glycolysis (Warburg effect). Like glucose, FDG is taken up by the cancer cells through facilitative glucose transporters (GLUTs). Once in the cell, glucose or FDG is phosphorylated by hexokinase to glucose-6-phosphate or FDG-6-phosphate, respectively. Expression of GLUTs and hexokinase, as well as the affinity of hexokinase for phosphorylation of glucose or FDG, is generally higher in cancer cells than in normal cells. Glucose-6-phosphate travels farther down the glycolytic or oxidative pathways to be metabolized, in contrast to FDG-6-phosphate, which cannot be metabolized. In normal cells, glucose-6-phosphate or FDG-6-phosphate can be dephosphorylated and exit the cells. In cancer cells, however, expression of glucose-6-phosphatase is usually significantly decreased, and glucose-6-phosphate or FDG-6-phosphate therefore can become only minimally dephosphorylated and remains in large part within the cell. Because FDG-6-phosphate cannot be metabolized, it is trapped in the cancer cell as a polar metabolite; thus, it constitutes the basis for tumor visualization on FDG-PET scans. The intensity of a malignant tumor on PET is dependent on the histology and number of malignant cells in the tumor mass. Hodgkin lymphoma and melanoma are markedly intense on FDG-PET. Other tumors, such as bronchioloalveolar lung cancer, mucinous adenocarcinomas, or mucosal-associated lymphoid tissue (MALT) lymphomas, may have only modest FDG activity. In addition, FDG is also taken up in benign processes such as infection and inflammation because white blood cells and fibroblasts are highly avid for FDG. The major causes for false-positive and false-negative FDG-PET activity are summarized in Box 12.1.

Radiation therapy can elicit a chronic accumulation of metabolically active macrophages that are avid on FDG-PET scans. The time course is variable and is dependent on the tumor site, but FDG activity may persist for months in the radiation treatment field. An example of evolving postradiation therapy changes in lung cancer is shown in Fig. 12.3. Interestingly, FDG-PET may be obtained during chemoradiation therapy to evaluate early response in patients with non–small cell lung cancer (NSCLC), suggesting that this inflammatory activity may be delayed until some time after therapy.2,3 In contrast, radiation therapy may result in false-positive FDG activity when evaluating early response to neoadjuvant therapy in esophageal cancer; FDG-PET is typically used to evaluate early response to the chemotherapy alone prior to adding radiation therapy.

PATIENT PREPARATION FOR FDG-PET To minimize FDG uptake in the muscle while maximizing its uptake in tumor, patients are instructed to fast for at least 4 hours and avoid excessive physical activity for 24 hours before the PET appointment. Glucose-containing drinks and intravenous glucose should be avoided at least 4 hours before FDG injection. The fasting state lowers the serum level of glucose so that FDG has less competition for uptake by the tumor; muscle uptake is minimized by fasting (by lowering the serum insulin level) and by avoiding excessive physical activity. Low FDG uptake in the muscles improves the tumor-to-background ratio and the image quality. Since high glucose levels in patients can degrade image quality, serum glucose is routinely measured at many institutions prior to injecting FDG. Although a normal glucose level in diabetic patients is desirable, it often cannot be achieved. Most institutions perform PET for diabetics after one or two attempts to reduce the serum glucose level below an empirically set level of 200 to 250 mg/dL. Although the positive predictive value of the findings on such a scan remains high, the negative predictive value may be reduced, and quantitative measurements of tumor activity are not reliable.

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Potential Pitfalls in Oncologic Imaging With FDG-PET BOX 12.1

I. False-Positive Uptake 1. Variant physiological activity a. Cardiac b. Thyroid c. Gastrointestinal tract d. Genitourinary tract e. Brown fat, muscle 2. Nonmalignant conditions a. Inflammation, particularly chronic b. Atypical infection, including fungal c. Granulomatous diseases, sarcoidosis d. Pneumoconioses e. Benign neoplasms (adenomas) f. Reactive lymph nodes 3. Posttreatment changes a. Prior radiotherapy b. Talc pleurodesis c. Postsurgical II. False-Negative Uptake 1. Variable FDG metabolism a. Prostate adenocarcinoma b. Renal cell carcinoma c. Neuroendocrine tumors, carcinoid d. Bronchoalveolar lung cancer (adenocarcinoma in situ, minimally invasive adenocarcinoma) e. Lobular breast cancer f. Mucinous neoplasms g. Low-grade lymphomas, mucosa-associated lymphoid tissue lymphoma h. Hepatocellular carcinoma i. Sclerotic osseous metastases j. Necrotic or cystic tumors and nodes k. Small or superficial lesions l. Sentinel lymph nodes 2. High adjacent FDG background activity a. Cerebral cortex b. Gastrointestinal tract c. Genitourinary tract d. Cardiac e. Activated bone marrow FDG, Fluorodeoxyglucose; PET, positron emission tomography.

FDG uptake within brown fat in the neck and supraclavicular regions is a common artifact that may obscure pathological findings; careful anatomic correlation with the CT images is required to exclude superimposed pathology. FDG uptake in brown fat is more common and extensive in pediatric patients—it can be seen in the mediastinum, paraspinal region, and upper abdomen. It has been shown that diazepam administration4 or warm blankets5 can be used to reduce the FDG uptake in brown fat.

PET QUANTIFICATION One of the advantages of PET imaging with attenuation correction is the ability to measure activity within target lesions. The standardized uptake value (SUV) is a semiquantitative measure of the tracer uptake in a region of interest that normalizes the lesion activity to the

decay-corrected injected activity and a measure of the volume of distribution (usually total body weight or lean body mass). For FDG-PET, it is generally accepted that SUV alone is not reliable to differentiate malignant from benign processes and that other factors—including lesion location, size, CT morphology, pattern of contrast enhancement, and symmetry— contribute to this evaluation. In addition, there are many technical and biological factors that can influence the observed SUV, such as the patient’s serum glucose, the time between tracer injection and image acquisition, the detector technology of the PET scanner, attenuationcorrection map (differences in energy of CT and PET photons), imaging field of view, and the image reconstruction parameters.6,7 Nonetheless, the SUV may be useful as a measure to follow the metabolic activity of a tumor over time within the same patient and to compare different subjects within a research study under defined conditions. For FDG-PET, the magnitude of early response to therapy varies with tumor histology. Most malignancies responding to therapy exhibit a 20% to 35% reduction in SUV early in the course of therapy; these changes have prognostic significance.8 On the other hand, tumors such as Hodgkin lymphoma, diffuse large B-cell lymphoma, and gastrointestinal stromal tumors (GISTs) have a dramatic response on FDG-PET soon after initiation of therapy, which can be assessed visually (see lymphoma section to follow). Several clinical trials are investigating the ability of PET to direct therapy at various organ sites based on metabolic response early in the course of therapy. Currently, SUV measurements are not sufficiently standardized between PET/CT scanners; thus, the baseline and follow-up scans should be performed on the same PET/CT scanner for reliable assessment of early response to therapy. General criteria for quantitative assessment of PET response to therapy have been outlined (PET response criteria in solid tumors [PERCIST]),9 although these criteria primarily apply to cytotoxic therapy and FDG-PET scanning. However, PET response criteria for non-FDG tracers as well as for targeted therapy and immunotherapy require further development. Global parameters that describe overall metabolically active tumor burden may become more important for determining treatment response.

COMMON INDICATIONS FOR FDG-PET/CT IN ONCOLOGY Lung Cancer FDG-PET/CT has an overall sensitivity higher than 90% and specificity of about 85% for diagnosing malignancy in primary and metastatic lung lesions; the sensitivity and specificity of FDG-PET for small-cell lung cancer are similar. The sensitivity of FDG-PET for bronchioloalveolar lung cancer and carcinoid of the lung is about 60%, and the specificity of PET for lung cancer is lower in areas with a high prevalence of granulomatous lung disease. FDG-PET is particularly useful in patients with a low (5%–20%) or intermediate (20%–70%) risk of lung cancer, as determined by an evaluation of symptoms, risk factors, and radiographic appearance. In these cases, FDG-PET is helpful in moving the patient to the very-low-risk (70%) category.10 It is expected that the use of FDG-PET for diagnosing malignancy in indeterminate lung nodules will continue to grow as more patients are diagnosed with nodules on CT performed for other indications or as a screening test. In mediastinal staging of NSCLC, patients with clinical stage I and stage II disease have, by definition, a radiographically negative mediastinum. However, in patients with central tumors, adenocarcinoma, or N1 lymph node enlargement, the false-negative rate of CT for mediastinal involvement is 20% to 25%. It is unclear whether FDG-PET should be used instead of mediastinoscopy in staging the disease of these patients. In mediastinal staging of clinical stage III tumors, positive results of FDG-PET need to be confirmed by tissue diagnosis because

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CHAPTER 12 Pre-XRT

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2 months post-XRT

B 5 months post-XRT

C

10 months post-XRT

D Fig. 12.3 Evolution of posttreatment changes in the lung following radiation therapy. Pretherapy positron emission tomography/computed tomography (PET/CT) scan (A) demonstrates bilateral hilar masses, predominantly on the left. PET/CT at 2, 5, and 10 months following radiation therapy (B–D) include evolving atelectasis and bronchiectasis on CT, with associated mild homogeneous fluorodeoxyglucose (FDG) accumulation. The geographic distribution and absence of focal FDG accumulation are characteristic of expected postradiation changes. XRT, Radiotherapy.

of a relatively high false-positive rate (15%–20%). The false-negative rate of FDG-PET and mediastinoscopy in assessing enlarged mediastinal lymph nodes is 5% to 10%. Therefore, some authorities do not pursue biopsy in the case of a negative FDG-PET result for disease in the mediastinum. Others, however, argue that mediastinoscopy can detect “microscopic” metastases—thus, they are not comfortable accepting a negative FDG-PET result.11 Practically, in larger centers, patients with stage III tumors undergo both FDG-PET to assess for distant metastases and mediastinoscopy, but a strong argument for staging of the mediastinum with FDG-PET can be made in communities without an experienced mediastinoscopy service. In any case, it should be noted that the term microscopic is not well defined and that routine pathological tissue processing may be a limiting factor in detecting microscopic disease. For patients with clinical stage I peripheral tumors, most authorities do not request mediastinoscopy before surgery because the rate of mediastinal or systemic involvement is very low (about 5%). Among patients with clinical stage II tumors, the rate of metastatic disease is higher—there is a debate about whether FDG-PET is warranted in these patients to assess for systemic disease. For stage III tumors, the false-negative rate of clinical evaluation for systemic disease is about 15% to 30%, and FDG-PET, therefore, is justified instead of a battery of other tests (e.g., bone scan, CT, and MRI) to assess for distant metastases.11 According to the most recent recommendations of the American College of Chest Physicians, in patients with a normal clinical evaluation and no suspicious extrathoracic abnormalities on chest CT who are being considered for curative-intent treatment, FDG-PET is

recommended to evaluate for metastases.12 FDG-PET is more sensitive (90% vs. 80%) and more specific (90% vs. 70%) than bone scan in detecting bone metastases from NSCLC; FDG-PET has a sensitivity and specificity of greater than 90% in detecting adrenal metastases from NSCLC. Brain CT or MRI is still needed because FDG-PET cannot reliably detect brain metastases owing to physiologically intense brain uptake of FDG. For patients with stage IV tumors, FDG-PET can potentially indicate the best accessible site for biopsy. PET is also useful in restaging NSCLC. In particular, FDG-PET appears to be more sensitive than CT in differentiating postirradiation change from local recurrence, although differentiating these two entities remains a challenge. The postirradiation change in the chest can remain intense on FDG-PET for up to several years. In differentiating local recurrence from postirradiation change, the intensity of uptake and focality should be taken into account (Figs. 12.3 and 12.4).

Head and Neck Cancers Most patients with head and neck cancers present for FDG-PET with a known diagnosis. However, cervical lymph node metastases from an unknown primary constitute about 5% of newly diagnosed head and neck cancer cases; CT and MRI can identify up to 50% of the primary tumors in patients with no findings on physical examination. The overall FDG-PET detection rate in patients with negative results of physical examination, CT or MRI, and endoscopy is about 25%. However, this number is probably higher if PET is performed before endoscopy. In one prospective study, patients underwent FDG-PET prior to endoscopy but the results were not revealed to surgeons before performing the

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A

B

C

D

Fig. 12.4 Recurrence following radiotherapy. Contrast-enhanced computed tomography (CT) with lung (A) and soft-tissue (B) windows demonstrates opacity in the left upper lung in a geographic distribution consistent with postradiotherapy changes. Fused PET (positron emission tomography)/CT (C) and PET (D) images reveal expected mild activity within the radiation treatment field, but superimposed focal activity (arrow) on FDG (fluorodeoxyglucose)-PET corresponds to a focal area of nodular pleural thickening on CT (light-blue arrows), which was subsequently shown to represent recurrent tumor.

procedure under anesthesia. The surgeons were able to find the primary site of the disease in only 5 out of 20 patients. When FDG-PET information was revealed to the surgeons during the procedure, they were able to find the primary site of the disease in another 6 patients, which improved the detection rate to a total of 11 out of 20 patients.13 It should be noted that knowledge of the variable benign and physiological uptake patterns of FDG in the head and neck region is essential to minimize false-positive interpretations. In initial staging of head and neck tumors, FDG-PET has a sensitivity and specificity of about 90% for nodal staging. Therefore, FDG-PET is more sensitive and specific than CT or MRI. A weakness of FDG-PET is its low sensitivity (30%) for nodal disease in patients with clinically N0 necks. Given the high specificity of FDG-PET in nodal staging, it appears reasonable to perform neck dissection in patients with a positive PET result, whereas those with a negative FDG-PET result may be able to undergo sentinel node localization and biopsy.14 In addition to local staging, FDG-PET can detect synchronous malignancies and distant metastases. In initial staging of head and neck malignancies, an FDG-PET scan is overall most helpful in patients with locally advanced disease because these patients have a risk of 10% or greater for distant disease. Furthermore, FDG-PET has been playing an increasingly important role in planning radiation treatment in patients with head and neck cancers because it helps to better delineate the primary tumor from surrounding tissue and differentiate between metastatic and benign lymph nodes. For restaging of head and neck tumors after radiation therapy, FDG-PET is highly sensitive for detecting residual disease but should be performed at least 3 months after irradiation to avoid false-positive findings. Patients with a negative scan at 3 months after irradiation can be followed without intervention (i.e., high negative predictive value),

but those with a positive scan need to undergo further evaluation and possibly biopsy.14 For follow-up of the patients with a negative FDG-PET 3 months after completion of radiation therapy, there are currently no definitive data (particularly for the HPV+ population) to indicate the time interval and total duration of the follow-up, which should depend on the patient’s individual risk factors.

Lymphoma Hodgkin disease and high-grade non-Hodgkin lymphoma are mostly markedly avid for FDG and almost always visible on FDG-PET. Low-grade non-Hodgkin lymphoma may be only mildly intense and, in rare cases, completely invisible on FDG-PET. FDG-PET is superior to CT in staging lymphoma and is recommended by the International Harmonization Project (IHP) for staging Hodgkin lymphoma and aggressive nonHodgkin lymphoma because of their consistent FDG avidity and potential curability. It is reasonable to use FDG-PET in all lymphomas except chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), and some peripheral T-cell lymphoma (PTCL).15 However, there is no definite evidence that FDG-PET changes the initial management in a significant number of patients with these types of lymphoma. In patients presenting with adenopathy but nondiagnostic biopsies, FDG-PET may be useful for guiding tissue sampling to the most metabolically active targets. For staging lymphoma, the incorporation of CT with intravenous and oral contrast may be helpful to better delineate intraabdominal disease and for reliable measurement of lymph node size.15 Intense splenic uptake (i.e., more intense than the liver) before chemotherapy is a reliable indicator of lymphomatous involvement, but spleen involvement by lymphoma cannot be excluded with normal uptake. Physiological marrow activity on FDG-PET can be variable and

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CHAPTER 12 may be increased following chemotherapy or hematopoietic-stimulating drugs, decreasing FDG-PET sensitivity for detecting marrow involvement. However, focal FDG activity within the marrow or osseous structures should raise suspicion for metastatic involvement. One of the most important roles of FDG-PET in lymphoma management is in early evaluation of response to chemotherapy (i.e., interim PET) and evaluation of a residual mass for active lymphoma at the completion of chemotherapy (i.e., end-of-treatment PET). The decrease of uptake associated with effective chemotherapy seen on interim FDG-PET precedes the anatomic changes seen on CT; at the completion of chemotherapy, CT demonstrates a residual mass at the initial site of disease in as many as 50% of patients. In both situations, response to therapy is assessed visually by comparing the FDG activity within residual mass to the activity within the liver and mediastinal blood pool (Deauville criteria).16,17 Residual FDG activity below that of the liver is generally considered to reflect a complete metabolic response for Hodgkin and diffuse large B-cell lymphoma. The positive predictive value of residual uptake at the completion of chemotherapy is more than 90%. The negative predictive value is likely lower and associated with microscopic remnant disease. In follow-up of lymphoma patients in remission, FDG-PET is more sensitive than CT in detecting recurrent disease. However, there are no guidelines as to how often follow-up FDG-PET scans should be performed.

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Colorectal Cancer FDG-PET plays no role in the diagnosis or initial staging of primary colorectal cancer, as neither the depth of the tumor nor the local lymph node status can be effectively assessed by FDG-PET. However, FDG-PET is highly sensitive in detecting distant hepatic and extrahepatic metastases. A meta-analysis of the literature on detection of hepatic metastases from colorectal, gastric, and esophageal cancers by ultrasound, CT, MRI, and FDG-PET found that in studies with a specificity higher than 85%, the mean weighted sensitivity was 55% for ultrasound, 72% for CT, 76% for MRI, and 90% for FDG-PET. Results of pairwise comparison between imaging modalities demonstrated a greater sensitivity of FDG-PET compared with ultrasound (p = 0.001), CT (p = 0.017), and MRI (p = 0.055). The conclusion was that at equivalent specificity, FDG-PET is the most sensitive noninvasive imaging modality for the diagnosis of hepatic metastases from colorectal, gastric, and esophageal cancers.18 Considering the higher sensitivity of FDG-PET in detecting distant metastases, it is conceivable that contrast-enhanced FDG-PET/ CT in preoperative staging of colorectal cancer can be used instead of conventional CT or MRI for evaluation of anatomic resectability of liver metastases. FDG-PET can play an important role in restaging colorectal cancer. FDG-PET can visualize the site of the local and distant disease when recurrence is suspected based on the clinical findings, findings on other imaging modalities, or an increasing carcinoembryonic antigen level with sensitivity and specificity higher than 90% (Fig. 12.5).

Breast Cancer FDG-PET can increase the detectability of small primary breast cancers and may be useful especially in evaluating patients with dense breasts. In evaluating the axillary lymph nodes, FDG-PET does not play any role because of its low sensitivity (60%) despite relatively high specificity (80%).19 In contrast, FDG-PET is relatively sensitive (85%) and specific (90%), and it is superior to CT (sensitivity of 54%, specificity of 85%) in evaluation of the internal mammary chain lymph node for metastases. The primary role of FDG-PET in breast cancer lies in the investigation of distant metastases for high-risk patients and response monitoring. Compared with CT, FDG-PET has a higher sensitivity (90% vs. 40%) but lower specificity (80% vs. 95%) in detecting metastatic disease. Overall, FDG-PET has the same sensitivity as bone scan in detecting

B Fig. 12.5 Positron emission tomography/computed tomography (PET/ CT) for differentiating local recurrence from scar in a patient with colon cancer, status after low anterior resection. Recurrent disease was suspected based on increasing carcinoembryonic antigen (CEA) level. CT is not able to differentiate between scar and local recurrence. (A) FDG (fluorodeoxyglucose)-PET indicated an intense focus (arrow) suspicious for malignancy. A second mild focus was interpreted as scar (arrowhead). (B) The diagnosis was confirmed surgically and the recurrent tumor was removed.

bone metastases (both about 90%) and is overall more sensitive than bone scan for osteolytic lesions and somewhat less sensitive than bone scan for osteoblastic lesions. However, FDG-PET has a higher specificity than bone scan in detecting bone metastases (95% vs. 80%). This may be explained by the fact that FDG-PET captures the metabolic activity of the tumor cells independently of changes in the bone, whereas bone scan reflects remodeling, which can result from metastatic disease as well as other benign causes. In patients with advanced breast cancer undergoing neoadjuvant chemotherapy, FDG-PET can differentiate responders from nonresponders as early as after the first cycle of therapy. This may help improve patient management by avoiding ineffective chemotherapy and supporting the decision to continue dose-intensive preoperative chemotherapy in responding patients, although universal criteria for assessing response have not been established. Although still under investigation, PET imaging with 18F-fluoroestrodiol (FES-PET) has been shown to identify sites of estrogen receptor–positive breast cancer. The in vivo identification of receptor-positive disease may be important as a predictive biomarker for response to hormonal therapy, especially since different tumor sites in the same patient may have variable receptor density.20 Breast-specific gamma imaging (BSGI) is gaining interest in breast imaging. The limitations and controversies surrounding mammography are well known. Single-photon gamma devices have now been developed for specifically imaging the breast. These use 99mTc-Hexakis

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(2-methoxy-2-methylpropylisonitrile), also known as sestamibi, a tracer that has been used for imaging in malignancies before the rise of FDG-PET or where PET was not readily available. The modality may be particularly useful in denser breasts, for which traditional mammographic evaluation is more limited. Recent publications have shown good ability to evaluate lesions, with an overall accuracy of about 91%.21 Positron emission mammography (PEM) similarly uses breast-specific PET imaging technology with FDG. Again, this holds promise in mammography, demonstrating significant improvement in diagnostic accuracy. Studies have demonstrated a similar performance as compared with breast MRI, providing complementary information in the evaluation of breast cancer. Still, even combining these modalities shows some limitations in the initial surgical management of disease.22

FDG-PET/CT APPLICATIONS IN OTHER MALIGNANCIES In esophageal and gastric cancer, FDG-PET is useful for initial staging and has the potential to be used to determine early response to neoadjuvant therapy. In ovarian, uterine, and cervical cancer, FDG-PET can be used to assess for recurrent disease. Evaluation for pelvic nodal involvement in gynecological tumors is especially challenging since early involved nodes may be small and difficult to resolve among the pelvic organs and vascular structures. Combined FDG-PET/CT with intravenous and oral contrast is particularly valuable for evaluating pelvic nodes. Malignant melanoma has very high FDG metabolism, but FDG-PET still lacks the sensitivity required to detect the microscopic disease within sentinel nodes and thus cannot replace lymphoscintigraphy. FDG-PET is most valuable for staging patients with positive sentinel nodes or other high-risk features and is useful for restaging patients following therapy, although the role of FDG-PET in the assessment of response to immunotherapy is still being defined. In sarcoma, the most intense areas on FDG-PET usually have the highest grade and should be considered for biopsy.

PET Imaging for Prostate Cancer (Non-FDG) Adenocarcinoma of the prostate is the most common malignancy in men but typically has low glucose metabolism and is not metabolically active on FDG-PET. Two PET tracers have been FDA approved in the United

States for evaluating prostate cancer: 11C-choline and 18F-FACBC (fluciclovine). Prostate imaging with 11C-choline is available only at facilities with an on-site cyclotron (owing to the short half-life of 11C), while 18 F-FACBC is available by commercial distribution. 18F-choline has also been studied but is not currently approved for use in the United States. 11 C-choline was the first PET tracer approved for imaging prostate cancer in the United States. Tumor cells produce abundant quantities of choline because it is a precursor of phosphatidylcholine, a major constituent of membrane lipids that, along with proteins, are synthesized during cell proliferation. Choline kinase is upregulated in malignancy, which leads to incorporation and trapping of choline into lecithin. A recent study showed an accuracy of 99% when 11C-choline PET is used in a hybrid PET-MRI scanner.23 18F-fluorocholine (FCh)24 and 18F-FACBC (1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid)25 are also being analyzed for evaluating prostate cancer and will also likely benefit from the combination of PET/MRI. Fluciclovine (18F-FACBC) was approved by the FDA in May 2016 for evaluating patients who have biochemical recurrence following prostatectomy or primary radiation therapy and is now available through commercial distribution. An example of an FACBC-PET/CT scan in a patient with a rising prostate-specific antigen (PSA) level following radiation therapy is shown in Fig. 12.6. Other new promising PET tracers targeting prostate-specific membrane antigen (PSMA) levels are currently under active investigation,26 including both 68Ga- and 18F-labeled compounds. The sensitivity of these imaging agents is related to the serum PSA levels. Dietlein et al. compared two PSMA PET tracers (18F-DCFPyL and 68Ga-PSMA-HBEDCC) in patients with biochemical recurrence following prostatectomy or radiotherapy.27 In this study, both agents had relatively good sensitivity for detecting disease when the PSA was above 0.5 μg/L, but lacked sensitivity below this threshold. More investigation is warranted to determine the role that these tracers may have for initial staging of moderate/high-risk prostate cancer, guiding radiotherapy treatment planning, and managing patients with oligometastatic disease.

Bone Imaging Bone scanning remains one of the most common procedures in nuclear medicine. Follow-up of osseous metastases is particularly difficult using

A

B

C Fig. 12.6 A 68-year-old man with prostate cancer treated with radiotherapy and androgen-deprivation therapy, presenting with rapidly rising prostate-specific antigen level. 18F-FACBC (1-amino-3-fluorine 18-fluorocyclobutane1-carboxylic acid)-PET/CT scan demonstrates fiducial marker and heterogeneously increased activity within the prostate gland, nonspecific but concerning for residual/recurrent tumor (A). In addition, radiotracer-avid left pelvic (B) and para-aortic (C) nodes are suspicious for metastatic disease (red arrows).

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CHAPTER 12 anatomic imaging; bone scans provide a straightforward technique for imaging the entire skeleton. Traditionally, the study is done using planar whole-body studies employing 99mTc-labeled bisphosphonates, most commonly methylene diphosphonate (MDP) or hydroxyethylene diphosphonate (HDP), allowing the entire skeleton to be surveyed. Additional dedicated planar or SPECT views can also be obtained if needed to evaluate selected sites in more detail. MDP and HDP accumulation is related to the osteoblastic phase of bone remodeling; thus, planar bone scintigraphy is relatively insensitive for the detection of lytic lesions. In addition, bone remodeling occurs in many conditions, including arthritis, inflammation, trauma, benign and malignant neoplasms, and metastatic disease, reducing the specificity of the study. SPECT and SPECT/CT imaging can improve the accuracy of the study; however, a single SPECT acquisition can take 15 to 30 minutes and covers only a selected area of the body. Oncology patients undergoing bone scans for staging or follow-up frequently also undergo CT scanning; correlation of the CT and bone scan findings is often complementary and improves the specificity of skeletal scintigraphy. 99m Tc bone scans are not quantitative; thus, assessment of improving or progressive disease based on visual uptake has limitations. Moreover, since the scans reflect bone remodeling, uptake can be transiently increased as metastases respond to chemotherapy (the “flare” effect). For this reason, progressive disease typically requires the appearance of two or more lesions on bone scan. 18 F-sodium fluoride (NaF) was one of the first radiopharmaceuticals used for skeletal scintigraphy but was superseded by the development of 99mTc tracers and improved gamma camera technology. However, there has been renewed interest in bone imaging with NaF using PET/ CT technology.28 Additional advantages of NaF-PET/CT compared with 99m Tc bone scans include shorter uptake time (1 hour vs. 2–4 hours) and the ability to obtain diagnostic contrast-enhanced CT scans along with the NaF-PET images, and more accurate quantification of uptake. Although NaF is FDA approved, NaF-PET scanning does not have broad coverage by insurance at the time of this writing for reimbursement as a routine clinical procedure. However, NaF may have a clinical role as the most sensitive modality for assessing osseous metastatic disease and has potential application in assessing response to therapy.

Neuroendocrine Tumor Imaging: SPECT and PET Well-differentiated neuroendocrine tumors are not metabolically active on FDG-PET and are better imaged using iodinated norepinephrine analogs metaiodobenzylguanidine (123I-MIBG or 131I-MIBG) or somatostatin receptor (SSR) analogs. Somatostatin receptor imaging can be done with SPECT or SPECT/CT imaging using 111In-octreotide). 111 In-octreotide is a peptide that has been traditionally used for evaluating neuroendocrine tumors (NETs), including carcinoids, tumors associated with the multiple endocrine neoplasias, meningiomas, and lymphomas (i.e., Hodgkin disease and non-Hodgkin lymphoma). Increased activity can also be seen in benign disease, such as sarcoidosis and other inflammatory processes. 111In-octreotide has the highest affinity for SSR subtypes 2 and 5, with weaker affinities for others. This agent is still relevant in the era of FDG-PET because well-differentiated lesions typically do not take up FDG. Following injection of 111In-octreotide, whole-body imaging is typically obtained 4 and 24 hours later (further delayed images are also sometimes acquired at 48 hours). The 24-hour images have superior target-to-background but can be confounded by physiological GI activity; the 4-hour images allow evaluation prior to the appearance of this activity. SPECT or SPECT/CT images are also typically acquired at 24 hours. Radiolabeled metaiodobenzylguanidine (MIBG), a norepinephrine analog taken up by the uptake 1 mechanism in receptors, can also be

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used for evaluating neuroendocrine tumors. MIBG imaging is particularly effective for characterizing pheochromocytomas, paragangliomas, and neuroblastomas. MIBG can be labeled with either 131I or 123I for planar and SPECT or SPECT/CT imaging. Imaging is performed 24 hours after injection of 123I-MIBG or 48 hours after injection of 131I-MIBG. The sensitivity for lesion detection in neuroblastoma can exceed 90%, and specificity approaches almost 100% for SPECT imaging.29 Nevertheless, as tumors dedifferentiate or metastasize to other sites, MIBG becomes less sensitive in detecting active disease, particularly osseous metastatic disease. In these situations, bone scanning may be complementary. PET imaging using SSR analogs labeled with 68Ga (DOTANOC, DOTATOC, and DOTATATE) has been shown to be much more sensitive and accurate than SPECT imaging with 111In-octreotide for evaluating neuroendocrine tumors. In addition, PET scanning for these studies is performed 1 hour following injection, enabling the entire study to be completed in 2 hours. 68Ga is a PET radionuclide with a half-life of 68 minutes, which can be conveniently eluted from a commercially available 68 Ge/68Ga generator. Therefore, 68Ga PET tracers can be available at sites without a cyclotron. An example of a 68Ga-DOTATATE-PET/CT scan in a patient with hepatic metastases from a neuroendocrine tumor is illustrated in Fig. 12.7. This tracer has very high target-to-background ratio; therefore, it is very sensitive for SSR-positive tumors. In this case, the primary duodenal tumor was not identified with anatomic imaging but was well delineated by DOTATATE-PET. Several studies have demonstrated the clear superiority of SSR PET over 111In-octreotide imaging and the clinical value in managing patients with a variety of neuroendocrine tumors.30,31 In a study of 76 consecutive scans on patients with neuroendocrine tumors, Hofman et al. found that DOTATATE-PET/ CT had a moderate or high impact on treatment decisions in 58% of the cases.31 Dedifferentiated or poorly differentiated neuroendocrine tumors tend to lose their receptor avidity on DOTATATE-PET and become more active on FDG-PET, making these studies potentially complementary. In addition to imaging, MIBG and DOTATATE can be used to treat neuroendocrine tumors by substituting 131I and 177Lu, respectively, for the imaging radionuclide. Both 131I and 177Lu are beta emitters, delivering high local radiation dose to the target lesions identified on the diagnostic scans. Typically, 131I-MIBG is administered in a single dose of 300–500 mCi (11.1–18.5 GBq), and 177Lu-DOTATATE is administered using 4 doses (200 mCi, 7.4 GBq) 8 weeks apart.

Cellular Imaging Various agents being developed build on the newer understanding of cellular physiology, including angiogenesis, apoptosis, and other ideas. Some are routinely used clinically, but others show potential for future development and may revolutionize the way cancer is approached. 18 F-fluorothymidine (18F-FLT) is a thymidine analog and PET tracer, which is phosphorylated by thymidine kinase-1 (TK1) to FLTmonophosphate. FLT uptake correlates with TK1 activity and cellular proliferation. FLT may be more suitable than FDG to monitor the effect of chemotherapy and radiation therapy. Another important area of current PET tracer research concerns cell-cell and cell-matrix interaction. Tracers such as 18F-galacto-GRD (glycosylated Arg-Gly-Asp) enable the noninvasive determination of integrin αvβ3 expression and are being evaluated for use in assessing angiogenesis and metastatic potential of tumors. Annexin-V shows great promise for evaluating apoptosis; it is available as a single-photon and PET agent. Highly apoptotic areas in tumors may be more likely to be sensitive to irradiation or chemotherapy—there is the potential for evaluating therapy response or overall disease prognosis with such agents. Similarly, the field of tumor hypoxia is

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B

C

A

Fig. 12.7 A 56-year-old woman with metastatic carcinoid tumor and no evidence of primary tumor on conventional imaging. 68Ga-DOTATATE-PET/CT scan demonstrates diffuse receptor-positive metastases throughout the liver on maximum intensity projection (MIP) PET images (A), and axial fused PET/CT images (B). Focal intense activity in the second portion of the duodenum [(A), green arrow and (C), red arrow], consistent with primary neuroendocrine tumor.

central to the understanding of tumor response to irradiation. PET agents such as 18F-fluoromisonidazole (18F-MISO) and Cu-labeled diacetyl-bis(N[4]-methylthiosemicarbazone) (Cu-ATSM) can be used to detect intratumoral hypoxia. Although still in the evaluation phase, these agents could potentially be used to evaluate areas of hypoxia for targeting radiation delivery.32

SUMMARY Nuclear medicine techniques complement anatomic imaging by providing additional physiological and molecular information. The role of molecular imaging is rapidly evolving along with the practice of oncology. Currently, FDG-PET imaging is used to improve staging and restaging of malignancies and for determining early response to therapy. For targeted therapy and immunotherapy, receptor and other targeted molecular imaging will be used as predictive biomarkers prior to treatment. Understanding tumor heterogeneity will become increasingly important for targeted therapy, and molecular imaging techniques will be needed to guide biopsy targets and assess response. PET/CT with FDG and other PET tracers is a natural extension of CT-based treatment planning for radiation therapy that can be used to improve definition of treatment targets. Finally, new theranostic approaches using matched diagnostic and therapeutic radiopharmaceuticals will continue to be developed.

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CHAPTER 12 9. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(5 suppl):122s–150s. 10. Detterbeck FC, Falen S, Rivera MP, et al. Seeking a home for a PET. Part 1. Defining the appropriate place for positron emission tomography imaging in the diagnosis of pulmonary nodules or masses. Chest. 2004;125:2294–2299. 11. Detterbeck FC, Falen S, Rivera MP, et al. Seeking a home for a PET. Part 2. Defining the appropriate place for positron emission tomography imaging in the staging of patients with suspected lung cancer. Chest. 2004;125:2300–2308. 12. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non–small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl):e211S–e250S. 13. Rudmik L, Lau HY, Matthews TW, et al. Clinical utility of PET/CT in the evaluation of head and neck squamous cell carcinoma with an unknown primary: a prospective clinical trial. Head Neck. 2011;33:935–940. 14. Menda Y, Graham MM. Update on 18F-fluorodeoxyglucose/positron emission tomography and positron emission tomography/computed tomography imaging of squamous head and neck cancers. Semin Nucl Med. 2005;35:214–219. 15. Kostakoglu L, Cheson BD. Current role of FDG PET/CT in lymphoma. Eur J Nucl Med Mol Imaging. 2014;41:1004–1027. 16. Barrington SF, Kluge R. FDG PET for therapy monitoring in Hodgkin and non-Hodgkin lymphomas. Eur J Nucl Med Mol Imaging. 2017;44(suppl 1):S97–S110. 17. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–3067. 18. Kinkel K, Lu Y, Both M, et al. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology. 2002;224:748–756. 19. Wahl RL, Siegel BA, Coleman RE, et al. PET Study Group. Prospective multicenter study of axillary nodal staging by positron emission tomography in breast cancer: a report of the Staging Breast Cancer with PET Study Group. J Clin Oncol. 2004;22:277–285. 20. Liao GJ, Clark AS, Shubert EK, Mankoff DA. 18F-fluoroestradiol PET: current status and potential future clinical applications. J Nucl Med. 2016;57(8):1269–1275.

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21. Park JS, Lee AY, Jung KP, et al. Diagnostic performance of breast-specific gamma imaging (BSGI) for breast cancer: usefulness of dual-phase imaging with 99mTc-sestamibi. Nucl Med Mol Imaging. 2013;47:18–26. 22. Berg WA, Madsen KS, Schilling K, et al. Breast cancer: comparative effectiveness of positron emission mammography and MR imaging in presurgical planning for the ipsilateral breast. Radiology. 2011;258(1):59–72. 23. Piccardo A, Paparo F, Picazzo R, et al. Value of fused 18F-choline-PET/ MRI to evaluate prostate cancer relapse in patients showing biochemical recurrence after EBRT: preliminary results. Biomed Res Int. 2014;103718. 24. de Perrot T, Rager O, Scheffler M, et al. Potential of hybrid 18F-fluorocholine PET/MRI for prostate cancer imaging. Eur J Nucl Med Mol Imaging. 2014;41:1744–1755. 25. Turkbey B, Mena E, Shih J, et al. Localized prostate cancer detection with 18F FACBC PET/CT: comparison with MR imaging and histopathologic analysis. Radiology. 2014;270(3):849–856. 26. Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET in prostate cancer management. Nature Rev Urology. 2016;13:226–235. 27. Dietlein F, Kobe C, Neubauer S, et al. PSA-stratified performance of 18 F- and 68Ga-PSMA PET in patients with biochemical recurrence of prostate cancer. J Nucl Med. 2017;58:947–952. 28. Even-Sapir E, Metser U, Mishani E, et al. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-Fluoride PET, and 18F-Fluoride PET/CT. J Nucl Med. 2006;47:287–297. 29. Lumbroso JD, Guermazi F, Hartmann O, et al. Meta-iodobenzylguanidine (mIBG) scans in Neuroblastoma: sensitivity and specificity, a review of 115 scans. Prog Clin Biol Res. 1988;271:689–705. 30. Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68 Ga-DOTATOC PET and 111In-DTPAOC (octreoscan) SPECT in patients with neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2007;34:1617–1626. 31. Hofman MS, Kong G, Neels OC, et al. High management impact of 68 Ga-DOTATATE PET/CT for imaging neuroendocrine and other somatostatin expressing tumours. J Med Imaging Radiat Oncol. 2012;56:40–47. 32. Geets X, Grégoire V, Lee JA. Implementation of hypoxia PET imaging in radiation therapy planning. Q J Nucl Med Mol Imaging. 2013;57(3):271–282.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 12

REFERENCES 1. Wong TZ, Paulson EK, Nelson RC, et al. Practical approach to diagnostic CT combined with PET imaging. AJR Am J Roentgenol. 2007;188:622–629. 2. Kong FM, Frey KA, Quint LE, et al. A pilot study of [18F] fluorodeoxyglucose positron emission tomography scans during and after radiation-based therapy in patients with non small-cell lung cancer. J Clin Oncol. 2007;25:3116–3123. 3. Usmanij EZ, de Geus-Oei LF, Troost EG, et al. 18F-FDG PET early response evaluation of locally advanced non–small cell lung cancer treated with concomitant chemoradiotherapy. J Nucl Med. 2013;54:1528–1534. 4. Cousins J, Czachowski M, Muthukrishnan A, Currie G. Pediatric brown adipose tissue on 18F-FDG-PET: diazepam intervention. J Nucl Med Technol. 2017;45(2):82–86. 5. Skillen A, Currie GM, Wheat JM. Thermal control of brown adipose tissue in 18F-FDG PET. J Nucl Med Technol. 2012;40(2):99–103. 6. Adams MC, Turkington TG, Wilson JM, et al. A systematic review of the factors affecting accuracy of SUV measurements. AJR Am J Roentgenol. 2010;195(2):310–320. 7. Kinahan PE, Fletcher JW. Positron emission tomography-computed tomography standardized uptake values in clinical practice and assessing response to therapy. Semin Ultrasound CT MR. 2010;31(6):496–505. 8. Weber WA. Use of PET for monitoring cancer therapy and for predicting outcome. J Nucl Med. 2005;46(6):983–995. 9. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(5 suppl):122s–150s. 10. Detterbeck FC, Falen S, Rivera MP, et al. Seeking a home for a PET. Part 1. Defining the appropriate place for positron emission tomography imaging in the diagnosis of pulmonary nodules or masses. Chest. 2004;125:2294–2299. 11. Detterbeck FC, Falen S, Rivera MP, et al. Seeking a home for a PET. Part 2. Defining the appropriate place for positron emission tomography imaging in the staging of patients with suspected lung cancer. Chest. 2004;125:2300–2308. 12. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non–small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of chest physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl):e211S–e250S. 13. Rudmik L, Lau HY, Matthews TW, et al. Clinical utility of PET/CT in the evaluation of head and neck squamous cell carcinoma with an unknown primary: a prospective clinical trial. Head Neck. 2011;33:935–940. 14. Menda Y, Graham MM. Update on 18F-fluorodeoxyglucose/positron emission tomography and positron emission tomography/computed tomography imaging of squamous head and neck cancers. Semin Nucl Med. 2005;35:214–219. 15. Kostakoglu L, Cheson BD. Current role of FDG PET/CT in lymphoma. Eur J Nucl Med Mol Imaging. 2014;41:1004–1027. 16. Barrington SF, Kluge R. FDG PET for therapy monitoring in Hodgkin and non-Hodgkin lymphomas. Eur J Nucl Med Mol Imaging. 2017;44(suppl 1):S97–S110.

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17. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and nonHodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–3067. 18. Kinkel K, Lu Y, Both M, et al. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology. 2002;224:748–756. 19. Wahl RL, Siegel BA, Coleman RE, et al. PET Study Group. Prospective multicenter study of axillary nodal staging by positron emission tomography in breast cancer: a report of the Staging Breast Cancer with PET Study Group. J Clin Oncol. 2004;22:277–285. 20. Liao GJ, Clark AS, Shubert EK, Mankoff DA. 18F-fluoroestradiol PET: current status and potential future clinical applications. J Nucl Med. 2016;57(8):1269–1275. 21. Park JS, Lee AY, Jung KP, et al. Diagnostic performance of breast-specific gamma imaging (BSGI) for breast cancer: usefulness of dual-phase imaging with 99mTc-sestamibi. Nucl Med Mol Imaging. 2013;47:18–26. 22. Berg WA, Madsen KS, Schilling K, et al. Breast cancer: comparative effectiveness of positron emission mammography and MR imaging in presurgical planning for the ipsilateral breast. Radiology. 2011;258(1):59–72. 23. Piccardo A, Paparo F, Picazzo R, et al. Value of fused 18F-choline-PET/ MRI to evaluate prostate cancer relapse in patients showing biochemical recurrence after EBRT: preliminary results. Biomed Res Int. 2014;103718. 24. de Perrot T, Rager O, Scheffler M, et al. Potential of hybrid 18F-fluorocholine PET/MRI for prostate cancer imaging. Eur J Nucl Med Mol Imaging. 2014;41:1744–1755. 25. Turkbey B, Mena E, Shih J, et al. Localized prostate cancer detection with 18F FACBC PET/CT: comparison with MR imaging and histopathologic analysis. Radiology. 2014;270(3):849–856. 26. Maurer T, Eiber M, Schwaiger M, Gschwend JE. Current use of PSMA-PET in prostate cancer management. Nature Rev Urology. 2016;13:226–235. 27. Dietlein F, Kobe C, Neubauer S, et al. PSA-stratified performance of 18 F- and 68Ga-PSMA PET in patients with biochemical recurrence of prostate cancer. J Nucl Med. 2017;58:947–952. 28. Even-Sapir E, Metser U, Mishani E, et al. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-Fluoride PET, and 18F-Fluoride PET/CT. J Nucl Med. 2006;47:287–297. 29. Lumbroso JD, Guermazi F, Hartmann O, et al. Metaiodobenzylguanidine (mIBG) scans in Neuroblastoma: sensitivity and specificity, a review of 115 scans. Prog Clin Biol Res. 1988;271:689–705. 30. Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68 Ga-DOTATOC PET and 111In-DTPAOC (octreoscan) SPECT in patients with neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2007;34:1617–1626. 31. Hofman MS, Kong G, Neels OC, et al. High management impact of 68 Ga-DOTATATE PET/CT for imaging neuroendocrine and other somatostatin expressing tumours. J Med Imaging Radiat Oncol. 2012;56:40–47. 32. Geets X, Grégoire V, Lee JA. Implementation of hypoxia PET imaging in radiation therapy planning. Q J Nucl Med Mol Imaging. 2013;57(3):271–282.

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13 Tumor Ablation in Interventional Radiology A. Nicholas Kurup and Matthew R. Callstrom

Image-guided ablative techniques have been used by interventional radiologists and some surgeons to treat primary and metastatic tumors across several organ systems, including liver, kidney, lung, and the musculoskeletal system. Most treatments use percutaneous needle devices to deliver thermal or other energy to the tumor and its surrounding tissue, creating an ablation zone. These treatments may be performed for curative or palliative purposes, depending on tumor histology, extent of disease, and patient symptoms. Radiologists use medical imaging, most commonly computed tomography (CT), to guide placement of ablative devices into target tumors and to monitor ablation zones, although other imaging techniques, including fluoroscopy, magnetic resonance imaging (MRI), and ultrasound, are also used. Ablation procedures may be performed under conscious sedation or general anesthesia, depending on patient tolerance and planned procedural complexity. These ablation technologies and their most common applications are described herein.

ABLATIVE TECHNIQUES Radiofrequency, Microwave, and Laser Ablation Radiofrequency ablation (RFA) is the oldest and possibly still the most commonly used percutaneous thermal ablative technology. Single or multipronged devices are available, including straight and umbrellashaped needles. Some of these needles circulate cool fluid internally to maintain a sufficiently high temperature without charring the surrounding tissue, which can impede electrical and thermal conduction about the needle tip and thereby prevent complete treatment of target tumor with a sufficient margin. Most commercial devices are capable of creating ablation zones of approximately 3 cm diameter, and several overlapping ablations or multiple needles activated synchronously may be capable of creating even larger treatment zones. Deposition of the energy may be limited by tissue types that have poor conductivity, including air-filled lung, dense bone, or charred soft tissue. Moreover, RFA may be limited by the “heat sink” effect, also called perfusion-mediated tissue cooling, whereby flowing blood within peritumoral vessels of sufficient size prevents adjacent target tissue from achieving lethal high temperatures, resulting in inadequate treatment and residual viable tumor.1 More recent RFA systems have been developed that are bipolar rather than monopolar. With bipolar systems, current passed from the activated device returns to the electrode in a closed loop, avoiding the need for ground pads to be placed on the skin. These bipolar systems are much less stimulating than the monopolar systems, allowing treatment of patients under minimal conscious sedation.2 Microwave ablative (MWA) devices also use electromagnetic energy, albeit of higher frequency, to create a field about the needle tip or tips. Within this field, continuous oscillation of water molecules results in

rapid heating to more consistent and even higher temperatures than RFA. The needles for MWA devices are termed antennas and are linear in shape. Theoretic advantages for MWA include faster heating of a larger volume of tissue to more consistent temperatures.3 These devices can create ablation zones capable of treating tumors over 4 cm to 5 cm in diameter. MWA is less limited by the heat sink effect and does not rely on electrical or thermal conduction, unlike RFA.4 It is possible that these devices will lead to improved oncologic outcomes, particularly in the treatment of liver tumors.5–8 Laser ablation utilizes small caliber, flexible laser fibers to create thermal ablation zones using infrared photons rather than radiofrequency or microwave energy. Each burn with these devices is quite small and numerous overlapping ablations are required to produce large treatment areas like the other heat-based modalities. An advantage of laser systems is its compatibility with MRI guidance and monitoring.9 Heat-based technologies produce the fastest ablation zones, although they cannot be monitored accurately without advanced thermometry MRI techniques.10 They generate gas within the ablation zone, which is visible as a hypodense, hyperechoic area on CT and ultrasound, respectively, but this immediately visible change does not reliably correlate with the volume of necrotic tissue. These devices also cauterize the tissues, so the risk of significant bleeding from these procedures is low.

Cryoablation Cryotherapy using liquid nitrogen has been used for several decades, but smaller caliber segmentally insulated probes using the Joule-Thomson effect have vastly increased the application of tumor freezing by allowing percutaneous application of these devices. Modern cryoablation technology utilizes highly pressurized argon gas that expands within the sealed chamber of each needle probe to cause focal freezing of the surrounding tissue via a marked, rapid endothermic reaction (Joule-Thomson effect). Cell death occurs within the ablation zone from a combination of mechanical disruption of cell membranes by ice crystals, cellular dehydration, and delayed vascular thrombosis and ischemia. Helium gas flow or an electrical heater within the needles is subsequently used for tissue thawing to remove the needles. Several needles may be used simultaneously to produce large ablation zones and can be placed to create zones that match the morphology of tumors. Most importantly, the ice created by cryoprobes is readily visible within soft tissue on conventional CT, ultrasound, and MRI.11 Cryoablation has another advantage in that tissue freezing is generally less painful than heat-based ablation. This technique requires the use of tanks of argon and helium with associated gas regulators. Tissue freezing can cause platelet dysfunction with a slight increased risk of significant bleeding complications compared with heat-based therapies.

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CHAPTER 13

Irreversible Electroporation Irreversible electroporation (IRE) is a newer, nonthermal ablative technology that uses multiple linear needle probes to deliver high voltage pulses into the target tissue.12 These pulses create irreversible pores in cell membranes, leading to loss of cellular homeostasis and cell death by apoptosis with preservation of noncellular stroma. This mechanism may allow for treatment of tumors abutting critical structures, such as bowel, central bile ducts, major nerves, or spinal cord.13 As the newest commercial percutaneous ablative technique, the clinical literature concerning percutaneous IRE consists of small to moderate-sized single-center series, primarily in the liver and pancreas.14–18

Focused Ultrasound Focused ultrasound (FUS) therapy is a noninvasive method of tumor ablation that utilizes specialized ultrasound equipment, usually embedded within the MRI scanner table, to produce areas of coagulative necrosis through concentrated focal heating. Most of the published literature addresses FUS treatment of uterine fibroids, although it is also used commonly for superficial bone tumors in some centers.19,20 Lung tumors are not amenable to this technique owing to the lack of accessibility to ultrasound energy across aerated lung, and liver tumors are not frequently treated with this technique owing to motion.

CLINICAL APPLICATIONS Liver Hepatocellular Carcinoma Thermal ablation is an accepted treatment option for small hepatocellular carcinoma (HCC). In the Barcelona Clinic Liver Cancer staging system and treatment algorithm, thermal ablation is the preferred treatment for very early-stage HCC (single tumor up to 2 cm) and for early-stage HCC not going to liver transplantation (three or fewer tumors up to 3 cm in size or a single tumor up to 5 cm in size).21 Thermal ablation may also be used as a bridge to transplantation for patients living in regions with a lengthy wait list. Similarly, thermal ablation is listed as the preferred treatment for small HCC in the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines.22 A prospective trial and meta-analysis showed equivalent overall and recurrence-free survival and decreased complication rates for RFA compared with partial hepatectomy for very early-stage HCC, but slightly worse 5-year survival and higher local recurrences when larger HCC are included.23,24 One multicenter randomized controlled trial showed cryoablation to be superior to RFA for HCC,25 but widespread adoption of hepatic cryoablation has been limited by the very small, but significant mortality rate of cryoablation in the liver, particularly in those with underlying chronic parenchymal disease.26 The major complication rate for RFA of HCC remains low at 2.2% with the most significant complication of neoplastic seeding occurring rarely at 0.8% of cases.27

Liver Metastases Ablation of liver metastases is most commonly performed for eradication of limited metastatic disease, although other indications include local control of a nonresponding metastasis in the setting of systemic therapy, desire for a chemotherapy holiday with persistent hepatic metastases, and treatment of symptomatic metastases (Fig. 13.1). Most of the published literature supports ablation for local control of limited colorectal carcinoma liver metastases, with fewer early experience studies supporting its use for metastases from other primary tumors or for other indications.28 Numerous single-center and retrospective reviews of ablation of colorectal liver metastases have been published, most using early

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generation devices and several including tumors treated intraoperatively in addition to, or rather than, percutaneously. These studies generally show greater survival with the addition of thermal ablation for nonresectable disease on chemotherapy, but results are inferior to surgical resection in patients with more limited disease, although no prospective, randomized trial data exist.29–34 Some of these studies confirmed long-term survival in a subset of patients following RFA. More recently, a systematic review of thermal ablation of these metastases again suggests inferior oncologic outcomes with ablation compared with surgery, with low-quality evidence as support, but superior results for patients with ablation compared with chemotherapy alone with higher levels of evidence.35 The EORTC (European Organisation for Research and Treatment of Cancer) (40004) CLOCC (Chemotherapy + Local Ablation Versus Chemotherapy) Phase II trial randomized patients with nonresectable colorectal liver metastases to modern chemotherapy plus RFA (plus or minus partial hepatectomy) versus chemotherapy alone.36,37 It showed that median overall survival was significantly greater for chemotherapy plus RFA (45.60 months) compared with chemotherapy alone (40.54 months). Likewise, the 8-year overall survival rate was better at 35.9% compared with 8.9%. This trial was the first prospective, randomized trial to establish a survival benefit for RFA of colorectal liver metastases.

Comparison With Radiation Therapy: Liver Little data exist comparing thermal ablation and radiation therapy in the liver. A single center has compared its outcomes with RFA and stereotactic body radiotherapy (SBRT) for primary HCC and for liver metastases.38,39 Both of these studies showed improved local control with SBRT for tumors larger than 2 cm in size, using freedom from local progression as the imaging endpoint. These studies have several limitations, however, including differences between the patient populations treated with the two therapies, shorter follow-up for patients having SBRT, and different standards for diagnosing recurrent tumor following RFA and SBRT, given challenges of response assessment post SBRT.40,41 A comparative analysis of outcomes for HCC treatment with RFA versus SBRT using the National Cancer Database showed that overall survival was greater for patients treated with RFA.42 This analysis also had several shortcomings, including incomplete characterization of liver function and absence of local recurrence and cancer-specific survival data within the database. Finally, a Markov modeling study comparing cost effectiveness of SBRT and RFA for HCC concluded that SBRT for initial treatment of localized, inoperable HCC is not cost-effective, but that SBRT is the preferred salvage therapy for local progression after RFA.43 In summary, the optimal triage of patients with localized HCC or limited hepatic metastases between thermal ablation and SBRT remains unclear and requires multidisciplinary consultation to consider the appropriateness of each modality for a given patient and tumor.

Lung Thermal ablation has been applied to the treatment of both early stage non–small-cell lung cancer (NSCLC) and limited pulmonary metastatic disease. Several studies over the past two decades have demonstrated the effectiveness of RFA for both of these indications with more recent data emerging to show potential advantages with cryoablation and microwave ablation of lung tumors.44 These modalities all offer a minimally invasive approach to tumor eradication while preserving normal parenchyma, which is particularly important in patients with primary lung cancer in the setting of emphysema. However, in cases of primary lung cancer with early bronchovascular or lymphatic dissemination of disease, the localized approach of thermal ablation may lead to greater recurrence rates compared with surgical segmentectomy, lobectomy, or pneumonectomy. The inability to stage and/or treat mediastinal and hilar nodal disease as well as the primary tumor has

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D Fig. 13.1 Microwave Ablation of a Solitary Liver Metastasis. (A) A 71-year-old man with history of metastatic colon cancer to liver developed a new 3-cm metastasis (arrow) in the left hepatic lobe 1 year following hepatic wedge resection and resection of the primary tumor. Note the proximity of stomach to the subcapsular metastasis. (B) Intraprocedural computed tomography (CT) during microwave ablation shows gas within the ablation zone (arrow) and stomach displaced laterally by a blunt-tipped needle (arrowhead). (C) Ablation zone covers the entire tumor on the 3-month follow-up CT scan. (D) Ablation zone shows normal decrease in size on the 6-month follow-up CT scan.

limited the application of thermal ablation compared with surgery and radiation therapy (Fig. 13.2). The RAPTURE prospective, multicenter clinical trial of RFA for lung tumors was an important initial demonstration of the potential role of thermal ablation in lung. The trial included lung cancer and metastases from multiple primary tumors, most commonly colorectal carcinoma.45 This trial enrolled 106 patients with 183 nonresectable

tumors up to 3.5 cm in size. The local control rate was 88% with no significant difference between NSCLC and metastases. Complications included pneumothorax requiring chest tube placement in 25% and pleural effusion requiring drainage in 4%. Several studies have shown RFA to have higher complete ablation rates with lung tumors smaller than 2 cm in size.46 Adjacency of large vessels has also been shown to be a risk factor for local progression.

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Fig. 13.2 Cryoablation of Lung Metastases. A 53-year-old woman with five pulmonary metastases from rectal cancer was referred for thermal ablation. She had previously undergone right partial hepatectomy and left pulmonary wedge resection for metastases. (A) Maximum intensity projection (MIP) computed tomography (CT) image shows two of her metastases (arrows), a 1-cm tumor in the right middle lobe posteriorly and 0.5-cm tumor in the lingula. (B) Intraprocedural CT image shows a ground-glass attenuation ablation zone surrounding the lingular metastasis during cryoablation of the left pulmonary lesions. (C) Similar appearance of the ablation zone surrounding the right middle lobe metastases during cryoablation of the right-sided lesions performed 2 weeks later. (D) MIP image from the 3-month follow-up CT scan shows linear scars in the locations of these ablation zones with no recurrent tumor.

Primary Lung Cancer In 87 patients with NSCLC treated with RFA, Palussière et al.46 found a 5-year overall survival rate of 58.1% and disease-free survival rate of 27.9%. An American College of Surgeons Oncology Group trial of 51 patients with stage IA NSCLC tumors smaller than 3 cm reported 1- and

2-year survival rates of 86.3% and 69.8%, with 2-year survival rates increasing to 83% in the subgroup of patients with tumors less than 2 cm in size.47 Long-term data for patients with lung cancer treated with MWA or cryoablation are more limited. In a study of 183 patients with lung tumors (138 with primary lung cancer) and median duration

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of follow-up of 34.5 months following MWA, Zheng et al.48 reported a local progression rate of 19.1%, median progression-free survival of 16.5 months, and median cancer-specific survival of 29.0 months. In these studies, larger size (>2 cm or 3 cm) was associated with decreased disease-free survival or increased risk of progression.

Pulmonary Metastases Using RFA, a 4-year local control rate of 89% was reported in the RAPTURE (Radiofrequency Ablation of Pulmonary Tumors Response Evaluation) study for 61 patients at 15 months of follow-up as well as in a larger cohort of 566 patients with 1037 metastases and 35.5 months of follow-up.45,49 Median overall survival in this larger study was 62 months; survival rates at 1- and 5-years were 92.4% and 51.5%.49 Primary tumor, disease-free interval, size greater than 2 cm, and three or more metastases were associated with survival. The prospective, multicenter, Phase II ECLIPSE (Evaluating Cryoablation of Metastatic Lung Tumors in Patients—Safety and Efficacy) trial evaluated the use of cryoablation in 40 patients with 60 lung metastases (mean size 1.4 cm), showing local control rates of 96.6% at 6 months and 94.2% at 12 months, and a 1-year overall survival rate of 97.5%.50

Comparison With Radiation Therapy: Lung A systematic review comparing the effectiveness of RFA and SBRT for inoperable stage I NSCLC showed higher local tumor control rates for SBRT, whereas the overall survival rates were not significantly different.51 An analysis of the National Cancer Database for early stage NSCLC also showed no difference in the overall survival between RFA and SBRT, despite greater comorbidity among the patients treated with RFA.52 Nonetheless, thermal ablation offers some potential advantages, including the ability to treat multiple metastases in close proximity to one another and retreat tumors in the same location following local tumor progression, both of which are clinical scenarios that can prove difficult for radiation therapy because of dose limits.

Bone Musculoskeletal metastases may cause significant morbidity from cancer-related bone pain, pathologic fracture, and compromise of adjacent critical structures. Goals of percutaneous thermal ablation include palliation of pain, prevention of morbidity from skeletal-related events, and local tumor control. Ablation may also be used to treat oligometastatic disease or a solitary site of tumor progression in the setting of disease that is overall stable or responding to systemic therapy. In addition, ablation may be indicated to prevent tumor progression in locations close to critical structures, particularly vertebral tumors near the spinal cord and extraspinal metastases near major motor nerves or plexuses. It may be performed on patients with tumors refractory to radiation therapy, those with recurrent or new tumors nearby radiation fields when surrounding tissues have reached maximum radiation dose limits, patients for whom radiation therapy should be deferred in case of future need, or patients who otherwise decline radiation therapy. Most of the published experience in ablation of bone metastases used RFA or cryoablation devices. A few clinical series have been published on microwave ablation in bone metastases,53,54 whereas IRE remains in the early stages of investigation for skeletal applications.55 Newer bipolar RFA devices have been optimized to treat spine lesions with articulating probes or bipedicular probes that can create ablation zones conforming to the vertebral body.2 MWA and cryoablation have some advantages in energy conduction through intact bone and can produce larger ablation zones than RFA.56,57 Cryoablation has less immediate postablation pain and analgesic requirement and potentially more frequent complete pain responses compared with monopolar RFA following bone tumor ablation.58,59

Palliation of Painful Metastases Palliation of painful metastatic disease is the most common and wellestablished indication for ablation of bone metastases (Fig. 13.3). Many patients offered ablation present with pain refractory to, or recurrent after, radiation therapy. Patients selected for ablation should have a limited number of painful tumors, generally up to three, with moderate pain intensity or greater (i.e., pain scores at least 4 on a 10-point scale).60 Patients with diffuse skeletal metastatic disease and generalized pain are well suited to focal therapy; noninvasive treatment with increased oral analgesics may be more appropriate for patients with mild pain. Using ablation to treat neuropathic pain secondary to a musculoskeletal metastasis that encases an adjacent neural structure may require sacrifice of the nerve, which could improve, worsen, or not change neuropathic pain; in these patients, radiation therapy is usually more appropriate. Multiple prospective multicenter clinical trials have been performed to evaluate the use of ablation for painful skeletal metastases.61–65 In the first multicenter, prospective, single-arm trial, Goetz et al.63 reported a response rate of 95% in 43 patients with a mean score for worst pain decreasing from 7.9 (using a 10-point scale) pre-RFA to 1.4 at 24 weeks after ablation. Other trials have also shown a clinically significant 4- to 6-point (of 10) decrease in mean pain score with 3 to 6 months of follow-up. Several trials also showed a reduction in the use or dosage of analgesics required by the participants. Recently published systematic reviews of palliative RFA for painful metastases in the spine support similar pain reduction in this subset of patients.66,67 Adverse events are rare with rates ranging from 0% to 8% in published prospective trials with higher rates in series of ablation within the spine up to 16%. The most common, important complications include pain, fracture, and nerve injury.

Local Control of Oligometastatic Disease Image-guided thermal ablation may produce durable local tumor control in select patients with oligometastases. Several published series have reported outcomes of ablation in patients with limited renal, breast, lung, and prostate cancer metastases in multiple sites, including bone and soft tissue metastases, with additional studies specifically evaluating musculoskeletal metastasis ablation for any tumor histology type. These single-center, retrospective reports have shown moderate-to-good local tumor control rates of 67% to 97%, with variability likely related to different patient and tumor selection criteria and, to a lesser extent, technique.68–77 Focal metastasis-directed therapy can postpone or avoid the initiation of systemic therapy and its potential side effects.70 Major complication rates in reported series are 0% to 11%, depending on the patient population and tumor location treated.

Comparison With Radiation Therapy: Bone No published data compare pain relief or oncologic outcomes after thermal ablation versus radiation therapy for bone tumors. Radiation therapy is the standard treatment for palliation of cancer-related bone pain with a long record of safety and effectiveness. However, patients may have refractory or recurrent pain after radiotherapy, or they may not be candidates for radiotherapy when radiation dose limits have been reached.78 The published prospective trials of bone tumor ablation included many patients with persistent pain despite radiation therapy, and one small noncomparative series specifically evaluated the combination of radiation therapy and ablation for spinal metastases, finding significant pain relief.79 Intriguingly, a single retrospective matched cohort study by Di Staso et al.80 showed that combined RFA and radiation therapy (15 patients) for solitary painful osteolytic bone metastases resulted in greater pain relief than radiation therapy alone (30 patients). Specifically, the overall response rate for combination therapy at 12

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C Fig. 13.3 Palliative Cryoablation and Cementoplasty for Painful Bone Metastasis. (A) A 68-year-old man with metastatic lung adenocarcinoma presented with a mixed osteolytic and sclerotic left iliac bone metastasis causing moderate hip and groin pain, subjectively graded as 6 of 10 points, despite two courses of palliative radiotherapy. (B) Coronal reformatted computed tomography image during cryoablation shows a hypodense ice ball (arrows) encasing the metastasis and avoiding the hip joint and femoral head. (C) Coronal maximum intensity projection image shows cement filling the osteolytic portions of the metastasis and forming a vertical strut for improved axial loading strength following cementoplasty. The patient reported no pain in his left hip at the 1-month follow-up visit.

weeks was 93.3% compared with 59.9% for the group treated with radiation therapy alone (p = 0.048). These findings suggest a synergistic effect between thermal ablation and radiation therapy.

ADJUNCTIVE DISPLACEMENT, MONITORING, AND CONSOLIDATIVE TECHNIQUES A number of adjunctive techniques allow the application of percutaneous ablation to a wide variety of tumors and help to minimize the risk of collateral injury or other complications. Tumors may be displaced from vital structures intraprocedurally by insertion of fluid, gas, or balloon catheters81,82 or by manual retraction or levering of the ablation probes.83,84 In addition, the ablation zone may be monitored with imaging, temperature probes, and neurophysiologic techniques.81 Ultrasound can provide continuous imaging feedback during thermal ablation or CT/ MR images may be obtained every few minutes during cryoablation to visualize ablative ice as a hypodense or hypointense area surrounding the target tumor, respectively. Temperature monitoring probes placed between the planned ablation zone and critical structures can alert the radiologist to cease the ablation prior to injury. Patients under conscious sedation can provide feedback related to pain in the distribution of a nerve at risk, allowing the ablation to be terminated. Neurophysiologic monitoring with somatosensory or motor-evoked potentials or direct nerve stimulation is also very useful.85,86

Because many bone metastases are osteolytic and located within the axial skeleton, structural stability and weight-bearing capacity are frequently compromised. These lesions may be associated with or be at risk for pathologic fracture, and thermal ablation may be combined with cementoplasty to strengthen axial-load bearing. In these cases, ablation may sterilize the medullary cavity prior to cement instillation in order to minimize the potential risk of cement displacing viable tumor into extraosseous locations. Bone metastases in locations subject to torsional or shear forces can be combined with other percutaneous stabilization techniques.87–89

CONCLUSION Percutaneous image-guided ablation techniques offer an important treatment alternative for patients with various tumors in liver, lung, or bone. Ablation may result in significant palliation of pain or other tumor-related symptoms, prevention of morbidity from local tumor progression in sensitive locations, and durable local control or cure in select patients. This minimally invasive approach has unique advantages and a complementary role to systemic, surgical, and radiation therapies, adding to the traditional armamentarium of the treatment team. Treatment decisions are complex and should be tailored to individual patients, depending on patient fitness and comorbidity; tumor size, location, and histology; and prior therapies. A multidisciplinary approach, including

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medical oncology, radiation oncology, surgery, and interventional radiology, is best suited to collaborate in the treatment of patients with cancer and to ensure that all available techniques are considered.

CRITICAL REFERENCES 8. Vietti Violi N, Duran R, Guiu B, et al. Efficacy of microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma in patients with chronic liver disease: a randomised controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2018;3:317–325. 19. Hurwitz MD, Ghanouni P, Kanaev SV, et al. Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results. J Natl Cancer Inst. 2014;106. 23. Peng ZW, Lin XJ, Zhang YJ, et al. Radiofrequency ablation versus hepatic resection for the treatment of hepatocellular carcinomas 2 cm or smaller: a retrospective comparative study. Radiology. 2012;262:1022–1033. 24. Wang Y, Luo Q, Li Y, et al. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinomas: a meta-analysis of randomized and nonrandomized controlled trials. PLoS ONE. 2014;9:e84484. 31. Solbiati L, Ahmed M, Cova L, et al. Small liver colorectal metastases treated with percutaneous radiofrequency ablation: local response rate and long-term survival with up to 10-year follow-up. Radiology. 2012;265:958–968. 35. Meijerink MR, Puijk RS, van Tilborg A, et al. Radiofrequency and microwave ablation compared to systemic chemotherapy and to partial hepatectomy in the treatment of colorectal liver metastases: a systematic review and meta-analysis. Cardiovasc Intervent Radiol. 2018;41:1189–1204. 37. Ruers T, Van Coevorden F, Punt CJ, et al. Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial. J Natl Cancer Inst. 2017;109. 39. Wahl DR, Stenmark MH, Tao Y, et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol. 2016;34:452–459. 42. Rajyaguru DJ, Borgert AJ, Smith AL, et al. Radiofrequency ablation versus stereotactic body radiotherapy for localized hepatocellular carcinoma in nonsurgically managed patients: analysis of the national cancer database. J Clin Oncol. 2018;36:600–608. 43. Pollom EL, Lee K, Durkee BY, et al. Cost-effectiveness of stereotactic body radiation therapy versus radiofrequency ablation for hepatocellular carcinoma: a Markov modeling study. Radiology. 2017;283:460–468.

44. Mouli SK, Kurilova I, Sofocleous CT, Lewandowski RJ. The role of percutaneous image-guided thermal ablation for the treatment of pulmonary malignancies. AJR Am J Roentegenol. 2017;209:740–751. 45. Lencioni R, Crocetti L, Cioni R, et al. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol. 2008;9:621–628. 46. Palussière J, Marcet B, Descat E, et al. Lung tumors treated with percutaneous radiofrequency ablation: computed tomography imaging followup. Cardiovasc Intervent Radiol. 2011;34:989–997. 49. de Baère T, Auperin A, Deschamps F, et al. Radiofrequency ablation is a valid treatment option for lung metastases: experience in 566 patients with 1037 metastases. Ann Oncol. 2015;26:987–991. 50. de Baere T, Tselikas L, Woodrum D, et al. Evaluating cryoablation of metastatic lung tumors in patients–Safety and efficacy: The ECLIPSE trial–Interim analysis at 1 year. J Thorac Oncol. 2015;10:1468–1474. 51. Bi N, Shedden K, Zheng X, Kong FS. Comparison of the effectiveness of radiofrequency ablation with stereotactic body radiation therapy in inoperable stage I non-small cell lung cancer: a systemic review and pooled analysis. Int J Radiat Oncol Biol Phys. 2016;95(5):1378–1390. doi:10.1016/j.ijrobp.2016.04.016. 52. Lam A, Yoshida EJ, Bui K, et al. A national cancer database analysis of radiofrequency ablation versus stereotactic body radiotherapy in early-stage non-small cell lung cancer. J Vasc Interv Radiol. 2018;29:1211–1217, e1211. 62. Callstrom MR, Dupuy DE, Solomon SB, et al. Percutaneous image-guided cryoablation of painful metastases involving bone: multicenter trial. Cancer. 2013;119:1033–1041. 63. Goetz MP, Callstrom MR, Charboneau JW, et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol. 2004;22:300–306. 65. Dupuy DE, Liu D, Hartfeil D, et al. Percutaneous radiofrequency ablation of painful osseous metastases: a multicenter American College of Radiology Imaging Network trial. Cancer. 2010;116:989–997. 80. Di Staso M, Zugaro L, Gravina GL, et al. A feasibility study of percutaneous radiofrequency ablation followed by radiotherapy in the management of painful osteolytic bone metastases. Eur Radiol. 2011;21:2004–2010.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 13

REFERENCES 1. Kang TW, Lim HK, Cha DI. Percutaneous ablation for perivascular hepatocellular carcinoma: refining the current status based on emerging evidence and future perspectives. World J Gastroenterol. 2018;24:5331–5337. 2. Hillen TJ, Anchala P, Friedman MV, Jennings JW. Treatment of metastatic posterior vertebral body osseous tumors by using a targeted bipolar radiofrequency ablation device: technical note. Radiology. 2014;273:261–267. 3. Lubner MG, Brace CL, Hinshaw JL, Lee FT Jr. Microwave tumor ablation: mechanism of action, clinical results, and devices. J Vasc Interv Radiol. 2010;21:S192–S203. 4. Dodd GD 3rd, Dodd NA, Lanctot AC, Glueck DA. Effect of variation of portal venous blood flow on radiofrequency and microwave ablations in a blood-perfused bovine liver model. Radiology. 2013;267:129–136. 5. Huo YR, Eslick GD. Microwave ablation compared to radiofrequency ablation for hepatic lesions: a meta-analysis. J Vasc Interv Radiol. 2015;26:1139–1146, e1132. 6. Potretzke TA, Ziemlewicz TJ, Hinshaw JL, et al. Microwave versus radiofrequency ablation treatment for hepatocellular carcinoma: a comparison of efficacy at a single center. J Vasc Interv Radiol. 2016;27:631–638. 7. Shady W, Petre EN, Do KG, et al. Percutaneous microwave versus radiofrequency ablation of colorectal liver metastases: ablation with clear margins (A0) provides the best local tumor control. J Vasc Interv Radiol. 2018;29:268–275, e261. 8. Vietti Violi N, Duran R, Guiu B, et al. Efficacy of microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma in patients with chronic liver disease: a randomised controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2018;3:317–325. 9. Woodrum DA, Kawashima A, Gorny KR, Mynderse LA. Targeted prostate biopsy and MR-guided therapy for prostate cancer. Adv Exp Med Biol. 2018;1096:159–184. 10. Ahrar K, Stafford RJ. Magnetic resonance imaging-guided laser ablation of bone tumors. Tech Vasc Interv Radiol. 2011;14:177–182. 11. Callstrom MR, Kurup AN. Percutaneous ablation for bone and soft tissue metastases–why cryoablation? Skeletal Radiol. 2009;38:835–839. 12. Vroomen L, Petre EN, Cornelis FH, et al. Irreversible electroporation and thermal ablation of tumors in the liver, lung, kidney and bone: what are the differences? Diagn Interv Imaging. 2017;98:609–617. 13. Charpentier KP, Wolf F, Noble L, et al. Irreversible electroporation of the liver and liver hilum in swine. HPB (Oxford). 2011;13:168–173. 14. Martin RC 2nd, Kwon D, Chalikonda S, et al. Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg. 2015;262:486–494, discussion 492–494. 15. Silk M, Tahour D, Srimathveeravalli G, et al. The state of irreversible electroporation in interventional oncology. Semin Intervent Radiol. 2014;31:111–117. 16. Silk MT, Wimmer T, Lee KS, et al. Percutaneous ablation of peribiliary tumors with irreversible electroporation. J Vasc Interv Radiol. 2014;25:112–118. 17. Sutter O, Calvo J, N’Kontchou G, et al. Safety and efficacy of irreversible electroporation for the treatment of hepatocellular carcinoma not amenable to thermal ablation techniques: a retrospective single-center case series. Radiology. 2017;284:877–886. 18. Tian G, Zhao Q, Chen F, et al. Ablation of hepatic malignant tumors with irreversible electroporation: a systematic review and meta-analysis of outcomes. Oncotarget. 2017;8:5853–5860. 19. Hurwitz MD, Ghanouni P, Kanaev SV, et al. Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results. J Natl Cancer Inst. 2014;106. 20. Napoli A, Anzidei M, Marincola BC, et al. Primary pain palliation and local tumor control in bone metastases treated with magnetic resonanceguided focused ultrasound. Invest Radiol. 2013;48:351–358. 21. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–1314.

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22. Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv238–iv255. 23. Peng ZW, Lin XJ, Zhang YJ, et al. Radiofrequency ablation versus hepatic resection for the treatment of hepatocellular carcinomas 2 cm or smaller: a retrospective comparative study. Radiology. 2012;262:1022–1033. 24. Wang Y, Luo Q, Li Y, et al. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinomas: a meta-analysis of randomized and nonrandomized controlled trials. PLoS ONE. 2014;9:e84484. 25. Wang C, Wang H, Yang W, et al. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. Hepatology. 2015;61:1579–1590. 26. Seifert JK, Morris DL. World survey on the complications of hepatic and prostate cryotherapy. World J Surg. 1999;23:109–113, discussion 113–114. 27. Shiina S, Tateishi R, Arano T, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol. 2012;107:569–577, quiz 578. 28. Breen DJ, Lencioni R. Image-guided ablation of primary liver and renal tumours. Nat Rev Clin Oncol. 2015;12:175–186. 29. Aloia TA, Vauthey JN, Loyer EM, et al. Solitary colorectal liver metastasis: resection determines outcome. Arch Surg. 2006;141:460–466, discussion 466–467. 30. Gillams AR, Lees WR. Five-year survival in 309 patients with colorectal liver metastases treated with radiofrequency ablation. Eur Radiol. 2009;19:1206–1213. 31. Solbiati L, Ahmed M, Cova L, et al. Small liver colorectal metastases treated with percutaneous radiofrequency ablation: local response rate and long-term survival with up to 10-year follow-up. Radiology. 2012;265:958–968. 32. Wang LJ, Zhang ZY, Yan XL, et al. Radiofrequency ablation versus resection for technically resectable colorectal liver metastasis: a propensity score analysis. World J Surg Oncol. 2018;16:207. 33. Wong SL, Mangu PB, Choti MA, et al. American Society of Clinical Oncology 2009 clinical evidence review on radiofrequency ablation of hepatic metastases from colorectal cancer. J Clin Oncol. 2010;28:493–508. 34. Siperstein AE, Berber E, Ballem N, Parikh RT. Survival after radiofrequency ablation of colorectal liver metastases: 10-year experience. Ann Surg. 2007;246:559–565, discussion 565–567. 35. Meijerink MR, Puijk RS, van Tilborg A, et al. Radiofrequency and microwave ablation compared to systemic chemotherapy and to partial hepatectomy in the treatment of colorectal liver metastases: a systematic review and meta-analysis. Cardiovasc Intervent Radiol. 2018;41:1189–1204. 36. Ruers T, Punt C, Van Coevorden F, et al. Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann Oncol. 2012;23:2619–2626. 37. Ruers T, Van Coevorden F, Punt CJ, et al. Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial. J Natl Cancer Inst. 2017;109. 38. Jackson WC, Tao Y, Mendiratta-Lala M, et al. Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases. Int J Radiat Oncol Biol Phys. 2018;100:950–958. 39. Wahl DR, Stenmark MH, Tao Y, et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol. 2016;34:452–459. 40. Mendiratta-Lala M, Masch W, Shankar PR, et al. Magnetic resonance imaging evaluation of hepatocellular carcinoma treated with stereotactic body radiation therapy: long term imaging follow-up. Int J Radiat Oncol Biol Phys. 2019;103:169–179. 41. Haddad MM, Merrell KW, Hallemeier CL, et al. Stereotactic body radiation therapy of liver tumors: post-treatment appearances and evaluation of treatment response: a pictorial review. Abdom Radiol (NY). 2016;41:2061–2077. 42. Rajyaguru DJ, Borgert AJ, Smith AL, et al. Radiofrequency ablation versus stereotactic body radiotherapy for localized hepatocellular carcinoma in

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nonsurgically managed patients: analysis of the national cancer database. J Clin Oncol. 2018;36:600–608. 43. Pollom EL, Lee K, Durkee BY, et al. Cost-effectiveness of stereotactic body radiation therapy versus radiofrequency ablation for hepatocellular carcinoma: a Markov modeling study. Radiology. 2017;283:460–468. 44. Mouli SK, Kurilova I, Sofocleous CT, Lewandowski RJ. The role of percutaneous image-guided thermal ablation for the treatment of pulmonary malignancies. AJR Am J Roentgenol. 2017;209:740–751. 45. Lencioni R, Crocetti L, Cioni R, et al. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol. 2008;9:621–628. 46. Palussiere J, Marcet B, Descat E, et al. Lung tumors treated with percutaneous radiofrequency ablation: computed tomography imaging follow-up. Cardiovasc Intervent Radiol. 2011;34:989–997. 47. Dupuy DE, Fernando HC, Hillman S, et al. Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. Cancer. 2015;121:3491–3498. 48. Zheng A, Ye X, Yang X, et al. Local efficacy and survival after microwave ablation of lung tumors: a retrospective study in 183 patients. J Vasc Interv Radiol. 2016;27:1806–1814. 49. de Baere T, Auperin A, Deschamps F, et al. Radiofrequency ablation is a valid treatment option for lung metastases: experience in 566 patients with 1037 metastases. Ann Oncol. 2015;26:987–991. 50. de Baere T, Tselikas L, Woodrum D, et al. Evaluating cryoablation of metastatic lung tumors in patients–Safety and efficacy: The ECLIPSE trial–Interim analysis at 1 year. J Thorac Oncol. 2015;10:1468–1474. 51. Bi N, Shedden K, Zheng X, Kong FS. Comparison of the effectiveness of radiofrequency ablation with stereotactic body radiation therapy in inoperable stage I non-small cell lung cancer: a systemic review and pooled analysis. Int J Radiat Oncol Biol Phys. 2016;95:1378–1390. 52. Lam A, Yoshida EJ, Bui K, et al. A national cancer database analysis of radiofrequency ablation versus stereotactic body radiotherapy in early-stage non-small cell lung cancer. J Vasc Interv Radiol. 2018;29:1211– 1217, e1211. 53. Kastler A, Alnassan H, Pereira PL, et al. Analgesic effects of microwave ablation of bone and soft tissue tumors under local anesthesia. Pain Med. 2013;14:1873–1881. 54. Pusceddu C, Sotgia B, Fele RM, Melis L. Treatment of bone metastases with microwave thermal ablation. J Vasc Interv Radiol. 2013;24:229–233. 55. Tam AL, Abdelsalam ME, Gagea M, et al. Irreversible electroporation of the lumbar vertebrae in a porcine model: is there clinical-pathologic evidence of neural toxicity? Radiology. 2014;272:709–719. 56. Brace CL. Radiofrequency and microwave ablation of the liver, lung, kidney, and bone: what are the differences? Curr Probl Diagn Radiol. 2009;38:135–143. 57. Eckmann MS, Martinez MA, Lindauer S, et al. Radiofrequency ablation near the bone-muscle interface alters soft tissue lesion dimensions. Reg Anesth Pain Med. 2015;40:270–275. 58. Thacker PG, Callstrom MR, Curry TB, et al. Palliation of painful metastatic disease involving bone with imaging-guided treatment: comparison of patients’ immediate response to radiofrequency ablation and cryoablation. AJR Am J Roentgenol. 2011;197:510–515. 59. Zugaro L, DI Staso M, Gravina GL, et al. Treatment of osteolytic solitary painful osseous metastases with radiofrequency ablation or cryoablation: a retrospective study by propensity analysis. Oncol Lett. 2016;11:1948–1954. 60. Kurup AN, Morris JM, Callstrom MR. Ablation of musculoskeletal metastases. AJR Am J Roentgenol. 2017;209:713–721. 61. Bagla S, Sayed D, Smirniotopoulos J, et al. Multicenter prospective clinical series evaluating radiofrequency ablation in the treatment of painful spine metastases. Cardiovasc Intervent Radiol. 2016;39:1289–1297. 62. Callstrom MR, Dupuy DE, Solomon SB, et al. Percutaneous image-guided cryoablation of painful metastases involving bone: multicenter trial. Cancer. 2013;119:1033–1041. 63. Goetz MP, Callstrom MR, Charboneau JW, et al. Percutaneous imageguided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol. 2004;22:300–306.

64. Tanigawa N, Arai Y, Yamakado K, et al. Phase I/II study of radiofrequency ablation for painful bone metastases: Japan Interventional Radiology in Oncology Study Group 0208. Cardiovasc Intervent Radiol. 2018;41:1043–1048. 65. Dupuy DE, Liu D, Hartfeil D, et al. Percutaneous radiofrequency ablation of painful osseous metastases: a multicenter American College of Radiology Imaging Network trial. Cancer. 2010;116:989–997. 66. Cazzato RL, Garnon J, Caudrelier J, et al. Percutaneous radiofrequency ablation of painful spinal metastasis: a systematic literature assessment of analgesia and safety. Int J Hyperthermia. 2018;34:1272–1281. 67. Rosian K, Hawlik K, Piso B. Efficacy assessment of radiofrequency ablation as a palliative pain treatment in patients with painful metastatic spinal lesions: a systematic review. Pain Physician. 2018;21:E467–E476. 68. Bang HJ, Littrup PJ, Currier BP, et al. Percutaneous cryoablation of metastatic lesions from non-small-cell lung carcinoma: initial survival, local control, and cost observations. J Vasc Interv Radiol. 2012;23:761–769. 69. Bang HJ, Littrup PJ, Goodrich DJ, et al. Percutaneous cryoablation of metastatic renal cell carcinoma for local tumor control: feasibility, outcomes, and estimated cost-effectiveness for palliation. J Vasc Interv Radiol. 2012;23:770–777. 70. Erie AJ, Morris JM, Welch BT, et al. Retrospective review of percutaneous image-guided ablation of oligometastatic prostate cancer: a singleinstitution experience. J Vasc Interv Radiol. 2017;28:987–992. 71. Welch BT, Callstrom MR, Morris JM, et al. Feasibility and oncologic control after percutaneous image guided ablation of metastatic renal cell carcinoma. J Urol. 2014;192:357–363. 72. White ML, Atwell TD, Kurup AN, et al. Recurrence and survival outcomes after percutaneous thermal ablation of oligometastatic melanoma. Mayo Clin Proc. 2016;91:288–296. 73. Barral M, Auperin A, Hakime A, et al. Percutaneous thermal ablation of breast cancer metastases in oligometastatic patients. Cardiovasc Intervent Radiol. 2016;39:885–893. 74. Gardner CS, Ensor JE, Ahrar K, et al. Cryoablation of bone metastases from renal cell carcinoma for local tumor control. J Bone Joint Surg Am. 2017;99:1916–1926. 75. Littrup PJ, Bang HJ, Currier BP, et al. Soft-tissue cryoablation in diffuse locations: feasibility and intermediate term outcomes. J Vasc Interv Radiol. 2013;24:1817–1825. 76. Deschamps F, Farouil G, Ternes N, et al. Thermal ablation techniques: a curative treatment of bone metastases in selected patients? Eur Radiol. 2014;24:1971–1980. 77. Cazzato RL, Auloge P, De Marini P, et al. Percutaneous image-guided ablation of bone metastases: local tumor control in oligometastatic patients. Int J Hyperthermia. 2018;35:493–499. 78. Lutz S, Berk L, Chang E, et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;79:965–976. 79. Greenwood TJ, Wallace A, Friedman MV, et al. Combined ablation and radiation therapy of spinal metastases: a novel multimodality treatment approach. Pain Physician. 2015;18:573–581. 80. Di Staso M, Zugaro L, Gravina GL, et al. A feasibility study of percutaneous Radiofrequency Ablation followed by Radiotherapy in the management of painful osteolytic bone metastases. Eur Radiol. 2011;21:2004–2010. 81. Kurup AN, Schmit GD, Morris JM, et al. Avoiding complications in bone and soft tissue ablation. Cardiovasc Intervent Radiol. 2017;40:166–176. 82. Tsoumakidou G, Buy X, Garnon J, et al. Percutaneous thermal ablation: how to protect the surrounding organs. Tech Vasc Interv Radiol. 2011;14:170–176. 83. Froemming A, Atwell T, Farrell M, et al. Probe retraction during renal tumor cryoablation: a technique to minimize direct ureteral injury. J Vasc Interv Radiol. 2010;21:148–151. 84. Schmit GD, Kurup AN, Schmitz JJ, Atwell TD. The “leverage technique”: using needles to displace the stomach during liver ablation. J Vasc Interv Radiol. 2016;27:1765–1767. 85. Kurup AN, Morris JM, Boon AJ, et al. Motor evoked potential monitoring during cryoablation of musculoskeletal tumors. J Vasc Interv Radiol. 2014;25:1657–1664.

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CHAPTER 13 86. Tsoumakidou G, Garnon J, Ramamurthy N, et al. Interest of electrostimulation of peripheral motor nerves during percutaneous thermal ablation. Cardiovasc Intervent Radiol. 2013;36:1624–1628. 87. Deschamps F, Farouil G, Hakime A, et al. Percutaneous stabilization of impending pathological fracture of the proximal femur. Cardiovasc Intervent Radiol. 2012;35:1428–1432. 88. Hartung MP, Tutton SM, Hohenwalter EJ, et al. Safety and efficacy of minimally invasive acetabular stabilization for periacetabular metastatic

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disease with thermal ablation and augmented screw fixation. J Vasc Interv Radiol. 2016;27:682–688, e681. 89. Kelekis A, Filippiadis DK, Kelekis NL, Martin JB. Percutaneous augmented osteoplasty of the humeral bone using a combination of microneedles mesh and cement. J Vasc Interv Radiol. 2015;26:595–597.

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14 Overview of Oncology Clinical Trial Design Chen Hu, James J. Dignam, and Peixin Zhang

Clinical trials began to emerge in their modern form only in the early 20th century, with the first randomized controlled trials conducted in the 1940s, but are now firmly established as the fundamental basis of modern evidence-based medicine. An evidence-based approach based on clinical trials enjoyed an early start in cancer, with a commitment and sponsorship by the US National Cancer Institute (NCI), beginning in the mid-1950s in partnership with academic investigators for the treatment of patients with acute leukemia.1 From these programs grew the multicenter Cancer Cooperative Groups (currently the National Clinical Trials Network program2) and other academic-based cancer centers and institutes that are now the mainstay of clinical cancer research and related translational science in the United States, with similar entities around the world. These programs and clinical trials have been invaluable in discovering and advancing effective therapies while greatly enhancing our understanding of cancer. Despite their primacy, clinical trials are under challenge to continually innovate and adapt as new knowledge is gained and as patients and caregivers seek treatments that are better on many measures, including effectiveness, safety, economics, and long-term welfare. For example, with the development of “omics”-based technology, different cancer types are no longer narrowly and purely defined based on clinical and pathological taxonomic systems. Instead, the so-called precision medicine paradigm that uses biologically relevant and molecular-level information is becoming a reality in some cancer types. Also, cancer treatment has more frequently become multidisciplinary, requiring collaborative investigations between surgeons, medical oncologists, and radiation oncologists to advance new therapies. Moreover, medical oncologists often face myriad options with combinations of traditional cytotoxic, cytostatic, molecularly targeted, and, more recently, immunotherapy agents, while radiation oncologists and surgeons have available a wide array of continually evolving technologies. In conjunction with these developments, advances in computing and the advent of electronic storage of virtually all medical and scientific information has led to an interest in “big data” sources as an alternative to clinical trials for evidence generation. All of these developments have posed new challenges in the design and analysis of all phases of oncology clinical trials. In this chapter, we present readers with a concise review of the fundamentals of clinical trials that have remained largely unchanged. With it, we aim to provide an appreciation of the current critical issues in clinical trial design and conduct needed to ensure that trials continue to provide state-of-the-art therapy evaluation. The focus here is predominantly on study design, as analysis naturally follows a well-specified and purposeful trial design. The material is presented conceptually; we refer the reader to several more comprehensive texts that present details of oncology clinical trial design and conduct3–6 as well as recommend close collaboration with biostatisticians well versed in cancer clinical trials.

SOME FUNDAMENTAL CONCEPTS IN CANCER CLINICAL TRIALS In the clinical trial–based development paradigm, there are a series of sequential steps that advance a new cancer treatment from first use in humans to establishment as clinically effective therapy. These steps, referred to as phases, are designed to answer certain questions. If a candidate treatment is successful in one phase, it will proceed to further testing in the next phase. More broadly, trial phases can be conceived of as developmental stages for which there may be overlap in goals and information obtained. During early development (Phases I and II), researchers determine whether a new treatment is safe, what may be the best dose, and which specific adverse effects, both expected and unexpected, may be encountered. In the latter portion of early development, moving into Phase II, whether the treatment demonstrates some benefit, such as slowing tumor growth or influencing other intermediate disease endpoints, is formally assessed. In the later phase (Phase III), researchers definitively evaluate whether the treatment works better than the current standard therapy and further evaluate safety. In addition to comparing safety of the new treatment with that of the current standard in an objective manner, additional adverse-event information is obtained that may emerge as the new regimen is used in larger numbers of patients with longer follow-up. Phase III trials typically include randomized treatment assignment (the virtues of which are discussed later) and a sufficient number of participants to ensure that the result is valid and reliable. The specific statistical considerations for each phase will be elaborated later in this chapter. From a statistical design perspective, there are five key components in any cancer clinical trial regardless of its phase: (1) clearly written objectives, (2) well-defined endpoints, (3) a rigorous study design appropriate for the question, (4) a well-justified sample size, and (5) an appropriate and detailed statistical analysis plan. Cursory attention to any of these five components could lead to a trial with flawed or uninterpretable results.

Objectives Identifying the primary objective requires careful thought about what key conclusions are to be made at the end of the trial. In Phase I trials, the primary objective typically is to identify a suitable dose (which may be optimal by some metric) and summarize the toxicities observed. In Phase II trials, the types of objectives may vary depending on the specific context and situations. Historically, the primary objective is to evaluate preliminary efficacy at the established dose to (1) aid in determining whether there is sufficient cause to warrant a more definitive (Phase III) trial and (2) to obtain preliminary clinical efficacy estimates to help plan the Phase III trial. Phase II trials also provide for further explorations of safety and toxicity of the experimental regimens. The primary objective

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of a Phase III trial is to provide a definitive head-to-head comparison of alternative treatment regimens, typically an experimental regimen versus a standard-of-care comparator. All clinical trials most appropriately have a single primary objective. While there may be numerous secondary objectives, the distinction should be clear. It is generally not appropriate to assume or plan for additional development goals being met—for example, planning an early-phase trial with hope of an extraordinary benefit leading to rapid adoption as established treatment. Sufficient rigor should be focused on the developmental objective of the trial instead.

Endpoints The selection of endpoints for a clinical trial is the next critical step in determining the appropriate design and analysis for a trial. An endpoint generally refers to a measure of disease status, symptom, or laboratory value that constitutes one of the target outcomes of the trial. It requires the following traits: it should be clearly defined, quantitatively measurable in an unbiased fashion, and directly linked to the trial primary objective. Choice will depend on the phase of the trial and other factors, such as cost and feasibility of assessment. In early-phase safety development, endpoints may be simple frequencies of adverse events, but even these must be carefully defined with respect to type(s) of interest, time frame of occurrence, probable attribution to the intervention, and other constraints. Examples of early efficacy endpoints in pilot efficacy (Phase II) trials include tumor response (i.e., reduction, stabilization), which is generally based on radiographic tumor measurements and expressed through the proportion responding, or response rate, and time free of evidence of further disease progression. In later-phase definitive trials, overall survival (time surviving with respect to death from any cause) is historically considered the most meaningful efficacy endpoint. However, depending on the context, diseasespecific endpoints may be considered definitive. Often in time-to-event data, composite endpoints, in which several different event types such as disease progression or death from any cause are combined to define progression-free survival (or disease-free survival), which may include second primary cancers as events, are the endpoint of choice in definitive trials and may also be used in Phase II trials. A large body of health-related quality of life (HRQoL) endpoints—which may include various caregiver assessments and, increasingly, patient-reported outcome (PRO) endpoints—are also used in all phases of trials. Depending on the trial question, they may serve as primary endpoints as well.

Study Cohort and Comparative Design The general study design is the structure under which the inferential procedure will address the trial objective. The merits of an experimental treatment are assessed against either target specifications (such as a maximum adverse-event rate permissible), an expected clinical outcome based on historical experience in a similar clinical scenario, or a concurrent control group incorporated into the study. Depending on the trial objective, type, and other factors, one of these may form the basis of valid inference, but all require careful design considerations in order to ultimately provide reliable conclusions.

Single or Sequential Patient Cohorts In dose establishment and safety evaluation, there is critical concern with proceeding deliberately so that patients do not incur excess risk while at the same time seeking to avoid administering subtherapeutic doses to many patients (although therapeutic benefit is not an explicit goal of the study). For this reason, Phase I trials enroll patients singly or in small cohorts and proceed through dose determination sequentially. In some cases, there may be multiple substudies enrolling concurrently. Then, groups may be randomized or deterministically assigned, but the same deliberate enrollment scheme pertains.

For pilot efficacy evaluation, the most economical design from a resource perspective is a single cohort, all receiving the experimental regimen. This approach provides the maximum information about the new intervention under study and may have ease of enrollment because all patients have an opportunity to receive what is usually perceived (correctly or otherwise) as a promising treatment. In a traditional single-arm pilot efficacy (Phase II) trial, all patients receive the same treatment; typically, results are assessed against previous historical experience (historical control). The historical control patient population should have similar patient characteristics, similar standard of care, and use the same diagnostic and screening procedures as patients anticipated to be entered into the new study. In addition, the primary outcome should be objective and consistently defined so that results are comparable and interpretable when comparing with historical estimates. Unfortunately, a historical estimate may not always be available when, for example, the patient population for a current study is defined by newly discovered biomarkers. In addition, historical estimates for the apparent same treatment and same patient population may vary substantially and be subject to temporal changes in prognosis due to influences of ancillary care, diagnostic definitions, and other unknown factors. These issues make it difficult to choose an appropriate value against which the new treatment should be assessed, introducing the possibility of uncertainty and lack of reliability in findings from singlearm trials (considerations to mitigate them are discussed in more detail later). Nonetheless, the single-cohort design remains an important part of oncology clinical trials.

Parallel Cohorts and Randomization Trials may alternately include a parallel cohort receiving a different intervention, to which randomization is invariability employed to assign patients to the treatment groups. Randomization ensures that patients are assigned to treatment arms without systematic differences in any and all characteristics that may influence outcomes. Randomization is the cornerstone of clinical trials methodology as it pertains to evidence generation, addressing the fundamental problem of confounding treatment effect. Confounding factors are those that are related to both treatment assignment (choice or receipt) and outcomes. These can be any known demographic or disease prognostic factors or other yet unknown factors. Confounding factors also include characteristics that might influence someone to participate in, or withdraw from, a trial, or potential conscious or unconscious bias in patient selection by treating physicians, or self-selection bias by patients themselves. Randomization does not completely ameliorate these concerns (although consistent, well-defined trial entry criteria does), but still promotes external validity, as patients in each of the treatment arms have similar characteristics to the sample obtained from the population. That said, randomization itself does not ensure that the study will include a representative sample of all patients with the disease. However, internal validity is ensured, as patients are similar between arms and the confounding of treatment effect by both known and unknown factors is minimized. In large studies, simple randomization is sufficient to guarantee that treatment arms will be balanced with respect to patient characteristics, while in small or moderately sized studies, imbalances in important patient characteristics can occur by chance. In all randomized studies, additional design features (i.e., stratified randomization and analysis, discussed later) can correct this influence.

Parameters Relevant to Sample Size Development and Inference Under the classical (frequentist) hypothesis testing paradigm, which continues to be the dominant approach, the inferential (i.e., testing) procedure and subsequent material decision regarding a treatment

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CHAPTER 14 evaluation depends critically on a small number of quantities that must be specified as part of trial design. Alternative frameworks, such as the Bayesian inference paradigm (which is not covered in detail here), likewise require some conditions and assumptions that will determine the scope of the study and ensure an informative conclusion. Type I and type II errors. In the classical statistical decision framework, one posits a null hypothesis (e.g., absence of a treatment effect) and alternative hypothesis (presence of a treatment effect) and collects data from a sample to provide an estimate of the true state of nature in the population. A decision in favor of the null or alternative hypothesis follows. The type I error probability—or α, or significance level—is the probability that we conclude that a treatment effect is present (based on the data) when, in fact, it is not (false-positive conclusion). This is an inevitable consequence of using sampling from a population and probabilistic reasoning and, thus, is not an “error.” The acceptable type I error rate is decided on in the planning stages of the trial; the conventional 0.05 level may or may not fit a particular problem. A closely related concept to the significance level α of a test is the p value, the probability under the null hypothesis of a result equal to or more extreme than the one that we observed. When it is smaller than a given prespecified α level, the result is declared statistically significant, as the observed effect is unlikely to have arisen under the null hypothesis (of no treatment effect). While, by definition, the smaller the p value the less likely the observed result under the null hypothesis, it must be recognized that false declaration of an effect when there is none is a real and natural phenomenon when using this decision paradigm. To decrease falsepositive findings in trials in certain circumstances (discussed later) the significance probabilities are altered to be more stringent. Even outside of these circumstances, historically and more recently, there has been a general call for redefining significance criteria in order to address multiple problems with too much emphasis on statistical significance as a hallmark of meaningful findings.7,8 The statistical power of a test for a particular alternative hypothesis is defined to be 1−β, where the quantity β (or type II error) represents the probability of not rejecting the null hypothesis when, in fact, a treatment effect is manifest in the population (i.e., the alternative hypothesis is the true state). Thus, power equals the probability of detecting a difference that is really there. Ideally, trials should be designed to provide high power for differences that are realistic and clinically meaningful. This is mostly driven through adequate sample size relative to variability of the outcome measure. In designing trials, it is important for the researchers and statistician to discuss the magnitudes of the clinical improvement that would be meaningful to detect in order to design a study with a small enough type II error to make the conclusions credible irrespective of the conclusion. If the true treatment effect were very large, it might be relatively easy to detect even with a small sample size. However, when the treatment effect is more modest, yet meaningfully different clinically, an adequately large number of patients is required to detect this effect with high probability. Thus, a trial that failed to detect an effect, but was based on a small sample size, does not provide reliable evidence of no effect and should be interpreted with caution (since a type II error or false-negative result is likely). In general, we set β to 0.1–0.2, for example, we aim to have at least 80% to 90% power to detect a truly effective treatment. Effect size. As alluded to earlier, in conjunction with the somewhat abstract type I and type II error parameters, the most critical aspect of the study design is the expected effect size, or magnitude of effect that one aims to detect, as from these arises the sample size. Inherent in this formulation is also the expected outcome under the standard or comparator treatment upon which we aim to improve, represented by the alternative hypothesis outcome. Historical information from earlier studies is useful in specifying the assumptions required for sample size

Overview of Oncology Clinical Trial Design

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calculations and must be accurate in single-arm noncomparative studies (because otherwise, “improvements” in outcome will be falsely attributed to treatment) and in randomized comparative studies (because, although the comparison remains internally valid, the scope and scale of the study is affected by these quantities). For fixed-time endpoints, such as the proportion responding or failure free at a given time landmark, the total sample size is then implied based on absolute difference or relative difference (often expressed as a rate ratio). For time-to-event endpoints (e.g., overall survival), the effect to be detected is typically expressed in terms of a failure rate (event/time) ratio, known as a hazard ratio (HR). The required sample size is then driven by the number of failure events required rather than the number of patients accrued. Hypothetically speaking, if all patients were followed to the failure event, the number to be accrued would be the same as the number of events expected. While the number of events is determined by α, β, and HR, the total number of patients to be accrued will be influenced by several additional factors: the failure rate under standard therapy, any study attrition or loss of event observation due to other factors, the accrual rate, and the amount of follow-up time to be allowed until planned study reporting. A relatively small study of patients with rapidly lethal disease may have the same power as a very large study of patients with a low death rate and lengthy follow-up as long as the numbers of deaths are same. Furthermore, the rate of accrual to the trial and the total calendar time in which the trial is aimed to be completed are two factors that must be considered together, as there are trade-offs between them to arrive at the requisite patients needed. In addition, if the expected rate of failure among enrolled patients is substantially inaccurate, the timeline of the trial will also be affected. Last, it should be noted that when we express the effect size in terms of HR, it may be worth considering whether there is evidence that this standard assumption is suitable for the particular disease under study, as power may be reduced if the assumption is incorrect. In terms of effect size, ideally, a trial should be designed to have sufficient power to detect the smallest difference that is clinically meaningful. A study is doomed to failure if it is designed to have sufficient power to detect only unrealistically large differences. In practice, trials are often designed to have adequate power only to detect the smallest feasible difference, where feasibility is dictated by funding resources, the available patient population and timeframe of trial conduct, and other practical constraints. Consideration should be given to whether the feasible difference is plausible enough to warrant doing the study at all, since it is considered a waste of resources and by some even an ethical breach to conduct a trial with little chance of yielding a definitive conclusion.9

DESIGN FEATURES BY DEVELOPMENTAL PHASE Each design phase of trials has specific critical design features, although some are shared across phases. Also, increasingly, there is a movement toward approaches that combine phases, facilitating transitions between developmental steps in a more seamless and efficient manner. In this section, we review some general design considerations for Phase I through Phase III trials and recent innovations related to trial design. Table 14.1 provides representative examples of many of the trial designs discussed here. The reader may wish to use these as a reference point for concepts discussed put into practice in trial conduct.

Phase I Phase I trials are perhaps the most specialized and context-specific to oncology of the clinical trials development paradigm; it is difficult to adequately cover design issues in brief. The key design feature for these trials, which are not oriented toward testing hypotheses, is the dose

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TABLE 14.1

Scientific Foundations of Radiation Oncology

Examples of Design Types From Among Completed or Active Oncology Trials

Study Title

Type of Trial

Primary Trial Questiona

NRG-DT001: A Phase Ib Trial of Neoadjuvant AMG 232 Concurrent with Preoperative Radiotherapy in Wild-Type P53 Soft-Tissue Sarcoma

Phase I “3 + 3” dose finding, with expansion cohorts

To assess the maximum tolerated dose of AMG 232 in combination with standard-dose radiotherapy.

NRG-BN002: Phase I Study of Ipilimumab, Nivolumab, and the Combination in Patients with Newly Diagnosed Glioblastoma

Phase I rolling 6-dose finding, with modification to slow accrual

To evaluate the safety of (i) single-agent treatment with ipilimumab, (ii) nivolumab, and (iii) the combination of ipilimumab and nivolumab, each with maintenance temozolomide.

NRG/RTOG 0813: Seamless Phase I/II Study of Stereotactic Lung Radiotherapy (SBRT) for Early Stage, Centrally Located, Non–Small Cell Lung Cancer (NSCLC) in Medically Inoperable Patients

Phase I time to event continual reassessment (TITE-CRM), followed by Phase II single-arm response evaluation

To test the safety of stereotactic body radiation therapy (SBRT) at a range of increasing dose levels.

NRG/RTOG 0933: A Phase II Trial of Hippocampal Avoidance during Whole Brain Radiotherapy for Brain Metastases

Phase II pilot efficacy: nonrandomized design

To evaluate delayed recall as assessed by the Hopkins Verbal Learning Test–Revised (HVLT-R) 4 months after hippocampal avoidance during whole brain radiotherapy (HA-WBRT).

NRG/RTOG 0712: A Phase II Randomized Study for Patients with Muscle-Invasive Bladder Cancer Evaluating Transurethral Surgery and Concomitant Chemoradiation by Either BID Irradiation plus 5-Fluorouracil and Cisplatin or QD Irradiation plus Gemcitabine Followed by Selective Bladder Preservation and Gemcitabine/ Cisplatin Adjuvant Chemotherapy

Phase II pilot efficacy: randomized noncomparative design with clinical efficacy endpoint

To estimate the rate of distant metastasis at 3 years of two induction chemoradiotherapy regimens, including 5-FU, cisplatin, and BID irradiation (FCI) or gemcitabine and QD irradiation (GI), followed by radical cystectomy if the tumor response is incomplete or by consolidation chemoradiotherapy if the tumor has cleared, with both followed by adjuvant chemotherapy.

NRG/RTOG 0915: A Randomized Phase II Study Comparing 2 Stereotactic Body Radiation Therapy (SBRT) Schedules for Medically Inoperable Patients with Stage I Peripheral Non–Small Cell Lung Cancer

Phase II pilot efficacy: randomized noncomparative design with adverse event endpoint

To evaluate the rate of 1-year grade 3 or higher adverse events that are definitely, probably, or possibly related to SBRT treatment.

NRG-BN001: Randomized Phase II Trial of Hypofractionated Dose-Escalated Photon IMRT or Proton Beam Therapy versus Conventional Photon Irradiation with Concomitant and Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma

Phase II pilot efficacy: two-arm randomized design

To determine whether dose-escalated photon IMRT or proton beam therapy with concomitant and adjuvant temozolomide improves overall survival as compared with standard-dose photon irradiation with concomitant and adjuvant temozolomide.

NRG-GY003: A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard PlatinumBased Chemotherapy in Women with Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Phase III: superiority design with clinical efficacy endpoint

To assess the efficacy of either single-agent olaparib or the combination of cediranib and olaparib, as measured by progression-free survival, as compared with standard platinum-based chemotherapy.

NRG-CC001: A Randomized Phase III Trial of Memantine and Whole-Brain Radiotherapy with or without Hippocampal Avoidance in Patients With Brain Metastases

Phase III: superiority design with neurocognitive toxicity endpoint

To determine whether HA-WBRT increases time to neurocognitive decline on a battery of tests: the Hopkins Verbal Learning Test–Revised (HVLT-R) for Total Recall, Delayed Recall, and Delayed Recognition, Controlled Oral Word Association (COWA), and the Trail Making Test (TMT) Parts A and B.

NRG/RTOG 0415: A Phase III Randomized Study of Hypofractionated 3DCRT/IMRT versus Conventionally Fractionated 3DCRT/IMRT in Patients Treated for Favorable-Risk Prostate Cancer

Phase III: noninferiority design with clinical endpoint

To determine whether hypofractionated 3D-CRT/IMRT will result in disease-free survival (DFS) that is no worse than DFS following conventionally fractionated 3D-CRT/IMRT

NRG-GU003: A Randomized Phase III Trial of Hypofractionated Post-Prostatectomy Radiation Therapy (HYPORT) versus Conventional Post-Prostatectomy Radiation Therapy (COPORT) in Treating Patients with Prostate Cancer

Phase III: noninferiority design with adverse event endpoint

To demonstrate whether hypofractionated postprostatectomy radiotherapy does not increase 2-year patient-reported GI and GU symptoms over conventionally fractionated postprostatectomy radiotherapy.

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CHAPTER 14

TABLE 14.1

Trials—cont’d

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241

Examples of Design Types From Among Completed or Active Oncology

Study Title NRG/RTOG 1216: Randomized Phase II/III Trial of Surgery and Postoperative Radiation Delivered with Concurrent Cisplatin versus Docetaxel versus Docetaxel and Cetuximab for High-Risk Squamous Cell Cancer of the Head and Neck

Type of Trial Phase II/III integrated design

Primary Trial Questiona Phase II: To select the better of two experimental arms to potentially improve disease-free survival over radiation and cisplatin. Phase III: To determine whether the selected experimental arm will improve overall survival over a radiation and cisplatin control arm.

a

Trial synopsis and current status available at https://www.nrgoncology.org/Clinical-Trials/Protocol-Table. 3D-CRT, Three-dimensional conformal radiation therapy; GI, gastrointestinal; GU, genitourinary; IMRT, intensity-modulated radiation therapy.

determination scheme. While the methodology literature is vast—with much effort spent developing designs that are at once ethical, efficient, and accurate in identifying the best dose—in practice, there is a dominance of empirical approaches that are relatively simple to carry out, despite having known limitations. Simple stage-wise designs comprise small cohorts enrolled to a given dose and, depending on the outcome (usually, adverse events of specified types), an adjacent lower- or higherdose tier begins enrolling or additional patients are added at the current dose tier. The so-called “3+3” design is most familiar, but there are many variations with respect to the approach,10 the hallmark of which is that the escalation/de-escalation scheme is specified at the outset. Despite numerous shortcomings, these approaches still enjoy wide use. Designs that select dose based on accruing information and a mathematical dose-response model offer an alternative with better performance characteristics at the cost of more complexity to implement. Modification of the original Continual Reassessment Method (CRM) proposal11 have provided many practical implementations in oncology.12 Particularly relevant to radiation oncology and other settings where long-term or late toxicity may be of interest in evaluating dose is the time-to-event CRM (TITE-CRM),13,14 which has been successfully implemented in the multicenter setting despite the additional logistical overhead.15 In general, there continues to be an impetus toward using designs that can outperform the original stepwise approaches.16,17 Most recently, Phase I designs that offer the advantage of upfront dosespecification grids (i.e., not determined algorithmically as data accrues) but having superior performance to 3+3 are gaining wider use.18,19 As mentioned earlier, the Phase I trial is a special area that requires close collaboration with experienced investigators.

Phase II Trials Phase II trials provide the testing ground for the development of definitive Phase III trials through the screening of new agents for antitumor activity and by piloting new treatment combinations and schedules. The essential elements of Phase II designs are (1) a well-defined regimen from earlier phase work that will serve as the model for further scale-up to definitive testing; (2) to the extent possible, a limited sample size and short study period; and (3) focus on a pilot efficacy rather than a definitive clinical utility determination. In recent years, the focus of Phase II trial design has undergone a substantial shift in emphasis, partially in response to the development of targeted agents and a need to incorporate biomarkers and in part due to the increased use of randomized Phase II designs. We will discuss these new developments in later sections.

Single-Arm Phase II Trials Phase II trials traditionally have implemented a single-arm design in which all patients receive the experimental therapy. The efficacy measure

is typically based on a short-term endpoint and compared with that of a standard therapy realized among similar patients (i.e., the historical control group). The most common primary endpoint of Phase II cancer clinical trials is tumor response, which is measured by the change in tumor size after treatment (and binned into categories20), under the assumption that tumor size shrinkage is likely to occur with an effective experimental regimen. However, as many newer targeted therapies may have little impact on tumor shrinkage but rather may arrest tumor growth, resulting in longer progression-free survival (PFS) or overall survival (OS), as well as other shortcomings of tumor response as a universal endpoint, alternative endpoints such as 6-month failure-free survival proportions may be more appropriate. For both ethical and efficiency considerations, an important aspect of Phase II trials is to minimize patient exposure to ineffective regimens. These considerations have been reflected in trial designs going back many years, with the basic idea that if evidence of benefit does not emerge after a sufficient number of sequential patients, then continuation to a larger sample size is unnecessary.21,22 For single-arm trials, the so-called two-stage designs are now commonly used to address these considerations. In stage 1, we evaluate whether the regimen is unlikely to be effective and should stop when less than a1 responses are observed among the first n1 patients treated (a1 < n1). If at least a1 responses are observed, we proceed into stage 2 to treat an additional n2 patients and consider the experimental regimen promising if a sufficient number of responses are observed among n1 + n2 patients.23,24 Although the same idea can apply to multistage designs, with early stopping for both futility (negative results) and superiority (positive results), these are less frequently used. Designs with more than two stages of accrual are typically less practical. In addition, when early results appear positive, there is no ethical concern about accruing more patients; in this case, allowing early stopping would prevent us from collecting as much data as possible to better design a subsequent Phase III trial. Other variations include defining outcomes in terms of more than two categories.25 Of note, in Phase II trials, it is desirable to minimize the chance of failing to identify a potentially effective regimen. Therefore, it may be reasonable to allow a relatively larger type I error (e.g., 0.10 or 0.15) as a compromise in order to maintain a high power and sample size feasibility. Last, single-arm trials are most appropriate only if historical estimates are well characterized, consistent, and have been stable over time. If any of these conditions is not met, one should consider randomized Phase II designs.

Randomized Phase II Trials Randomized phase II “screening” designs. In recent years, there have been increasing concerns about the reliability of trials without a concurrent control group. For example, the introduction of targeted therapies that seek to redefine patient populations based on molecular

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information often makes historical control information simply unavailable. In addition, rapid clinical development changes in standard treatments make expected outcomes more difficult to characterize. Moreover, endpoints other than tumor response have been more often considered, either owing to the underlying treatment mechanism (e.g., cytostatic) or the aforementioned concerns. Therefore, there has been great interest in using randomized Phase II trials with a standardtreatment control to provide greater assurance that any observed preliminary treatment efficacy signal is genuine.26–28 However, there are substantive concerns regarding how to accommodate the increased sample size and study duration required as well as some other issues (described later) when adopting a randomized design at an early developmental stage. As a more rigorous approach to pilot efficacy evaluation, Rubinstein et al. advocated a wider use of nondefinite, randomized Phase II designs with comparison to a standard-of-care control group.29 They argued that the randomized design is a much better “screening” tool than the conventional single-arm design, provided that type I and type II errors and targeted treatment benefit (effect size) are carefully chosen. To maintain relatively small sample size, one needs to consider larger type I (e.g., up to 20%) and type II (20%) errors than typically used in single-arm trials while protecting against an overly large type I error that would essentially nullify the screening effect or overly large type II error that runs a higher risk of dismissing a potentially useful regimen. Likewise, the effect size may be optimistic but not so large as to risk rejecting a regimen with a more limited but still clinically significant benefit. How to balance among these conflicting demands requires thoughtful and thorough vetting across investigators, statisticians, and sponsors. Based on simulation studies and recent experience, these trials should offer more reliable results at the cost of greater sample size30 but will not eliminate the possibility that a positive Phase II trial will still be followed by lack of benefit in Phase III.31 One potential pitfall of a “positive” randomized Phase II screening trial is that researchers and practitioners may be inclined to view the results as conclusive, especially if the trial uses a more definitive endpoint, such as overall survival or, in some cases, PFS (vs. tumor response endpoints). It should be stressed that a “positive” finding at even a nominal significance level of 0.05 is often not sufficiently conclusive and that these trials are designed with larger type I error and power typically no greater than 80%. In order to base a broad efficacy conclusion on a randomized Phase II screening trial, the results might be more appropriately viewed in a manner similar to an interim analysis of a Phase III trial (discussed later), in which a much more stringent criterion is used to declare the trial positive. Only in the most extreme cases would a follow-up Phase III trial not be warranted. Randomized Phase II “selection” designs. Predating the comparative pilot efficacy screening trials described earlier, randomized Phase II “selection” designs were first proposed in the 1980s in oncology.32 Rather than evaluating against a standard of care, the aim of a randomized Phase II “selection” study is to decide which of several new regimens— such as multiple combination regimens with a common core regimen (X + A, X + B, X + C, etc.) or different doses or schedules of the same agent—should be taken to the next phase of testing. Of note, the intent of a selection design is not to compare directly among these candidate regimens but rather to choose at least one of the experimental treatments for further study, with an overall goal of having relative confidence that the chosen one is likely preferable to the others and that because of randomized assignment, any advantage is not due to confounding. Therefore, the selection design is appropriate for prioritizing between experimental regimens when there is no a priori reason (e.g., significant differences in toxicity or cost) to prefer one treatment over the others. It is also common and reasonable to require that any chosen regimen,

or the “winning arm,” must satisfy some minimum requirement (e.g., a minimum improvement compared with some historical control experience) prior to consideration for further testing.33 Despite the randomization to arms, the selection design should not be interpreted as demonstrating that the selected regimen is necessarily superior to the unselected arms. As the selection design itself guarantees that an arm is always chosen regardless of whether it is truly better than other candidates or the standard, it is not appropriate to perform and interpret direct comparisons of experimental agents or regimens with standardtreatment control arms, as type I error is not controlled and power is inadequate for these comparisons by design.34

Biomarker-Based Phase II Designs Increasingly, molecular features of tumors (broadly called biomarkers here) are incorporated into study designs, often at an earlier stage. Historically, as knowledge grew, biomarkers might be included in trials as important ancillary information that may inform response. Later, such factors might be used to selectively enroll patients more likely to benefit. In the modern era, biomarkers are often integral with treatment agents; thus at Phase II, they are introduced in various ways. A completely uniform nomenclature is still evolving, but the following terminology may be encountered with respect to Phase II trial designs. Phase II trials may selectively enroll patients most likely to respond based on presenting a biomarker value commensurate with a targeted mechanism (Fig. 14.1A). These “enrichment” designs, like all biomarker trials, rely on accurate and rapid biomarker value ascertainment. Furthermore, there must be confidence that potential benefit is limited to marker-positive cases and that the definition for marker-positive is established. There are consequences such as diluting the response rate or inadvertently omitting those who could benefit if the marker screen lacks these features. Alternatively, a marker-stratified design screens for the biomarker and randomizes to treatments within strata defined by status, permitting a formal test of differential benefit of treatment by biomarker status (see Fig. 14.1B). These studies are more demanding in terms of sample size but can permit discovery of who is likely to benefit and the correct biomarker classification cutpoint. Biomarkers may further be incorporated via a strategy design—in which, after determination, patients are stratified to treatment arms that either use the information for treatment selection or administer standard treatment (see Fig. 14.1C). All of these designs and variations and extensions are described in several reviews35–37 and research articles describing new designs increasingly in use (that also apply to Phase III evaluation).38–40

Phase III Trials Phase III represents the culmination of development for new therapeutic options, providing definitive testing for a novel intervention, establishing the best treatment course among various established therapies, and, in some cases, seeking to demonstrate that treatment can be safely “deescalated” while providing satisfactory clinical efficacy and benefits on other domains, such as convenience, HRQoL, or cost. Phase III trials contain some design and conduct features unique to late-stage development, although some also pertain to earlier-phase trials.

Study Entry Features—Stratified and Blocked Randomization Stratification factors are key patient and/or disease features that influence prognosis and possibly treatment response. In order to ensure that these factors are equally represented between treatment arms, stratified randomization is often used in Phase III trials (and many Phase II randomized trials). This approach avoids imbalance in key prognostic factors that can occur randomly and reduces the variability of the estimate of the difference between treatment arms, resulting in a more efficient study. If the number of participating institutions is

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New Rx Randomize M+

New Rx

M+

Randomize

Biomarker Assay

New Rx M−

Standard Rx M−

A

Standard Rx

Biomarker Assay Randomize

Off study

Standard Rx

B M+, New Rx Marker-based Strategy

Biomarker Assay

M−, Standard Rx

Randomize

Non-Markerbased Strategy

C

Standard Rx OR Randomize: New Rx vs. Standard Rx

Fig. 14.1 (A) An enrichment randomized Phase II trial. (B) A biomarker-stratified randomized Phase II trial. (C) Two variations on a biomarker-strategy randomized Phase II trial.

small, it may be best to stratify on this factor as well since there may be heterogeneity in outcomes and treatment effect by institution. However, any randomization scheme will fail to produce balance if there are too many factors included. Therefore, to avoid overstratification for a typical cancer clinical trial, one should try to consider no more than three stratification factors. Permuted block randomization is another commonly used approach to achieve numerical balance in patients assigned across treatment groups. The randomization scheme consists of a sequence of blocks such that each block contains a prespecified number of treatment assignments in random order. This ensures that the randomization scheme is balanced at the completion of each block.

Analysis Cohort: Intent-to-Treat Analysis and Per-Protocol Analysis Whom to include in the analysis cohort is a seemingly simple aspect of clinical trials that is surprisingly complex and problematic if not addressed properly.3,41 An intention-to-treat (ITT) analysis maintains the original treatment group composition achieved after the random allocation of the trial participants such that all randomized cases will be included in the treatment arm to which they were randomized regardless of what treatment the patients actually received. Therefore, any differences between the treatment groups at the end of the study will have been the result purely of differences in treatment assigned and not corrupted by confounding introduced between treatment groups by selectively omitting patients after randomization. In this way, ITT promotes internal validity at the cost of a possibly attenuated treatment effect. ITT analysis also promotes external validity because it pragmatically evaluates the effectiveness of the experimental intervention in routine practice where noncompliance may exist instead of that of a hypothetical world with perfect compliance.

In contrast, a per-protocol analysis excludes a number of randomized patients depending on the definition of per protocol being applied. Exclusions most commonly include those who were entered but are “protocol ineligible” but can extend to those who did not receive (or adequately receive) protocol intervention or received nonprotocol treatment, generally labeled as noncompliers. Because a per-protocol analysis (that excludes noncompliers) is restricted to those who complied with the trial treatment delivery protocol, it reflects the maximum potential benefits that the experimental regimen may achieve and is often advocated in explanatory trials that aim to measure the effects of an intervention under ideal or experimental conditions. However, this analysis is subject to bias, as exclusion of noncompliers does not maintain the original comparability of treatment groups in characteristics achieved after randomization. Furthermore, compliance itself may be related to prognosis, treatment tolerability, and treatment response. Modifications of the conventional ITT principle also exist in practice. For example, randomized Phase III trials, sponsored by the National Clinical Trial Network (NCTN) program of the NCI, often consider the sometimes named modified intent-to-treat (mITT) principle. The mITT analysis modifies the conventional ITT population by excluding a small fraction of patients who are deemed ineligible after randomization owing to prerandomization conditions (also, sometimes patients who never started treatment and have no follow-up information may be excluded) and all eligible cases are included in the treatment arm to which they were randomized. This practical modification accommodates the reality that patients may be registered while some eligibility criteria (e.g., confirming if pathology or imaging assessments are conducted within specified periods) are still being verified. Our experiences are that applying mITT analysis does not have any risks of biasing the treatment effect estimation, as the prerandomization ineligibility occurs randomly and infrequently. Also, when they do occur, it can be

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challenging to ensure follow-up data collection regardless of desire to include these patients.

Multiplicity and Subgroups Multiplicity issues occur when one considers a set of statistical inferences simultaneously. The more that statistical hypotheses are tested the more likely that erroneous inferences are to occur as a whole. The classic approach to the multiple comparison problem is to control the familywise error rate (FWER), instead of the significance level of individual comparisons, to a prespecified level of, say, 0.05, such that if all of the null hypotheses are true, the probability that the family of tests includes one or more false positives due to chance is 0.05. To achieve this, one may use a lower significance level per test to make it more difficult to reject the null hypothesis for each individual comparison such that the probability of getting one result that is significant across all tests in the family remains at 0.05 when the null hypothesis is true for all tests. The most common way to control the FWER is with the Bonferroni correction, although it is known to be overly conservative (rejecting the null hypothesis less often than warranted) when a large number of tests are performed simultaneously, particularly if these tests are positively correlated. Modifications of this approach and other less conservative approaches have been developed to overcome these criticisms.42,43 An alternative approach is to control the false discovery rate (FDR), defined as the proportion of “discoveries” (statistically significant results) that are actually false positives. Procedures for multiple testing can be devised that bound the FDR. Thus, for an FDR set at a given value (e.g., 10%), then from among a set of statistical tests that result in rejection of the null hypothesis, up to 10% can be expected to be an erroneous conclusion (e.g., 1 in 10 if 10 tests resulted in rejection of the null). The FDR approach offers more statistical power at the expense of less stringent type I error control than FWER procedures. The most popular approach for controlling FDR was formally developed by Benjamini and Hochberg44 and has found applications in clinical trials. In general, innovative approaches to error control continue to be developed, with better options now available to meet the needs of modern trials.45,46 Subgroup analysis typically refers to any evaluation of treatment effects for a specific endpoint in subgroups of patients defined by baseline characteristics. These analyses may reveal provocative results, perhaps— most importantly—apparent differential benefit according to some feature(s), known as interaction effects, with the features identified as predictive factors.47 However, it should be noted that many trials lack the power to formally detect any heterogeneity in treatment effect (e.g., interactions between treatments and subgroups) even if it does exist.46 Therefore, the inability to find significant interactions does not necessarily indicate that the treatment effect seen overall applies to all subjects in all subpopulations. Alternatively, claiming heterogeneity on the basis of separate tests of treatment effects within each of the levels of the baseline variable is equally problematic, as they do not guarantee that the interaction tests are also significant. Another potential pitfall of conducting subgroup analysis is that the multiple subgroup analyses inflate the risk of false-positive findings. Nonetheless, primary analysis reports of Phase III trials frequently show primary results in subgroups defined by each of multiple baseline characteristics of the patients to investigate the consistency of the trial conclusions among different subpopulations. In the absence of profound evidence of interaction, readers should be circumspect about differential benefit being suggested.

Interim Monitoring and Analyses Interim analyses are defined as those intended to evaluate the experimental treatment regimen with respect to efficacy or safety at any time

prior to the planned final analysis. These analyses are dictated by the general ethical imperative that in a trial, if evidence of profound efficacy or significant safety issues arises, then intervention (stopping treatment, changing treatment, etc.) or other actions (reporting trial results) are warranted and necessary. However, frequent analysis of the accruing data can seriously compromise reliable inference in the trial, largely due to the inflation of error rates as the result of multiple comparisons discussed earlier. In addition, due to the random variability, the estimation of true treatment effect can be unstable and lacks the planned estimation precision. Nonetheless, data suggesting extraordinary benefit can occur, but any early reporting decision made at the early stage of any trial regardless of design must be approached cautiously and interpreted critically. Therefore, a sound interim analysis plan must be installed to maintain the integrity of the trial design. The statistical solution to the multiplicity issues inherent in interim monitoring is to prospectively incorporate potential early stopping in designs such that the probability of a false-positive conclusion remains at the desired level (e.g., 0.05) despite the multiple analyses. Group sequential analysis (whereby accruing data is analyzed in batches or groups) for efficacy has been widely used and has arguably become the default approach to rigorously monitoring almost all randomized Phase III clinical trials (and randomized Phase II). One way that is conceptually similar to approaches used in controlling FWER is to use designs that limit the number of times the data are tested. That is, instead of stopping a trial whenever a p value is 0.05, we plan to stop only when the nominal p values are considerably below 0.05 at multiple prespecified times. There are numerous approaches, among the most common being the one proposed by O’Brien and Fleming,48 with most of the more popular rules fitting into the so-called alpha “spending function” approach,49,50 which provides a way to determine what the interim testing levels should be without prespecifying the testing times. Interested readers may refer to the comprehensive texts3–6 for more in-depth discussions of interim monitoring. We may also stop trials early when there is convincing early evidence to establish that the experimental regimen will either perform worse than the control comparator or at best not be superior to any meaningful degree. This determination presumes that the new regimen is more toxic or costly (i.e., it does not have other advantages, as we discuss in the Noninferiority Trials section later). That is, we may want to monitor studies for early evidence of lack of value, referred to as futility monitoring. The approach and goals share similarities to two-stage, single-arm Phase II designs reviewed earlier. It should be noted that the level of evidence required and the associated process to stop an ongoing trial is different and asymmetrical between efficacy and futility. For efficacy monitoring, we may need to (and probably should) have an extreme early criterion for declaring that the new treatment is better than the standard comparator. For futility monitoring, however, we would not require the same degree of evidence, that is, results that reflect strong inferiority of the new treatment. In fact, all that is required is compelling evidence showing lack of benefit (i.e., new treatment equal to or worse to a nominal degree) to stop early for futility. When applicable, the asymmetrical relationship between superiority and futility monitoring should be explicitly acknowledged during trial planning and conduct. More generally, formal futility monitoring guidelines are considered a critical design feature of oncology clinical trials,51 with recently developed methods providing useful and efficient tools for this purpose.52

Noninferiority Trials A noninferiority (NI) trial aims to establish that a given experimental intervention has satisfactory but not necessarily superior benefit relative to a currently established intervention. Typically, noninferiority trials are undertaken when the experimental treatment is, in fact, not expected

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CHAPTER 14 to be better than the comparison treatment on a primary efficacy endpoint but has advantages on other domains—such as reduced side effects, cost, or ease of administration. Of note, the statistical hypothesis of the study is that the difference in efficacy is not worse than the control group by more than a small amount (referred to as the noninferiority margin). In other words, NI is assessed by evaluating whether a deficit in efficacy no larger than a prespecified acceptably small magnitude can be ruled out with sufficient confidence. NI margin selection is the most controversial and important aspect of the NI trial design. Based on the statistical framework of NI testing, in which the specification of the null and alternative hypotheses are in effect “reversed,” the NI margin delta must be chosen to be small enough so that it does not represent an unacceptable degree of inferiority under the alternative hypothesis conclusion of “treatment difference less than margin delta.” Meanwhile, this margin cannot be too small, as it would lead to a prohibitively large sample size. NI trials are a critical tool in evaluation of cancer interventions, particularly in new radiation oncology technology innovations, with key examples being alternative delivery systems and altered doses and schedules for radiation therapy in numerous disease sites.53–55 Treatment differences can be diluted (intentionally or unintentionally) by reducing “assay sensitivity” through subtle choices in design and conduct, and subsequently result in an NI conclusion. Potential causes of dilution include poor adherence and treatment crossovers, noncompliance, loss of follow-up and missing data, use of concomitant medications, poorly defined endpoints, misclassification, and measurement error. All of these issues may introduce “bias toward the null,” that is, a true difference between treatments beyond the specified NI margin may not be detectable when these deficiencies exist. As a result, high-quality trial conduct becomes even more critical for NI trials than superiority trials. At the clinical trial design stage, one is advised to plan prospectively how to handle these potential deficiencies, especially missing data. Otherwise, a poorly conducted study can conclude that the treatment is noninferior to control while, in reality, it may be worse than the control. In other words, deficiencies such as missing data and noncompliance can also inflate type I error rate. It should be stressed that failure to reject the null hypothesis is not equivalent to proving the null hypothesis. In NI trials, we conceptually reverse the specification of the null and alternative in that the alternative provides evidence of no material difference. For this reason, sound design, including adequate sample size, is paramount. NI trials create some complexity in interpretation and, even after conduct, may be subject to a range of views and even misinterpretation regarding the utility of the findings.56,57 These trials may also warrant special considerations in monitoring to ensure welfare of participants.58

PHASE II/III, MASTER PROTOCOLS, AND OTHER INTEGRATIVE DESIGNS Integrated Randomized Phase II/III Designs Integrated Phase II/III clinical trial designs are those in which the Phase II and Phase III components are combined in a single trial and the data based on the Phase II component are used to provisionally test the study hypothesis of the Phase III component. The key advantages lie in allowing Phase II patient data to be included in the principal Phase III trial analysis and minimizing the delay between the completion of the Phase II study and the start-up of the Phase III study, as well as the need to develop and implement sequential studies. In the original Phase II/III design setting, as proposed by Inoue et al.59 and some subsequent work, the same endpoint is used for both the Phase II and Phase III components of the trial. These designs can effectively be viewed as a Phase III study with rather aggressive (i.e.,

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likely to stop) interim futility analyses. The futility boundary corresponds to the marginal or minimal improvement of the new regimen that the investigator would like to observe before continuing to the Phase III component. The type I error, power, and effect size for the Phase III study (taking into account the Phase II analysis decision) are used to determine the sample size, critical value, and the decision rule for proceeding to Phase III, which are prespecified in the protocol. Generally, the criteria for continuing to the end of the study correspond to a very modest observed benefit in the primary endpoint, which is necessary to maintain the overall power of the study. However, the use of these designs with an endpoint such as OS can be problematic when median OS is relatively long and accrual is rapid. In order to maintain power for the overall trial, the Phase II analysis must therefore be carried out when it is sufficiently informative, that is, an adequate number of events have been observed, and frequently, this could occur after accrual is complete, thereby negating a major potential benefit of the design and interim analysis (curtailing of accrual in absence of promising Phase II results). In order to address the issue of minimal savings in time and patient numbers when using endpoints with longer time horizons such as OS for both the Phases II and III portions of a trial, an endpoint is used for the Phase II component that can be realized earlier and is putatively reflective (but not necessarily as a true surrogate endpoint) of definitive clinical benefit, thereby providing confidence to proceed to Phase III evaluation using the more definitive endpoint.60–64 Examples of such an early endpoint include response rate, PFS, or any other endpoint that could portend benefit on a more robust endpoint such as OS. Fig. 14.2 provides a conceptual illustration of the Phase II/III design. Some disadvantages of Phase II/III trials are that the total sample size must be larger than separate trials in many cases, and the trial may require an extended infrastructure and provisional commitment to the Phase III component from the outset of Phase II. There are numerous considerations regarding whether and how to best implement a Phase II/III trial in oncology, with an excellent overview provided by Korn et al.65

Platform Trials/Master Protocols In the era of molecularly based therapy, whereby diseases may be classified into multiple subtypes, each with a different expected prognosis and putative target, the need for trial development and conduct is daunting. Rather than mounting separate trials, if a program of trial investigations can be implemented with an upfront molecular screen and enrollment into subtrials under a “master protocol,” logistical efficiency may be Phase II Initiate Phase II Trial

Phase III

Accrue N1 patients Assess Intermediate Endpoint (IE) Insufficient IE activity

Stop

Promising IE activity

Continue to follow for definitive endpoint Accrue additional N2 patients for definitive endpoint

Primary Analysis Fig. 14.2 A Phase II/III randomized trial.

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Targeted Therapy A

Molecular Target A

Standard Therapy

Biomarker Assays

Standard Therapy

Tumor Type B

...... Molecular Target Y

Molecular Target Z

A

Tumor Type A

Targeted Therapy B

Molecular Target B

Molecular Targeted Therapy X

Targeted Therapy Y

......

Standard Therapy

Tumor Type Y

Targeted Therapy Z Standard Therapy

Tumor Type Z

B

Fig. 14.3 (A) An umbrella-type master protocol. Each subtrial is a marker/agent-targeted randomized Phase II trial or Phase II/III trial. The standard-of-care arm may be subset specific. (B) A basket-type master protocol—typically, the individual trials are early phase, seeking initial evidence of response.

enhanced. Such a protocol can also provide flexibility in terms of discontinuing unpromising investigations, carrying forward favorable early results to definitive testing in a Phase II/III framework, and introducing new subtrials as targets and agents are identified. These trials have alternatively been referred to as platform trials or master protocols. A more recent term for them is umbrella protocols, following the notion that, for a given disease, under one umbrella resides a series of targeted investigations (resembling the enrichment trials described earlier), which may or may not share similar comparator control treatments (Fig. 14.3A). A prominent example is the LUNG-MAP study.66,67 A related approach that is more relevant to earlier-phase development places the focus on specific tumor features across disease sites and, thus, further broadens the notion of a common protocol to encompass many tumor types. The moniker basket trial (see Fig. 14.3B) has been applied here, with a prominent example being the NCI-MATCH trial.68 While conceptually offering efficiency and flexibility, these designs can be logistically complicated to carry out when several sponsors are involved who may have conflicting proprietary interests and regulatory concerns. This is a rapidly evolving area of oncology clinical trials for which recent overviews and commentaries provide an excellent resource for gaining familiarity.69,70

Common Standard Comparator Exp. Trt A Eligible for All Therapy Arms: Randomize 2:1:1:1:1

Exp. Trt B Exp. Trt C Exp. Trt D

Continue (and continue randomizing to) arms that pass comparison to standard on intermediate endpoint

Phase II Phase III accrual accrual Fig. 14.4 Multiarm, multistage design: Arms are compared against a common control group and move to Phase III testing only if sufficient evidence of benefit is realized on an intermediate endpoint.

Multiarm-Multistage Design

Response Adaptive Randomization

In a similar approach with some important distinctions, one or more experimental arms could also be tested against standard-of-care therapy in an integrated Phase II/III design. These trials resemble randomized “selection” designs32 and related approaches,33 but with somewhat more rigorous evaluation criteria, including direct interarm comparisons. Such a trial might begin with multiple candidate treatment arms, all to be compared against a common control group. As outcome information accrues, only the arms that cross a prespecified efficacy screening boundary in the Phase II stage would be carried forward to the Phase III stage.71 From the patient and system perspective, this multiple-arm design may accelerate development relative to separate trials72 and help determine best candidates from among many viable options. However, as is the case with platform trials, such designs can be logistically complex. As was the case in a major implementation of this trial in prostate cancer (STAMPEDE trial), these issues are lessened if the interventions in question are already in use.73 Fig. 14.4 shows a conceptual illustration of this trial design.

One frequently encounters the adjective adaptive in modern clinical trial design, referring to a design that evolves according to accruing information during conduct. Many trial designs and elements thereof already discussed here are adaptive: Phase I trials sequentially modify doses according to observed adverse events, two-stage Phase II trials continue or stop based on preliminary response information, and Phase II and Phase III trials use interim monitoring rules to make early determinations of results, among other examples. However, adaptive trials most frequently refer to outcome-adaptive randomization, whereby the allocation of patients to treatment assignment depends on provisional or definitive outcomes observed thus far. This idea was introduced over 4 decades ago as the “play the winner” design.74–76 In its modern implementation, adaptive designs use a Bayesian approach, although Bayesian concepts are not integral to response-adaptive randomization. The adaptive design in simplistic terms begins with equal randomization and posits a more or less equal probability of response among arms. Based on an intermediate response endpoint, these response probabilities

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CHAPTER 14

Run-in: Randomization 1:1 Arm 1 (p1) Rand. (p1 = p2) vs. Arm 2 (p2)

Assess Interim Estimate of Treatment Effect

Treatment Effect “sufficiently large”

STOP & Conclude New Rx Better:

Treatment Effect NOT “sufficiently large” Arm 1 Better

Arm 2 Better

Increase P1 Decrease P2

Increase P1 Decrease P2

Fig. 14.5 Conceptual diagram of response-adaptive randomization.

are updated and those arms with more favorable outcome have greater probability of being assigned patients. Eventually, some arms may discontinue and others will be carried forward for more definitive testing (Fig. 14.5). Proponents of adaptive randomization point to the adaptive scheme as resulting in fewer patients ultimately being treated on an inferior arm, which may be an attractive feature to participants, and the facilitation of flexible platform-type designs that can integrate information from the entire suite of subtrials included.77,78 Those more circumspect of the approach point to ethical concerns of altered randomization probabilities and efficiency considerations in that these trials must be larger than traditional designs.79–81 Regardless of these factors, one critical issue is that a reliable intermediate endpoint must be available on which to effectively adapt randomization, as definitive endpoints that are not realized until randomization approaches completion offer little advantage. Concerns about the adequacy of such endpoints have been raised.82 Prominent examples of these trials include I-SPY2 and BATTLE in breast and lung cancer, respectively.83,84 Trials of this type will continue to offer an innovative approach to the challenges of modern oncology trials.

SUMMARY Close collaboration between clinical investigators and statisticians is the hallmark of a strong clinical trial design that, regardless of specific findings, will prove informative in advancing cancer care.

ACKNOWLEDGMENT Support for this work was provided by U10CA180822 (NRG Oncology SDMC) from the US National Cancer Institute (NCI), National Institutes of Health.

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6. Crowley J, Hoering A, eds. Handbook of Statistics in Clinical Oncology. 3rd ed. Boca Raton, FL: Chapman and Hall/CRC; 2017. 12. Garrett-Meyer E. The continual reassessment method for dose-finding studies: a tutorial. Clin Trials. 2006;3(1):57–71. 14. Polley MY. Practical modifications to the time-to-event continual reassessment method for phase I cancer trials with fast patient accrual and late-onset toxicities. Stat Med. 2011;30(17):2130–2143. 16. Boonstra PS, Shen J, Taylor JM, et al. A statistical evaluation of dose expansion cohorts in phase I clinical trials. J Natl Cancer Inst. 2015;107(3). 18. Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method than the 3+3 design for practical phase I trials. J Clin Oncol. 2013;31(14):1785–1791. 23. Simon R. Optimal two-stage designs for phase II clinical trials. Contemp Clin Trials. 1989;10(1):1–10. 27. Seymour L, Ivy SP, Sargent D, et al. The design of phase II clinical trials testing cancer therapeutics: consensus recommendations from the clinical trial design task force of the National Cancer Institute Investigational Drug Steering Committee. Clin Cancer Res. 2010;16(6):1764–1769. 29. Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol. 2005;23(28):7199–7206. 31. Lara PN, Redman MW. The hazards of randomized phase II trials. Ann Oncol. 2012;23(1):7–9. 36. Mandrekar SJ, An MW, Sargent DJ. A review of phase II trial designs for initial marker validation. Contemp Clin Trials. 2013;36(2):597–604. 37. Wu W, Shi Q, Sargent DJ. Statistical considerations for the next generation of clinical trials. Semin Oncol. 2011;38(4):598–604. 38. Freidlin B, McShane LM, Polley MY, et al. Randomized phase II trial designs with biomarkers. J Clin Onc. 2012;30:3304–3309. 47. Polley MY, Freidlin B, Korn EL, et al. Statistical and practical considerations for clinical evaluation of predictive biomarkers. J Natl Cancer Inst. 2013;105(22):1677–1683. 50. DeMets DL, Lan KG. Interim analysis: the alpha spending function approach. Stat Med. 1994;13(13–14):1341–1352. 58. Korn EL, Freidlin B. Interim monitoring for non-inferiority trials: minimizing patient exposure to inferior therapies. Ann Oncol. 2018;29(3):573–577. 63. Redman MW, Goldman BH, LeBlanc M, et al. Modeling the relationship between progression-free survival and overall survival: the phase II/III trial. Clin Cancer Res. 2013;19(10):2646–2656. 65. Korn EL, Freidlin B, Abrams JS, et al. Design issues in randomized phase II/III trials. J Clin Oncol. 2012;30:667–671. 69. Renfro LA, Sargent DJ. Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples. Ann Oncol. 2017;28(1):34–43. 71. Sydes MR, Parmar MK, James ND, et al. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials. 2009;10(1):39. 72. Parmar MK, Barthel FM, Sydes M, et al. Speeding up the evaluation of new agents in cancer. J Natl Cancer Inst. 2008;100(17):1204–1214. 77. Lee JJ, Chu CT. Bayesian clinical trials in action. Stat Med. 2012;31:2955–2972. 79. Korn EL, Freidlin B. Outcome-adaptive randomization: is it useful. J Clin Onc. 2011;29(6):771–776. 80. Hey SP, Kimmelman J. Are outcome-adaptive allocation trials ethical. Clin Trials. 2015;12(2):102–106.

A complete reference list can be found online at ExpertConsult.com.

3. Green S, Benedetti J, Smith A, Crowley J. Clinical Trials in Oncology. 3rd ed. Boca Raton, FL: Chapman and Hall/CRC; 2016. 4. Kelly WK, Halabi S, eds. Oncology Clinical Trials: Successful Design, Conduct, and Analysis. New York: Springer Publishing Company; 2018.

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CHAPTER 14

REFERENCES 1. Keating P, Cambrosio A. Cancer on Trial: Oncology as a New Style of Practice. Chicago, IL: University of Chicago Press; 2012. 2. National Cancer Institute: NCTN: NCI’s National Clinical Trials Network. 2012. Available at: https://www.cancer.gov/research/areas/clinical-trials/nctn. 3. Green S, Benedetti J, Smith A, Crowley J. Clinical Trials in Oncology. 3rd ed. Boca Raton, FL: Chapman and Hall/CRC; 2016. 4. Kelly WK, Halabi S, eds. Oncology Clinical Trials: Successful Design, Conduct, and Analysis. New York: Springer Publishing Company; 2018. 5. Piantadosi S. Clinical Trials: A Methodologic Perspective. 3rd ed. Hoboken, NJ: John Wiley & Sons; 2017. 6. Crowley J, Hoering A, eds. Handbook of Statistics in Clinical Oncology. 3rd ed. Boca Raton, FL: Chapman and Hall/CRC; 2017. 7. Wasserstein RL, Lazar NA. The ASA’s statement on p-values: context, process, and purpose. Am Stat. 2016;70(2):129–133. 8. Ioannidis JP. The proposal to lower p value thresholds to .005. JAMA. 2018;319(14):1429–1430. 9. Halpern SD, Karlawish JH, Berlin JA. The continuing unethical conduct of underpowered clinical trials. JAMA. 2002;288(3):358–362. 10. Lin Y, Shih WJ. Statistical properties of the traditional algorithm-based designs for phase I cancer clinical trials. Biostatistics. 2001;2:203–215. 11. O’Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics. 1990;46:33–48. 12. Garrett-Meyer E. The continual reassessment method for dose-finding studies: a tutorial. Clin Trials. 2006;3(1):57–71. 13. Cheung YK, Chappell R. Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics. 2000;56(4):1177–1182. 14. Polley MY. Practical modifications to the time-to-event continual reassessment method for phase I cancer trials with fast patient accrual and late-onset toxicities. Stat Med. 2011;30(17):2130–2143. 15. Bezjak A, Paulus R, Gaspar LE, et al. Efficacy and toxicity analysis of NRG Oncology/RTOG 0813 trial of stereotactic body radiation therapy (SBRT) for centrally located non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 2016;96(2):S8. 16. Boonstra PS, Shen J, Taylor JM, et al. A statistical evaluation of dose expansion cohorts in phase I clinical trials. J Natl Cancer Inst. 2015;107(3). 17. Braun T. The current design of oncology phase I clinical trials: progressing from algorithms to statistical models. Chin Clin Oncol. 2014;3(1):2. 18. Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method than the 3+3 design for practical phase I trials. J Clin Oncol. 2013;31(14):1785–1791. 19. Yuan Y, Hess KR, Hilsenbeck SG, et al. Bayesian optimal interval design: a simple and well-performing design for phase I oncology trials. Clin Cancer Res. 2016;22(17):4291–4301. 20. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247. 21. Gehan EA. The determination of the number of patients required in a follow-up trial of new chemotherapeutic agent. J Chronic Dis. 1961;13:346–353. 22. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982;38:143–151. 23. Simon R. Optimal two-stage designs for phase II clinical trials. Contemp Clin Trials. 1989;10(1):1–10. 24. Green SJ, Dahlberg S. Planned versus attained design in phase II clinical trials. Stat Med. 1992;11(7):853–862. 25. Sargent DJ, Chan V, Goldberg RM. A three-arm design for phase II clinical trials. Control Clin Trials. 2001;22(2):117–125. 26. Cannistra SA. Phase II trials in Journal of Clinical Oncology. J Clin Oncol. 2009;27(19):3073–3076. 27. Seymour L, Ivy SP, Sargent D, et al. The design of phase II clinical trials testing cancer therapeutics: consensus recommendations from the clinical trial design task force of the National Cancer Institute Investigational Drug Steering Committee. Clin Cancer Res. 2010;16(6):1764–1769. 28. Ratain MJ, Sargent DJ. Optimising the design of phase II oncology trials: the importance of randomisation. Eur J Cancer. 2009;45(2):275–280.

Overview of Oncology Clinical Trial Design

247.e1

29. Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol. 2005;23(28):7199–7206. 30. Tang H, Foster NR, Grothey A, et al. Comparison of error rates in single-arm versus randomized phase II cancer clinical trials. J Clin Oncol. 2010;28(11):1936–1941. 31. Lara PN, Redman MW. The hazards of randomized phase II trials. Ann Oncol. 2012;23(1):7–9. 32. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep. 1985;69(12):1375–1381. 33. Sargent DJ, Goldberg RM. A flexible design for multiple armed screening trials. Stat Med. 2001;20(7):1051–1060. 34. Liu PY, LeBlanc M, Desai M. False positive rates of randomized phase II designs. Control Clin Trials. 1999;20(4):343–352. 35. Sargent DJ, Conley BA, Allegra C, et al. Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol. 2005;23(9):2020–2027. 36. Mandrekar SJ, An MW, Sargent DJ. A review of phase II trial designs for initial marker validation. Contemp Clin Trials. 2013;36(2):597–604. 37. Wu W, Shi Q, Sargent DJ. Statistical considerations for the next generation of clinical trials. Semin Oncol. 2011;38(4):598–604. 38. Freidlin B, McShane LM, Polley MY, et al. Randomized phase II trial designs with biomarkers. J Clin Onc. 2012;30:3304–3309. 39. Freidlin B, Sun Z, Gray R, et al. Phase III clinical trials that integrate treatment and biomarker evaluation. J Clin Oncol. 2013;31(25):3158–3161. 40. Redman MW, Crowley JJ, Herbst RS, et al. Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819. Clin Cancer Res. 2012;18:4004–4012. 41. Gail MH. Eligibility exclusions, losses to follow-up, removal of randomized patients, and uncounted events in cancer clinical trials. Cancer Treat Rep. 1985;69:1107–1113. 42. Holm S. A simple sequentially rejective multiple test procedure. Scand J Statist. 1979;6(2):65–70. 43. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988;75(4):800–802. 44. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B. 1995;57:289–300. 45. Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially rejective multiple test procedures. Stat Med. 2009;28(4):586–604. 46. Maurer W, Bretz F. Multiple testing in group sequential trials using graphical approaches. Stat Biopharm Res. 2013;5:311–320. 47. Polley MY, Freidlin B, Korn EL, et al. Statistical and practical considerations for clinical evaluation of predictive biomarkers. J Natl Cancer Inst. 2013;105(22):1677–1683. 48. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:549–556. 49. Kim K, DeMets DL. Design and analysis of group sequential tests based on the type I error spending rate function. Biometrika. 1987;74: 149–154. 50. DeMets DL, Lan KG. Interim analysis: the alpha spending function approach. Stat Med. 1994;13(13–14):1341–1352. 51. Freidlin B, Korn EL. Monitoring for lack of benefit: a critical component of a randomized clinical trial. J Clin Oncol. 2009;27(4):629–633. 52. Freidlin B, Korn EL, Gray R. A general inefficacy interim monitoring rule for randomized clinical trials. Clin Trials. 2010;7:197–208. 53. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet. 2010;376(9735):91–102. 54. Lee WR, Dignam JJ, Amin MB, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2016;34(20):2325–2332. 55. Jones WG, Fossa SD, Mead GM, et al. Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a report on Medical Research Council Trial TE18, European Organisation for the

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Research and Treatment of Cancer trial 30942. J Clin Oncol. 2005;23:1200–1208. 56. Piaggio G, Elbourne DR, Pocock SJ, et al. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012;308(24):2594–2604. 57. Acuna SA, Dossa F, Baxter NN. Frequency of misinterpretation of inconclusive noninferiority trials: the case of the Laparoscopic vs. Open Resection for Rectal Cancer Trials. JAMA Surg. 2018;doi:10.1001/ jamasurg.2018.3222. [Epub ahead of print]. 58. Korn EL, Freidlin B. Interim monitoring for non-inferiority trials: minimizing patient exposure to inferior therapies. Ann Oncol. 2018;29(3):573–577. 59. Inoue LY, Thall PF, Berry DA. Seamlessly expanding a randomized phase II trial to phase III. Biometrics. 2002;58(4):823–831. 60. Hunsberger S, Zhao Y, Simon R. A comparison of phase II study strategies. Clin Cancer Res. 2009;15(19):5950–5955. 61. Royston P, Parmar MK, Qian W. Novel designs for multi-arm clinical trials with survival outcomes with an application in ovarian cancer. Stat Med. 2003;22(14):2239–2256. 62. Royston P, Barthel FM, Parmar MK, et al. Designs for clinical trials with time-to-event outcomes based on stopping guidelines for lack of benefit. Trials. 2011;12(1):81. 63. Redman MW, Goldman BH, LeBlanc M, et al. Modeling the relationship between progression-free survival and overall survival: the phase II/III trial. Clin Cancer Res. 2013;19(10):2646–2656. 64. Wang M, Dignam JJ, Zhang QE, et al. Integrated phase II/III clinical trials in oncology: a case study. Clin Trials. 2012;9(6):741–747. 65. Korn EL, Freidlin B, Abrams JS, et al. Design issues in randomized phase II/III trials. J Clin Oncol. 2012;30:667–671. 66. Ferrarotto R, Redman MW, Gandara DR, et al. Lung-MAP—framework, overview, and design principles. Chin Clin Oncol. 2015;4(3):36. 67. National Cancer Institute: LUNG-MAP Trial. 2018. Available at https:// www.cancer.gov/types/lung/research/lung-map. 68. National Cancer Institute: NCI-MATCH Trial (Molecular Analysis for Therapy Choice). 2018. Available at: https://www.cancer.gov/about-cancer/ treatment/clinical-trials/nci-supported/nci-match.

69. Renfro LA, Sargent DJ. Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples. Ann Oncol. 2017;28(1):34–43. 70. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377(1):62–70. 71. Sydes MR, Parmar MK, James ND, et al. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials. 2009;10(1):39. 72. Parmar MK, Barthel FM, Sydes M, et al. Speeding up the evaluation of new agents in cancer. J Natl Cancer Inst. 2008;100(17):1204–1214. 73. James ND, Sydes MR, Clarke NW, et al. STAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer—a multi-arm multi-stage randomised controlled trial. Clin Oncol (R Coll Radiol). 2008;20:577–581. 74. Zelen M. Play the winner rule and the controlled clinical trial. J Am Stat Assoc. 1969;64(325):131–146. 75. Wei LJ, Durham S. The randomized play-the-winner rule in medical trials. J Am Stat Assoc. 1978;73(364):840–843. 76. Rosenberger WF, Lachin JM. The use of response-adaptive designs in clinical trials. Control Clin Trials. 1993;14(6):471–484. 77. Lee JJ, Chu CT. Bayesian clinical trials in action. Stat Med. 2012;31:2955–2972. 78. Lee JJ, Gu X, Liu S. Bayesian adaptive randomization designs for targeted agent development. Clin Trials. 2010;7:584–596. 79. Korn EL, Freidlin B. Outcome-adaptive randomization: is it useful? J Clin Oncol. 2011;29(6):771–776. 80. Hey SP, Kimmelman J. Are outcome-adaptive allocation trials ethical. Clin Trials. 2015;12(2):102–106. 81. Korn EL, Freidlin B. Commentary on Hey and Kimmelman. Clin Trials. 2015;12(2):122–124. 82. Korn EL, Sachs MC, McShane LM. Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. Ann Oncol. 2016;27(1):10–15. 83. Barker AD, Sigman CC, Kelloff GJ, et al. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009;86:97–100. 84. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1(1):44–53.

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15 Health Services Research in Radiation Oncology: Toward Achieving the Achievable for Patients With Cancer William J. Mackillop, Timothy P. Hanna, and Michael D. Brundage

WHAT IS HEALTH SERVICES RESEARCH? Medical research may be considered as a continuum of four overlapping domains: basic or biomedical research, clinical research, health services research (HSR), and population health research. HSR aims to create the knowledge required to improve population health by improving the delivery of health services. Although there is some overlap between the domains of clinical research and HSR, their purposes are distinct. Clinical research describes the natural history of diseases, investigates their pathophysiology, and seeks to discover more effective treatments. HSR describes how health systems work, investigates how they go wrong, and seeks to discover better ways to deliver health services. The results of clinical research are primarily intended to guide physicians’ decisions about the care of individual patients, whereas the results of HSR are intended to guide the decisions of managers and policy makers about the design and implementation of health care programs.

Need for Health Services Research in Radiation Oncology Clinical radiation oncology is a mature science. It has a sound theoretical basis in both biology and physics. We have a universal language for describing the diseases we treat, the treatments we use, and the outcomes we achieve. Much is now known about the factors that influence outcomes in the individual case. We have a well-established process for evaluating the efficacy of treatment, and a large body of empirical information now permits evidence-based decisions about the use of radiotherapy (RT) in the majority of cases. In contrast, the science of HSR in radiation oncology is at a very much earlier stage of development. There is no comparable universal language for describing the performance of RT programs. There is only limited information available about the factors that influence the performance of RT programs in the population at large. There is no well-established process for measuring the effectiveness of RT programs at the population level. In the absence of empirical evidence, most decisions about the design and management of RT services are guided only by theory and expert opinion, and their consequences are unpredictable. Given that we would no longer tolerate this unscientific approach to decision-making in the care of individual patients, it is anomalous that it should still be used in making decisions about health systems that may affect tens of thousands of patients. The challenges for the HSR community in radiation oncology are to create the knowledge required for evidence-based management of RT programs and to promote the use of evidence in their design and management.

How Can Health Services Research Help to Improve the Outcomes of Cancer? At any point in time, the state of scientific knowledge and technological development sets an upper limit on what is achievable for patients with cancer. What is achievable in any particular society is also limited by how much that society is able and willing to spend on cancer care. However, what is actually achieved depends not only on what would be achievable if we made optimal use of the available knowledge, technology, and resources, but also on how close we get to attaining the achievable, a quantity that we have termed the attainment factor: Attainment Factor = Achieved outcome Achievable outcome The achieved and the achievable outcomes are measured in units that correspond to the outcome of interest. Attainment can have any value between 0 and 1 or may be multiplied by 100 and expressed as a percentage. The equation may be rewritten as: Achieved outcome = Achievable outcome × Attainment factor Cancer outcomes can be improved by increasing the achievable or by increasing the attainment factor. Biomedical and clinical research aim to improve outcomes by increasing the achievable. HSR aims to improve outcomes by increasing the attainment of what is already potentially achievable within the limits of existing knowledge, technology, and resources.

What Is the Scope of Health Services Research? Health system performance has three dimensions: accessibility, quality, and efficiency. Together, these determine the extent to which we attain the achievable in health care. Accessibility describes the extent to which patients are able to get the care they need when they need it. Quality describes the extent to which the right care is delivered in the right way. Efficiency describes the extent to which accessibility and effectiveness are optimized in relation to the resources expended. HSR is concerned with measuring these quantities, understanding the factors that influence them, and discovering and evaluating ways of enhancing them. The scope of health services research in oncology covers the entire continuum of cancer care. In a systematic cross-sectional study of 1113 HSR publications from 2009, the majority of HSR focused on active treatment (32%), with fewer studies addressing survival rates (19%) or screening (16%), and even fewer focused on diagnosis/assessment (10%), palliation (8%), or prevention (4%).1 Across this continuum,

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CHAPTER 15 the focus of HSR was most commonly on quality of care (56%), with fewer studies focused on accessibility (25%), efficiency (5%), or general well-being of subjects (14%).1 Fig. 15.1 shows a general framework for a program of HSR aimed at improving a specific aspect of health system performance. The first step is to select, define, and validate appropriate indicators of the aspect of performance that has been targeted for investigation. The next two steps are (1) to develop methods of measuring system performance in terms of the chosen indicator(s) and (2) to prescribe standards or targets for system performance in terms of the chosen indicators. These two steps, which often involve the use of very different methods, can sometimes be undertaken in parallel. Once standards have been set and methods for measuring performance have been established and validated, it becomes possible to evaluate the performance of the system against the standards. This, in turn, permits further explanatory studies aimed at identifying factors that are associated with better or worse performance. This information can be used to design interventions aimed at improving performance. The interventions may then be implemented and systematically evaluated. Interventions may be refined through further cycles of improvement before they are suitable for dissemination and incorporation into routine practice.

STUDIES OF THE ACCESSIBILITY OF RADIOTHERAPY Concept of Health Care Accessibility The term accessibility was originally used narrowly to describe the ability of patients to obtain entry into the health system.2 It is now used more broadly to represent the overall “degree of fit between the clients and the system.”2,3 Accessibility can be seen as having a number of dimensions that determine that overall degree of fit (Box 15.1). Availability describes the total volume of the service available in relation to the total number of clients that would benefit from it. Availability depends on the adequacy of supply of health care workers and on the adequacy of facilities and equipment. For any given level of resources, availability also depends on the degree of efficiency in production of services. Spatial accessibility describes the geographic relationships between the places where services are provided and the places where potential clients reside. The term accommodation describes the extent to which the system is designed and operated to facilitate clients’ access to service, for example, by operating at convenient hours or by providing transportation for patients who may need it. Affordability describes the relationship between the Choose and define indicators of performance

The HSR process

Describe performance

Set standards of performance

249

cost of health services and clients’ ability and willingness to pay. It depends not only on the direct cost of services but also indirect costs, for example, loss of earnings during a protracted course of treatment. Awareness describes the extent to which those who need the service know that it is available and that they might benefit from it. In the context of a specialized service such as RT, patients’ awareness of the potential benefits of RT depends largely on their attending physician’s awareness of the indications for RT.

Need for Studies of Access to Radiotherapy There are compelling reasons for doing research aimed at optimizing the accessibility of RT. In order to achieve optimal cancer outcomes at the population level, it is necessary to make effective treatments accessible to every patient who needs them. RT is known to be effective in many clinical situations; the World Health Organization (WHO) recognizes RT as a key component of any overall program of cancer control. In its 2005 declaration on Cancer Control, the WHO states that “…recognizing that the technology for treatment of cancer is mature and that many cases of cancer can be cured…., all nations should improve access to appropriate technologies.”4 Many nations aspire to providing adequate and equitable access to health care for all of their citizens, but there is remarkably little information available about how successful they are in achieving this laudable goal with respect to RT. In reality, the widespread reports of waiting lists for RT in the medical literature and news media and the limited supply of radiotherapy equipment and personnel in many developed and developing countries suggest that access to RT remains suboptimal in many parts of the world.

Waiting Lists for Radiotherapy Long waiting times for RT were first identified as a cause for concern in the medical literature in a report from Norway from three decades ago.5 Waiting lists for RT have since been reported in many other countries, including Australia,6 the UK,7 Canada,8 New Zealand,9 Denmark,10 Germany,11 Spain,12 and Italy.13 In countries affected by waiting lists for RT, they have been a major concern for both patients and providers. The problem of waiting lists for RT is an ongoing challenge for health services researchers in radiation oncology, but the first step in dealing with the problem is to learn how to measure waiting times for RT.

BOX 15.1

Accessibility

The Dimensions of Health Care

Availability Total system capacity in relation to total needs Total resources, efficiency, flexibility Spatial Accessibility Distance, travel times, costs of transportation Accommodation Hours of operation Transportation services Lodges/hostels

Evaluate performance

Implement intervention(s)

Health Services Research in Radiation Oncology

Identify factors that affect performance

Design intervention(s) to enhance performance Fig. 15.1 A general scheme for research on health system performance. HSR, Health services research.

Affordability Prices in relation to patients’ ability and willingness to pay Indirect costs Awareness Physicians’ awareness of patients’ needs and of potentially useful services Patients’ awareness of needs and services

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60 Median value of ttotal Median value of t1 Median value of t2 Median value of t3

50 60

Canada

USA

40

20

Median waiting time (days)

Proportion of departments (%)

80

40

30 20

10

3-4 4-5 5-6 6-7 7-8 Waiting time (wk) Fig. 15.2 Waiting times for radiotherapy (RT) for carcinoma of the larynx in Canada and the United States. The frequency distributions illustrate the time from referral to initiation of RT for a T2N0M0 carcinoma of the larynx in Canada and the United States based on the results of a mail survey. (Adapted from Mackillop WJ, Zhou Y, Quirt CF. A comparison of delays in the treatment of cancer with radiation in Canada and the United States. Int J Radiat Oncol Biol Phys. 1995;32:531-539.) !1

1-2

2-3

Measuring Waiting Times for Radiotherapy Different methods are available for quantifying waiting times and waiting lists for RT, including mail surveys, retrospective reviews of preexisting administrative data, and prospective collection of information about delays as patients pass through the system. Mail surveys and email surveys can provide a lot of information about waiting times from multiple institutions and can also be used to compare waiting times between different centers within one country or to compare waiting times between different countries. In the 1990s, a survey of heads of radiation oncology at comprehensive cancer centers in the United States and Canada showed that waiting lists for RT were widespread throughout Canada but revealed no evidence of similar problems anywhere in the United States. Median waiting times for a range of indications for RT were two to three times longer in Canada than in the United States.14 Fig. 15.2 shows, for example, that at almost every Canadian center, patients with laryngeal cancer waited longer for RT than they did at almost any US center. However, the validity of such surveys may be questioned because they rely on the veracity of self-reports and because the primary information on which each report is based may differ from center to center. Retrospective analysis of data that have been gathered for other purposes can provide more objective information about waiting times for RT. This may be an important first step in addressing this type of problem. At the beginning of the 1990s, reports of long waiting lists for RT in Ontario were frequently in Canadian news media. Health system managers felt that these reports were unduly alarmist and at first denied that there was any systemic problem.8 To clarify the situation, we undertook an analysis of waiting times for RT based on computerized electronic records of all visits to the province’s radiotherapy centers over the preceding decade. Once these administrative records had been linked to the province’s cancer registry, we were able to describe waiting times for RT for various specific conditions.8 For example, Fig. 15.3A shows that waiting times from diagnosis to start of radical RT for laryngeal cancer increased dramatically through the late 1980s and early 1990s. Similar large increases in waiting times were found in many

1982

1984

A

1986

1988

1990

Calendar year 100 Proportion of patients with t2 !2 wk Proportion of patients with t3 !2 wk

80 Proportion of patients (%)

0

60

40

20

1982

1984

1986

1988

1990

B

Calendar year Fig. 15.3 Waiting times for radiotherapy (RT) for carcinoma of the larynx in Ontario. (A) Temporal trends in median waiting time for RT in Ontario, for which ttotal is the interval between diagnosis and start of RT, t1 is the interval between diagnosis and referral to RT, t2 is the interval between referral and consultation, and t3 is consultation and start of RT. Data needed to measure t1 and t2 were available only from 1984. (B) The proportion of patients meeting the standards of the Canadian Association of Radiation Oncology, which states that patients are to be seen in consultation within 2 weeks of referral (i.e., t2 < 2 weeks) and started on RT within 2 weeks of consultation (i.e., t3 < 2 weeks). (Adapted from Mackillop WJ, Fu H, Quirt CF, et al. Waiting for radiotherapy in Ontario. Int J Radiat Oncol Biol Phys. 1994;30:221-228.)

other clinical situations. Further, as shown in Fig. 15.3A, the observed increases in overall waiting time between diagnosis and treatment were entirely due to increases in the waiting time between the first visit to a radiation oncologist and the start of RT. There was no increase in the interval between diagnosis and referral to radiation oncology or between referral and consultation. These findings pointed to rate-limiting problems in access to planning and/or treatment machines. It is useful, whenever possible, to report observed waiting times in relation to

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CHAPTER 15 standards or guidelines. At the time of this first report, the Canadian Association of Radiation Oncology (CARO) had already set standards for acceptable waiting times for RT: the maximum acceptable delay between referral to, and consultation by, a radiation oncologist was deemed to be 2 weeks, and the maximum acceptable delay between consultation and the start of RT was deemed to be 2 weeks.8 Although these standards were based only on expert opinion, they provided a useful framework for comparison. Fig. 15.3B shows trends in compliance with these standards over time. Most patients met the CARO standard for prompt consultation throughout the study period, but the proportion of patients meeting the CARO standard for prompt start of RT fell from 90% to 10%. This simple study, which merely quantified the magnitude of the problem in our community, was useful because it led to public recognition of the seriousness of the problem.8 This proved to be an important first step in promoting reinvestment in the infrastructure of the provincial RT system. There are limitations to the retrospective analysis of waiting times. First, this approach is blind to patients who dropped off the waiting list before they were treated, because it starts by identifying patients treated with RT and then follows them backwards to measure waiting times from date of diagnosis or some other milestone. Second, it is unlikely that any database created for other purposes will provide all of the information necessary to identify the rate-limiting step in the RT process. The date of the decision to treat with RT, for example, is an important milestone that signals the transition from pretreatment assessment to planning, and this is collected only in systems designed specifically to monitor flow through the RT process. Administrative databases may also lack information about other elements of the patient’s care that are necessary to interpret waiting times for RT. For example, planned deferral of the start of postoperative RT because of delayed wound healing is indistinguishable from unscheduled delay unless the date when the patient is ready to be treated is recorded prospectively. Finally, the retrospective approach does not provide the real-time information needed to fine-tune the performance of an RT program. Prospective collection of the pertinent information is the preferred approach for tracking patients through the system. This approach has now been adopted by the Ontario RT system (see “A Canadian Case Study” section to come).

Causes of Waiting Lists for Radiotherapy Kinetics of waiting lists. When demand for RT exceeds supply, waiting times inevitably increase and a waiting list for RT starts to grow. In theory, the waiting list will then continue to grow for as long as demand continues to exceed supply. In reality, waiting lists for RT do not grow indefinitely. When waiting times for RT become longer than the referring physicians believe is acceptable, they may begin to offer their patients alternative treatments in circumstances in which RT would normally have been their first choice. For example, when long waiting lists for RT developed in Ontario in the early 1990s, there was a significant decline in the use of primary RT in the management of head and neck cancer, followed by a rebound when waiting lists decreased after a major reinvestment in facilities.15,16 It has also been shown that there is a significant negative association between the prevailing waiting time for RT and the proportion of patients receiving postoperative RT following a partial mastectomy for breast cancer.17 Furthermore, tumor progression or deterioration in patients’ general condition during the delay may render them ineligible for RT that would initially have been appropriate; these cases drop off the list. Decreasing referrals and increasing dropoffs from the waiting list reduce demand for RT. As demand declines, the balance between supply and demand is eventually restored; the waiting list then ceases to grow, waiting times stabilize at a higher level, and RT utilization rates stabilize at a lower level. This phenomenon has

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been referred to as implicit rationing because it limits utilization without explicitly limiting access to care.18 Even when average supply is equal to average demand for RT, random fluctuations in referral rates may produce transient peaks in demand that exceed supply, which may be sufficient to cause a substantial waiting list.19 This risk can be reduced by forward planning that provides a buffer of reserve capacity or by building flexibility of capacity into the system. The smaller the functional unit, the greater is the impact of random fluctuations and the more reserve capacity is required to avoid a waiting list.19 Even in the absence of any shortfall in supply, quite long delays may develop in a complex process such as RT planning, simply because of the many serial steps involved. Process mapping and redesign can be useful in streamlining health systems and can reduce delays in some situations. For example, a French proton therapy center applied such an approach to reduce average wait times by 4 or more weeks and to increase the annual number of treatment sessions from 4000 in 2007 to 4500 in 2009.20 Investigators at the University of Michigan examined streamlining the referral-to-treatment process for patients requiring palliative radiation for bone and brain metastases. They standardized processes and cut the number of individual steps to begin treatment from 27 to 16. The proportion of patients receiving consultation, simulation, and treatment within the same day was increased from 43% to nearly 95%.21 However, no amount of fine-tuning will impact waiting times for RT if total demand greatly exceeds total supply.

Consequences of Waiting Lists for Radiotherapy Delays in starting RT are a source of great concern both to the patients and to those involved in their care. Box 15.2 summarizes the potential adverse effects of waiting lists for RT. Delays have both direct and indirect effects on the well-being of patients, and waiting lists also have broader economic and social consequences. It is useful to classify the direct effects of delay on the well-being of individual patients as nonstochastic or stochastic.22 We use these terms as they have been used in the field of radiation protection, in which they provide a useful distinction between the effects of radiation that depend on chance and those that do not. The nonstochastic effects of delay include the psychological distress due to the delay and the physical symptoms due to the untreated cancer. They occur in most cases and often increase in intensity with time, although they may not occur at all before some initial threshold period has been exceeded. The stochastic effects of treatment delay include the development of metastases and failure to achieve local control with radiation. These are all-or-nothing phenomena. Their probability increases as a function of time, but their severity is independent of time, and there is no lower limit of waiting time below which they will not occur. Waiting lists may also have indirect adverse effects on patient care, mediated by changes in medical practice. In addition to their effects on health outcomes, waiting lists have important economic and societal implications.22 Measuring the direct effects of delays in radiotherapy. Some of the direct effects of delays in RT are self-evident. Delays in cancer treatment cause psychological distress and patients who are symptomatic wait longer for relief. There are also good reasons to believe that delays may adversely affect the long-term outcomes of RT. Delay provides an opportunity for tumor progression. There is abundant evidence that the probability of local control decreases as tumor volume increases and that the risk of metastasis increases over time.23 These arguments are probably sufficient to persuade most radiation oncologists that unnecessary delays in RT should be avoided. However, in a publicly funded health system, in which waiting lists are endemic and widespread, many different specialties may each use their own waiting list problems to try to lever additional funding from a limited overall pool. In this context, direct evidence that delays in RT have an adverse effect on

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clinical outcomes is necessary to ensure that the needs of the RT sector are given appropriate priority. Given the very scant direct evidence that was initially available about the impact of delay on outcomes, we used a mathematical modeling approach to estimate the risks of treatment delay.22 The model was based on radiobiological principles that had been validated in experimental systems. It incorporated the best available clinical information about tumor doubling times and the relationship between tumor volume and local control in the context of cancer of the tonsils.22 The model predicted a decrease in local control rates of between approximately 10% per month of delay in the start of RT. Others have since made similar predictions.23,24 However, although this approach was credible to radiation oncologists, it was not readily understood by those outside our field and had no impact on public policy. In order to make our case for increased resources, we therefore needed to provide direct clinical evidence of the adverse effects of delay. Measuring the magnitude of the stochastic effects of treatment delay is not straightforward. It is inherently difficult to measure the risk of treatment failure due to delay, because local failures caused by delay are absolutely indistinguishable from treatment failures due to other causes. The problem is analogous to that of defining the risk of carcinogenesis associated with low-dose radiation. One cannot simply count the cancers due to radiation because they are usually indistinguishable from the many other cancers that may occur due to causes other than radiation. Therefore, rates of failure must be compared in groups of patients who have been exposed to longer and shorter delays; the challenge is to ensure that those groups are comparable with respect to all other relevant prognostic factors. A randomized trial would be the best way of creating truly comparable groups, but it would be unethical to randomize patients to timely RT versus delayed RT, because there is no conceivable benefit in delay. Comparisons of the outcomes of RT in nonrandomized groups of patients who have waited longer or shorter periods of time are subject to all of the biases that may affect any retrospective observational study. However, in this context, such studies are very important since they represent the best available direct source of information.25,26 Recent systematic reviews have identified a growing number of observational studies that have investigated the association between treatment delay and the outcome of radiotherapy in certain clinical situations.27 Fig. 15.4 summarizes the results of the 20 high-quality studies included in a recent published meta-analysis.27 Most of these studies had been done in the context of head and neck cancer and breast cancer. In these two disease groups, meta-analysis has showed a significant increase in the risk of local recurrence in patients who waited longer for RT.27 A very large population-based outcomes study, not included in this meta-analysis, recently confirmed that delay was associated with a higher risk of local failure following postlumpectomy RT for breast cancer.28 We found no evidence of a threshold below which delay was free of risk. Moreover, although there was less evidence of an association between delay and local control in sites other than breast and head and neck, there was insufficient data available to conclude that delay in RT is free of this risk in any situation. We found no significant association between delay in RT and the risk of distant metastasis although there was less information available about this outcome.27 There was a small but significant decrease in survival with increasing delay in head and neck cancer.27 The relative risk of local recurrence of 1.1 per month of delay in starting postoperative RT for breast cancer translates into an absolute increase in recurrence rate of about 1% per month of delay in a population with a baseline rate of local recurrence of 10%.27 Although this is a small risk for any individual, it has the potential to cause an important increase in the number of recurrences at the population level. The increase in the relative risk of recurrence by 1.15 per month of delay

in patients undergoing definitive RT for head and neck cancer translates into an absolute increase in risk of recurrence of 3% in a population with a baseline risk of failure of 20% or an absolute increase of 6% in a population with a baseline risk of failure of 40%.27 Interestingly, these findings are consistent with those predicted by the mathematical models described earlier.22,24 Thus, a few weeks’ delay in RT may have an adverse effect on outcome that is sufficient to cancel out all of the improvements in outcome achieved by advances in the practice of RT over the last 20 years.24,25 Given that there is no theoretical reason to believe that there is a threshold below which delay is safe, we have recommended that it would be prudent to adopt the principle that delays in RT should be As Short As Reasonably Achievable (ASARA), modeled on the ALARA (As Low As Reasonably Achievable) principle, which guides risk management in the field of radiation protection.25 Indirect effects of waiting lists for radiotherapy on patient care. Box 15.2 summarizes the indirect effects of waiting lists on patient care and population health. The phenomenon of implicit rationing by which waiting lists reduce the use of RT has already been described and the consequences of underutilization of RT will be discussed later. Waiting lists may also increase the use of alternative treatments that may be less effective, more morbid, and more expensive than RT. There is evidence that long waiting lists may cause radiation oncologists to modify the

BOX 15.2 The Effects of Waiting Lists for Radiotherapy Direct Effects of Delay in RT on the Well-Being of Patients 1.0 Nonstochastic effects 1.1 Persistence or worsening of symptoms while waiting for treatment 1.2 Psychological distress 2.0 Stochastic effects 2.1 Decreased probability of local control 2.2 Increased probability of spread beyond the irradiated field 2.3 Decreased probability of cure because of Items 2.1 and 2.2 2.4 Increased probability of complications due to compensatory increases in dose and/or volume Indirect Effects of Waiting Lists for RT on the Well-Being of Patients 3.0 Decreased probability of being referred for RT when appropriate 3.1 Omission of necessary RT 3.2 Exposure to less effective and/or more toxic alternatives to RT 4.0 Re-referral to a distant center for RT, with loss of continuity of care 5.0 Decreased quality of practice of radiation oncology 5.1 Risk of cutting corners to treat more patients 5.2 Decreased quality of personal care because of the imperative to maximize technical productivity 5.3 Decreased scope for innovation Economic Effects of Waiting Lists 6.0 Decreased efficiency of RT programs 6.1 Decreased net benefits of RT (see Items 1.0 and 2.0) 6.2 Increased costs associated with care for patients during delay 7.0 Decreased overall efficiency of cancer treatment programs 7.1 Decreased benefits of RT because of treatment delayed or denied 7.2 Increased costs because of the requirement for additional care during delay and/or use of more expensive alternatives to RT Other Societal Effects of Waiting Lists 8.0 Legal liability of providers for failure to provide adequate access to care 9.0 Decreased public confidence in the health care system

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CHAPTER 15

Breast Studies Postop RT without chemo Froud, 2000 Vujovic, 1998 Whelan, 1996 Clarke, 1985

RR (95% Cl)

3.35% 3.66% 1.09% 0.91%

10.08% 10.39% 0.83% 6.67% 0.80% 10.10% 12.59%

SUBTOTAL

1.18 (1.00, 1.39) 1.13 (0.96, 1.33) 1.11 (0.62, 1.98) 1.12 (0.91, 1.37) 2.62 (1.45, 4.72) 0.95 (0.81, 1.12) 1.11 (0.96, 1.29) 1.11 (1.03, 1.19)

ALL BREAST STUDIES

1.11 (1.04, 1.19)

Postop RT with chemo Hebert-C, 2004 Benk, 2004 Wallgren,* 1996 Wallgren, 1996 Slotman, 1994 Yock, 2004 Recht, 1996

Head and Neck Studies Definitive RT Leon, 2003 Fortin, 2002 Brouha, 2000 O’Sullivan, 1998 Lee, 1994

1.08 (0.94, 1.23) 2.03 (1.24, 3.33) 1.03 (0.68, 1.56) 1.52 (1.07, 2.17) 0.63 (0.23, 1.70) 1.15 (1.02, 1.29)

15.09% 1.14% 1.63% 2.22% 0.28%

0.34% 7.59% 1.42%

SUBTOTAL

1.63 (0.67, 4.01) 1.22 (1.01, 1.48) 1.56 (1.01, 2.43) 1.28 (1.08, 1.52)

ALL HEAD AND NECK STUDIES

1.19 (1.08, 1.31)

Sarcoma Ballo, 2004

1.23 (1.04, 1.45)

ALL STUDIES COMBINED

1.14 (1.09, 1.21)

SUBTOTAL

Postop RT Marshak, 2004 Suwinski, 2003 Kajanti, 1991

253

Weight (%)

0.91 (0.69, 1.22) 1.06 (0.80, 1.39) 1.46 (0.88, 2.42) 2.07 (1.19, 3.59) 1.11 (0.94, 1.33)

SUBTOTAL

Health Services Research in Radiation Oncology

9.82%

0.2

0.5

1.0

2.0 5.0 RR Fig. 15.4 The association between delay in radiotherapy (RT) and the risk of local recurrence. The plot shows the results of a meta-analysis that included 20 high-quality studies that compared rates of local recurrence following RT. *The Wallgren study was separated into two groups as two independent populations were examined. CI, Confidence interval; RR, relative risk. (From Chen Z, King W, Pearcey R, et al. The relationship between waiting time for radiotherapy and clinical outcomes: A systematic review of the literature. Radiother Oncol. 2008;87:3-16.)

way that they prescribe RT. A study from the Queensland Radium Institute, for example, showed a significant negative correlation between waiting times and the number of fractions prescribed per course, due primarily to decreases in palliative fractionation as waiting times increased.29 We have found a similar association between prevailing waiting time and the choice of fractionation for bone metastases in Ontario.30 There are obviously serious risks in deviating from accepted practice in radiation oncology for the sole purpose of getting more patients treated. However, in circumstances in which randomized trials have demonstrated that shorter courses of RT are equivalent to longer courses of treatment, adoption of the more parsimonious approach has the potential to reduce overall workload and greatly increase the availability of RT without adversely affecting outcomes.31 The challenge is to ensure that shorter-than-standard courses of RT are used only in circumstances in which they have been shown to be medically appropriate.

10.0

Explicit standards of care are required to prevent deterioration of quality in an attempt to maintain accessibility. Societal effects of waiting lists for radiotherapy. Waiting lists for RT are potentially costly (see Box 15.2). Patients require both care and counseling during delays and the costs of alternative treatments may be considerably higher than those of RT. Waiting lists have sometimes caused patients to be referred to distant centers for RT with loss of continuity of care and support for those patients, plus added costs to the health system. The inability to provide timely RT may also be frustrating and distressing for the staff of RT programs. Waiting lists also expose RT providers to legal liability. In Quebec, a class action suit was launched against the hospitals responsible for providing RT on behalf of approximately 10,000 women who had to wait long periods for adjuvant RT following surgery for breast cancer. At trial, the judge accepted the evidence that delay was associated with an increase in the

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risk of local failure and the case was ultimately settled with financial compensation for women who had waited for longer than 12 weeks to begin postoperative RT following lumpectomy.32 Chronic waiting lists for RT and other important medical services eventually became an important political issue. Waiting lists are often used as evidence of the need for change both by advocates of privatization of the health system and by those who favor reinvestment in the public system. By the early 2000s, public opinion polls showed that “wait times” for medical care had become the greatest concern of most Canadian voters and there were increasing demands that government should set waiting time standards. A Canadian case study. Why did waiting lists for RT become such a widespread problem around the world in the 1990s? Was there an increase in demand or a decrease in supply or both? Ontario’s experience serves as a useful case study. Analysis of historical data showed that three different factors conspired to cause a huge increase in demand for RT over the critical period.16 First, the incidence of cancer increased inexorably by approximately 3% per year, due primarily to the aging of the Ontario population.16 Second, there was a dramatic increase in the number of patients referred for RT for breast cancer (consistent with the evidence-based trend toward breast conservation surgery),16 for rectal cancer (consistent with the evidence-based adoption of postoperative RT and chemotherapy),31 and for prostate cancer (due to a large increase in the number of early cases detected following the widespread adoption of prostate-specific antigen screening).16 Third, there was a significant increase in the average number of fractions prescribed per course of RT. This was driven by an increase in the number of fractions per curative or adjuvant course, which outweighed a concomitant but smaller decrease in the number of fractions per palliative course of RT.16 There was no decrease in treatment capacity. In fact, the number of treatment machines in the province increased faster than the incidence of cancer.16 The demographic trends responsible for increasing cancer incidence and the changing patterns of practice that were responsible for Ontario’s

waiting list crisis are international phenomena, which explains why waiting lists developed more or less simultaneously in many other countries at about the same time. Countries where most or all of the RT system was publicly funded were hardest hit. The fact that the United States did not experience similar problems probably reflects the much greater reserve capacity available in its large private sector and its ability to increase capacity rapidly in response to increased demand. In the private sector, increased demand represents an opportunity to increase revenues. When demand begins to outgrow supply, providers titrate additional resources into the system until demand is once again saturated. In contrast, in a publicly funded system operating on a fixed global budget, there is rarely any reserve capacity, and it may be impossible to expand capacity rapidly. Increasing capacity often requires expanding facilities and acquisition of new equipment. Approval processes for new capital projects in publicly funded systems may take years to complete. These built-in delays may make it impossible to catch up on a growing problem once it becomes established. Only accurate forecasting of the future need for RT linked to a proactive planning process for facilities, equipment, and personnel can provide a way of avoiding similar problems in the future in slow-to-react public systems. In Ontario, additional steps were used to prospectively monitor waiting times for radiotherapy as an indicator of quality of care. Prospective data collection was required to overcome the limitations to the retrospective analysis of waiting times, since such analyses are “blind” to patients who dropped off the waiting list before they were treated. Further, the data used in retrospective analyses may lack the information necessary to define the rate-limiting steps in the RT process or may lack information about other elements of the patient’s care that are necessary to interpret waiting times for RT or to fine-tune the performance of an RT program. Prospective collection of the pertinent information is the preferred approach for tracking patients through the system. Fig. 15.5 illustrates how this approach was adopted by the Ontario RT system using the framework presented earlier (see Fig. 15.1). Definitions were developed for overall wait times (and by

Develop definitions of wait times (overall and by waiting period)

CARO consensus on maximum acceptable wait times

Choose and define indicators of performance

Set standards of performance

Evaluate performance on indicators using retrospective data

Describe performance Publicly-reported program performance reports

Implement intervention(s)

Apply methods to prospectively collect data

Identify factors that affect performance

Design intervention(s) to enhance performance Institution-specific approaches

Fig. 15.5 An illustration of the use of health services research to improve quality of care with regard to radiation wait times. CARO, Canadian Association of Radiation Oncology.

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CHAPTER 15 waiting period) as indicators of performance; the CARO definitions were used to set standards of performance as described earlier. Methods were developed to prospectively collect wait-time data for each treating center, and the proportion of patients meeting performance standards was routinely monitored and publicly reported. To improve wait times, investment in infrastructure was made. Further, each cancer center evaluated its treatment processes relevant to wait times and implemented process improvements (e.g., by running appropriate processes in parallel rather than sequentially). Patients with delays that were medically indicated (e.g., delayed wound healing) or with personal circumstances requesting delay were identified prospectively and accounted for in the analyses. As a result, analyses now reveal that the vast majority of patients meet wait-time standards once ready to treat; the provincial programmatic focus is now, however, on overall waiting times from date of diagnosis to start of definitive treatment, as these times still exceed guidelines for some complex case groups, such as oropharynx cancers.33

Measuring Access to Radiotherapy

Limitations of Waiting Times as an Indicator of Access to Radiotherapy The existence of a long waiting list for RT is a symptom of inadequate access to RT. The duration of the waiting time for RT may be directly related to the probability of an adverse outcome; therefore, waiting times may serve as a quantitative measure of the quality of care. The length of a waiting list, however, provides no information about the magnitude of the shortfall between supply and demand. Thus, waiting times cannot serve as a quantitative measure of accessibility. The absence of a waiting list does not mean that access is optimal. Waiting lists develop only in response to supply-side problems in the availability of services. Waiting times are entirely insensitive to demand-side problems with respect to spatial accessibility, accommodation, affordability, or awareness (see Box 15.1). Problems in those dimensions of accessibility, in fact, reduce demand and may serve to reduce or avoid waiting lists. Thus, the absence of a waiting list does not imply that access is optimal. To ensure appropriate access to RT, it is also necessary to monitor RT utilization rates.

Defining Accessibility of Radiotherapy The best quantitative measure of the accessibility of any service is the rate of its appropriate utilization; that is, the proportion of patients that need a service who actually receive it. The term need is used here as defined by Cuyler,34 who states that “the need for medical care exists when an individual has an illness for which there is effective and acceptable treatment.” Accessibility Number of patients who need and receive treatment = Total number who need treatment Accessibility can have any value between 0 and 1, where 1 corresponds to optimal access. These values can also be multiplied by 100 and expressed as a percentage. Thus, to determine the accessibility of RT directly, we must measure both the utilization of RT and the need for RT in the cancer population. In practice, the number of patients in a population who receive RT is relatively easy to determine, but the number who need RT is usually unknown. Therefore, proxy measures of need have to be chosen.

Measuring Accessibility of RT The incidence of cancer (i.e., number of new cases diagnosed in the population of interest over the period of interest) may be used as the denominator for describing the rate use of RT in the initial management

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of the disease. The best way to establish the proportion of cases that are treated with RT is to follow all of them forward in time from the date of diagnosis and find out if and when the patient received RT. The approach was first used in the Netherlands.35 We subsequently used it to describe the use of RT in Ontario.15 The estimated rate of use of RT in the initial management of cancer depends on the cutoff point in time used to define initial RT. If a short cutoff point is chosen to define initial RT (e.g., RT within 3 months of diagnosis), the indicator will miss some patients who receive adjuvant RT following surgery. If a longer cutoff point is chosen (e.g., RT within 1 year), the indicator will include almost all patients who receive RT as part of their initial management, but it will also wrongly include some patients who are actually receiving RT for an early recurrence following primary surgery. The best cutoff point depends on the specific disease under consideration. For practical purposes, we have chosen to use the proportion of incident cases treated within 1 year of diagnosis to describe the initial use of RT in the general cancer population.15 Fig. 15.6A describes variations in the use of RT in the initial management of cancer in Ontario in terms of this indicator (RT1 year). The incidence of cancer is a less suitable denominator for describing the utilization of palliative RT. This is because a high proportion of incident cases will never develop indications for palliative RT and many who ultimately do need it will not require it until years after the diagnosis. It is preferable to describe the use of palliative RT among patients who die of their cancer. This can be accomplished by identifying patients who died of their disease in a population-based cancer registry and following them back in time to identify those who received RT within a defined interval before death.36 Fig. 15.6B describes variations in the use of palliative RT in the last 2 years of life among patients who died of their disease in Ontario. The same approach lends itself well to the description of the rates of use of other types of care in the terminal phase of the illness. What factors affect the rate of RT in the general cancer population? Fig. 15.6 illustrates geographic variations in the rate of use of RT in Ontario, with the highest rates being observed in the counties where RT facilities are located.15 It has generally been found that rates of RT use are higher in urban than in rural areas37 and that proximity to an RT facility is associated with higher utilization rates.15 Taken together, these observations suggest that spatial accessibility is an important determinant of the accessibility of RT. In studying geographic variations in practice, it is obviously important to be able to distinguish systematic variation from variations due to chance alone. Modeling techniques have been developed that can be used to isolate the systematic component of variation.15 Multivariate analysis is helpful in distinguishing the impact of health system–related factors from other factors that are legitimately involved in determining patients’ eligibility for RT. These include differences in cancer incidence, stage distribution, evolution of evidence supporting use of radiotherapy, patient functional status, and patient preference. Patient functional status and preference are important factors but are usually not available in administrative health data. Patient preference plays a significant role in observed rates of RT in cases in which there is more than one treatment option, such as for men with low-risk prostate cancer. Measurements of RT use have revealed unexpected inequities in access to care. One example is from a study investigating factors associated with use of palliative RT among patients who died of their cancer in Ontario (Table 15.1). In multivariate analysis, rates of use of palliative RT proved to be significantly lower among patients in whom the diagnosis was made in a hospital without an RT facility,36 which confirms the concern of others that lack of awareness of the indications among other health professionals for RT may also be a significant factor in determining accessibility.39 Additionally, even in the context of a publicly

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256

SECTION I

Scientific Foundations of Radiation Oncology Quintile 17.5% - 24.3% 25.1% - 26.8% 27.2% - 29.1% 29.2% - 30.7% 30.8% - 35.2% Data not available

Ottawa

Kingston Thunder Bay

Toronto Windsor

A

Northern Ontario 0 250

Sudbury 500 Miles

London

Hamilton Southern Ontario 100 200 Miles

0

Quintile 10.9% - 23.5% 23.5% - 24.5% 24.5% - 26.5% 26.5% - 29.6% 29.6% - 35.5% Data not available

Ottawa

Kingston Thunder Bay

Toronto Windsor

B

Northern Ontario 0 250

Sudbury 500 Miles

London

Hamilton 0

Southern Ontario 100 200 Miles

Fig. 15.6 Geographic variations in the use of radiotherapy (RT) in Ontario. (A) Intercounty variations in the rate of use of RT in the initial management of cancer within 1 year of diagnosis. (B) Intercounty variations in the use of palliative RT in the last 2 years of life among patients who died of their cancer. The location of the provincial RT centers is shown for comparison. (A, Adapted from Mackillop WJ, Groome PA, Zhou Y, et al. Does a centralized radiotherapy system provide adequate access to care? J Clin Oncol. 1997;15:12611271; B, adapted from Huang J, Zhou S, Groome P, et al. Factors affecting the use of palliative radiotherapy in Ontario. J Clin Oncol. 2001;19:137-144.)

funded health system, the socioeconomic status of the patient influences the likelihood of receiving palliative RT. Fig. 15.7 shows that rates of use of palliative and adjuvant RT decrease with increasing age and that this decrease is far greater than can be explained due to declining performance status.38

Measuring the Need for Radiotherapy Given that the use of RT varies widely, it is important to ask what proportion of patients with cancer need RT. In the past, it was often stated that approximately 50% of patients with cancer should receive RT at some point in the course of the illness, but that recommendation was based almost entirely on expert opinion.39 Two more objective methods have since been developed for estimating the need for RT. Evidence-based requirements analysis. Evidence-based requirements analysis (EBRA) is an objective method that has been used to estimate

the need for RT. The indications for RT are first identified by systematic review. Next, an epidemiological approach is used to estimate how frequently each indication for RT occurs in the population of interest. Finally, the results of the systematic review and the epidemiological analysis are combined to estimate the overall need for RT. In this context, the term need can be equated with the appropriate rate of utilization of RT36 and the two terms may be used interchangeably. Tyldesley et al. discovered this method and used it first to estimate the need for RT for lung cancer.40 We have subsequently refined the method and used it in several other major cancer sites.41 The strengths of the method are (1) that it is transparent in that all of the assumptions involved are explicit and (2) that it is flexible and models can be adapted to reflect the case mix in any community of interest or to explore the implications of changes in the indications for RT. The main weaknesses of the approach are (1) that it is complex and time-consuming; and (2) like any other

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CHAPTER 15

Factors Affecting the Use of Palliative Radiotherapy in Ontarioa

100%

Median Household Income Low, < Can $20,000 1.00

95% Confidence Interval —

Medium, Can $20,000-$50,000

1.09

1.04–1.15

High, > Can $50,000

1.17

1.11–1.24

RT Department in Diagnosing Hospital No 1.00 Yes

1.35

80%

60%

40%

20%

— 1.30–1.40

Proximity of Patient’s Home to Nearest RT Center No RT center in 1.00 — county of residence RT center in county of residence

RT rate or performance status relative to 45-54 age group

TABLE 15.1

Odds Ratio

257

Health Services Research in Radiation Oncology

1.24

1.21–1.27

Region Northeast Ontario

0.84

0.79–0.90

Toronto

0.88

0.84–0.92

Windsor

0.90

0.84–0.97

Ottawa

1.00

—

London

1.02

0.97–1.07

Northwest Ontario

1.04

0.96–1.13

Kingston

1.17

1.11–1.26

Hamilton

1.20

1.14–1.26

a

From a logistic regression that controlled for age, sex, and primary site. RT, Radiotherapy.

type of modeling, its results are only as good as the information on which it is based. EBRA can be expected to produce valid results when it is applied to major cancers for which the indications for RT are well defined and there is sufficient epidemiological information available to estimate the frequency with which each indication occurs. Delaney et al. extended the use of this method to measure the need for RT across the whole spectrum of malignant disease—it is now being widely used to predict requirements for RT equipment.42 Criterion-based benchmarking. An alternative way of estimating the appropriate rate of the use of RT is to use a series of observations to derive a “benchmark.” In the business world, benchmarking has been defined as “measuring products against the toughest competitors or those recognized as industry leaders.”43 In the field of health care, the equivalent is to measure outcomes against the best achieved anywhere or against those achieved in recognized centers of excellence. The same concept may be applied in setting benchmarks for the appropriate rate of utilization of any given treatment. The rate observed under certain very specific conditions may be equated with the appropriate rate of utilization—in other words, with the need for treatment. Benchmarks for the utilization of RT should be set in communities where there is unimpeded access to RT and expert decision-making about the use of RT. To ensure unimpeded access, there should be no financial barriers, referring physicians should be aware of the indications for RT, and patients should have convenient access to a nearby RT center that has sufficient capacity to provide prompt treatment. To ensure optimal

0% 45-54

55-64 65-74 Age groups

!75

Radical RT for oropharyngeal cancer Adjuvant RT for breast cancer Palliative RT in last year of life with prostate cancer Performance status Fig. 15.7 The effect of age on the use of radiotherapy (RT). The proportion of patients who received RT for specified indications is shown for older age groups and compared with the rate observed in patients between 45 and 54 years old. The expected decline in performance status with increasing age is shown for comparison. (Adapted from Tyldesley S, Zhang-Salomons J, Groome P, et al. Association between age and the utilization of radiotherapy in Ontario. Int J Radiat Oncol Biol Phys. 2000;47:469-480.)

decision-making, decisions about the use of RT should be made by experts practicing in a multidisciplinary setting and, ideally, the decision to treat should not affect their remuneration. If these criteria are met, it is reasonable to expect that the observed rate of utilization of RT will approximate the appropriate rate. We call this approach Criterion-Based Benchmarking (CBB).44 We have been able to select a few communities in Ontario that meet most of the listed criteria and have used them to set benchmarks for the appropriate rate of utilization of RT for lung cancer.44 Fig. 15.8 shows that, in this context, estimates of the appropriate rate of RT generated by this method are very similar to those derived from the evidence-based approach. The CBB method has several strengths: (1) It is an inductive method that is grounded in observations in the real world; (2) it is applicable to both rare and common cancers because it does not require an accurate, comprehensive catalog of indications for treatment or detailed information about case mix; (3) it is relatively inexpensive and can be repeated easily if the indications for treatment change; and (4) it can be validated by replication in different communities. It also has several weaknesses: (1) It assumes that optimal structures and processes are associated with optimal practice, which has not been proven; (2) the structures and processes that support optimal access and optimal decision-making are not well defined; and (3) it requires a detailed knowledge of the structures in place in communities that are candidates to be benchmarks, information that may not readily be available. This CBB approach has been adopted by Ontario’s provincial cancer agency and is now used for RT system planning. It is also used in the ongoing evaluation of the performance of the RT system by the Cancer Quality Council of Ontario, which routinely reports on rates of RT use in relation to benchmarks established for the major malignant diseases.

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Percentage of Incident Cases Treated With RT within 1 Year of Diagnosis

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50% Evidence-based estimate of the appropriate rate = 41.6% 40% 30% Observed provincial rate = 32.5% 20%

Benchmark counties Other counties

10%

20 30 40 10 Counties in Order or Rate of Use of RT Fig. 15.8 Evidence-based estimates and benchmarks of the appropriate rate of use of radiotherapy (RT) in the initial management of lung cancer. The rates of RT in the initial treatment of lung cancer are shown for each county in Ontario. The error bars represent the 95% confidence limits for these observations. Benchmark counties are those where cancer centers with relatively short waiting lists were located. The evidence-based estimate of the appropriate rate and the overall provincial rate are shown as horizontal lines; the distance between the lines represents the unmet need for RT. (Adapted from Barbera L, ZhangSalomons J, Huang J, et al. Defining the need for radiotherapy for lung cancer in the general population: a criterion-based, benchmarking approach. Med Care. 2003;41:1074–1085.)

Once utilization and need have been measured, it is straightforward to calculate the level of unmet need. Consider the data shown for lung cancer in Fig. 15.8. It was estimated that approximately 41.5% of cases of lung cancer need RT as part of their initial management, but the observed rate of RT use was only 32.5%. Thus, only 32.5/41.5 = 78.3% of cases who needed RT actually received it. The ~ 22% shortfall between the observed rate and the appropriate rate represents an important opportunity for improving outcomes of lung cancer.

The Consequences of Underutilization of Radiotherapy Adequate access to RT is a necessary component of any comprehensive cancer control program. At present, many patients who might benefit from RT have no access to the treatment that they need. This is a global problem that affects both developed and developing countries, but it is most prevalent and severe in low-resource settings where RT services are either nonexistent or so limited as to be essentially nonexistent (see later discussion).45 The consequences of lack of access to RT are most devastating for patients who have a radiocurable condition for which no other standard curative treatment is available, for example, those with locally advanced cervical cancer. In situations such as this, the lack of access to RT inevitably translates into an avoidable and often very unpleasant death. In contrast, failure to provide adjuvant RT when indicated does not make death inevitable but does increase the risk of local recurrence and may also compromise long-term outcomes. Many patients who do not get palliative RT when they need it to relieve their pain or other symptoms will continue to suffer, while others who are more fortunate must accept the lesser benefits and perhaps greater toxicity of alternative treatments. Beyond its effects on the patients themselves, the lack of access to RT may have serious consequences for their families and their communities. The unnecessary death of a young man or woman may have devastating economic and social consequences for their surviving family. The broader economic consequences of failure to use RT vary depending

on the patient’s condition and the socioeconomic status of the community. In rich countries, where a range of other services are more readily available, failure to use RT when indicated may lead to the increased use of other, less cost-effective treatments, with a consequent overall increase in the cost of care. Even in poor countries where no alternative treatments are available, it may ultimately cost more not to treat a curable young patient than it would have cost to provide the necessary RT, because failure to treat the patient results in the loss of a productive member of society.

STUDYING THE QUALITY OF RADIOTHERAPY This section introduces the concept of quality in health care, describes what HSR has taught us so far about the quality of RT, and identifies what we still need to learn.

Concepts of Quality and Effectiveness in Health Care In the field of HSR, the term efficacy is used to describe the extent to which a treatment achieves its objectives in the controlled setting of a clinical trial. The term effectiveness is reserved for describing the extent to which a health program meets its stated objectives in the real world. The term quality is used to describe the effectiveness of the care provided relative to the effectiveness of the best possible care. In this context, the term quality is therefore synonymous with the term attainment factor as defined earlier. Donabedian46,47 defined quality as “a property of, and a judgement upon, some definable unit of health care, and that care is divisible into at least two parts: technical and interpersonal.” The quality of technical care is measured by the extent to which “the application of medical science and technology maximizes its health benefits without correspondingly increasing its risks.” The quality of interpersonal care is measured by “how well the physician-patient interaction meets the socially defined norms of the relationship.”46 Although others may define it somewhat differently today, there is universal agreement that quality is a multidimensional concept that embraces both the technical and personal elements of care. Donabedian47 also provided an approach for evaluating and improving quality, which Kramer and Herring soon astutely recognized as being appropriate for use in radiation oncology.48 Donabedian’s approach was to analyze the quality of programs in terms of structure, process, and outcome. The term process is used here to describe the way that care is delivered. In the context of radiation oncology, it includes pretreatment assessment, medical decision-making, planning, delivery of RT, supportive care during RT, and more. The term structure is used broadly to include facilities, equipment, human resources, and organizational structures. The term outcome is used here, as in clinical practice, to describe the consequences of the care that has been provided. It is reasoned that (1) optimal process is necessary for optimal outcome; (2) adequate structure is necessary, though not sufficient, for optimal process; and (3) outcomes may be enhanced by identifying and correcting deficiencies in structure and/or deficiencies in process. This became the philosophy of the US Patterns of Care Study that was established by Kramer in 1970. It operates on the premise that practice variations exist, differences in process and outcome can be measured, and deficiencies can be corrected.48 The Patterns of Care Study (PCS) continues this important work today under the new title of Quality Research in Radiation Oncology (QRRO).

Studies of the Structure of Radiotherapy Programs Two different types of research are being undertaken in this area. First, there are descriptive studies of the physical and organizational structures that prevail in RT programs around the world. In some instances, the

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CHAPTER 15 observed structures are compared with predetermined standards. In others, the description of structures has been linked to studies of process and outcome with the goal of establishing which types of structure are associated with the best results. These studies may rely on mail surveys or involve on-site visits, but they are all cross-sectional or retrospective in design. Second, there is the field of technology evaluation, which is essentially prescriptive rather than descriptive in intent. It seeks to establish prospectively the usefulness of new technologies in patient care and thus contributes information that is important in setting standards for equipment in an RT program.

Descriptive Studies of the Structure of Radiotherapy Programs In a highly technical specialty such as radiation oncology, optimal care can be provided only when the necessary technological infrastructure is in place, including the correct mix and quantity of equipment and the correct mix and quantity of personnel. Nationwide surveys of RT facilities have now been done in many different countries. In the United States, the QRRO study has taken the lead in describing the basic structural characteristics of radiation oncology facilities for the entire country. Its comprehensive survey of the structure of US facilities serves as the starting point for national surveys of treatment processes and outcomes, and permits stratified sampling of different types of facilities.49 In addition to evaluating equipment and personnel, QRRO has described the structure of RT facilities in the following terms: (1) whether they have resident training programs or not, (2) volume of new cases treated per annum, (3) whether they were headed by a full-time or part-time radiation oncologist, and (4) participation in clinical trials. In Europe, a variety of governments,50 agencies,51 and individual investigators52 have conducted national surveys of RT program infrastructure, primarily as a basis for planning. Most national surveys reveal considerable diversity with respect to the level of technology and expertise that is available in different RT centers, particularly with respect to brachytherapy. The European Society for Radiotherapy and Oncology (ESTRO) has more recently taken the lead describing and comparing the infrastructure of RT programs across Europe in a project called Quantification of Radiation Therapy Infrastructure and Staffing (QUARTS), funded by the European Commission.53 QUARTS involves an international survey of equipment and personnel, the establishment of guidelines for levels of staffing and equipment, and the estimation of future needs based on projected incidence and estimates of the need for RT. International comparisons of radiotherapy structure have been performed by the International Atomic Energy Agency (IAEA). These studies have covered Europe, Asia, Africa, and Latin America.54-57 A common theme has been wide variation in the supply of radiotherapy resources, with undersupply a common international problem, especially in low-income (gross national income (GNI) per capita, US$995 or less) and middle-income countries (GNI per capita, US$996–$12,055).54-56, 58 A strong relationship exists between a lower national economic status and the degree of greater undersupply of radiotherapy equipment.59 At its extreme, 29 of 52 African countries, with a total population of 198 million people, have no known external beam radiotherapy facility.54 The concept of program structure embraces not only physical infrastructure but also organizational structures, including systems of funding, management, and governance. These elements of structure in radiation oncology may also have important effects on processes, but they have generally received less attention than the physical elements of structure. Funding arrangements at European RT centers listed in the ESTRO directory were investigated as part of an international study of palliative RT.60 A broad range of funding mechanisms for RT departments is described, including a global budget, per-case payments, fee for service, and all possible combinations thereof. RT centers in Spain,

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the United Kingdom, and the Netherlands were mainly funded by a global budget plus or minus per-case payments, while the majority of centers in Germany and Switzerland received most of their funding through a fee-for-service arrangement.60

Prescribing Technology Assessment New technologies are being developed rapidly; our specialty needs to develop better ways of evaluating them and determining their appropriate place in routine clinical practice.61,62 Wherever possible, new treatment techniques should be evaluated in randomized clinical trials, but it is clear that this approach lends itself only to the study of relatively common presentations of relatively common diseases. A large component of the practice of radiation oncology, however, is directed toward patients who have one of the many less common cancers or one of the infinite range of unusual presentations of a common cancer. In neither of these situations is there ever going to be “level 1 evidence” to guide our practice and it would be impossible for a new approach to treatment to achieve its full potential if we demanded level 1 evidence for its use in every situation. On the other hand, if we choose to make our decisions about the acquisition and use of new technologies based only on the manufacturers’ claims of enhanced precision, we may expose our patients to added risks and added costs without real benefits.61

Studies of Process in Radiotherapy The term quality assurance (QA) is used to describe processes intended to avoid error in medical care, that is, to ensure that every patient gets the right treatment delivered the right way. Much of what has been written about QA in radiation oncology concerns the avoidance of error in delivering RT, but avoidance of error in case selection for RT deserves equal attention. The term error is used here to describe a deviation from appropriate care. Operationally, deviations from appropriate care can be identified only when the boundaries of appropriate care have been defined. Therefore, any QA program falls into two parts: (1) setting standards, that is, deciding what is appropriate; and (2) ensuring compliance with standards, that is, making sure that every patient is treated appropriately. Some processes in an RT program have the potential to affect every patient, while others concern specific groups of patients. We deal first with research in the area of general QA before considering the process of care for specific groups of cancer patients.

Research on Quality Assurance Processes in Radiotherapy The RT community has long recognized the importance of routine QA because of the potential for a malfunctioning or wrongly calibrated machine to cause systematic errors in the treatment of a large number of patients. Detailed guidelines and protocols have been developed for commissioning, maintenance, and calibration of treatment machines.62 However, neither the existence of such guidelines nor an organizational commitment to adhere to them is sufficient to guarantee patient safety. A seminal study undertaken some years ago by Horiot et al. on behalf of the European Organization for Research and Treatment of Cancer (EORTC) revealed that some centers made systematic errors in radiation dosimetry.63 It also showed that feedback of the results of the initial survey diminished the frequency of such errors when the study was later repeated.64 Although QA on equipment reduces the chance of systematic error, the requirement for individualization of treatment plans creates the added risk of random error caused, for example, by lapses in human judgment or miscommunication. It has been shown that although well-defined care paths or intervention-specific guidelines can minimize the frequency of this type of error, it does not eliminate them. Real-time auditing is necessary to avoid rare, but potentially serious, errors in the context of routine practice65 and even in the controlled setting of clinical trials.66

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Scientific Foundations of Radiation Oncology

The general rule that emerges from these analyses is that human errors cannot all be avoided, but the vast majority can be detected before they have any adverse impact on the patient. Understanding why errors occur is now recognized as the key to development of better processes for their avoidance in future. Therefore, the epidemiology of medical errors is a growing field of study.67 Because actual errors are rare, it is important also to investigate near misses.68 This is the approach that is now widely being used in the field of RT.69,70 Although several recent accidents have heightened awareness of the dangers of RT,71 serious errors that result in harm to patients are exceptionally rare in comparison to error rates in other fields of medicine.72 The low error rates in RT were not achieved by chance; they reflect a long-standing awareness of the dangers of RT and a tradition of commitment to QA that antedates the intense media attention directed to medical error over the last decade. Nonetheless, new technologies bring new risks of error; thus, there is a need for continuing research in the field of QA in RT.

Research on Practice Patterns in Radiotherapy During the past 30 years, there have been numerous studies of patterns of care in radiation oncology using methods primarily developed by the PCS.73 Many different clinical situations have been studied. Most work has been done in the major sites in which RT plays an important role in curative treatment, but there have also been a number of studies of the practice of palliative RT, particularly in the context of bone metastasis. Striking variations in practice have been discovered in every situation that has been studied in detail. Practice has been shown to vary at many different points in the pathway of care: in pretreatment assessment; in fundamental aspects of the RT prescription, including target volumes, treatment techniques, and dose and fractionation; in decisions about adjunctive systemic treatment; in the planning process; in treatment delivery; in the way that treatment details are recorded; in supportive care during and after treatment; and in arrangements for long-term follow-up. Why study practice variations in RT? Practice variations have been identified in every field of medicine where anyone has taken the trouble to look for them. As discussed earlier, radiation oncology is no exception. In the era of evidence-based medicine, practice variations represent a threat to the credibility of any medical specialty; it is difficult to defend variations in patient care except insofar as they reflect variations in the needs of individual patients or unavoidable variations in the availability of resources. Practice variations in radiation oncology represent not only a threat but also an opportunity for improving practice and outcomes. The opportunities to improve the quality of care depend on the state of knowledge in the particular clinical situation under study. If optimal practice has already been established or can be established for the purposes of the study, deviations from the optimal represent opportunities for improving quality of care. It then becomes important to understand why practice deviates from the optimal in order to design interventions that will improve practice. If, on the other hand, optimal practice has not yet been established, practice variations represent an opportunity for learning. Studies of practice patterns may identify controversies that should be addressed in clinical trials. In certain very specific circumstances, it may be possible to explore the relationship between treatments and outcomes in order to determine which approach is superior. The scope and limitations of this type of study are discussed in the upcoming section entitled “Relating Structure and Process to Outcomes.” Why does practice vary in radiation oncology? In an ideal world, cancer treatment would be guided only by precise classification of the case and the application of scientific knowledge about the optimal treatment of that class of cases, taking into account the patient’s personal values and preferences. In the real world, however, other environmental factors may influence patient care. Treatment options are often

constrained by the resources available. Scientific knowledge is variably disseminated and may be interpreted differently by individual physicians depending on their training, experience, and work environment. Moreover, financial considerations have the potential to influence medical decisions whenever there is more than one defensible treatment option available. We now review what is known about the impact of each of these factors on the practice of RT. Impact of program structure on the practice of radiotherapy. Consistent with Donabedian’s concept, there is abundant evidence that physical and organizational structures determine processes in RT (see Fig. 15.12). If the total availability of personnel and equipment is not adequate to permit prompt access to RT, referring physicians may choose alternative forms of treatment. Many studies have revealed that radiation oncologists’ choices of investigations, treatment techniques, and fractionation schemes are influenced by the resources available. The PCS consistently found significant associations between the structural characteristics of facilities and the quality of processes involved in patient care. For example, in a now-classic study of work-up and treatment procedures in head and neck cancer,74 the PCS found significantly poorer compliance with its criteria of appropriateness of assessment, treatment, and other aspects of care among patients treated at facilities headed by a part-time, rather than full-time, radiation oncologist (Fig. 15.9A) and at nontraining facilities compared with training facilities (see Fig. 15.9B).

15 Frequency of facilities

SECTION I

Full time Part time 10

5

0 0

A

10

20

30

40

50

60

Facility average nonperformance rate 15

Frequency of facilities

260

Training Nontraining

10

5

0 0

10

20

30

40

50

B

60

Facility average nonperformance rate Fig. 15.9 Relationships between the structural characteristics of radiotherapy (RT) programs and quality of practice. (A) Nonperformance rates for part-time and full-time facilities. (B) Frequency polygons of nonperformance scores for training and nontraining facilities. (Adapted from MacLean CJ, Davis LW, Herring DF, et al. Variation in work-up and treatment procedures among types of radiation therapy facilities: the Patterns of Care Process Survey for three head and neck sites. Cancer. 1981;48:1346-1352.)

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CHAPTER 15 Impact of scientific evidence on the practice of radiotherapy. Practice varies most where there is least evidence available. Decision-making about the use of RT has been shown to be highly variable in the context of adjuvant RT. This is most evident where the value of RT has not been confirmed in randomized trials. Although many indications for RT are supported by the results of randomized trials, there have been far fewer formal comparative studies of the details of RT prescriptions and techniques. Not surprisingly, technical practice of RT is even more variable than clinical decision-making in radiation oncology. Even in situations in which there have been several consistent published reports that appear to indicate that one approach is superior to another, it has been shown that physicians may interpret these data very differently and, therefore, may still vary widely in their treatment recommendations.75 There has been much interest in enhancing the practice of medicine through the synthesis and dissemination of scientific knowledge in the form of treatment guidelines. Guidelines are clearly valuable for reference purposes, but it is not clear to what extent they have actually succeeded in modifying practice in the general population. For example, we observed no impact of a provincial guideline promoting shorter fractionation for postlumpectomy radiotherapy over and above changes attributable to earlier reports of randomized trial evidence supporting this practice.76 Changes in practice have sometimes been reported after the introduction of treatment guidelines, but it is usually impossible to conclude that the guidelines themselves were responsible for those changes.77 The existence of treatment guidelines does not guarantee appropriate clinical decision-making. Misclassification of patients may lead to selection of an inappropriate care path or treatment plan. This may be caused by inadequate or inaccurate pretreatment assessment or misinterpretation of the results of an adequate assessment. If QA is directed only at the avoidance of errors in delivery of RT, patients remain at risk of receiving the wrong treatment, albeit flawlessly delivered. Clear specification of eligibility criteria for RT and real-time audit of compliance with those criteria are required to avoid this type of error. Scientific evidence appears to vary in its impact depending on the practice environment and on the demographic characteristics of the patients. In 2001, the US Commission on Cancer reported that breastconserving surgery was still used in less than 50% of US patients with stage I and stage II breast cancer and that variations in its use were not consistent with existing practice guidelines.78 Breast conservation was more rapidly and completely adopted in urban than in rural areas and there were large geographic variations in its adoption across the United States, with much higher rates in the northeast than elsewhere. Older patients and patients from lower socioeconomic groups were less likely than others to have a partial mastectomy, and those who did were less likely to receive postoperative RT. There is also evidence that the characteristics of physicians and their type of practice influence the extent to which they rely on guidelines or other published information in reaching treatment decisions. Reliance on published information in decision-making is greater in academic centers and decreases the longer the physician has been in practice.79 Local policies may affect practice more than national guidelines. A study from the United Kingdom, for example, showed that much of the variation in the use of postoperative RT for breast cancer was attributable to variations in the local management protocols of surgical units.80 Impact of physicians’ beliefs on the practice of radiotherapy. There is abundant evidence that physicians’ beliefs about appropriate treatment are shaped by factors other than universal knowledge. Physicians’ views about the indications for RT are strongly influenced by their training and experience. Because the key decisions about referral are usually made by surgeons, the views of the surgical community are a major determinant of the role that RT plays in cancer care at the population level. It has repeatedly been shown that surgeons are less likely to

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recommend RT than radiation oncologists, particularly when a choice has to be made between primary RT and primary surgery. For example, in comparison with radiation oncologists, urologists are less likely to recommend primary RT for prostate cancer81 and otolaryngologists are less likely to recommend RT for laryngeal cancer.82 Medical oncologists today have acquired a significant role in initiating referrals to radiation oncology, but their views about the indications for RT also differ significantly from ours.75 Impact of financial incentives and disincentives on the practice of radiotherapy. There is evidence that funding mechanisms may affect case selection for RT. For example, a study based on administrative claims data from Pennsylvania showed that the patient’s health insurance status was associated with the chance of receiving RT following partial mastectomy. Postoperative RT was given in only 45% of Medicaid patients compared with greater than 75% of privately insured and Medicare patients; similar observations have been made elsewhere.83 Funding arrangements have also been shown to influence choices of fractionation in some studies. Lievens et al. has explored the effects of funding on patterns of palliative RT in Belgium.84 She found that fractionated courses of RT were prescribed more frequently than single treatments for bone metastases, at least in part because the funding mechanism in place at that time penalized the use of single fractions. In 2001, a new mechanism of funding of palliative RT was introduced in Belgium that removed the disincentive to single treatments. Since that time, there has been a trend to reduce the number of fractions prescribed in all except 3 of the 23 centers that responded to her most recent survey. Many of those centers reported that the change in the fee schedule was a significant factor in their decision to change practice.84 Lievens et al. have also shown significant associations between funding models and the practice of palliative RT in an international survey of RT centers across Europe.84 They found a relationship between funding by a global budget or per case payment and lower number of fractions per course and less use of shielding blocks compared to funding by fee for service.60 The growing evidence that funding may shape the way that RT is practiced suggests that it may be possible to improve practice by appropriately manipulating reimbursement systems. However, there is also a high risk that poorly designed fee schedules may compromise quality of care.85 It has also been pointed out that, under per-case funding arrangements, profits may be inversely related to quality, making it very important to set clear baseline quality standards.86

Role of Quality Indicators in the Practice of Radiotherapy Assessment of quality of care allows health care providers to examine their clinical performance against established standards of care, allows payers to assess the quality of care that they are purchasing, and is an increasingly important area of HSR.87 As described earlier, the general framework (see Fig. 15.1) for a program of HSR describes how quality indicators may be used to assess quality of care and to improve health system performance. Quality indicators may be selected, defined, validated, and applied in order to target observed variations in practice by evaluating actual practice against targeted performance and to conduct explanatory studies aimed at identifying factors that are associated with better or worse performance. Quality indicators specific to radiation oncology have been developed across the framework of structure, process, and outcome domains of quality of care, and across a spectrum of clinical settings.87-89 A recent comprehensive review by Albert and Das summarizes the current scope of quality indicator development and application in radiation oncology.90 The setting of radiation used in the curative management of prostate cancer can illustrate these general principles of quality measurement. Prostate cancer has a high incidence and is commonly managed with either external-beam radiotherapy or brachytherapy as definitive

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262

SECTION I

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treatment. The RT is highly technical, and continuous advances in technology require consideration in the definition and application of quality indicators in this setting.89 In Canada, radiotherapy is delivered exclusively in 37 publicly funded cancer centers across the country, staffed by approximately 400 radiation oncologists. A Canadian HSR team undertook a modified Delphi process to identify existing candidate quality indicators for measuring the quality of technical medical care and to develop consensus on a suite of quality indicators based on best available evidence.89 This process identified a suite of 25 quality indicators covering all aspects of prostate cancer radical RT management: pretreatment assessment, external-beam RT, brachytherapy, androgen deprivation therapy (ADT), and follow-up. These selected quality indicators were then used as criteria in an audit of patterns of practice and to develop benchmarks of performance in highest-performing centers.91 Of 37 RT centers, 32 (84%) participated, providing 810 cases in total. Analysis of these cases revealed that compliance with12 pretreatment assessment indicators varied considerably across indicators: from 56% (sexual function documented) to 96% (staging bone scan obtained in high-risk patients). For cases treated with external-beam radiotherapy (EBRT), 100% were treated using three-dimensional conformal radiotherapy (3DCRT) or intensitymodulated radiotherapy (IMRT) techniques with computed tomography or magnetic resonance imaging planning, whereas 81% of planned cases recorded dose-volume histograms for planning target, rectum, and bladder volumes. For patients treated with conventional fractionation, the dose to the prostate was greater than 70 Gy in 100% of low-risk patients, greater than 70 Gy in 92% of high-risk cases, but greater than 74 Gy in only 78% of intermediate-risk patients treated without ADT. ADT was used in 92% of high-risk cases. Fig. 15.10 illustrates that centers varied with regard to how many indicators they were fully

compliant with; all centers were fully compliant with 4 or more of 16 indicators, though no center was fully compliant with all indicators.91 Given that each quality indicator was selected as representing a minium standard of care,89 these data suggest room for improvement in quality of care, particularly for indicators such as dose, in which variation can affect cancer outcome.

Studies of Outcomes in Radiotherapy Programs It is important to appreciate that although outcomes may seem to be the ultimate measure of quality, one cannot fine-tune the operation of a cancer program by measuring the long-term outcomes by which we usually judge the success of cancer treatment. It may take a decade to measure the 5-year recurrence-free rates associated with a particular pattern of practice. Any feedback from audit of outcome comes far too slowly to permit optimization of program performance. Quality improvement programs in oncology largely have to operate on the principle that if you get the structure and the process right, the outcomes will look after themselves. That being said, there is some value in measuring outcomes and the opportunity to do this should not be overlooked. Surprisingly, it may be easier to measure outcomes than processes in the general population. Accurate information about vital status is usually available in cancer registries, and it may be quite straightforward to measure survival at the population level. Hospital records and billing files may provide information about subsequent surgical procedures that can sometimes provide surrogate measures of local control by RT. For example, survival without subsequent laryngectomy has been used as a surrogate for local control in measuring the success of radical RT for laryngeal cancer, and survival without subsequent cystectomy has been used as a surrogate for local control after radical RT for bladder cancer (Fig. 15.11). The high statistical power of population-based

Number of Quality Indicators on which Each Radiation Oncology Center Was 100% Compliant 16

Number of quality indicators (max = 16)

14 12 10 8 6 4 2 0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Center Fig. 15.10 Center performance on a suite of 16 quality indicators across Canadian radiotherapy centers. The graph shows the number of indicators on which all cases sampled from that center met the specific quality indicator (demonstrating 100% compliance on that indicator). (Data from Brundage M, Danielson B, Pearcey R, et al. A criterion-based audit of the technical quality of external beam radiotherapy for prostate cancer. Radiother Oncol. 2013;107:339-345.)

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CHAPTER 15

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100

Rank relative survival

Survival (%)

10

Dead from bladder cancer

80

60

40

Dead from other causes

Alive with cystectomy

Spain England Denmark

8 Germany 6 Italy 4

Netherlands France

2

R = 0.82 p !0.01

Switzerland

20

US/SEER 0

Alive without cystectomy

0 0

1

2

3

4

5

Time from radical RT (yr) Fig. 15.11 Outcome of radical radiotherapy (RT) for bladder cancer in Ontario. The graph illustrates the results of a population-based study of the outcome of radical RT for bladder cancer in Ontario. The curves show the probability of survival and cystectomy-free survival in 1370 patients who received radical RT for bladder cancer between 1982 and 1984. Deaths from cancer are differentiated from deaths from other causes. (Adapted from Hayter CRR, Paszat LF, Groome PA, et al. A population-based study of the use and outcome of radical radiotherapy for invasive bladder cancer. Int J Radiat Oncol Biol Phys. 1999;45:1239-1245.)

studies also makes it possible to detect and quantify rare but serious late effects that might be impossible to detect based on the analysis of experience of any individual institution.92 Large variations in outcome have been observed among different countries and among different regions, demographic groups, and institutions within the same country. The challenge lies in distinguishing the component of variation in outcome attributable to differences in quality from the inevitable variations in outcome due to differences in case mix. International variations in cancer outcomes are inevitably multifactorial in origin, and it is difficult to attribute them to any individual aspect of health system performance. Nonetheless, such comparisons have proven to be useful.93,94 Fig. 15.12 shows international variations in cancer survival as a function of proportion of gross domestic product spent on health care. It demonstrates a remarkably clear relationship between investment in health care and cancer survival. It is impossible to determine whether the worse outcome observed in countries that spent less on health care was due to more advanced stage of disease at diagnosis, higher levels of comorbidity, poorer access to care, or poorer quality of care. However, despite these uncertainties, the message is clear that you get what you pay for. These results had a direct influence on public policy in the United Kingdom and were used to justify an expansion in the budget of the National Health Service’s cancer programs by almost $1 billion, permitting a massive expansion in the equipment and staffing of its radiation oncology programs. It has also been shown that cancer outcomes are worse in residents of poorer communities than in residents of richer communities within the same country.93 Fig. 15.13 shows variations in 5-year survival among patients from richer and poorer communities in Canada and the United States. There is a clear gradient in survival across socioeconomic strata in both countries. Some, but not all, of the observed variation is due to more advanced stage at diagnosis among the poorer groups, probably reflecting differences in access to care.93 Differences in quality of care may be responsible for some of the observed differences in survival not

2

4

6

8

10

Rank % GDP spent on health Fig. 15.12 Correlation between relative survival and expenditure on health care. The scatter plot shows the relationship between relative survival for all cancer in female patients and the percentage of gross domestic product (GDP) spent on health care in 10 developed countries. (Adapted from Evans BT, Pritchard C. Cancer survival rates and GDP expenditure on health: a comparison of England and Wales and the USA, Denmark, Netherlands, Finland, France, Germany, Italy, Spain, and Switzerland in the 1990s. Public Health. 2000;114:336-339.)

5-yr cause-specific survival

0

Finland

60

55

50

Ontario USA

45 1 Highest quintile

2

3

4

5 Lowest quintile

Median household income Fig. 15.13 Associations between socioeconomic status (SES) and cancer survival in the United States and Canada. The graph shows 5-year, cause-specific cancer survival as a function of SES for all cancers combined (excluding prostate) in the Canadian province of Ontario and in the regions of the United States covered by the Surveillance, Epidemiology, and End Results (SEER) cancer registries. (Data from Boyd CJ, ZhangSalomons J, Groome PA, et al. Associations between community income and cancer survival in Ontario and the United States. J Clin Oncol. 1999;17:2244-2255.)

explained by differences in stage mix. These differences in outcome represent potential opportunities for improving overall outcomes at the population level. Before we can develop strategies for reducing these disparities, further studies are needed to explore their causes. Although the socioeconomic status–survival gradient is steeper in the United States, there is still a significant difference in outcome among residents of richer and poorer communities in Canada. This may seem somewhat surprising because Ontario has a single-payer, universal health care system with no parallel private health care sector; in theory, the rich do not have better access to care or quality of care than the poor in these circumstances. Clearly,

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1.50 Relative risk of death

1.25 1.00

0.75

0.50 0.40

RRs from Cox regression RR adjusted by removing random variation Pancreas

Colon

Cervix

Head and neck

Hodgkin disease

Testis

Primary site Fig. 15.14 Interregional variations in cancer survival in Ontario. The scatter plot shows the relative risk (RR) of death from cancer in seven geographic regions of Ontario derived from a Cox regression that controlled for age, sex, and socioeconomic status. The purple circles represent the observed variations in survival. The blue circles represent the remaining variation after subtraction of the expected random component of variation. (Adapted from Zhang-Salomons J, Groome PA, Mackillop WJ. Estimating the best achievable cancer survival by eliminating regional variations in Ontario. Clin Invest Med. 1999;22(Suppl 4):S48.)

however, the removal of financial barriers to access to care does not in itself abolish differences in outcome between rich and poor.93 Interregional comparisons within the same country may also be informative. When dissimilar populations are compared, it is necessary to control for differences in case mix, but in the absence of any major interregional variations in socioeconomic status, systematic variations in case mix are unlikely. Under these circumstances, variations in outcome, which exceed those expected due to chance alone, may reasonably be attributed to variations in access or quality. Fig. 15.14 shows the observed 5-year survival for several major cancer sites in seven different regions of Ontario. Once the observed variations are reduced to take account of the expected variation due to chance alone, the best observed outcomes may be used as a benchmark for the achievable outcome. Fig. 15.14 shows that, after adjusting for variation due to chance alone, there were no residual geographic variations in the outcome of cancers of the pancreas, colon, or cervix, but there remained important geographic variations of survival for head and neck cancer, Hodgkin disease, and testicular cancer. Table 15.2 shows the observed 5-year survival for the province as a whole compared with the estimated achievable survival for several diseases in which geographic variation in outcome exceeded that expected due to chance alone. Although such studies can demonstrate the potential to improve outcome by improving quality, they do not reveal where the defects in quality lie. Further studies are required to identify specific defects in the underlying processes and structures.

Relating Structure and Process to Outcomes Whether you begin with variations in outcome and work back to try to find their causes or begin with variations in process and work forward to try to identify their consequences, there are significant problems that must be addressed before a causal relationship between process and outcome can be established. We will discuss these problems and describe how they should be addressed in the context of outcomes research. Limitations of outcomes research. Studies that examine treatment and outcome in the context of routine care are often today referred as

outcomes research. This type of study generally should not be used to try to evaluate the efficacy of treatment. It is notoriously difficult to control for bias in retrospective reviews of institutional experience.95 Comparisons of outcomes achieved in contemporaneous groups of patients who have received different types of treatment at the same institution are inevitably confounded by “treatment selection bias.” Comparisons of outcomes between groups of patients who received different treatments more or less contemporaneously at different institutions are less subject to treatment selection bias but are vulnerable to “referral bias” due to interinstitutional differences in case mix.95,96 The use of “historical controls” (i.e., the comparison of outcomes between patient groups who have received different treatment at different points in time) is also fraught with hazard.97 Case mix may change systematically over time; investigations may change, resulting in “stage migration”; and collateral aspects of care may also change. It is possible to reduce the impact of these types of bias by controlling for known prognostic factors, but these usually leave much of the variance in outcome unaccounted for. For these reasons, none of these types of retrospective, observational studies can substitute for prospective, experimental studies (i.e., randomized controlled trials) in the evaluation of efficacy of treatment. The credibility of our discipline is weakened to the extent that we rely on these less valid methods in situations in which a randomized trial is possible. Legitimate roles of outcomes research in evaluating effectiveness. It is important to recognize that there are some aspects of medical practice that cannot be evaluated in randomized trials and must be explored using observational methods. There are some important aspects of treatment that cannot and should not be studied in a randomized trial. It may be important, for example, to know how much outcomes are affected by deviation from standard practice, such as by delay in initiation of RT, protraction of overall treatment time, the use of lower-than-standard doses, or reliance on antiquated equipment. However, one cannot ethically randomize patients to receive nonstandard versus standard treatment when the only real purpose of the exercise is to measure the adverse consequences

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CHAPTER 15

TABLE 15.2

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Observed Versus Achievable 5-Year Survival for Selected Cancer Sites in Ontarioa OBSERVED 5-YEAR SURVIVAL RATE (95% CONFIDENCE INTERVAL)

Primary Site

Achievable 5-Year Survival Rate (95% Confidence Interval)

All Ontario

Head and neck

64% (63–65)

60% (59–61)

54% (49–59)

Hodgkin disease

88% (86–90)

86% (84–87)

81% (73–89)

Worst Region

Testis

97% (97–98)

95% (94–96)

92% (89–95)

Central nervous system

32% (31–34)

28% (27–29)

27% (24–30)

Rectum

52% (51–54)

50% (49–51)

48% (45–51)

Stomach

21% (20–22)

20% (19–21)

15% (12–17)

Lung

18% (18–19)

15% (15–16)

12% (11–13)

Ovary

49% (47–51)

46% (44–47)

40% (33–48)

Prostate

77% (76–77)

75% (74–75)

71% (69–72)

Bladder

74% (72–75)

73% (72–74)

68% (65–71)

a

The best achievable survival was estimated from the highest observed survival in any of the seven regions in Ontario by subtracting deviations from the provincial averages that are expected due to random variation. Cox regression was used to control for age, sex, and socioeconomic status. This model assumes that there are no systematic variations in case mix among the regions.

of the nonstandard approach. Therefore, we can learn about this type of issue only by investigating the impact of inadvertent or unavoidable deviations from standard practice in retrospective, observational studies of the type discussed earlier.25,26 It is important to be very cautious in the interpretation of “negative findings” in studies that attempt to explore the consequences of deviations from standard practice. Studies that fail to show a statistically significant difference in outcome between nonstandard and standard treatments often lack the statistical power that would be necessary to rule out small but clinically important adverse effects. When patient safety is on the table, the absence of evidence of adverse effects should never be misconstrued as evidence of their absence. When a randomized trial is not feasible. Some issues should ideally be addressed in a randomized trial but either cannot, or will not, be addressed in this way. Rare clinical problems are often impossible to study in randomized trials because it is difficult to sustain enthusiasm for any trial or maintain the infrastructure necessary to support it over a very protracted period of slow accrual. Large, well-organized, multicenter clinical trial groups have a greater chance of success in this situation than any individual institution, but there are limits to what any group can do. Nearly all of what we know about the relationship between treatment and outcome in rare situations has to come from observational studies. In other situations, a clinical trial may be theoretically feasible but is rendered impossible by entrenched opposing views about treatment that effectively preclude recruitment to any trial. One such example was the controversy regarding the primary management of more advanced cancers of the larynx. The issue was hotly debated for decades and opinions were highly polarized. The depth of the controversy is clearly illustrated in the results of an international mail survey of patterns of care in laryngeal cancer done in the early 1990s.82 This showed, for example, that most otolaryngologists in Canada, the United Kingdom, and Scandinavia regarded primary RT as the standard approach for T3 glottic cancer, reserving surgery for salvage, while most of their counterparts in the United States and Australia favored primary total laryngectomy or conservative surgery. Under these circumstances, it may be possible to learn about the relative effectiveness of the competing approaches by comparing the outcome that they achieve at the population level. The rationale for this approach is that variations in practice driven by differences in

physicians’ beliefs, or any other factors unrelated to the characteristics of the patients, can be treated as a natural experiment.98,99 For example, Groome et al. performed a study comparing the outcomes of treatment for locally advanced laryngeal cancer between Ontario, Canada and the United States.100 They found that primary laryngectomy was used much more frequently in the United States than in Ontario, consistent with the results of the previous mail survey.82 Survival at 5 years proved to be identical in the two populations while laryngectomy-free survival was significantly higher in Ontario than in the United States. These observations lend support to the position that primary RT, reserving surgery for salvage, permits retention of natural voice without compromising survival. Evaluating the adoption and generalizability of the results of clinical trials. Randomized clinical trials are unquestionably the best way of comparing the efficacy of a new treatment with the previous standard treatment. However, clinical trials have rarely involved more than a small fraction of potentially eligible cases. Therefore, it cannot be taken for granted that the benefits observed in the context of the trial will be reproduced when the treatment is adopted in the general population. It thus has been argued that population-based Phase IV studies should be carried out as new treatments are introduced into routine practice to evaluate their effectiveness in the real world.101,102 Box 15.3 describes some of the unique advantages of Phase IV studies. Many Phase IV studies have used temporal changes in practice to evaluate the effectiveness of radiotherapy. For example, Pearcey et al. studied the impact of the rapid adoption of concurrent cisplatin-based chemoradiotherapy (C-CRT) in 1999 on population-based outcomes of cervical cancer in Ontario.102 Use of C-CRT increased from less than 10% of RT cases diagnosed between 1992 and 1998 to greater than 60% in 1999 to 2001. There was no observable change in survival for the subgroup of patients treated with surgery alone. Among those treated with primary radiotherapy ± chemotherapy, survival significantly increased from 58.6% in 1995 to 1998 to 69.8% in 1999 to 2001 (p < 0.01). The magnitude of change in survival was in keeping with randomized trials. These findings supported the population-based effectiveness of C-CRT for cervical cancer. An important assumption of a Phase IV study is the comparability of treatment groups. This may often be assured through ecological comparisons such as those in the study by Pearcey et al. of C-CRT for

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Proposed Roles of Phase IV, Population-Based Outcomes Studies BOX 15.3 1

To describe uptake of new therapy. What is the prevalence or incidence of eligible cases? What proportion of eligible patients have received therapy? Are quasi-eligible patients receiving therapy? To what extent is therapy appropriately delivered (i.e., complete vs. partial adoption)?

2.

To evaluate the association among a change in practice or policy and outcomes. Is there benefit at the population level? Is the magnitude of benefit commensurate with that observed in clinical trials? Are there previously unrecognized (or under-recognized) adverse events?

3.

To explore the real-world economic ramifications of a new medical therapy.

4.

To provide an empirical process to determine which aspects of the randomized controlled trial design are associated with a minimal efficacy-effectiveness gap.

5.

To provide a measure of the societal benefit of medical research.

From Booth CW, Mackillop WJ. Translating New medical therapies into society benefit: the role of population-based outcome studies. JAMA. 2008;300:2177-2179.

cervical cancer.102 Over modest time periods, the spectrum of cases in the population usually does not change sufficiently to threaten study validity. This stability is not always the case, however, as demonstrated by the study by Gupta et al. of the impact of C-CRT on head and neck cancer population outcomes in Ontario.103 In this study, an increase in survival from 43.6% in the preadoption cohort to 51.8% in the postadoption cohort was observed. However, the survival increase for oropharynx cancer was greater than predicted based on randomized trials of C-CRT (38.8% preadoption, 57% postadoption). The observed findings were in keeping with known increases in incidence of the prognostically favorable human papillomavirus–associated oropharyngeal cancer over the study period. Notably, the survival increase for all other head and neck sites combined was in keeping with randomized trials (45.6% preadoption, 48.3% postadoption). Phase IV studies provide information on treatment adoption and its consequences that is not available through any other means. For example, in the study of adoption of C-CRT for head and neck cancer, it was possible to study the impact of C-CRT on hospitalization rates in the general population. There was a significant increase in hospitalizations after C-CRT adoption for head and neck cancer (23.4% vs. 43.3%), but no increase in treatment-related deaths. Additionally, the adoption of C-CRT was far more gradual for head and neck cancer than for cervical cancer. In both cases, however, when superiority of one treatment over another was demonstrated in randomized trials, practice changed. In the case of equally effective options, this may not always be the case. Ashworth et al. studied fractionation of postlumpectomy radiation for invasive breast cancer in Ontario before and after the publication of the Ontario Clinical Oncology Group (OCOG) trial that demonstrated equivalence of 16- and 25-fraction schedules.76 They found that after completion of the OCOG trial, shorter fractionation schedules increased from 48% to 71% of cases, though large intercenter variation existed, including two of nine centers treating the majority of patients with longer schedules.

There are a number of statistical techniques available to minimize treatment selection bias and confounding in observational studies of effectiveness. These include multivariable model risk adjustment, propensity score methods, stratification, time series analysis, matching, restriction, and instrumental variable analysis. A full discussion of the relative merits of these techniques is beyond the scope of this chapter. As a general rule, validity is strengthened when multiple techniques produce comparable results.

STUDYING THE EFFICIENCY OF RADIOTHERAPY Health economics is the area of specialization within the field of economics that concerns itself with all economic aspects of health and health care. Much of health economics deals with health-related issues on a higher plane than HSR. Macroeconomic analysis of the societal impact of health and health care at the national and international levels lies well beyond the scope of HSR. On the other hand, microeconomic analysis of the costs and benefits of specific health care programs usually lies squarely within the domain of HSR. We briefly describe how health economic analysis fits into HSR, introduce the methods that are commonly used, and illustrate their relevance to radiation oncology. The resources available for health care in any society are finite. What is achievable for cancer patients depends on the size of the total health care budget, on how much of that total budget is directed to cancer care, and on how efficiently the available resources are used in providing cancer care. Health economics aims to provide the information necessary to make rational choices about how to deploy funding for health care and how to make the best possible use of the funds available. Economic analyses are useful at many levels in the health system. High-level decisions about allocation of resources to different health care programs are increasingly based on a comparison of their impact on health in relation to their cost. These decisions are most clearly visible in publicly funded systems; in the private sector, however, decisions made by insurers about which services will be reimbursed are based on similar considerations and have a similar effect. Therefore, information about the benefits of RT in relation to its costs is required to ensure that an appropriate slice of the cancer budget is allocated to radiation oncology. Economic analyses are also needed to optimize the internal efficiency of RT programs. To ensure that we get the maximum value per dollar invested in RT, it is important that we should be aware of the relative costs of alternative approaches for providing RT. Health economics involves much more than the measurement of health care costs, which most economists would regard as no more than accounting. However, economic analysis does require the measurement of costs; a number of useful studies have been done in comparing alternative approaches for measuring the cost of RT104 and in defining units of workload to which costs can be assigned.105 In assessing the overall costs of RT, it is important to consider not only the direct costs of providing treatment but also the indirect costs of supportive care for complications of RT. It is important to specify the perspective from which an economic analysis is carried out. If the analysis is being conducted from the perspective of the RT provider, it may be appropriate to focus primarily on direct costs, whereas if the perspective is that of the health system as a whole, indirect costs incurred in other sectors must also be considered. If the analysis is being conducted from the societal perspective, loss of productivity as a consequence of the treatment needs to be included and balanced against loss of productivity due to the untreated disease. Economic analyses typically consider the benefits of health care as well as its costs. Four different types of study are usually distinguished: cost-minimization studies, cost-benefit studies, cost-effectiveness studies, and cost-utility studies.

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CHAPTER 15 Cost-minimization studies, often simply called cost studies, compare the costs of alternative treatments or processes on the explicit or implicit assumption that each produces similar health outcomes. In RT, this type of study has provided information pertinent to decisions about the acquisition of new equipment,106 about the decision to purchase or lease equipment,107 about service contracts,108 and so on. In some instances, simple cost comparisons have been done between slightly different approaches to treatment, such as high-dose rate versus low-dose rate brachytherapy.109 In cost-benefit analysis, the health benefits of treatment are described only in terms of their dollar value; health outcomes are considered only insofar as they have an impact on costs or affect the productivity of those affected. This type of analysis may be useful in some circumstances in demonstrating to policy makers that apparently expensive programs of treatment or prevention may, in fact, be cost neutral or even save money when the overall financial consequences of providing the program are compared to those of not providing it. However, the idea that the benefits of health care can be adequately described in terms of the money that they save is counterintuitive to most clinicians—this type of analysis has not been widely used in the field of radiation oncology. Cost-effectiveness studies compare alternative treatments or processes with respect to their effectiveness as well as their cost. Effectiveness is usually described in terms of a single objective outcome measure, such as survival. This is useful in that it enables us to put a dollar value on the outcomes achieved by RT and it has often revealed that RT is relatively inexpensive in relation to the benefits that it delivers.110,111 Because cost-effectiveness analysis describes the benefits of treatment in terms of a single measure of outcome, it does not provide a satisfactory way of describing and comparing the value of treatments that are associated with different types of health benefits, such as radical RT for cervical cancer and palliative RT for bone metastases. Survival alone is an inadequate measure of palliative RT, and quality of life is an inadequate measure of the effectiveness of curative treatment. The concept of utility, a measure of the relative value of different life states, is useful in reducing the benefits of treatment to a common currency. If utility can be measured, years of survival can be adjusted for relative value and outcomes expressed as quality-adjusted life years (QALYs). This measure is sensitive to both duration of survival and quality of life. Cost per QALY can be used to compare the value of treatment in curative and palliative contexts. The value of other forms of medical care has been measured in cost per QALY, which permits comparison of the value of RT with the value of other treatments both in oncology and other spheres of medicine.112,113 Information about the relative benefits of RT in different clinical contexts could be used as a basis for assigning priorities to one type of case over another in circumstances in which resources are insufficient to provide RT for everyone who needs it. This type of explicit rationing, to our knowledge, has not been used to control access to RT in any of the countries where access to RT is constrained by inadequate supply. Although this approach would serve to mitigate the adverse effects of inadequate access to RT and maximize the societal benefits of the available resources, it seems to have little appeal to policy makers. It has, however, been proposed that cost-effectiveness or cost-utility analysis be used as the basis for selecting the most effective components of care for inclusion in health care programs. In the future, as both the demand for health services and the cost of care continue to increase across the developed world, we anticipate that decisions about which services will be provided within publicly funded systems or managed care programs will increasingly be based on these types of economic analysis. Research in the economics of radiation oncology is likely to be of increasing practical importance in optimizing the effectiveness of RT programs in the future.

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SUMMARY In the past, radiation oncologists and their traditional partners in physics and radiobiology have devoted most research efforts to creating the knowledge necessary to optimize the outcomes of RT in the individual patient. There is a lot of evidence to suggest that we currently fall far short of making the benefits of that research available to all of the patients who might benefit from it. It has been demonstrated that, in many parts of the world, access to RT is both inadequate and inequitable and that the quality of RT is variable and often suboptimal. These deviations from optimal practice cause us to fall far short of achieving what is theoretically achievable for cancer patients today within the limits of existing scientific knowledge and technology. Deviations from optimal practice represent real opportunities for enhancing the results of RT without placing reliance on the uncertain outcome of the slow process of basic research, which frequently promises much but delivers little. While fundamental and clinical research must continue, a greater proportion of our efforts should be devoted to enhancing our understanding of the factors that influence access to RT and determine the effectiveness and efficiency of RT programs. RT provides major health benefits for a large proportion of cancer patients; even a small incremental gain in health system performance would be expected to translate itself into large societal benefits. HSR in radiation oncology is still a relatively new field that offers new investigators a great opportunity to make a real difference. There are a number of good opportunities for training in health services and policy research, and the funding for HSR has greatly increased in recent years. There is real need for radiation oncologists to become involved in leadership roles in HSR because the clinician’s insights are vital in choosing the right research questions. Getting the right answers, however, may require a high level of methodological expertise in areas that are unfamiliar to most radiation oncologists. Success in HSR often depends on building effective collaborations with scientists in other fields, such as epidemiology, health economics, and the social sciences. Those who enter the field should also be aware that getting the most out of HSR requires a degree of diplomacy and academic ability. Clinicians involved in HSR need to remember that, in the pursuit of the goal of evidencebased management of health care programs, they need to influence health system managers as well as their peers. Investigators need to learn the skill of working collaboratively with the health system managers and policy makers who hold the power to implement some of the changes necessary to optimize outcomes while keeping some control of the research agenda.

CRITICAL REFERENCES 1. Brundage MD, Snyder CF, Bass B. A year in the life of health services research in oncology. Expert Rev Pharmacoecon Outcomes Res. 2012;12(5):615–622. 3. Penchansky R, Thomas JW. The concept of access: definition and relationship to consumer satisfaction. Med Care. 1981;19:127–140. 15. Mackillop WJ, Groome PA, Zhou Y, et al. Does a centralized radiotherapy system provide adequate access to care? J Clin Oncol. 1997;15:1261–1271. 22. Mackillop WJ, Bates JHT, O’Sullivan B, et al. The effect of delay in treatment on local control by radiotherapy. Int J Radiat Oncol Biol Phys. 1996;34:243–250. 25. Mackillop WJ. Killing time: the consequences of delays in radiotherapy. Radiother Oncol. 2007;84:1–4. 27. Chen Z, King W, Pearcey R, et al. The relationship between waiting time for radiotherapy and clinical outcomes: a systematic review of the literature. Radiother Oncol. 2008;87:3–16. 37. Denham JW. How do we bring an acceptable level of radiotherapy services to a dispersed population? Australas Radiol. 1995;39:171–173.

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38. Tyldesley S, Zhang-Salomons J, Groome P, et al. Association between age and the utilization of radiotherapy in Ontario. Int J Radiat Oncol Biol Phys. 2000;47:469–480. 40. Tyldesley S, Boyd C, Schulze K, et al. Estimating the need for radiotherapy for lung cancer: an evidence-based, epidemiological approach. Int J Radiat Oncol Biol Phys. 2001;49:973–985. 42. Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129–1137. 44. Barbera L, Zhang-Salomons J, Huang J, et al. Defining the need for radiotherapy for lung cancer in the general population: a criterion-based, benchmarking approach. Med Care. 2003;41:1074–1085. 45. Barton MB, Frommer M. Shafig J. Role of radiotherapy in cancer control in low-income and middle-income countries. Lancet Oncol. 2006;7(7):584–595. 47. Donabedian A. Evaluating the quality of medical care. Milbank Q. 1966;44:166–206. 54. Abdel-Wahab M, Bourque JM, Pynda Y, et al. Status of radiotherapy resources in Africa: an International Atomic Energy Agency Analysis. Lancet Oncol. 2013;14(4):e168–e175. 59. Levin V, Tatsuzaki H. Radiotherapy services in countries in transition: gross national income per capita as a significant factor. Radiother Oncol. 2002;63(2):147–150. 65. Brundage MD, Dixon PF, Mackillop WJ, et al. A real-time audit of radiation therapy in a regional cancer center. Int J Radiat Oncol Biol Phys. 1999;43:115–124. 70. Holmberg O, McClean B. Preventing treatment errors in radiotherapy by identifying and evaluating near misses and actual incidents. J Radiother in Practice. 2002;3:13–25. 75. Raby B, Pater J, Mackillop WJ. Does knowledge guide practice? Another look at the management of non-small cell-lung cancer. J Clin Oncol. 1995;13:1904–1911.

82. O’Sullivan B, Mackillop WJ, Gilbert R, et al. Controversies in the management of laryngeal cancer: results of an international survey of patterns of care. Radiother Oncol. 1994;31:23–32. 84. Lievens Y, van den Bogaert W, Kesteloo K. The palliative treatment of bone metastases: an update on practice patterns and incentives in Belgium. Radiother Oncol. 2004;73(suppl):324. 90. Albert JM, Das P. Quality indicators in radiation oncology (Review). Int J Radiat Oncol Biol Phys. 2013;85:904–911. 91. Brundage M, Danielson B, Pearcey R, et al. A criterion-based audit of the technical quality of external beam radiotherapy for prostate cancer. Radiother Oncol. 2013;107:339–345. 94. Evans BT, Pritchard C. Cancer survival rates and GDP expenditure on health: a comparison of England and Wales and the USA, Denmark, Netherlands, Finland, France, Germany, Italy, Spain, and Switzerland in the 1990’s. Public Health. 2000;114:336–339. 100. Groome PA, O’Sullivan B, Irish JC, et al. Glottic cancer in Ontario, Canada and the SEER areas of the United States: do different management philosophies produce different outcome profiles? J Clin Epidemiol. 2001;54:301–315. 101. Booth CM, Mackillop WJ. Translating new medical therapies into societal benefit: the role of population-based outcome studies. JAMA. 2008;300:2177–2179. 102. Pearcey R, Miao Q, Kong W, et al. Impact of adoption of chemoradiotherapy on the outcome of cervical cancer in Ontario: results of a population-based cohort study. J Clin Oncol. 2007;25:2383–2388.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 15

REFERENCES 1. Brundage MD, Snyder CF, Bass B. A year in the life of health services research in oncology. Expert Rev Pharmacoecon Outcomes Res. 2012;12(5):615–622. 2. Salkever DS. Economic class and differential access to care; comparisons among health systems. Int J Health Serv. 1975;5:373. 3. Penchansky R, Thomas JW. The concept of access: definition and relationship to consumer satisfaction. Med Care. 1981;19:127–140. 4. The 58th World Health Assembly Declaration. WHA 58.22: Cancer Prevention and Control. http://www.who.int/cancer/media/news/ WHA58%2022-en.pdf 2005. 5. Klausen OG, Olofsson J, Rosengren B. A long waiting time for radiotherapy: not acceptable for patients with neoplasms. Tidsskr Nor Laegeforen. 1989;109:2324–2325. 6. Denham JW, Hamilton CS, Joseph DJ. How should a waiting list for treatment be managed? Australas Radiol. 1992;36:274–275. 7. Junor EJ, Macbeth FR, Barrett A. An audit of travel and waiting times for outpatient radiotherapy. Clin Oncol. 1992;4:174–276. 8. Mackillop WJ, Fu H, Quirt CF, et al. Waiting for radiotherapy in Ontario. Int J Radiat Oncol Biol Phys. 1994;30:221–228. 9. Anonymous. Radiotherapy services. Ministry of Health, New Zealand, N Z Health Hospital 1996;48:23–24. 10. Jensen AR, Nellemann HM, Overgaard J. Tumor progression in waiting time for radiotherapy in head and neck cancer. Radiother Oncol. 2007;84:5–10. 11. Schafer C, Nelson K, Herbst M. Waiting for radiotherapy a national call for ethical discourse on waiting lists in radiotherapy: findings from a preliminary survey. Strahlenther Onkol. 2005;181:9–19. 12. Esco R, Palacios A, Pardo J, et al. Infrastructure of radiotherapy in Spain: a minimal standard of radiotherapy resources. Int J Radiat Oncol Biol Phys. 2003;56:319–327. 13. Gabriele P, Malinverni G, Bona C, et al. Are quality indicators for radiotherapy useful in the evaluation of service efficacy in a new based radiotherapy institution? Tumori. 2006;92:496–502. 14. Mackillop WJ, Zhou Y, Quirt CF. A comparison of delays in the treatment of cancer with radiation in Canada and the United States. Int J Radiat Oncol Biol Phys. 1995;32:531–539. 15. Mackillop WJ, Groome PA, Zhou Y, et al. Does a centralized radiotherapy system provide adequate access to care? J Clin Oncol. 1997;15:1261–1271. 16. Mackillop WJ, Zhou S, Groome PA, et al. Changes in the use of radiotherapy in Ontario: 1984-1995. Int J Radiat Oncol Biol Phys. 1999;44:355–362. 17. Zhang-Salomons J, Huang J, Mackillop WJ. Health system effects on the use of post-lumpectomy radiotherapy. Int J Radiat Oncol Biol Phys. 2001;50:1385. 18. Mechanic D. Dilemmas in rationing health care services: the case for implicit rationing. BMJ. 1995;310:1655–1659. 19. Thomas SJ, Williams MV, Burnet NG, et al. How much surplus capacity is required to maintain low waiting times? Clin Oncol. 2001;13:24–28. 20. Trilling L, Pellet B, Delacroix S, Marcon E Improving care efficiency in a radiotherapy center usisng lean philosophy. A case study of the Proton Therapy Center of Institut Curie – Orsay. 2010 IEEE workshop on Health Care Management (WHCM); HAL, 2010. p.1-6. 21. Kim CS, Hayman JA, Billi JE, et al. The application of lean thinking to the care of patients with bone and brain metastasis with radiation therapy. J Oncol Pract. 2007;3(4):189–193. 22. Mackillop WJ, Bates JHT, O’Sullivan B, et al. The effect of delay in treatment on local control by radiotherapy. Int J Radiat Oncol Biol Phys. 1996;34:243–250. 23. Waaijer A, Terhaard CH, Dehnad H, et al. Waiting times for radiotherapy: consequences of volume increase for the TCP in oropharyngeal carcinoma. Radiother Oncol. 2003;66:271–276. 24. Jensen AR, Nellemann HM, Overgaard J. Tumor progression in waiting time for radiotherapy in head and neck cancer. Radiother Oncol. 2007;84:5–10. 25. Mackillop WJ. Killing time: the consequences of delays in radiotherapy. Radiother Oncol. 2007;84:1–4.

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26. Sackett DL, Haynes BR, Guyatt GH, Tugwell P. Deciding whether your treatment has done harm. In: Clinical Epidemiology: A Basic Science for Clinical Medicine. Boston: Little Brown and Company; 1991. 27. Chen Z, King W, Pearcey R, et al. The relationship between waiting time for radiotherapy and clinical outcomes: a systematic review of the literature. Radiother Oncol. 2008;87:3–16. 28. Punglia RS, Saito A, Neville BA, et al. Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis. BMJ. 2010;340:cd845. 29. Franklin CI, Poulsen M. How do waiting times affect radiation dose fractionation schedules? Australas Radiol. 2000;44:428–432. 30. Kong W, Zhang-Salomons J, Hanna TP, Mackillop WJ. A populationbased study of the fractionation of palliative radiotherapy for bone metastasis in Ontario. Int J Radiat Oncol Biol Phys. 2007;69:1209–1217. 31. Dixon PF, Mackillop WJ. Could changes in clinical practice reduce waiting lists for radiotherapy? J Health Serv Res Policy. 2001;6:70–77. 32. Anonymous. The “Cilinger” Case. http://www.mmflegal.com/en/media/ recoursCollectif/settlement_agreement.pdf. 33. Anonymous, Cancer Care Ontario. Cancer Care Ontario Cancer System Quality Index (last accessed September 2018): http://www.csqi.on.ca/ by_patient_journey/treatment/ wait_times_from_diagnosis_to_radiation_therapy/. 34. Cuyler AJ. Need and the National Health Service: Economics and Social Choice. Lanham, MD: Rowman and Littlefield; 1976. 35. de Jong B, Crommelian M, Heijden LH, et al. Patterns of radiotherapy for cancer patients in the south eastern Netherlands, 1975-1989. Radiother Oncol. 1994;31:213–221. 36. Huang J, Zhou S, Groome P, et al. Factors affecting the use of palliative radiotherapy in Ontario. J Clin Oncol. 2001;19:137–144. 37. Denham JW. How do we bring an acceptable level of radiotherapy services to a dispersed population? Australas Radiol. 1995;39:171–173. 38. Tyldesley S, Zhang-Salomons J, Groome P, et al. Association between age and the utilization of radiotherapy in Ontario. Int J Radiat Oncol Biol Phys. 2000;47:469–480. 39. Intersociety Council for Radiation Oncology. Radiation Oncology in Integrated Cancer Management. Report to the Director of NCI. Washington, DC: NCI; 1991. 40. Tyldesley S, Boyd C, Schulze K, et al. Estimating the need for radiotherapy for lung cancer: an evidence-based, epidemiological approach. Int J Radiat Oncol Biol Phys. 2001;49:973–985. 41. Usmani N, Foroudi F, Du J, et al. An evidence-based estimate of the appropriate rate of utilization of radiotherapy for cancer of the cervix. Int J Radiat Oncol Biol Phys. 2005;63:812–827. 42. Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129–1137. 43. Bogan CE, English MJ. Benchmarking for Best Practices: Winning Through Innovative Adaptation. New York: McGraw-Hill; 1994. 44. Barbera L, Zhang-Salomons J, Huang J, et al. Defining the need for radiotherapy for lung cancer in the general population: a criterionbased, benchmarking approach. Med Care. 2003;41:1074–1085. 45. Barton MB, Frommer M. Shafig J. Role of radiotherapy in cancer control in low-income and middle-income countries. Lancet Oncol. 2006;7(7):584–595. 46. Donabedian A. The Definition of Quality and Approaches to Its Assessment. Ann Arbor: Michigan Health Administration Press; 1980. 47. Donabedian A. Evaluating the quality of medical care. Milbank Q. 1966;44:166–206. 48. Kramer S, Herring D. The patterns of care study: a nation-wide evaluation of the practice of radiation therapy in cancer management. Int J Radiat Oncol Biol Phys. 1976;1:1231–1236. 49. Owen JB, Coia LR, Hanks GE. The structure of radiation oncology in the United States in 1994. Int J Radiat Oncol Biol Phys. 1997;39:179–185. 50. Moller TR, Einhorn N, Lindholm C, et al; for the SBU Survey Group. Radiotherapy and cancer care in Sweden. Acta Oncol. 2003;42:366–375. 51. Esco R, Palacios A, Pardo J, et al. Infrastructure of radiotherapy in Spain: a minimal standard of radiotherapy resources. Int J Radiat Oncol Biol Phys. 2003;56:319–327.

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52. Slotman BJ, Leer JW. Infrastructure of radiotherapy in the Netherlands: evaluation of prognoses and introduction of a new model for determining needs. Radiother Oncol. 2003;66:345–349. 53. Bentzen Søren M., Heeren Germaine, Cottier Brian, et al. Towards evidence-based guidelines for radiotherapy infrastructure and staffing needs in Europe: the ESTRO QUARTS project. Radiother Oncol. 2005;75:355–365. 54. Abdel-Wahab M, Bourque JM, Pynda Y, et al. Status of radiotherapy resources in Africa: an International Atomic Energy Agency Analysis. Lancet Oncol. 2013;14(4):e168–e175. 55. Tatsuzaki H, Levin CV. Quantitative status of resources for radiation therapy in Asia and Pacific region. Radiother Oncol. 2001;60(1):81–89. 56. Zubizarreta EH, Poitevin A, Levin CV. Overview of radiotherapy resources in Latin America: a survey by the International Atomic Energy Agency (IAEA). Radiother Oncol. 2004;73(1):97–100. PubMed PMID: 15465152. 57. Rosenblatt E, Izewska J, Anacak Y, et al. Radiotherapy capacity in European countries: an analysis of the Directory of Radiotherapy Centres (DIRAC) database. Lancet Oncol. 2013;14(2):e79–e86. 58. The World Bank. How we classify countries. http://data.worldbank.org/ about/country-classifications. Washington, DC. The World Bank Group, 2013. 59. Levin V, Tatsuzaki H. Radiotherapy services in countries in transition: gross national income per capita as a significant factor. Radiother Oncol. 2002;63(2):147–150. 60. Lievens Y, Van den Bogaert W, Rijnders A, et al. Palliative radiotherapy practice within western European countries: impact of the radiotherapy financing system. Radiother Oncol. 2000;56:289–295. 61. Glatstein E. The return of the snake oil salesmen. Int J Radiat Oncol Biol Phys. 2003;55:561–562. 62. Mackillop WJ, O’Brien P, Brundage M, et al. Radiotherapy quality and access issues. In: Sullivan T, Evans W, Angus H, Hudson A, eds. Strengthening the Quality of Cancer Services in Ontario. Ottawa, Ontario: CHA Press; 2003:95–124. 63. Horiot JC, Johansson KA, Gonzalez DG, et al. Quality assurance control in the EORTC Cooperative Group of Radiotherapy. 1. Assessment of radiotherapy staff and equipment. European Organization for Research and Treatment of Cancer. Radiother Oncol. 1986;6:275–284. 64. Horiot JC, van der Schueren E, Johansson KA, et al. The program of quality assurance of the EORTC radiotherapy group: a historical overview. Radiother Oncol. 1993;29:81–84. 65. Brundage MD, Dixon PF, Mackillop WJ, et al. A real-time audit of radiation therapy in a regional cancer center. Radiat Oncol Biol Phys. 1999;43:115–124. 66. Peters LJ1, O’Sullivan B, Giralt J, et al. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. J Clin Oncol. 2010;28(18):2996–3001. 67. Weingart SN, Wilson RM, Gibbard RW, Harrison B. Epidemiology of medical error. BMJ. 2000;320:774–777. 68. Barach P, Small SD. Reporting and preventing medical mishaps: lessons from non-medical near miss reporting systems. BMJ. 2000;320:759–763. 69. Williams MV. Improving patient safety in radiotherapy by learning from near misses, incidents and errors. Br J Radiol. 2007;80:297–301. 70. Holmberg O, McClean B. Preventing treatment errors in radiotherapy by identifying and evaluating near misses and actual incidents. J Radiother in Practice. 2002;3:13–25. 71. Derreumaux S, Etard C, Huet C, et al. Lessons from recent accidents in radiation therapy in France. Radiat Prot Dosimetry. 2008;131:130–135. 72. Shafiq J, Barton M, Noble D, et al. An international review of patient safety measures in radiotherapy practice. Radiother Oncol. 2009;92:15–21. 73. Owen JB, Sedransk J, Pajak TF. National averages for process and outcome in radiation oncology: methodology of the PCS. Semin Radiat Oncol. 1997;7:101–107. 74. MacLean CJ, Davis LW, Herring DF, et al. Variation in work-up and treatment procedures among types of radiation therapy facilities: the patterns of care process survey for three head and neck sites. Cancer. 1981;48:1346–1352.

75. Raby B, Pater J, Mackillop WJ. Does knowledge guide practice? Another look at the management of non-small cell-lung cancer. J Clin Oncol. 1995;13:1904–1911. 76. Ashworth A, Kong W, Whelan T, Mackillop WJ. A population-based study of the fractionation of postlumpectomy breast radiation therapy. Int J Radiat Oncol Biol Phys. 2013;86:51–57. 77. White V, Pruden M, Giles G, et al. The management of early breast carcinoma before and after the introduction of clinical practice guidelines. Cancer. 2004;101:476–485. 78. Morrow M, White J, Moughan J, et al. Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol. 2001;19:2254–2262. 79. Maggino T, Romagnolo C, Zola P, et al. An analysis of approaches to the treatment of endometrial cancer in western Europe: a CTF study. Eur J Cancer. 1995;31:1993–1997. 80. Dobbs HJ, Henderson S, et al. Variations in referral patterns for postoperative radiotherapy of patients with screen-detected breast cancer in the south Thames (east region). Clin Oncol. 1998;10:24–29. 81. Fowler FJ Jr, McNaughton CM, Albertsen PC, et al. Comparison of recommendations by urologists and radiation oncologists for treatment of clinically localized prostate cancer. JAMA. 2000;283:3217–3222. 82. O’Sullivan B, Mackillop WJ, Gilbert R, et al. Controversies in the management of laryngeal cancer: results of an international survey of patterns of care. Radiother Oncol. 1994;31:23–32. 83. Richardson LC, Schulman J, Sever LE, et al. Early-stage breast cancer treatment among medically underserved women diagnosed in a national screening program, 1992-1995. Breast Cancer Res Treat. 2001;69:133–142. 84. Lievens Y, van den Bogaert W, Kesteloo K. The palliative treatment of bone metastases: an update on practice patterns and incentives in Belgium. Radiother Oncol. 2004;73(suppl):324. 85. Borgelt BB, Stone C. Ambulatory patient classifications and the regressive nature of Medicare reform: is the reduction in outpatient health care reimbursement worth the price? Int J Radiat Oncol Biol Phys. 1999;45:729–734. 86. Schulz U, Schroder M. Quality and the profit situation in ambulatory radiotherapy. Strahlenther Onkol. 1996;172:121–127. 87. Hayman JA. Measuring the quality of care in radiation oncology. Semin Radiat Oncol. 2008;18:201–206. 88. Owen JB, White JR, Zelefsky MI, et al. Using QRRO survey data to assess compliance with quality indicators for breast and prostate cancer. J Am Coll Radiol. 2009;6(6):442–447. 89. Danielson B, Brundage M, Pearcey R, et al. Development of indicators of the quality of radiotherapy for localized prostate cancer. Radiother Oncol. 2011;99(1):29–36. 90. Albert JM, Das P. Quality indicators in radiation oncology (Review). Int J Radiat Oncol Biol Phys. 2013;85:904–911. 91. Brundage M, Danielson B, Pearcey R, et al. A criterion-based audit of the technical quality of external beam radiotherapy for prostate cancer. Radiother Oncol. 2013;107:339–345. 92. Potosky AL, Warren H, Riedel ER, et al. Measuring complications of cancer treatment using the SEER-Medicare data. Med Care. 2002;40(suppl 8):62–68. 93. Boyd CJ, Zhang-Salomons J, Groome PA, et al. Associations between community income and cancer survival in Ontario and the United States. J Clin Oncol. 1999;17:2244–2255. 94. Evans BT, Pritchard C. Cancer survival rates and GDP expenditure on health: a comparison of England and Wales and the USA, Denmark, Netherlands, Finland, France, Germany, Italy, Spain, and Switzerland in the 1990’s. Public Health. 2000;114:336–339. 95. Feinstein AR. Clinical Epidemiology: The Architecture of Clinical Research. Philadelphia: WB Saunders; 1985. 96. Sackett DI, Haynes RB, Guyatt GH, et al. Clinical Epidemiology: A Basic Science for Clinical Medicine. 2nd ed. Boston: Little, Brown and Company; 1991. 97. Mackillop WJ, Dixon PD. Oesophageal carcinoma: the problems of historical controls. Radiother Oncol. 1986;6:327–328. 98. Newhouse JP, McClellan M. Econometrics in outcomes research: the use of instrumental variables. Annu Rev Public Health. 1998;19:17–34.

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CHAPTER 15 99. Groome PA, Mackillop WJ. Uses of ecologic studies in the assessment of intended treatment effects. J Clin Epidemiol. 1999;52:903–904. 100. Groome PA, O’Sullivan B, Irish JC, et al. Glottic cancer in Ontario, Canada and the SEER areas of the United States: do different management philosophies produce different outcome profiles? J Clin Epidemiol. 2001;54:301–315. 101. Booth CM, Mackillop WJ. Translating new medical therapies into societal benefit: the role of population-based outcome studies. JAMA. 2008;300:2177–2179. 102. Pearcey R, Miao Q, Kong W, et al. Impact of adoption of chemoradiotherapy on the outcome of cervical cancer in Ontario: results of a population-based cohort study. J Clin Oncol. 2007;25:2383–2388. 103. Gupta S, Kong W, Booth CM, Mackillop WJ. Impact of concomitant chemotherapy on outcomes of radiation therapy for head-and-neck cancer: a population-based study. Int J Radiat Oncol Biol Phys. 2014;88:115–121. 104. Hayman JA, Lash KA, Tao ML, et al. A comparison of two methods for estimating the technical costs of external beam radiation therapy. Int J Radiat Oncol Biol Phys. 2000;47:461–467. 105. Griffiths S, Delaney G, Jalaludin B. An assessment of basic treatment equivalent at Cookridge Hospital. Clin Oncol. 2002;14:399–405.

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106. Dobson J. The impact of health care economics on the selection of new radiation therapy equipment. Prog Clin Biol Res. 1986;216:175–182. 107. Nisbet A, Ward A. Radiotherapy equipment—purchase or lease? Br J Radiol. 2001;74:735–744. 108. Rhine K, Fodor J 3rd. Assessing equipment repair and asset management. Adm Radiol J. 1998;17:22–25. 109. Bastin K, Buchler D, Stitt J, et al. Resource utilization: high dose rate versus low dose rate brachytherapy for gynecologic cancer. Am J Clin Oncol. 1993;16:256–263. 110. Malin JL, Keeler E, Wang C, et al. Using cost-effectiveness analysis to define a breast cancer benefits package for the uninsured. Breast Cancer Res Treat. 2002;74:143–153. 111. Barbera L, Walker H, Foroudi F, et al. Estimating the benefit and cost of radiotherapy for lung cancer. Int J Technol Assess Health Care. 2004;20:1–7. 112. Coy P, Schaafsma J, Schofield JA. The cost-effectiveness and cost-utility of high-dose palliative radiotherapy for advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2000;48:1025–1033. 113. Polsky D, Mandelblatt JS, Weeks JC, et al. Economic evaluation of breast cancer treatment: considering the value of patient choice. J Clin Oncol. 2003;2:1139–1146.

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16 Radiation Therapy in the Elderly Noam VanderWalde and Grant Williams

Before discussing the implications of old age on cancer care, a definition of old age or geriatric seems needed. Unfortunately, a chronological definition of older age is difficult to provide. Old is a relative term. How societies define old age has several implications for their health, labor force, economy, laws, and family roles. In 1965, when the Social Security Act was passed, the average life expectancy for a US male was 66.8 years. Thus, defining older age as 65 years and older seemed legitimate. In 2014, US males had an average life expectancy of 76.5 years.1 With the US population now living longer, should we still consider a 65-year-old male to be geriatric? If the average retirement age in the United States is now 70 years, should that same chronological definition be used in an underdeveloped country where the average retirement age is 55 years? Thus, the chronological definition of old age is and will always be a moving target. Additionally, even if one were to attempt to define old age by a chronological cutoff, one would likely find a large amount of heterogeneity of biological and functional statuses among that older population. Humans, even within the same society, do not all age biologically at the same rate. Perhaps a definition of old age that includes the biological changes that lead to physical or functional decline is better suited for the needs of physicians attempting to care for this population. As detailed later in this chapter, the aging process is associated with the decline of multiple organ systems over time.2 This decline also leads to a loss of functional reserve and ability to recover from harm that may occur to those organs. Patients with functional decline associated with aging may have less tolerance to and thus less benefit from standard cancer therapies, including chemotherapy, immunotherapy, surgery, and radiation. Therefore, “older” patients should not necessarily be approached or treated in the same manner as healthier, functionally intact, younger patients. At present, how these patients should be treated is still unclear. Older patients are poorly represented in standard setting trials,3 leaving physicians with little data to support their treatment decisions. Additionally, important functional assessment information is often not collected or not reported in large clinical trials or in most oncology clinics. Thus, the generalizability of the standard setting study results to our specific older patients in clinic is often murky. With the increasing number of older adults in the United States, it is critical for oncologists to understand common issues faced by older adults. By 2030, it is projected that the United States will have more adults age 65 years and above than children age 18 years or younger.4 As cancer is often a disease of aging, oncologists can expect to see an increasing number of older patients, often with multiple comorbidities and/or geriatric syndromes that can impact treatment decisions and treatment tolerance. Radiation oncologists, in particular, may see a greater portion of older patients who are deemed ineligible for surgery or high-dose systemic chemotherapy due to the potentially lower rate of systemic toxicities from radiotherapy compared with cytotoxic drugs

or general anesthesia. Thus, it is critical for radiation oncologists to understand how age and the aging process can impact our choices for best care. Owing to the local nature of radiotherapy, the impact that comorbidities have on tolerance to radiotherapy may be very different from how they impact surgery or systemic therapy. With local therapy, comorbidities may interact with treatment very differently depending on the area of the body being irradiated. Additionally, owing to the daily nature of many radiotherapy treatments, decline in physical function or social function, such as inability to drive or find transportation, could impact these treatments more so than with other modalities. However, the daily visits often required for radiotherapy also allow multiple opportunities for interventions to help improve possible syndromes associated with aging. Despite the increasing number of older adults, many radiation oncologists feel undereducated on geriatric principles and the aging process.5 With this chapter, we hope to improve the readers’ understanding of geriatric principles and how the aging process may impact antineoplastic therapies and their outcomes. The chapter will detail the incidence of cancer in older adults and background of geriatric oncology in the United States, discuss the biology of the aging process, introduce the concept of the geriatric assessment and its clinical use, summarize key radiotherapy-related older adult studies, and offer future directions to improve evidence-based approaches and minimize key knowledge gaps for our increasing older adult cancer population. If the former president of the International Society of Geriatric Oncology (SIOG) is correct when he stated that “all oncologists are geriatric oncologists,” then it is our responsibility to improve our understanding of geriatric principles in order to better treat the increasing number of older adult patients in our clinics.

INCIDENCE AND PREVALENCE OF CANCER IN THE ELDERLY Based on data from the Surveillance Epidemiology End Results (SEER) database, through 2012 the median age at diagnosis of cancer in the United States is 65 years.6 Almost half (47%) of cancer survivors are 70 years or older.7 Additionally, the number of older patients with cancer is expected to continue to rise significantly over the next 20 to 30 years.8,9 Using incidence data from SEER and US census data from 2008, Smith et al. projected an increase in cancer incidences of 67% for adults over 65 years of age between 2010 to 2030, compared with only an 11% increase in those younger than 65 years.8 In a separate more recent study on increasing prevalence, Bluethmann et al. used a prevalence incidence approach statistical model with data from SEER, SEERMedicare, and 2014 National Projections (estimated from the 2010 US census) to find that by 2040, roughly 73% of survivors of cancer will be 65 years or older.9 This rise in older adults in the United States is

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often referred to as the “silver tsunami,”9 owing to the number of older adult patients expected to inundate oncology clinics. In 2018, many radiation oncologists are already experiencing the beginnings of this wave. The “aging” of cancer patients not only affects clinicians’ initial treatment choices but can also impact supportive care throughout the treatment period and survival rates following therapy. Despite the increase in older adults with cancer, the proportion of older patients enrolled in clinical studies remains low.10,11 A secondary analysis of greater than 160 consecutive non-age-restricted SWOG cooperative group studies from 1993 to 1996 demonstrated that although 63% of the estimated US cancer population in SEER was greater than or equal to 65 years of age, only 25% of the patients accrued to SWOG studies were 65 years and older.12 One of the potential reasons of low relative accrual of older patients is thought to be related to physician concern for higher toxicity rates among experimental systemic agents.13,14 However, an analysis of surgical oncology studies through the National Cancer Institute (NCI) showed significantly lower rates of older adult participation in surgical studies as well (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.18–0.21, p < 0.001).15 Additionally, several recent site-specific (breast and lung) analyses of cooperative group studies have also demonstrated lower rates of accrual of older patients despite higher incidences of these cancers in older patients in the general population.16,17 Thus, for most cancer types (with the possible exception of genitourinary cancers12), clinicians are forced to extrapolate treatment outcomes data from younger, healthier patients in order to make treatment decisions for older and possibly less functional patients. Extrapolating results from clinical trials on younger patients to older adults in clinic can often be inappropriate for a number of reasons.18 First, in certain disease types, the biological behavior of cancers in older individuals may be either more indolent (as in breast and prostate cancer) or significantly more aggressive (glioblastoma and endometrial cancer) than for younger individuals. Second, increasing rates of comorbidities and other competing risks of mortality can vastly alter the risk-benefit ratio of treatments for older adults compared with their younger peers (Fig. 16.1).9 Third, common aging-related syndromes that lead to physical, social, and cognitive dysfunction may impact an older adult’s ability to tolerate or comply with standard cancer therapies. For example, doses of radiotherapy to the pelvis that typically lead to grade 2 diarrhea are usually tolerated in younger adults but may lead

some older adults with poor functional reserve to experience severe dehydration, hospitalizations, and treatment delays.19 Last, goals of antineoplastic treatments may be different with older adults favoring quality of life or quantity of life in certain situations. Of course, these four potential differences between older and younger adults with cancer are generalizations and may not apply to individual patients. Thus, a personalized approach to cancer care among older adults is critical. A personalized approach to the treatment of older adults with cancer has been one of the major focuses of the geriatric oncology field since its inception in the early 1980s. In 1981, Dr. Rosemary Yancik organized a symposium entitled “Perspectives on Prevention and Treatment of Cancer in the Elderly,” co-sponsored by the NCI and the National Institute on Aging (NIA).20 This conference set the tone for the research agenda and education/training within the field of geriatric oncology and is considered to be one of the first steps in building and developing the field.21 Since then, several other organizations and individuals have continued to move the field forward through research and education. The American Society of Clinical Oncology (ASCO)22 continues to have separate geriatric oncology tracks at their annual meeting and occasionally publishes special issues of the Journal of Clinical Oncology focused on cancer in the elderly.23,24 SIOG (www.siog.org), has established annual meetings for education, research, and international collaboration, and sponsors the Journal of Geriatric Oncology. The Cancer in the Older Adult Committee of the Alliance for Clinical Trials Cooperative Group (formerly the Cancer in the Elderly Committee for the Cancer and Leukemia Group B [CALGB]) helps establish research protocols and secondary analyses focusing on older adult populations. The Cancer and Aging Research Group (CARG; www.mycarg.org) has made great strides in coordinating studies to develop screening geriatric assessments and toxicity score calculators.19,25 These organizations and groups have helped established the importance of prioritizing the personalized care of older adults with cancer. The field of radiation oncology has been a little slower to recognize and prioritize older adults but has been catching up over the last few years. In October 2012, Seminars in Radiation Oncology published an issue focused on the impact of aging and comorbidities on cancer care.26 In 2014, the NRG clinical trials cooperative group established an elderly working group (incorporating the elderly working group from the Gynecologic Oncology Group). In 2016, the National Comprehensive Cancer Network (NCCN) updated

Comorbidity Burden by Age and Cancer Site 100% 90% Severe Comorbidity

80% 70% 60%

Breast

50%

Lung

40%

Oral

30% 20% 10% 0%

66−69

70−74

75−79

80−84

85+

Fig. 16.1 Severe comorbidity burden by age and cancer type. (Adapted from data in Bluethmann SM, Mariotto AB, Rowland JH. Anticipating the “silver tsunami”: prevalence trajectories and comorbidity burden among older cancer survivors in the United States. Cancer Epidemiol Biomarkers Prev. 2016;25:1029–1036.)

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CHAPTER 16 the radiotherapy-related recommendations within the Older Adult Oncology Committee.27 In 2017, the International Journal of Radiation Oncology, Biology, Physics—the journal of the American Society for Radiation Oncology (ASTRO)–published a special issue on treatment of the elderly.28 All of these initiatives are rooted in the understanding that older adults cannot necessarily be assessed and treated in the same way as their younger peers and that a personalized approach will need to be established in order to improve the care of this growing population.

BIOLOGY OF AGING The treatment of older adults with cancer is not inherently different from that of younger patients such that treatment decisions are based on the anticipated benefits and risks from treatment in light of a patient’s tumor characteristics, organ function, performance status, and comorbid conditions. However, the presence of clinically significant comorbid diseases and organ function is significantly higher in older adults compared with younger populations, both of which may alter the potential benefit from treatment due to competing risks of death and may adversely affect tolerability of cancer treatments.29,30 Although some age-related changes may be easily apparent from the “eyeball test” in clinic—such as the use of a walker or wheelchair—often, outward impressions can be deceiving. Many impairments and vulnerabilities in older adults, such as the presence of falls or impairments in instrumental activities of daily living (IADL; e.g., self-transportation, managing medication, telephone use, shopping, housework, paying bills, and preparing meals), are overlooked by traditional oncologic assessment but can have a tremendous impact on treatment tolerability and outcomes.31–33 In addition, the preferences in treatment outcomes may vary among older adults; many older patients differ in their willingness to trade increased survival for decreased quality of life compared with younger patients.34 The majority of older adults would decline treatments that may result in severe cognitive or functional declines.35 A host of biological changes accompany the aging processes that have potential implications for cancer treatment planning and decisionmaking. Gradual losses in overall physiological and/or functional reserve are a hallmark of aging. Loses in renal function, hepatic function, muscle mass and strength, cardiac functional reserve, and pulmonary reserve all commonly accompany the aging process.36 These aging-related loses culminate in a reduced ability to adapt to stressful circumstances—such as surgery, chemotherapy, or radiation therapy—and increase the rate of potential complications.29 For example, age-dependent loses in skeletal muscle occur as early as the 4th decade of life and progress linearly with increasing age.37 With the increased use of routine computed tomography (CT) to assess body composition, numerous oncological studies have repeatedly demonstrated an association of low muscle mass with increased chemotherapy toxicities, surgical complications, hospitalizations, and reduced survival.38–40 Similarly, cardiorespiratory fitness declines with increasing age and can be measured by assessing peak oxygen consumption, known as VO2 max.41,42 Low VO2 max is an independent predictor of survival in patients with breast and lung cancer.43,44 Moreover, cancer and cancer treatments can also result in accelerated declines in both cardiorespiratory fitness and muscle mass that may have implications for cancer survival care in older adults.42,45 Becoming familiar with these age-related physiological changes and how they may impact cancer therapies is an important part of providing appropriately tailored treatments and survival care to the growing number of older adults with cancer. As older adults age, they are increasingly likely to develop a physical or cognitive impairment that limits their ability to function and/or live independently.46 Many older adults with such limitations require assistance and support from family and/or friends to accomplish routine

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271

tasks, such as transportation to and from appointments or assistance with taking daily medications. Over half (58.5%) of older adults between the ages of 85 to 90 years receive caregiver assistance and, in adults over the age of 90, only a minority (24%) of individuals do not require assistance.47 Older adults are also at increased risk for disruptions to their social relationships, with 60% of women and 22% of men becoming widowed by their mid-70s and about half of older adults over the age of 85 years reporting the loss of a close friend in the past year.48 Assessing the social support system of older patients and identifying the role of caregivers is an important part of cancer treatment planning in older adults and may have significant implications for treatment (especially those who require frequent clinic visits). Patients without adequate social support may be at increased risk of health-related reduced quality of life and increased mortality. These individuals can often benefit from meeting with a social worker to identify available community resources.49,50

COMPREHENSIVE GERIATRIC ASSESSMENT Given the complexities inherent in the management of older adults with cancer as detailed earlier, a comprehensive assessment is necessary to complement cancer staging and laboratory information for treatment decision-making and planning. Geriatric assessment (GA) is a multidimensional evaluation and diagnostic process used to determine the functional, medical, and psychosocial abilities of older patients.33 A GA provides a broad assessment of many important health domains, including functional status, physical function, comorbid diseases, nutrition, cognition, psychological health, and social support. Although a traditional GA is performed by a geriatrician in conjunction with a multidisciplinary team that may entail several hours, short and primarily patient-reported versions have been developed specifically for use in older adults with cancer.25,51,52 The GA has been demonstrated to be feasible in both the academic and community sites as well as within the cooperative group setting.25,53,54 There are several advantages to incorporating a GA in the management of older adults with cancer.33 The GA has been routinely shown to identify vulnerabilities, such as impairments in ADLs (dressing, eating, ambulating, toileting, and hygiene) or falls, that are often overlooked by traditional oncological evaluations but have been associated with increased mortality and chemotherapy toxicity.31,55 The GA has demonstrated superior ability to identify frail patients, particularly those who may have preserved performance status.32 Performing a GA may improve prognostication of the risk of adverse outcomes, including chemotherapy toxicity,19,51 surgical morbidity,52 and quality-of-life recovery following radiotherapy,56 which may all inform treatment decision-making when weighing the risks and benefits of treatment options.33,57 Similarly to how oncologists use imaging and clinical examinations to stage a cancer, the GA can be used to “stage” the patient. Many of the GA tools can be found online and performed in clinic with the patients using these websites: www.mycarg.org/SelectQuestionnaire or www.moffitt.org/ eforms/crashscoreform. Additionally, tools to calculate life expectancy for older adults are available at http://eprognosis.ucsf.edu and can be used to help frame expectations for patients regarding the benefit of certain treatments. Last, many identified vulnerabilities have beneficial interventions. GA-guided care processes have been developed to address many identified impairments and vulnerabilities.58–60 Table 16.1 has a list of common GA-identified impairments with related potential interventions. Although no randomized trial has yet to demonstrate that GA-guided care interventions definitely improve outcomes in older adults with cancer, these interventions have been demonstrated to improve outcomes in older noncancer populations. Several ongoing studies have been designed to specifically address this gap.33,61

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TABLE 16.1

Scientific Foundations of Radiation Oncology

Geriatric Assessment Components and Triggers for Intervention58–60

GA-Domain

Test

Overall Score Range

Dichotomized Score

Intervention Triggered

Physical function

Timed Up and Go Test

Higher score = Lower function (seconds)

≥14 s = dysfunction

Referral to PT

I-ADL

0–14, 14 no limitations

50% of vertebral body involved, or none of these), and involvement of posterolateral elements, including the facet, pedicle, or costovertebral joint (bilateral, unilateral, or none). A total score is assigned with a minimum of 0 and

Fig. 17.2 Epidural Spinal Cord Compression Scale. Grade 0, disease confined to bone; 1a, epidural impingement without indentation of the thecal sac; 1b, indentation of the thecal sac but not touching the cord; 1c, abutting the spinal cord but without compression; 2, spinal cord compression but cerebrospinal fluid (CSF) is visible; and 3, spinal cord compression and no CSF visible. (Adapted from Bilsky MH, Laufer I, Fourney DR, et al. Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine. 2010;13(3):324-328.)

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a maximum of 18, where stability is assumed with scores of 0 to 6, instability with scores of 13 to 18, and intermediate instability with scores of 7 to 12 (Table 17.3). The value of surgical decompression in addition to conventional radiotherapy was demonstrated by a randomized trial by Patchell et al.94 Approximately 100 patients with magnetic resonance imaging-confirmed spinal cord compression of one contiguous area (multiple vertebral levels allowed), who were paraplegic for less than 48 hours and had a life expectancy of greater than 3 months, were randomized to radiotherapy alone with 30 Gy in 10 fractions versus surgery (primarily corpectomy) and postoperative radiation, 30 Gy in 10 fractions. Ambulation rates (ability to walk four steps unassisted, with or without a cane/walker), the primary endpoint, were significantly improved in the surgery arm (84% vs. 57%, p = 0.001). Ambulation retention time

TABLE 17.3

Score

Spinal Instability Neoplastic

SINS Components

Score

Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1)

3

Mobile (C3-C6, L2-L4)

2

Semirigid (T3-T10)

1

Rigid (S2-S5)

0

Pain Mechanical (pain with increased load on spine or relief with decreased load)

3

Occasional, but not mechanical

1

No pain

0

Type of Bone Lesion Lytic

2

Mixed (lytic and blastic)

1

Blastic

0

Radiographic Spinal Alignment Subluxation/translation

4

Kyphosis/scoliosis

2

Normal alignment

0

Vertebral Body Collapse and Involvement >50% collapse

3

50% vertebral body involvement

1

None of the above

0

Posterolateral Spinal Element Involvement (Facet, Pedicle, or Costovertebral Joint) Bilateral

3

Unilateral

1

None

0

Total score: 0-6 stable; 7-12 indeterminate instability; 13-18 instability Adapted from Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976). 2010;35(22):E1221-E1229.

was significantly improved as well (122 days vs. 13 days, p = 0.003). Median survival time was prolonged (126 days vs. 100 days, p = 0.03). Among patients not undergoing surgery and who had poor to intermediate life expectancy with metastatic epidural spinal cord compression, Rades et al. conducted a randomized noninferiority trial comparing 20 Gy in 5 fractions to the more standard 30 Gy in 10 fractions.95 Approximately 200 patients were randomized. The overall motor response rate at 1 month, the primary endpoint, was not statistically different between arms (87% vs. 90%, p = 0.73). Comparing the 5-fraction versus 10-fraction arms, there was no statistical difference between ambulatory rates at 1 month (72% vs. 74%), local progression-free survival at 6 months (75% vs. 82%), and overall survival at 6 months (42% vs. 38%). A matched-pair analysis among patients with short expected survival and metastatic epidural spinal cord compression was performed to compare 8 Gy in a single fraction to 20 Gy in 5 fractions.96 Performance status was 3 to 4 in 76% of patients, and median overall survival was 3 months. Rates of retreatment with radiation between the single-fraction and five-fraction groups was 18% versus 9% at 6 months and 30% versus 22% at 12 months, respectively (p = 0.11). There was no statistically significant impact on survival between groups. Likewise, improvement in motor function did not vary substantially as a function of treatment. These data, although not randomized, support the option of a single fraction of 8 Gy for metastatic epidural spinal cord compression in patients with an expected prognosis of a few months or less.

STEREOTACTIC BODY RADIATION THERAPY FOR BONE METASTASES The role of SBRT for bone and spine metastases is rapidly evolving. Advances in image guidance and the ability to safely deliver ablative doses have led to its adoption in many centers for primary treatment, reirradiation, and in the postoperative setting (Fig. 17.3). Available data are almost entirely retrospective or prospective but not randomized. The scope of this chapter does not permit an in-depth discussion and evaluation of current evidence and data forthcoming; however, we will provide highlights and salient points on this topic. Spine SBRT for de novo metastases has been the subject of many retrospective and prospective studies with promising results. Local control at 1 year is excellent, ranging between 80% and 96% with complete response rates of 46% to 92%, depending on the series.97–99 Spine SBRT has also been used in the reirradiation and salvage setting with promising results.100–102 Owing to reports of high failure rates in the postoperative setting (exceeding 60% in some series), even with conventional radiation, SBRT has been used, with reports suggesting local control in excess of 80%.103–105 While all of these data are promising, high-quality randomized data are lacking. The first randomized study comparing SBRT and conventional radiation for untreated painful vertebral metastases was recently published.106 Fifty-five patients were randomized to SBRT (24 Gy in 1 fraction) or multifraction conventional radiotherapy (30 Gy in 10 fractions). The primary endpoint was pain response at 3 months. The authors report no statistically significant difference in pain response at 3 months between SBRT and conventional radiotherapy (p = 0.13). At 6 months, however, there was lower reported pain in the SBRT arm (p = 0.002). Interestingly, the authors report a faster decrease in pain in the SBRT arm (p = 0.01). This trial is important, as it presents the first randomized evidence in this context comparing SBRT with conventional radiation; however, much uncertainty remains. The trial was small and the primary endpoint negative. It does provide evidence of rapidity of response perhaps being superior when using SBRT as well as significantly improved pain response at 6 months. The reporting of the rapidity of response data, however, makes it difficult to quantify

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CHAPTER 17

A

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287

B Fig. 17.3 Representative (A) axial and (B) sagittal images of a spine stereotactic body radiation therapy (SBRT) plan for vertebral metastases. Two vertebral levels were treated in 1 plan with 24 Gy in 2 fractions. The planning target volume (PTV) is depicted in blue colorwash and spinal cord planning organ at risk volume (PRV) in green colorwash. PTV was generated by expanding the clinical target volume (CTV) by 2 mm and the spinal cord was expanded by 1.5 mm to generate the spinal cord PRV. In this case the spinal cord PRV was limited to a max dose of 17 Gy. Note the conformality of the isodose lines around the vertebral body and spinal canal with a steep gradient representing rapid dose fall-off to spare normal tissue and meet spinal cord constraints.

aside from saying that it was superior in this trial. As mentioned earlier, up to 40% of patients being treated with a single 8 Gy fraction may experience pain response as well as QOL improvement by day 10. The clinical benefit of a more rapid pain response using SBRT in comparison with conventional radiotherapy is an area ripe for further research. RTOG 0631 is a randomized Phase II to Phase III study comparing single-fraction SBRT (16-18 Gy) versus 8 Gy in a single fraction of conventional radiotherapy with pain as the primary outcome.107 At the time of this writing, accrual and data collection has been completed and the publication is eagerly awaited. Questions will remain regarding the dose of SBRT in comparison with other regimens and whether the use of a single 8-Gy fraction in the comparator arm is the most appropriate if there are patients with paraspinal or epidural soft-tissue disease. Sahgal et al. are currently accruing patients on SC24, a randomized Phase II to Phase III trial comparing SBRT (24 Gy in 2 fractions) and conventional radiotherapy (20 Gy in 5 fractions), also with pain as the primary outcome measure.108 These data are eagerly awaited, as they will also provide crucial QOL data. These randomized studies will influence use of SBRT for palliation of pain, but regardless of the outcomes of these trials, SBRT for vertebral metastases will likely have an important role going forward, particularly when the desired outcome for treatment is local control or tumor ablation. Many patients, especially with oligometastatic disease, are being managed on a treatment paradigm of locally aggressive therapy, including surgery. Data for this approach is rapidly evolving but limited, and SBRT will continue to be an important component of this approach. Time will tell whether these approaches ultimately provide benefit for the only oncological treatment outcomes that matter—to “live longer” or to “live better”—but early data are encouraging. Evaluating SBRT for palliation of spine metastases from another perspective, Kim et al. performed a cost-effectiveness analysis comparing a single fraction of spine SBRT versus a single fraction of conventional radiotherapy.109 They found that SBRT is cost effective only if expected median survival is greater than or equal to 11 months, as then the cost is less than or equal to $100,000 per quality-adjusted life year (QALY) gained, using this as the willingness to pay (WTP) threshold per QALY gained. If survival is less, then the incremental cost-effectiveness ratio

(ICER) is $124,552 per QALY gained. This study is from the perspective of a third-party payer and therefore omits opportunity costs such as lost productivity and travel costs, which are relevant when viewed from a societal perspective. More work is needed in this area, especially if level 1 evidence is generated supporting its use in the standard setting, but indicates that there likely exists a patient population for which spine SBRT is cost-effective. Given the current state of evidence, the ASTRO bone metastases guidelines recommend the use of SBRT in the setting of a clinical trial or data collected in a registry; the authors agree with this recommendation.110 The field of radiation oncology is rapidly progressing, and future research will need to evaluate optimal dose and fractionation of spine SBRT as well as patient selection, balancing efficacy with toxicity, such as vertebral fracture. Combination of SBRT with minimally invasive surgical techniques and “separation surgery” are exciting prospects. Finally, rigorous determination of how to incorporate radiotherapy with systemic therapy—in particular, immunotherapy—is a promising area of research, and reports are eagerly awaited.

OLIGOMETASTATIC DISEASE The term oligometastasis was coined in 1995 by Samuel Hellman and Ralph Weichselbaum, two radiation oncologists working at the University of Chicago, to describe a metastatic state wherein cancer cells from the primary tumor travel through the body and form a small number of metastases in one or two other areas of the body.111 Hellman and Weichselbaum formalized the concept that a spectrum existed within the metastatic state. As stereotactic ablative procedures became available, clinicians hurried to apply the novel therapeutic approach to this new niche disease entity. In fact, from a survey of over 1000 radiation oncologists from 43 counties, we learned that among those using SABR, 100% of our colleagues had used SABR for oligometastasis prior to the existence of level 1 evidence, and 8% of practitioners were already applying stereotactic principles in the mid-1990s (i.e., concomitant with the emergence of the term oligometastasis!).112 Three experiences will be briefly presented here because they are based on prospective randomized investigation.

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Gomez and colleagues designed a multicenter, randomized Phase II study for patients with NSCLC who developed a maximum of three oligometastases.113 All of the patients received first-line systemic therapy prior to randomization to either local consolidative therapy (with or without maintenance treatment) or maintenance treatment alone. The study was terminated early after 49 patients were accrued when it was clear that there was a maintainable, statistically significant benefit in progression-free survival among those treated on the experimental arm. Although the study was noteworthy for providing the first shreds of prospective randomized data, it has been criticized because of the selection of PFS as an endpoint. It is no surprise that patients receiving local treatments would derive a benefit in PFS, and it is unfortunate that overall survival and QOL endpoints were not prioritized. The more provocative result that the authors reported was the benefit in “new lesion-free survival” among those receiving local treatments. By increasing the time to appearance of new sites of disease, there is a hint that local treatments may alter the natural history of disease (e.g., metastasis-tometastasis spread).113,114 A final important caveat pertains to the intervention itself, which was not necessarily stereotactic radiation therapy but rather “local” therapy (at times, surgery alone). Within a year, Iyengar et al. published the results of another Phase II clinical trial for patients who manifest oligometastases from NSCLC.115 The randomization was between maintenance chemotherapy alone and SABR followed by maintenance chemotherapy. Unlike the previous experience, all patients were treated at one medical center according to uniform prescriptions of radiotherapy. Here, too, there was a statistically significant benefit in PFS. Although the work of Iyengar et al. can also be criticized because of the selection of a suboptimal endpoint, the data are more robust given the standardization of care. Finally, Ost et al. reported comparable results in a different clinical population: patients with oligometastases from prostate cancer.116 In their Phase II trial, patients who were never exposed to androgendeprivation therapy (ADT) were randomized between surveillance and “metastasis-directed therapy (MDT)” (the latter consisting of surgery or SBRT). In the case of SBRT, 30 Gy was delivered in three fractions. The primary outcome measure was ADT-free survival. The indication to start ADT was symptomatic progression, progression to more than three metastases, or local progression of the metastasis detected at baseline. The authors enlisted 62 patients to participate in the trial. The median ADT-free survival was 13 months for the surveillance group and 21 months for the MDT group. No patients had symptomatic progression in the MDT group in contrast to three that arose in the surveillance arm. There were no changes in quality of life endpoints (HRQOL) between the two arms. In other words, ADT can be deferred, as local treatments (primarily SBRT) can be safely delivered.

FUTURE DIRECTIONS The lexicon of modern medicine applauds the notion of the paradigm shift. Indeed, the field of radiation oncology, with its curiosity about a diversity of novel approaches (e.g., hypofractionation, stereotaxy, image guidance, and more) has demonstrated a willingness to confront and incorporate shifting paradigms. The integration of palliative care— particularly early palliative care—into clinical practice has been heralded by paradigm-changing studies that have provided an evidence base to justify and pursue the principles of palliative care. In 2014, the Society of Palliative Radiation Oncology (SPRO) was established as a mechanism to pose questions and spawn data-driven conversations on education (e.g., incorporation of meaningful teaching modules into residency programs), to conduct research (clinical and basic investigation), and to advocate for contemporary issues in palliative medicine. The SPRO derives input from multiple organizations, including

ASTRO, the Canadian Association of Radiation Oncology (CARO), and ESTRO. At approximately the same time, a dedicated symposium was launched by ASTRO, ASCO, the American Academy of Hospice and Palliative Medicine (AAHPM), and the Multinational Association of Supportive Care in Cancer (MASCC) to convene annually for the exchange of ideas in the rapidly advancing discipline of palliative medicine. Through these respective forums, palliative radiotherapy will be systematically integrated into the broader field of palliative medicine. Meanwhile, specialized arrangements, such as dedicated palliative care programs and subspecialty programs for the delivery of palliative care in the hospice environment, have been developed.1,2,52,53,55,67 Such innovative programming was once thought to be oxymoronic with regard to palliative care, but the dynamism of the times has dictated adaptation on the part of the radiation oncology community. We have the privilege of practicing medicine at an exciting juncture. Today, there is little doubt that palliative radiation therapy can improve the overall level of care for some of the most debilitated and vulnerable patients encountered in oncology.

CRITICAL REFERENCES 1. Chow E, et al. Referring physicians’ satisfaction with the rapid response radiotherapy programme: survey results at the Toronto-Sunnybrook Regional Cancer Centre. Support Care Cancer. 2000;8:405–409. 2. Stavas MJ, Pagan JD, Varma S, et al. Building a palliative radiation oncology program: from bedside to B.E.D. Pract Radiat Oncol. 2017;7:203–208. 3. WHO | WHO Definition of Palliative Care. WHO; 2012. Available at: http:// www.who.int/cancer/palliative/definition/en/. Accessed July 30, 2018. 4. Clinical ESMO. Practice Guidelines on Supportive and Palliative Care. Available at: https://www.esmo.org/Guidelines/Supportive-and-Palliative-Care. Accessed July 30, 2018. 7. Temel JS, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med. 2010;363:733–742. 8. Zimmermann C, et al. Early palliative care for patients with advanced cancer: a cluster-randomised controlled trial. Lancet. 2014;383:1721–1730. 11. Bakitas MA, et al. Early versus delayed initiation of concurrent palliative oncology care: patient outcomes in the ENABLE III randomized controlled trial. J Clin Oncol. 2015;33:1438–1445. 47. Wei RL, et al. Palliative care and palliative radiation therapy education in radiation oncology: a survey of US radiation oncology program directors. Pract Radiat Oncol. 2017;7:234–240. 49. Hansen HH, et al. Recommendations for a global core curriculum in medical oncology. Ann Oncol. 2004;15:1603–1612. 50. Dittrich C, et al. ESMO/ASCO recommendations for a global curriculum in medical oncology edition 2016. ESMO Open. 2016;1. 51. Cherny NI, et al. ESMO takes a stand on supportive and palliative care. Ann Oncol. 2003;14:1335–1337. 52. Fairchild A, et al. The rapid access palliative radiotherapy program: blueprint for initiation of a one-stop multidisciplinary bone metastases clinic. Support Care Cancer. 2009;17:163–170. 53. Gorman D, Balboni T, Taylor A, Krishnan M. The supportive and palliative radiation oncology service: a dedicated model for palliative radiation oncology care. J Adv Pract Oncol. 2015;6:135–140. 55. Mitin T, Thomas CR, Jaboin JJ. PRADO: a palliative care model for every radiation oncology practice. Int J Radiat Oncol Biol Phys. 2017;99:518–519. 57. Lutz S, Spence C, Chow E, et al. Survey on Use of Palliative Radiotherapy in Hospice Care. J Clin Oncol. 2004;22:3581–3586. 59. Jones JA, Lutz ST, Chow E, Johnstone PA. Palliative radiotherapy at the end of life: a critical review. CA Cancer J Clin. 2014;64:295–310. 62. Krishnan MS, et al. Predicting life expectancy in patients with metastatic cancer receiving palliative radiotherapy: the TEACHH model. Cancer. 2014;120:134–141.

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CHAPTER 17 65. Schuster J, Han T, Anscher M, Moghanaki D. Hospice providers awareness of the benefits and availability of single-fraction palliative radiotherapy. J Hosp Palliat Nurs. 2014;16:67–72. 77. Chow E, et al. Update on the Systematic Review of Palliative Radiotherapy Trials for Bone Metastases. Clin Oncol. 2012;24:112–124. 79. ASTRO - Extended fractionation schemes | Choosing Wisely. Available at: http://www.choosingwisely.org/clinician-lists/american-society -radiation-oncology-extended-fractionation-schemes-for-palliationof-bone-metastases/. Accessed July 30, 2018. 94. Patchell RA, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366:643–648. 95. Rades D, et al. Radiotherapy with 4 Gy × 5 versus 3 Gy × 10 for metastatic epidural spinal cord compression: final results of the SCORE-2 Trial (ARO 2009/01). J Clin Oncol. 2016;34:597–602.

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109. Kim H, Rajagopalan MS, Beriwal S, et al. Cost-effectiveness analysis of single fraction of stereotactic body radiation therapy compared with single fraction of external beam radiation therapy for palliation of vertebral bone metastases. Int J Radiat Oncol Biol Phys. 2015;91:556–563. 110. Lutz S, et al. Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol. 2017;7:4–12. 113. Gomez DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17:1672–1682.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 17

REFERENCES 1. Chow E, et al. Referring physicians’ satisfaction with the rapid response radiotherapy programme: survey results at the Toronto-Sunnybrook Regional Cancer Centre. Support Care Cancer. 2000;8:405–409. 2. Stavas MJ, Pagan JD, Varma S, et al. Building a palliative radiation oncology program: from bedside to B.E.D. Pract Radiat Oncol. 2017;7:203–208. 3. WHO | WHO Definition of Palliative Care. WHO; 2012. Available at: http:// www.who.int/cancer/palliative/definition/en/. Accessed July 30, 2018. 4. ESMO Clinical Practice Guidelines on Supportive and Palliative Care. Available at: https://www.esmo.org/Guidelines/Supportive-and-Palliative -Care. Accessed July 30, 2018. 5. Potters L. Personal communication. 6. VanLare JM, Conway PH. Value-based purchasing — national programs to move from volume to value. N Engl J Med. 2012;367:292–295. 7. Temel JS, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med. 2010;363:733–742. 8. Zimmermann C, et al. Early palliative care for patients with advanced cancer: a cluster-randomised controlled trial. Lancet. 2014;383:1721–1730. 9. Bakitas M, et al. Project ENABLE: a palliative care demonstration project for advanced cancer patients in three settings. J Palliat Med. 2004;7:363–372. 10. Bakitas M, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the project ENABLE II randomized controlled trial. JAMA. 2009;302:741–749. 11. Bakitas MA, et al. Early versus delayed initiation of concurrent palliative oncology care: patient outcomes in the ENABLE III randomized controlled trial. J Clin Oncol. 2015;33:1438–1445. 12. Dionne-Odom JN, et al. Benefits of early versus delayed palliative care to informal family caregivers of patients with advanced cancer: outcomes from the ENABLE III randomized controlled trial. J Clin Oncol. 2015;33:1446–1452. 13. Palos GR, et al. Caregiver symptom burden: the risk of caring for an underserved patient with advanced cancer. Cancer. 2011;117:1070–1079. 14. Perkins M, et al. Caregiving strain and all-cause mortality: evidence from the REGARDS study. J Gerontol B Psychol Sci Soc Sci. 2013;68:504–512. 15. Smith TJ, Schnipper LJ. The American Society of Clinical Oncology program to improve end-of-life care. J Palliat Med. 1998;1:221–230. 16. Smith TJ, et al. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol. 2012;30:880–887. 17. Ferris FD, et al. Palliative cancer care a decade later: accomplishments, the need, next steps - from the American Society of Clinical Oncology. J Clin Oncol. 2009;27:3052–3058. 18. Ferrell BR, et al. Integration of palliative care into standard oncology care: American society of clinical oncology clinical practice guideline update. J Clin Oncol. 2017;35:96–112. 19. Jordan K, et al. European Society for Medical Oncology (ESMO) position paper on supportive and palliative care. Ann Oncol. 2017;29:36–43. 20. Clayton JM, Butow PN, Tattersall MHN. When and how to initiate discussion about prognosis and end-of-life issues with terminally ill patients. J Pain Symptom Manage. 2005;30:132–144. 21. Parker SM, et al. A systematic review of prognostic/end-of-life communication with adults in the advanced stages of a life-limiting illness: patient/caregiver preferences for the content, style, and timing of information. J Pain Symptom Manage. 2007;34:81–93. 22. Sapir R, et al. Cancer patient expectations of and communication with oncologists and oncology nurses: the experience of an integrated oncology and palliative care service. Support Care Cancer. 2000;8:458–463. 23. Hagerty RG, et al. Cancer patient preferences for communication of prognosis in the metastatic setting. J Clin Oncol. 2004;22:1721–1730. 24. Clayton JM, Butow PN, Arnold RM, Tattersall MHN. Discussing life expectancy with terminally ill cancer patients and their carers: a qualitative study. Support Care Cancer. 2005;13:733–742.

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25. Groopman JE. A strategy for hope: a commentary on necessary collusion. J Clin Oncol. 2005;23:3151–3152. 26. Helft PR. Necessary collusion: prognostic communication with advanced cancer patients. J Clin Oncol. 2005;23:3146–3150. 27. El-Jawahri A, et al. Associations among prognostic understanding, quality of life, and mood in patients with advanced cancer. Cancer. 2014;120:278–285. 28. Tariman JD, Doorenbos A, Schepp KG, et al. Information needs priorities in patients diagnosed with cancer: a systematic review. J Adv Pract Oncol. 2014;2014:115–122. 29. The Michigan Physician Guide to End-of-Life Care; 2010. 30. Cherny NI, et al. Words matter: distinguishing ‘personalized medicine’ and ‘biologically personalized therapeutics’. J Natl Cancer Inst. 2014;106:dju321. 31. Kolata G. ‘Desperation Oncology’: When Patients Are Dying, Some Cancer Doctors Turn to Immunotherapy - The New York Times; 2018. 32. Hairon N. Patients need more information on palliative chemotherapy. Nurs Times. 2008;104:21–22. 33. Epstein RM, et al. Effect of a patient-centered communication intervention on oncologist-patient communication, quality of life, and health care utilization in advanced cancer: the VOICE Randomized Clinical Trial. JAMA Oncol. 2017;3:92–100. 34. Brandes K, Linn AJ, Butow PN, van Weert JCM. The characteristics and effectiveness of Question Prompt List interventions in oncology: a systematic review of the literature. Psychooncology. 2015;24:245–252. 35. Cherny N, et al. A GUIDE FOR PATIENTS WITH ADVANCED CANCER GETTING THE MOST OUT OF YOUR ONCOLOGIST; 2012. 36. Cherny N, et al. A User’s Manual For Oncology Clinicians To Accompany The Guide For Patients With Advanced Cancer; 2013. 37. Rhondali W, et al. Depression assessment by oncologists and palliative care physicians. Palliat Support Care. 2012;10:255–263. 38. Moghaddam N, Coxon H, Nabarro S, et al. Unmet care needs in people living with advanced cancer: a systematic review. Support Care Cancer. 2016;24:3609–3622. 39. Dittrich C, et al. Global curriculum edition 2016: European society for medical oncology/American society of clinical oncology recommendations for training in medical oncology. J Clin Oncol. 2017;35:254–255. 40. Clayton JM, Butow PN, Arnold RM, Tattersall MHN. Fostering coping and nurturing hope when discussing the future with terminally ill cancer patients and their caregivers. Cancer. 2005;103:1965–1975. 41. Nunn KP. Personal hopefulness: a conceptual review of the relevance of the perceived future to psychiatry. Br J Med Psychol. 1996;69:227–245. 42. Hagerty RG, et al. Communicating with realism and hope: incurable cancer patients’ views on the disclosure of prognosis. J Clin Oncol. 2005;23:1278–1288. 43. Reynolds MAH. Hope in adults, ages 20-59, with advanced stage cancer. Palliat Support Care. 2008;6:259–264. 44. Lynn J. Sick to Death and Not Going to Take It Anymore!; 2000. 45. Calvert M, et al. Guidelines for inclusion of patient-reported outcomes in clinical trial protocols the spirit-pro extension. JAMA. 2018;319:483–494. 46. Tepper JE. Ethics in clinical care. Int J Radiat Oncol Biol Phys. 2017;99:250–254. 47. Wei RL, et al. Palliative care and palliative radiation therapy education in radiation oncology: a survey of US radiation oncology program directors. Pract Radiat Oncol. 2017;7:234–240. 48. Wei RL, et al. Attitudes of radiation oncologists toward palliative and supportive care in the United States: report on national membership survey by the American Society for Radiation Oncology (ASTRO). Pract Radiat Oncol. 2017;7:113–119. 49. Hansen HH, et al. Recommendations for a global core curriculum in medical oncology. Ann Oncol. 2004;15:1603–1612. 50. Dittrich C, et al. ESMO/ASCO recommendations for a global curriculum in medical oncology edition 2016. ESMO Open. 2016;1. 51. Cherny NI, et al. ESMO takes a stand on supportive and palliative care. Ann Oncol. 2003;14:1335–1337.

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52. Fairchild A, et al. The rapid access palliative radiotherapy program: blueprint for initiation of a one-stop multidisciplinary bone metastases clinic. Support Care Cancer. 2009;17:163–170. 53. Gorman D, Balboni T, Taylor A, Krishnan M. The supportive and palliative radiation oncology service: a dedicated model for palliative radiation oncology care. J Adv Pract Oncol. 2015;6:135–140. 54. Tseng YD, et al. Supportive and palliative radiation oncology service: impact of a dedicated service on palliative cancer care HHS Public Access. Pract Radiat Oncol. 2014;4:247–253. 55. Mitin T, Thomas CR, Jaboin JJ. PRADO: a palliative care model for every radiation oncology practice. Int J Radiat Oncol Biol Phys. 2017;99:518–519. 56. Medicine, I. of. Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life. The National Academies Press; 2015. doi:10.17226/18748. 57. Lutz S, Spence C, Chow E, et al. Survey on Use of Palliative Radiotherapy in Hospice Care. J Clin Oncol. 2004;22:3581–3586. 58. Gripp S, Mjartan S, Boelke E, Willers R. Palliative radiotherapy tailored to life expectancy in end-stage cancer patients: reality or myth? Cancer. 2010;116:3251–3256. 59. Jones JA, Lutz ST, Chow E, Johnstone PA. Palliative radiotherapy at the end of life: a critical review. CA Cancer J Clin. 2014;64:295–310. 60. Tseng YD, et al. Use of radiation therapy within the last year of life among cancer patients. Int J Radiat Oncol Biol Phys. 2018;101:21–29. 61. Chow E, et al. Recursive partitioning analysis of prognostic factors for survival in patients with advanced cancer. Int J Radiat Oncol Biol Phys. 2009;73:1169–1176. 62. Krishnan MS, et al. Predicting life expectancy in patients with metastatic cancer receiving palliative radiotherapy: the TEACHH model. Cancer. 2014;120:134–141. 63. Puckett LL, Luitweiler E, Potters L, Teckie S. Preventing discontinuation of radiation therapy: predictive factors to improve patient selection for palliative treatment. J Oncol Pract. 2017;13:e782–e791. 64. Vigano A, Dorgan M, Buckingham J, et al. Survival prediction in terminal cancer patients: a systematic review of the medical literature. Palliat Med. 2000;14:363–374. 65. Schuster J, Han T, Anscher M, Moghanaki D. Hospice providers awareness of the benefits and availability of single-fraction palliative radiotherapy. J Hosp Palliat Nurs. 2014;16:67–72. 66. Jarosek SL, Virnig BA, Feldman R. Palliative radiotherapy in Medicarecertified freestanding hospices. J Pain Symptom Manage. 2009;37:780–787. 67. Schuster JM, et al. Clinic offering affordable radiation therapy to increase access to care for patients enrolled in hospice. J Oncol Pract. 2014;10:e390–e395. 68. Daily K. The toxicity of time. J Clin Oncol. 2018;36:300–301. 69. Van Oorschot B, Rades D, Schulze W, et al. Palliative radiotherapy-New approaches. Semin Oncol. 2011;38:443–449. W.B. Saunders. 70. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12:6243s–6249s. 71. Allemani C, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25 676 887 patients from 279 populationbased registries in 67 countries (CONCORD-2). Lancet. 2015;385:977–1010. 72. De Angelis R, et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE-5 - a population-based study. Lancet Oncol. 2014;15:23–34. 73. Marshall DC, et al. Trends in UK regional cancer mortality 1991-2007. Br J Cancer. 2016;114:340–347. 74. Steenland E, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol. 1999;52:101–109. 75. Harstell WF, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97:798–804. 76. Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007;25:1423–1436. 77. Chow E, et al. Update on the Systematic Review of Palliative Radiotherapy Trials for Bone Metastases. Clin Oncol. 2012;24:112–124.

78. Dennis K, Makhani L, Zeng L, et al. Single fraction conventional external beam radiation therapy for bone metastases: a systematic review of randomised controlled trials. Radiother Oncol. 2013;106:5–14. 79. ASTRO - Extended fractionation schemes | Choosing Wisely. Available at: http://www.choosingwisely.org/clinician-lists/american-societyradiation-oncology-extended-fractionation-schemes-for-palliation-ofbone-metastases/. Accessed July 30, 2018. 80. ChoosingWiselyCanada/Oncology; 2017. Available at: https:// choosingwiselycanada.org/oncology/. 81. Howell DD, et al. Single-fraction radiotherapy versus multifraction radiotherapy for palliation of painful vertebral bone metastases - equivalent efficacy, less toxicity, more convenient: a subset analysis of Radiation Therapy Oncology Group trial 97-14. Cancer. 2013;119:888–896. 82. Yarnold JR. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Radiother Oncol. 1999;52:111–121. 83. McDonald R, et al. Effect of radiotherapy on painful bone metastases: a secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23. JAMA Oncol. 2017;3:953–959. 84. Hird A, et al. Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: results from three Canadian cancer centers. Int J Radiat Oncol Biol Phys. 2009;75: 193–197. 85. Gomez-Iturriaga A, et al. Incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: multicenter prospective observational study. BMC Palliat Care. 2015;14:48. 86. Loblaw DA, et al. Pain flare in patients with bone metastases after palliative radiotherapy - A nested randomized control trial. Support Care Cancer. 2007;15:451–455. 87. Chiang A, et al. Pain flare is a common adverse event in steroid-naïve patients after spine stereotactic body radiation therapy: a prospective clinical trial. Int J Radiat Oncol Biol Phys. 2013;86:638–642. 88. Yousef AAAM, El-Mashad NM. Pre-emptive value of methylprednisolone intravenous infusion in patients with vertebral metastases. A doubleblind randomized study. J Pain Symptom Manage. 2014;48:762–769. 89. Chow E, et al. Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a doubleblind, randomised placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:1463–1472. 90. Huisman M, et al. Effectiveness of reirradiation for painful bone metastases: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2012;84:8–14. 91. Chow E, et al. Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol. 2014;15:164–171. 92. Bilsky MH, et al. Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine. 2010;13:324–328. 93. Fisher CG, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the spine oncology study group. Spine. 2010;35:E1221–E1229. 94. Patchell RA, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366:643–648. 95. Rades D, et al. Radiotherapy with 4 Gy × 5 versus 3 Gy × 10 for metastatic epidural spinal cord compression: final results of the SCORE-2 Trial (ARO 2009/01). J Clin Oncol. 2016;34:597–602. 96. Rades D, et al. Single-fraction versus 5-fraction radiation therapy for metastatic epidural spinal cord compression in patients with limited survival prognoses: results of a matched-pair analysis. Int J Radiat Oncol Biol Phys. 2015;93:368–372. 97. Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine. 2007;32:193–199. 98. Anand AK, et al. Hypofractionated stereotactic body radiotherapy in spinal metastasis – with or without epidural extension. Clin Oncol. 2015;27:345–352.

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CHAPTER 17 99. Tseng CL, et al. Spine stereotactic body radiotherapy: indications, outcomes, and points of caution. Global Spine J. 2017;7:179–197. 100. Garg AK, et al. Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy. Cancer. 2011;117:3509–3516. 101. Choi CYH, et al. Stereotactic radiosurgery for treatment of spinal metastases recurring in close proximity to previously irradiated spinal cord. Int J Radiat Oncol Biol Phys. 2010;78:499–506. 102. Sahgal A, et al. Stereotactic body radiotherapy is effective salvage therapy for patients with prior radiation of spinal metastases. Int J Radiat Oncol Biol Phys. 2009;74:723–731. 103. Klekamp J, Samii H. Surgical results for spinal metastases. Acta Neurochir (Wien). 1998;140:957–967. 104. Al-Omair A, et al. Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy. Neuro Oncol. 2013;15:1413–1419. 105. Laufer I, et al. Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine. 2013;18:207–214. 106. Sprave T, et al. Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy. Radiother Oncol. 2018;doi:10.1016/j.radonc.2018.04.030. 107. Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis. Available at: https://clinicaltrials.gov/ct2/show/ NCT00922974. Accessed July 30, 2018. 108. A Randomized Phase II/III Study Comparing Stereotactic Body Radiotherapy(SBRT) Versus Conventional Palliative Radiotherapy (CRT)

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for Patients With Spinal Metastases. Available at: https://clinicaltrials .gov/ct2/show/study/NCT02512965. Accessed July 30, 2018. 109. Kim H, Rajagopalan MS, Beriwal S, et al. Cost-effectiveness analysis of single fraction of stereotactic body radiation therapy compared with single fraction of external beam radiation therapy for palliation of vertebral bone metastases. Int J Radiat Oncol Biol Phys. 2015;91:556–563. 110. Lutz S, et al. Palliative radiation therapy for bone metastases: update of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol. 2017;7:4–12. 111. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13:8–10. 112. Lewis SL, et al. Definitive Stereotactic Body Radiotherapy (SBRT) for extracranial oligometastases. Am J Clin Oncol. 2017;40:418–422. 113. Gomez DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17:1672–1682. 114. Gundem G, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353. 115. Iyengar P, et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2018;4:e173501. 116. Ost P, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2017;36.

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18 Late Effects After Radiation Michael T. Milano, Lawrence B. Marks, and Louis S. Constine

INTRODUCTION AND GENERAL CONSIDERATIONS Statement of the Problem Incidental irradiation of normal tissues is unavoidable during radiotherapy. The primary determinants of injury are the radiation dose (total dose and dose per fraction) and the volume of normal tissue irradiated. Additional treatment factors that influence risk include dose rate, overall treatment time, treatment energy, the use of concurrent chemotherapy, radiation protectors or other biological modifiers, and the interval between radiation courses in patients undergoing a second course of radiation. Host-related factors include comorbid conditions (e.g., diabetes and collagen vascular disease), inherent radiation sensitivity (e.g., underlying genetics), and patient age. Organ-related variables include preradiation organ compromise or loss, development of severe acute toxicity (resulting in consequential late effects), regional variation of radiosensitivity within an organ, and hierarchical organization of the organ (i.e., whether damage to a portion of the organ affects only that portion or has a more widespread effect). Furthermore, an organ may have more than one type of late toxicity that may or may not have different tolerance doses. Tumors can infiltrate into normal tissues, either at presentation or after treatment (i.e., local failure), compromising organ function and leading to late sequelae.

What Are the Target Cells/Tissues for Radiation-Associated Normal Tissue Injury? Different organs have different dose/volume thresholds for the development of radiation-associated injury. The critical question arising from this observation is as follows: What are the dose-sensitive targets in normal tissues resulting in late toxicity? Damage to either the functional (parenchymal) or stromal cells of the organ, or the fine vasculature, have been implicated. Differences in radiation susceptibility of different organs, therefore, may be due to different sensitivities of these functional cells, regional variation in the susceptibilities of small vessels due to the stroma or microenvironment, different capacities for neovascularization, and/or differences in the redundancy of the blood flow (i.e., those tissues relying on fewer vessels may be more susceptible to radiation damage) or functional reserve.

Utility and Limitations of Dose-Volume Histograms The focus of this chapter will be on the review of credible data associating radiation dose/volume parameters with the risk of normal tissue injury. Three-dimensional (3D) planning has become standard practice, allowing the radiation oncologist to quantitate doses to normal tissues in the region of interest. 3D dose/volume data can be difficult for clinicians to easily comprehend since the distributions are 2D. Visualizing isodose distributions is challenging and comparing competing distributions is largely subjective. Therefore, dose-volume histograms (DVHs; essentially,

2D representations of the 3D data) have been embraced as a rapid way to summarize the dose distribution. A DVH is generated by tallying the doses delivered to each (or a representative sample of) voxel of tissue and representing that information as a cumulative histogram of dose (x-axis) and volume (y-axis). Each point along the histogram represents the volume of that organ receiving more than or equal to that dose (e.g., V20 is the volume of an organ receiving at least 20 Gy). A DVH can be readily visualized and provides a quick and easy way to describe the dose/volume characteristics of the 3D dose distribution. However, a DVH achieves this by discarding all spatial information and the DVH does not account for variations in fraction size. Functional and structural complexities, and spatial variations in function/sensitivity, are thus not considered in DVHs. Possible interactions between organs is also not considered with this construct. Beyond the marked data reduction in going from a 3D plan to a DVH, DVHs also remain challenging for clinicians to consider and compare owing to the previously mentioned issues relating to functional heterogeneity and the incomplete knowledge about radiation sensitivity of tissues. Therefore, it has become attractive to further reduce data and extract “figures of merit” from the DVH. The critical metrics that will considered in this review are the mean organ dose and discrete points on the DVH. These include (Fig. 18.1): 1. Vx reflects the volume of tissue (generally a percentage) receiving ≥ X Gy. This is probably the most commonly used metric for parallel-type organs such as the lung and kidney, but also others such as the heart. For these, as discussed earlier, the portions of the organ exposed to a “regionally injuring” dose of radiation will become dysfunctional. Thus, the percentage of the organ exposed to that dose is a useful parameter. 2. Dx reflects the minimum dose to the hottest x% (generally percentage of total volume) of tissue. This parameter is not widely used clinically. It might be most useful for parallel-type organs in which the percentage of an organ’s function that can be lost is known (e.g., say, 30%). Then, if the D30 is less than the locally injuring dose, global organ function should remain. Similarly, for organs in which an injury might be clinically manifest if there is a hot spot of a particular size, the Dx, where x is equal to that critical size, might be a useful parameter to predict outcomes. 3. Dmax is the maximum dose delivered to an organ and is most useful for series organs. Dmax is analogous to Dx, as the volume x decreases toward zero. 4. Mean dose is the simple arithmetic average of the dose to an organ. For parallel organs in which there is a gradual dose-response function for radiation-induced regional injury, the mean dose might reasonably correlate with outcomes. More complex modeling has also been widely used to extract factors that better reflect the entire DVH rather than a single point (e.g., Dmax,

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CHAPTER 18

Late Effects After Radiation

291

Lung V20

Heart D50

Spinal canal maximum dose

Mean lung dose

Fig. 18.1 Illustration of Vx, Dx, and Dmax. Mean organ dose is calculated by averaging the dose to each voxel of a tissue and is generally calculated by the treatment planning software. The volume of lung receiving > 20 Gy (V20) and mean lung dose are shown (37% and 20.2 Gy, respectively). The dose to 50% of the heart (D50) is shown (13.3 Gy), which is not a commonly used dose-volume metric but is presented for illustrative purposes. The maximal dose to the spinal canal is depicted as well (49.5 Gy).

Dx, Vx). These models will “sum up” the risk associated with each component of a DVH and apply different methods of summing depending on the type (or architecture/structure) of the organ. For example, for a series-structured organ, the high-dose region of the DVH might be most weighted more heavily in the “summing” while this is less strongly considered in a parallel-structured organ. Early work in this area led to the Lyman Kutcher Burman (LKB) model and more recently the equivalent uniform dose (EUD) model, both of which reduce a DVH to a single normal tissue complication probability (NTCP). These models and their relationships are summarized elsewhere.1

The Opportunities and Challenges of Modern Radiation Technologies More conformal radiation planning and delivery tools—such as intensitymodulated radiation therapy (IMRT), image-guided radiotherapy (IGRT), stereotactic body radiotherapy (SBRT), and charged particle irradiation— give the physician increased flexibility in determining how to deliver the desired target dose while minimizing and/or redistributing the dose exposure to normal tissue. The clinical application of these new technologies requires that the physician and dosimetrists/physicists have an in-depth knowledge of the dose/volume/outcome relationships for critical normal tissues. However, these new technologies have altered the relationship between the target doses and the doses to surrounding normal tissues that might impact on the applicability of historical data for our modern era. With conventional beams (often opposed beam pairs treated sequentially), the normal tissues were exposed to fraction sizes similar to that of the tumor. With these newer approaches, the fractional radiation doses delivered to the normal tissues adjacent to the target are typically lower than that received by the target. Further,

there is a movement toward the use of shorter hypofractionated regimens. Ironically, the use of increasing fraction sizes, along with an increasing number of beams, leaves (at least some of) the surrounding normal tissue receiving a daily fraction size close to what is typically seen with conventional approaches. However, with the more modern techniques, the heterogeneity of dose within the normal tissues is increased. Despite these caveats, much of the published data regarding radiation-associated normal tissue injury remains applicable in the modern era. Continued study of this important topic is clearly needed.

Defining Organ Structure Normal tissues can be functionally defined as “serial,” “parallel,” or a combination of both, analogous to the terminology used for electrical circuits (Fig. 18.2). In parallel functioning organs, the functional subunits function independently (i.e., functional redundancy exists). Thus, when some functional subunits of a parallel organ are damaged, the surrounding functional subunits continue to function. Examples of parallel functioning organs include the lung, liver, and kidney. Small to moderate, and perhaps even large, volumes of parallel organs can be damaged without causing global dysfunction since there is enough reserve in the undamaged portion of the organ and/or there is a capacity to regenerate (e.g., the liver). In “serial” organs, the functional subunits are arranged in a linear or branching fashion; hence, there is interdependence. Damage to the subunits of a serial organ can result in compromise or incapacity of the entire organ. Examples of series organs include the spinal cord, portions of the central nervous system, peripheral and cranial nerves, the gastrointestinal tract, and the tracheal-bronchial tree. While the concept of serial and parallel functioning organs is useful in assessing risk to tissues, it should be appreciated that this is only a model. The

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Serial Organ Distribution of surviving cells within FSUs (after radiation) for a serially arranged organ

Functional status of each subunit, following cell death, is illustrated

Three functional subunits depleted Functional status of entire organ is illustrated; complete loss of organ function results

A

Complete compromise of all FSUs Parallel Organ

Distribution of surviving cells within functional subunits (after radiation) for a parallel arranged organ

Functional status of each subunit, following cell death, is illustrated

Three functional subunits depleted

Remaining functional subunits are functional. Organ functions normally (or partially).

B Fig. 18.2 Illustrative comparison of serial versus parallel organs. In this figure, a hypothetical example of 10 cells (circles) per functional unit (square) is shown, after radiation in which 50% of cells are killed (black circles), and functional subunits (FSUs) with 5 or more cells remain functional after radiation. (A) shows an organ in which FSUs are arranged in series; the organ’s function is dependent on connectivity to its neighboring FSUs. For organs with FSUs arranged in series (A), damage to 1 or more FSUs (3 are damaged in the figure) results in complete compromise of that component (i.e., loop of bowel or region of spinal cord). For organs in which FSUs are arranged in parallel (B), damage to a portion of FSUs (3 shown in the figure) results in partial or no apparent organ compromise. Repopulation within the FSUs is not shown.

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CHAPTER 18 function of many organs requires the integrity of both serial and parallel components (e.g., the lung requires the “parallel” alveoli as well as the “series” conducting airways). Further complicating this issue is the fact that, in both serial and parallel organs, there are often regional heterogeneities in function (e.g., gray matter and white matter tracts of the “parallel” spinal cord). These anatomic subregions may have different functions and different susceptiblities to treatment-related damage.

QUANTEC This chapter will summarize and expand on several reviews published as a special issue in the International Journal of Radiation Oncology Biology Physics (Volume 76, Issue 3, Supplement), all of which were written as part of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) initiative. As the QUANTEC reviews were published in 2010, this chapter also summarizes relevant studies published after QUANTEC. QUANTEC arose from a proposal from the Science Council of the American Association of Physicists in Medicine (AAPM) to revise

TABLE 18.1

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and update guidelines published by Emani in 1991.2 QUANTEC’s goals were (1) to provide a critical review of the current literature on quantitative dose-response and dose-volume relationships for clinically relevant normal-tissue endpoints, (2) to produce practical guidelines to allow reasonable toxicity risks based on dose-volume parameters, and (3) to identify future research initiatives. Using the QUANTEC reviews as a backbone, this chapter will focus on recently published data relevant to late toxicity from radiation, with an emphasis on relevant dose-volume metrics. Key summary points of the QUANTEC reviews are briefly summarized at the end of each section, and the QUANTEC reviews are referenced after each subheading. Table 18.1 summarizes the dose-volume metrics that are supported by the literature; this table was modified from the one published in the QUANTEC issue.1 Although the QUANTEC initiative and associated reviews addressed a broad range of issues relating to normal tissue damage, this chapter will focus on late toxicity after an initial course (i.e., excluding reirradiation) of conventional radiation (i.e., excluding hypofractionated regimens). Many of the individual QUANTEC reviews discussed

Dose-Volume Metrics Supported by Published Data

Organ

Volume Segmented: Irradiation Type

Endpoint

Dose-Volume Parameters

Rate

Comments

Brain

Whole organ: 3DRT

Symptomatic necrosis

Dmax < 60 Gy

< 3%

Whole organ: 3DRT

Symptomatic necrosis

Dmax < 72 Gy

5%

Data at 72 and 90 Gy, extrapolated from BED models

Whole organ: 3DRT

Symptomatic necrosis

Dmax < 90 Gy

10%

Whole organ: whole brainstem

Permanent cranial neuropathy or necrosis

Dmax < 54 Gy

< 5%

Whole organ: 3DRT

Permanent cranial neuropathy or necrosis

D1-10 mL ≤ 59 Gy

< 5%

Whole organ: 3DRT

Permanent cranial neuropathy or necrosis

Dmax < 64 Gy

< 5%

Point dose < 1 mL

Whole organ: 3DRT

Optic neuropathy

Dmax < 55 Gy

< 3%

Given the small size, 3DCRT is often whole organ.

Whole organ: 3DRT

Optic neuropathy

Dmax 55-60 Gy

3%-7%

Brain stem

Optic nerve/ chiasm

Whole organ: 3DRT

Optic neuropathy

Dmax 60 Gy

7%-20%

Partial organ: 3DRT

Myelopathy

Dmax 50 Gy

0.2%

Partial organ: 3DRT

Myelopathy

Dmax 60 Gy

6%

Partial organ: 3DRT

Myelopathy

Dmax 69 Gy

50%

Cochlea

Whole organ: 3DRT

Sensory neural hearing loss

Mean dose ≤ 45 Gy

< 30%

Mean dose to cochlea, hearing at 4 kHz

Parotid

Bilateral whole parotids: 3DRT

Long-term parotid salivary function reduced to < 25% of pre-RT level

Mean dose < 25 Gy

< 20%

For combined parotid glands

Unilateral whole parotid: 3DRT

Long-term parotid salivary function reduced to < 25% of pre-RT level

Mean dose < 20 Gy

< 20%

At least one parotid gland spared to < 20 Gy

Bilateral whole parotids: 3DRT

Long-term parotid salivary function reduced to < 25% of pre-RT level

Mean dose < 39 Gy

< 50%

For combined parotid glands

Pharyngeal constrictors: 3DRT

Symptomatic dysphagia and aspiration

Mean dose < 50 Gy

< 20%

Spinal cord

Pharynx Larynx

Including full-cord cross-section

Whole organ: 3DRT

Vocal dysfunction

Dmax < 66 Gy

< 20%

With chemotherapy

Whole organ: 3DRT

Aspiration

Mean dose < 50 Gy

< 30%

With chemotherapy

Whole organ: 3DRT

Edema

Mean dose < 44 Gy V50 < 27%

< 20%

Without chemotherapy Continued

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Scientific Foundations of Radiation Oncology

Dose-Volume Metrics Supported by Published Data—cont’d

Volume Segmented: Irradiation Type Whole organ: 3DRT

Endpoint Symptomatic pneumonitis

Dose-Volume Parameters Mean dose 7 Gy

Rate 5%

Whole organ: 3DRT

Symptomatic pneumonitis

Mean dose 13 Gy

10%

Whole organ: 3DRT

Symptomatic pneumonitis

Mean dose 20 Gy

20%

Whole organ: 3DRT

Symptomatic pneumonitis

Mean dose 24 Gy

30%

Whole organ: 3DRT

Symptomatic pneumonitis

Mean dose 27 Gy

40%

Whole organ: 3DRT

Grade ≥ 3 acute esophagitis

Mean dose < 34 Gy

Whole organ: 3DRT

Grade ≥ 2 acute esophagitis

V35 < 50%

Whole organ: 3DRT

Grade ≥ 2 acute esophagitis

V50 < 40%

Whole organ: 3DRT

Grade ≥ 2 acute esophagitis

V70 < 20%

Pericardium: 3DRT

Pericarditis

Mean dose < 26 Gy

Pericardium: 3DRT

Pericarditis

V30 < 46%

Whole organ: 3DRT

Long-term cardiac mortality

V35 < 10%

Whole liver – GTV: Whole liver or 3DRT

Classic RILD

Mean dose < 30-32 Gy

< 5%

Whole liver – GTV: 3DRT

Classic RILD

Mean dose < 42 Gy

< 50%

Whole liver – GTV: Whole liver or 3DRT

Classic RILD

Mean dose < 28 Gy

< 5%

Whole liver – GTV: 3DRT

Classic RILD

Mean dose < 36 Gy

< 50%

Bilateral kidneys (not TBI): Bilateral kidneys or 3DRT

Clinically relevant renal dysfunction

mean dose < 15-18 Gy

< 5%

Bilateral kidneys (not TBI): Bilateral kidneys

Clinically relevant renal dysfunction

Mean dose < 15-18 Gy

< 50%

Bilateral kidneys (not TBI): 3DRT (combined kidney)

Clinically relevant renal dysfunction

V12 < 55% V20 < 32% V23 < 30% V28 < 20%

< 5%

Stomach

Whole organ: Whole stomach

Ulceration

D100 < 45 Gy

< 7%

Small bowel

Individual small-bowel loops: 3DRT

Grade ≥ 3 toxicity (acute)

V15 < 120 mL

< 10%

Peritoneal cavity: 3DRT

Grade ≥ 3 toxicity (acute)

V45 < 195 mL

< 10%

Whole organ: 3DRT

Grade ≥ 2 toxicity Grade ≥ 3 toxicity

V50 < 50%

< 15% < 10%

Whole organ: 3DRT

Grade ≥ 2 toxicity Grade ≥ 3 toxicity

V60 < 35%

< 15% < 10%

Whole organ: 3DRT

Grade ≥ 2 toxicity Grade ≥ 3 toxicity

V65 < 25%

< 15% < 10%

Whole organ: 3DRT

Grade ≥ 2 toxicity Grade ≥ 3 toxicity

V70 < 20%

< 15% < 10%

Whole organ: 3DRT

Grade ≥ 2 toxicity Grade ≥ 3 toxicity

V75 < 15%

< 15% < 10%

Organ Lung

Esophagus

Heart

Liver

Kidney

Rectum

Comments Excludes purposeful whole lung irradiation

A variety of alternate threshold doses have been implicated. Appears to be a dose/volume response Similar constraints are applicable to late toxicity.

Overly safe risk estimate based on model predictions Excluding patients with preexisting liver disease or hepatocellular carcinoma In patients with Child-Pugh A preexisting liver disease or hepatocellular carcinoma, excluding hepatitis B reactivation

Dose-volume data on late toxicity is lacking; data for acute toxicity may be a reasonably good surrogate. Data derived mostly from prostate cancer treatment

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CHAPTER 18

TABLE 18.1 Organ Bladder

Penile bulb

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295

Dose-Volume Metrics Supported by Published Data—cont’d

Volume Segmented: Irradiation Type Whole organ: 3DRT

Endpoint RTOG Grade ≥ 3 late toxicity

Dose-Volume Parameters Dmax < 65 Gy

Whole organ: 3DRT

RTOG Grade ≥ 3 late toxicity

V65 < 50% V70 < 35% V75 < 25% V80 < 15%

< 6%

Whole organ: 3DRT

Severe erectile dysfunction

Mean dose to 95% of gland < 50 Gy

< 35%

Whole organ: 3DRT

Severe erectile dysfunction

D90 < 50 Gy

< 35%

Whole organ: 3DRT

Severe erectile dysfunction

D60-70 < 70 Gy

< 35%

Rate < 6%

Comments Based on bladder cancer treatment. Variations in bladder size/shape/ location during RT hamper ability to generate accurate data.

All at standard fractionation (i.e., 1.8-2.0 Gy per daily fraction). All data are estimated from the literature summarized in the QUANTEC reviews and in this chapter. Clinically, these data should be applied with caution. Clinicians are strongly advised to use the individual QUANTEC articles to check the applicability of these limits to the clinical situation at hand. They largely do not reflect modern IMRT. 3DCRT, Three-dimensional conformal radiotherapy; 3DRT, three-dimensional conformal radiotherapy; BED, biologically effective dose; Dmax, maximum radiation dose; Dx, minimum dose received by the “hottest” X% (or X ccs) of the organ; IMRT, intensity-modulated radiation therapy; RILD, radiation-induced liver disease; RT, radiotherapy; TBI, total body irradiation; Vx, volume of the organ receiving ≥ X Gy.

brachytherapy, reirradiation, and/or hypofractionated radiation, particularly in the context of hypofractionated stereotactic body radiation and stereotactic radiosurgery. The AAPM initiatives for hypofractionated tumor and tissue effects in the clinic (HYTEC) will focus on hypofractionated stereotactic radiation, a topic that is also reviewed elsewhere.3,4 A separate initiative is underway addressing quantitative dose-volume relationships for pediatric cancer survivors (PENTEC). This chapter will primarily focus on studies relating 3D dose-volume metrics to clinical outcomes in adults treated with conventionally fractionated radiation.

NERVOUS SYSTEM: BRAIN Organ Function and Clinical Significance The structural and functional complexity of the brain puts this organ at risk for a spectrum of radiation-associated toxicities. Some specific functions of the brain can be correlated with discrete location(s) within the brain, whereas others are spread throughout the brain. Primary toxicity endpoints include frank brain necrosis with associated symptoms or signs and neurocognitive decline.

Dose-Volume Data Prospective studies in adults have shown that partial (and limited) brain irradiation in the dose range of 50 to 60 Gy causes minimal to no discernible effect on memory and cognition.5–10 However, another study has suggested that patients undergoing partial brain radiation for low-grade glioma versus patients that do not undergo radiation are at greater risk for neurocogntive deficits, particularly attention, executive functioning, and information processing.11 More detailed studies correlating neurocognition with susceptible regions within the brain are needed. The volume of irradiated brain seemingly affects the degree of radiation-associated neurocognitive decline (with whole-brain radiation faring worse).12 The degree to which brain radiation (versus other factors, such as surgery, a history of hydrocephalus, other chronic diseases and comorbid illnesses, chemotherapy exposure, and tumor progression) impacts neurocognitive function is not clear.10,13,14 Chemotherapy-induced cognitive impairment (colloquially referred to as “chemo-brain”) is becoming better characterized.15,16

There has been growing interest in the hypothesis that minimizing radiation dose to the hippocampal and/or subventricular zone stem cell niches, which are involved in neurogenesis, can reduce the risk of neurocognitive deficits.17 However, it is not known if there are particularly critical individual avoidance structures (or regions) or a combination of avoidance structures, nor whether there are welldefined dose-volume thresholds and what these dose-volume limits might be. Identifying correlates of dosimetric exposure to putative neuroanatomic structures to cognitive outcomes remains an active area of investigation.18 In the RTOG (Radiation Therapy Oncology Group) 0933 Phase II study of hippocampal sparing (100% dose and maximum dose to not exceed 10 Gy and 17 Gy, respectively) in 113 patients with brain metastases, memory preservation at 4 and 6 months (measured by the Hopkins Verbal Learning Test Delayed Recall) was significantly better than historical controls.19 In a study of 75 patients with pituitary adenoma, 30 of whom had undergone 3- to 5-field pituitary irradiation to a dose of 45 Gy, neither hippocampal dose nor prefrontal cortex dose correlated with cognitive outcomes.20 The NRG studies, randomizing patients to receive hippocampal sparing or standard brain radiation, are accruing patients undergoing prophylactic brain radiation for small-cell lung cancer (NCT02635009) and patients undergoing therapeutic whole-brain radiation for brain metastases (NCT02360215). Radiation necrosis can occur in any part of the brain. While there may be regional variations of susceptibility within the brain related to differences in vascularity, glial cell population, and so on, this data is sparse. Thus, it is generally believed that location does not generally affect susceptibility to necrosis. However, certain regions, such as the brainstem, are more likely to cause symptoms. There is a paucity of data correlating dose-volume parameters with the risk of radiation necrosis with conventional fractions, though many studies have documented an association of fraction size with the risk of necrosis. In a study from Queen Elizabeth Hospital in China, 1008 patients with nasopharyngeal cancer treated prior to 1985 received 45.6 to 53.2 Gy in 3.8 Gy fractions, 50.4 Gy in 4.2 Gy fractions or 60 Gy in 2.5 Gy fractions.21 The 10-year risk of temporal lobe necrosis was 18.6% in those treated with 4.2 Gy fractions versus less than 5% for the other dose schemes (p < 0.001). A multi-institutional Chinese study examined

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1032 patients with nasopharyngeal cancer treated after 1990 with one of several fractionation schemes (mostly 2.0-3.5 Gy fractions, though one scheme used a 1.6-Gy twice-daily component).22 The 5-year actuarial incidence of necrosis ranged from 0% (after 66 Gy in 2-Gy fractions) to 14% (after 2.5 Gy × 8 followed by 1.6 Gy twice daily to 71.2 Gy). In both of the studies mentioned earlier, the product of total dose and dose per fraction significantly impacted risk; shorter overall treatment time and twice-daily fractionation also increased risk. A Chinese study comparing the 71.2 Gy in 1.6-Gy twice-daily fractions versus 60 Gy in 2.5-Gy fractions was terminated early owing to excessive neurological toxicity, including temporal lobe toxicity, in both arms. The risk of toxicity was greater and the interval to developing toxicity was shorter with the twice-daily regimen.23 In another Chinese study, 27% of patients receiving an accelerated hyperfractionated regimen (64 Gy in 1.6-Gy twice-daily fractions) versus 0% receiving hyperfractionated radiation (70.8 Gy in 1.2-Gy twice-daily fractions) developed symptomatic radiation necrosis.24 Radiation necrosis has also been studied in patients with primary brain tumors. The risk is dose dependent, with doses of less than 50 Gy rarely causing necrosis.25–27 In patients treated for brain metastases, there was a low (< 2%) risk of necrosis developing after 1.6 Gy twice daily to the whole brain (32 Gy) followed by a boost to 54.4 to 74.4 Gy, and no necrosis was seen after a boost to 48 Gy.28,29

Summary and Other Key Points From QUANTEC Review30 A high level of evidence to quantify the risks of radiation-induced brain injury is lacking. For brain necrosis, the brain appears to be especially sensitive to fraction size in excess of 2 Gy and to twice-daily fractionated treatment. Symptomatic necrosis is uncommon with doses less than 60 Gy with conventional (1.8-2 Gy) fractionation, though the risk increases with increasing dose (see Table 18.1). More detailed studies correlating neurocognition with susceptible regions within the brain are needed. Long-term (> 5 years) follow-up is necessary to best assess neurological/cognitive decline. For children, younger age and higher whole-brain dose strongly correlate with cognitive decline. Future studies should provide a clear definition of toxicity and report actuarial (as opposed to crude) rates that can be correlated with detailed normal brain dose-volume metrics.

NERVOUS SYSTEM: BRAINSTEM Organ Function and Clinical Significance The brainstem serves as a conduit from the brain to the cranial nerves and spinal cord. As a result, the brainstem is involved with motor, sensory, and special sensory function, as well as regulation of temperature, cardiac function, respiratory function, and consciousness. It is well accepted that the entire brainstem may be treated with 54 Gy using conventional fractionation with minimal risk of late brainstem toxicity. Small volumes of brainstem may tolerate higher doses. Similar to the brain, the brainstem is a very heterogeneous organ, and it is not clearly known which regions are most susceptible to radiation-induced damage. Complicating this matter are uncertainties about the radiobiological differences (relative biological effectiveness [RBE]) between photons and protons where the linear energy transfer (LET) differs within the distal segments of the spread out Bragg peak.31,32

Dose-Volume Data Several institutions have published their dose-volume constraints for the brainstem, most of which have not reported any brainstem toxicity. These constraints for patients undergoing external beam radiation therapy for head and neck cancer include V60 < 5 mL, V65 < 3 mL,33

V55 < 0.1 mL,34 D1 < 54 Gy,35 and maximum < 50 Gy36; for patients undergoing proton or combined proton/photon therapy for base of the skull lesions, the constraints include < 63-64 Gy CGE to the brainstem surface and 53-54 CGE to the brainstem center.37–40 Some patients in these studies received a maximum brainstem dose of 66 to 68 CGE (greater than the recommended constraints) in order to adequately treat the tumor.37,39,40 In one study, the dose constraint of 63 CGE to the brainstem surface and 54 CGE to the brainstem center was “relaxed” in 38% and 17% of patients, respectively, with no reported neurological toxicity. In these patients, the volume receiving more than the threshold dose was 0.2 mL and 1.2 mL for the brainstem surface and center, respectively.39 In another study, 2 of 4 patients developing neurological toxicity received brainstem maximal doses in excess of 64 Gy CGE to the surface and 53 CGE to the center.40 In an analysis of 367 patients from Massachusetts General Hospital, an increased risk of late toxicity was associated with the maximal delivered dose (> 64 CGE), V50 (> 5.9 mL), V55 (> 2.7 mL), V60 (> 0.9 mL), history of diabetes, hypertension, and ≥ 2 surgical procedures of the base of skull on univariate analysis.41,42 On multivariate analysis, only V60, history of diabetes, and ≥ 2 surgical procedures remained significant. A V60 < 0.9 mL versus > 0.9 mL resulted in toxicity-free survival of 96% versus 79% (p = 0.0001), and on multivariate analysis resulted in an 11.4 risk ratio (p = 0.001). In a recent study of 216 pediatric patients with posterior fossa tumors treated with proton therapy, 5 developed brainstem injury; the authors predict that a Dmax < 55.8 Gy RBE and V55 < 6.0% would result in < 2% risks.31 In a study of 40 patients undergoing IMRT for meningioma, one patient developed fatal brainstem necrosis after receiving a maximum dose to the brainstem of 55.6 Gy, with 4.74 mL exceeding 54 Gy.43 This demonstrates that other poorly understood factors likely increase the risk of brainstem toxicity, as this dose constraint would be considered acceptable in most of the studies referenced earlier.

Summary and Other Key Points From QUANTEC Review44 Investigating radiation-induced brainstem injury is challenging because of the low incidence of toxicity with conventional doses, the short survival of patients, and the challenges of distinguishing between tumor progression and toxicity. Whole brainstem doses < 54 Gy appear to be safe. Small volumes of brainstem appear to tolerate doses in excess of 55 to 60 Gy. The risk of brainstem necrosis is low if the volume receiving > 60 Gy is < 0.9 mL. One proton therapy study predicts a 5-year rate of radiation brainstem injury < 2% with Dmax and V55 < 55.8 Gy RBE and ≤ 6.0%, respectively.

NERVOUS SYSTEM: SPINAL CORD Organ Function and Clinical Significance The spinal cord consists of the motor and sensory tracts, communicating information between the peripheral nerves and the brain. Radiationinduced spinal cord injury can result in pain, paresthesias, sensory deficits, paralysis, Brown-Séquard syndrome, and bowel/bladder incontinence.

Dose-Volume Data It is well accepted that the spinal cord can well tolerate 45 to 50 Gy with conventional fractionation, though the TD5 is most likely much higher. The spinal cord is generally limited to 45 to 50 Gy, since the anticipated risk of cord injury must be very low to be clinically acceptable. In an analysis of several studies, Schultheiss calculated the probability of cervical cord myelopathy after full cross-sectional irradiation as 0.03%

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CHAPTER 18 after 45 Gy, 0.2% after 50 Gy, and 5% after 59.3 Gy.45 The thoracic spinal cord was calculated to be less sensitive than the cervical spinal cord (though, because of the dispersion of data, a good fit could not be obtained). This model does not incorporate spinal cord volume, which might be acceptable given the “series” nature of the cord. Nevertheless, Schultheiss cautions that long lengths of cord, concomitant chemotherapy, and other factors may increase risk.45 Little data exists exploring the dose-volume tolerance of the spinal cord. No spinal cord toxicity was reported in a study in which the V50 was < 0.1 mL34 nor in another study in which the D1 was < 45 Gy.35 Massachusetts General Hospital studied 85 patients undergoing cervical spinal cord treatment in the range of 45 to 59.4 Gy (1.5 Gy equivalent fractions) EUD, 42 to 57.5 Gy maximal dose to cord center, and 57 to 74 Gy maximal dose to cord surface.46 Of these patients, 15% experienced Lhermitte syndrome (self-limited symptoms of electric shock–like sensation most notable with neck flexion, attributable to focal demyelination), and 5% developed objective neurological findings at or below the cord level treated. Toxicity was not significantly correlated with cord length, cord volume, maximal dose to cord center, maximal dose to cord surface, or effective uniform dose. The authors conclude that an EUD to the cervical cord of 60 Gy in 1.5-Gy fractions or 52.5 Gy in 2-Gy fractions is safe. In a study of 437 patients with laryngeal or oropharyngeal carcinoma (with maximum spinal cord dose of 22-69 Gy), none developed myelopathy (at a median follow-up 27 months), while 17 developed the Lhermitte sign; the average spinal cord V45 of these 17 patients was 14 mL versus 8 mL for those without the Lhermitte sign.47 It has been postulated that the dose to the spinothalamic tract is most clinically significant for the occurrence of the Lhermitte’s sign.48

Summary and Other Key Points From QUANTEC Review49 There is not yet a consensus on the best approach to delineating the spinal cord, with options including delineating the entire thecal sac, spinal canal, spinal cord (as seen on magnetic resonance imaging [MRI]), or spinal cord plus a several-millimeter margin. Though rare, radiation-induced spinal cord injury can be clinically devastating. With conventional fractionation of 1.8 to 2.0 Gy per fraction to the full thickness of the spinal cord, the estimated risk of spinal cord myelopathy is < 1%, < 10%, and 50% at 54 Gy, 61 Gy, and 69 Gy, respectively. While there is limited data on high dose per fraction using conventional radiation techniques, the estimated α/β ratio of 0.87 suggests a strong dependence of spinal cord toxicity on dose/fraction. Small volumes of the spinal cord can likely receive doses in excess of 55 to 60 Gy (with the high doses limited to the surface) with low risk of toxicity, though long-term data are lacking to derive a dose-volume relationship for myelopathy risk. Thus, recommendations for safe dose-volume metrics above 55 to 60 Gy are lacking.

NERVOUS SYSTEM: OPTIC NERVES AND CHIASM Organ Function and Clinical Significance The optic nerve and chiasm serve as the neural conduit connecting the retinal fibers to the optic tracts, which, via the lateral geniculate body, terminate in the visual cortex. It is well accepted that the entire optic nerves and chiasm may be treated with 54 Gy using conventional fractionation with minimal risk of late visual toxicity, though lower doses can result in other ophthalmological toxicity.50 A classic study showed that among patients treated with the same dose for pituitary adenomas or craniopharyngiomas, those who developed optic neuropathy (5-34 months after radiation) had received ≥ 2.5 Gy per fraction.51 In a study from the M. D. Anderson Cancer Center (MDACC), in which 219 patients were treated in the pre-3D radiation era, 10-year actuarial rates of optic neuropathy were 0%, 3%, and 34% for 43 to

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49 Gy at ~ 1.9 Gy/fraction, 50 to 60 Gy at ~ 2.1 Gy/fraction, and 61 to 76 Gy at ~ 2.2 Gy/fraction, respectively. Chiasm damage was similar, with rates of 0%, 8%, and 24% for 15 to 49 Gy at ~ 1.5 Gy/fraction, 50 to 60 Gy at ~ 2.0 Gy/fraction, and 61 to 76 Gy at ~ 2.1 Gy/fraction.52 Greater total dose as well as larger fraction size impact risk.53–56 With 3D planning, small volumes of optic nerve and chiasm may tolerate higher doses.

Dose-Volume Data Several institutions have published their dose-volume constraints for the optic nerves and chiasm, most of which have not reported any neurological visual toxicity. These constraints for patients undergoing external beam radiation therapy for head and neck cancer include V55 < 0.1 mL of optic nerves/chiasm,34 D1 < 54 Gy for optic nerves and D1 < 45 Gy for optic chiasm35 and maximum < 54 Gy to the optic nerves and 52 Gy for the chiasm. These dose constraints are more conservative compared with what has been reported with proton therapy for base of skull tumors; base of skull tumors may be in close proximity to the optic apparatus, and tumors such as chordomas and chondrosarcomas are prescribed relatively high doses. For patients undergoing proton or combined proton/photon therapy for base of skull lesions, published dose contraints include < 55 to 56 GGE38–40 or < 60 Gy CGE37 to optic nerves and optic chiasm. Several studies have reported ophthalmological toxicity after radiation. In a study from the University of Florida, the optic nerve dose (defined as the minimum dose delivered to one-third of the optic nerve) in patients who developed optic neuropathy was 50.4 to 79 Gy (median 68 Gy).56 In a University of Michigan study, 7 patients developed ophthalmological toxicity: 1 patient received a chiasm maximum of 59.5 Gy; 6 patients received an optic nerve maximum of 47.5 to 75.5 Gy (average 63 Gy).57 Moderate to severe optic nerve complications (4 patients) were associated with doses > 64 Gy. In one study, 4 patients developed ophthalmological toxicity, of which 3 received a maximal dose of 56 to 62 CGE to the optic chiasm/nerves and 1 received a maximum dose of > 62 CGE. In two studies, bilateral visual loss occurred, with no evidence of tumor progression, ~ 8 months after conventional radiation. In one study, the prescribed target dose was 49.3 Gy (maximum dose, 56.1 Gy; the chiasm maximum was not reported, but < 1 mL received >45 Gy)58; in the other, the chiasm maximum was < 58 CGE.38 Some patients appear to tolerate a maximum optic nerve or chiasm dose of > 60 Gy or > 63 to 69 CGE.36,37,39,40,57 This demonstrates that other poorly understood factors likely increase the risk of optic nerve and chiasm toxicity. Optic nerve maxima > 80 Gy and chiasm maxima > 70 Gy were tolerated in some patients in the University of Michigan study discussed earlier.57 In another study, the dose constraint of 56 CGE to the optic nerve and chiasm was “relaxed” in 28% and 48% of patients, respectively, with no reported visual toxicity. In these patients, the volume receiving above the threshold dose was 0.11 mL and 0.12 mL for the optic nerves and chiasm, respectively; the volume receiving > 105% of the threshold dose was 0.05 mL and 0.01 mL.39

Summary and Other Key Points From the QUANTEC Review59 Data clearly show that the total dose and fraction size are the most important treatment-related risk factors for optic nerve/chiasm injury. There is scarce data to suggest a dose-volume effect on the optic nerve and chiasm. The risk of visual problems is < 3% with < 55 Gy, 3% to 7% for 55 to 60 Gy, and > 7% for > 60 Gy. In the 55- to 60-Gy experience, almost all of the reported cases of optic nerve injury received doses in the 59- to 60-Gy range (i.e., the very high edge of that dose range).

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NERVOUS SYSTEM: HEARING Organ Function and Clinical Significance The cochlea and acoustic nerve are the essential auditory structures that are susceptible to radiation injury and consequential sensory neural hearing loss. These are small structures; therefore, dose-volume measures are less determinable and clinically relevant. Other dose-dependent susceptible parts of the auditory system include the external ear and ear canal, tympanic membrane, ossicles, and eustachian tube.60 Platinum-based chemotherapy also is a well-established cause of sensory-neural hearing loss. Other factors such as baseline function and patient age are also relevant.

Dose-Volume Data Several studies suggest that the dose to the cochlea correlates with the rate of sensory-neural hearing loss. A study from the University of Florida showed that incidence of sensory-neural hearing loss increased consistently with dose to the cochlea; the 10-year actuarial risk of sensory neural hearing loss was 3% at doses < 60.5 Gy versus 37% at doses > 60.5 Gy.60 Several other studies have shown hearing loss to be directly related to the inner-ear dose,61–66 with sensory neural hearing loss becoming more apparent at doses > 45 to 50 Gy.62,64,65,67 A German study examined hearing loss during and after radiotherapy for head and neck cancer patients; for bone and air conduction after radiation, a 15-dB reduction in 50% of patients over a range of frequencies was in the 20- to 30-Gy range of doses to the inner ear (which ranged from 1.7 to 64.3 Gy).66 Cisplatin dose is also relevant to the threshold for auditory impairment. In one study of head and neck cancer patients, in those treated with radiation alone, hearing loss developed with cochlear doses > 40 Gy; however, among those who received cisplatin (100 or 40 mg/m2) and radiation, hearing loss developed with cochlear doses > 10 Gy,68 although the risk is likely low below doses of 30 Gy. The sequence of chemoradiotherapy also appears to influence risk. Risk and severity of ototoxicity are greater when cisplatin is administered after cranial radiation. In a study of patients with base of skull tumors treated with radiation (median, 50.4 Gy), radiographic opacification of the middle ear and/ or mastoid, which correlates with subacute/chronic otitis media with effusion, occurred in 40 of 61 patients (with median follow-up of 21 months). This resolved in 17 of 40 patients 2 to 45 months (mean, 17 months) after radiation.69 Dose-volume analyses were performed for the eustachian canal, middle ear, mastoid air cells, vestibular apparatus, cochlea, internal auditory canal, lateral and posterior nasopharynx, and temporal lobes. Multivariate analysis showed that a mastoid dose > 30 Gy (odds ratio [OR], 28.0; 95% confidence interval [CI], 5.6-140.8; p < 0.001), and a posterior nasopharynx dose > 30 Gy (OR, 4.9; 95% CI, 1.5-16.3; p = 0.009) were associated with grade 2 to grade 3 middle ear effusions.

Summary and Other Key Points From the QUANTEC Review70 Owing to the small volume of the cochlea, quantifying mean dose to the cochlea is more feasible than a dose/volume measure. Based on available data, the cochlear mean dose should be limited to ≤ 45 Gy (or, more conservatively, ≤ 30 Gy) and should be more strictly limited when delivered with cisplatin chemotherapy.

SALIVARY GLANDS Organ Function and Clinical Significance The salivary glands produce saliva, which aids in swallowing, lubricating the oral cavity, taste, and food digestion. The parotid glands generate ~ 60% of saliva and the majority of serous saliva, with the remainder of saliva secreted by submandibular, sublingual, and minor salivary

glands. Radiation-induced salivary gland dysfunction, xerostomia, can result in difficulty swallowing, altered taste, and an increased risk of dental caries and oral infections. Owing to the proximity of the parotid glands to the level 2 lymphatics, IMRT is often used in the treatment of head and neck patients to reduce the parotid dose in an attempt to prevent xerostomia.

Dose-Volume Data The University of Michigan has published several studies investigating radiation dose-volume effects on serially measured stimulated and unstimulated salivary flow (directly from a given parotid gland). With salivary flow measured up to 12 months after radiation, significant parotid sparing was observed after a mean parotid dose below 24 Gy (for unstimulated flow) to 26 Gy (for stimulated flow).71–73 Mean doses correlated with V15 of ≤ 67%, V30 of ≤45%, and V45 of ≤ 24%. The 50% tolerance dose (TD50) was 28.4 Gy. Washington University also examined whole salivary flow. Their technique differed from that of the University of Michigan in that they measured flow from all glands, though they included only patients whose submandibular glands receiving > 50 Gy in an attempt to minimize this confounding variable.74,75 In an update, salivary flow was noted to be exponentially reduced by ~ 0.054/Gy of mean parotid dose, that is, e(−0.054* mean dose), equal to a reduction to 25% of the pretreatment salivary flow with a mean dose of 25.8 Gy, essentially equivalent to the University of Michigan number.76 The mean dose model was more predictive of the risk of late effects than threshold dose levels of V5 to V70 as well as other models studied. Other groups have corroborated the mean dose as a significant variable impacting salivary function,77–82 with a Belgian study suggesting a lower threshold mean dose of 22.5 Gy.83 A Dutch group demonstrated the TD50 for stimulated salivary function (risk of < 25% of pretreatment rates) to improve with time, with TD50s of 34 Gy at 6 weeks to 40 Gy at 6 months, 42 Gy at 12 months, and 46 Gy at 5 years.84,85 In a University of Michigan study, with flow rates measured in 142 patients up to 24 months after radiation, salivary flow rate was modeled as a function of time.86 With mean parotid doses < 25 Gy, the model predicted salivary function recovery to pretreatment functioning at 12 months. For mean parotid doses > 30 Gy, stimulated saliva did not return to pretreatment functioning after 2 years. In the parotid-sparing intensity-modulated versus conventional radiotherapy in head and neck cancer (PARSPORT) trial, 94 patients with T1-4N0-3M0 pharyngeal squamous cell carcinoma were randomized (of whom 73 were evaluable for xerostomia).87 IMRT versus conventional radiotherapy allowed significant lowering of the ipsilateral (mean, 25.4 vs. 61.0 Gy) and contralateral (mean, 47.6 vs. 61.0 Gy) parotid dose and resulted in a significantly lower incidence of xerostomia and greater recovery of salivary function 1 and 2 years after therapy. Randomized studies of IMRT in patients with nasopharyngeal cancer have shown similar findings.88,89 In a study of 126 patients from Germany, restraining the mean dose to both parotids < 26 Gy (versus only one) significantly reduced xerostomia and dysphagia.90 Radiation dose to the submandibular glands also impacts salivary function.91 In a study from Helsinki University, mean unstimulated salivary flow was 60% of the pretreatment function among patients who had one submandibular gland spared (mean dose 26 Gy and range from 21 to 34 Gy) and 25% among those who did not (p = 0.006).92 However, sparing of a submandibular gland did not affect the stimulated saliva flow rates. Another study showed that intentional sparing of submandibular glands (average mean dose 20.4 Gy and V30 of 14.7%) versus no submandibular gland sparing (average mean dose 57.4 Gy and V30 of 99.8%), resulted in a nonsignificant trend toward better recovery of salivary flow.93 VU University has demonstrated that mean

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CHAPTER 18 submandibular dose is a significant variable impacting the sensation of sticky saliva.94 In addition to submandibular dose and parotid gland dose, the University of Michigan group showed that oral cavity dose (containing the minor salivary glands) is also predictive; while no well-defined thresholds were observed, an oral cavity mean dose of < 40 Gy was associated with low xerostomia rates.95 The RTOG 0244 study demonstrated the feasibility and efficacy of surgically transferring the submandibular salivary gland to the submental space and shielding (> 70%) of this gland during radiation in order to mitigate xerostomia.96 NTCP modeling of 178 patients treated with IMRT showed that baseline salivary function and mean contralateral parotid gland dose were predictors for xerostomia and that mean contralateral submandibular gland dose, mean sublingual dose, and mean dose to minor salivary glands in the soft palate were predictive for sticky saliva.97,98

Summary and Other Key Points From QUANTEC Review99 Several studies have effectively demonstrated a dose-response relationship between the salivary flow and mean parotid dose. From the available data, it appears that severe long-term salivary dysfunction (generally defined as reduction of salivary flow to < 25% of baseline) can be avoided if one parotid gland is spared to a dose of < 20 Gy or if both parotid glands have a mean dose of < 25 Gy. A clinical study confirmed that adherence to these guidelines effectively avoids xerostomia.100 Much of the data on submandibular gland and minor salivary gland dosevolume effects discussed earlier were published recently, after QUANTEC was published.

LARYNX AND PHARYNX Organ Function and Clinical Significance The larynx and pharynx are involved with phonation and swallowing, respectively. Late complications include laryngeal edema and fibrosis, laryngeal dysfunction, dysphagia, and necrosis. A study from the University of Michigan showed that damage to the pharyngeal constrictors and the glottic and supraglottic larynx may cause dysphagia and aspiration after chemoradiation.101

Dose-Volume Data: Larynx For laryngeal edema, in a study from the University of Texas, Galveston (with most patients receiving radiation alone), the mean laryngeal dose and laryngeal V30 to V70 were significantly associated with grade 2 or higher edema with a univariate analysis, while mean laryngeal dose and N stage were significant with multivariate analysis.102 V50, which was highly correlated with mean laryngeal dose, was significant in a multivariate analysis in which mean laryngeal dose was replaced by V50. The 1-year rate of grade 2 or higher edema was 20% after a mean laryngeal dose of 43.5 Gy (or V50 < 27%) versus 45% after a mean dose of 44 to 57 Gy (or 94% < V50 > 27%) versus > 80% after a mean dose > 57 Gy (or V50 > 94%). There is a paucity of data correlating dose-volume metrics with vocal dysfunction. Generally, after therapeutic doses of 60 to 66 Gy for early-stage glottic cancer, the risks of vocal dysfunction are low. In a study from the University of Iowa, point doses in excess of 66 Gy to the aryepiglottic folds, preepiglottic space, false vocal cords, and lateral pharyngeal walls resulted in a sharp increase in risk of vocal dysfunction.103

Summary and Other Key Points From QUANTEC Review104 Radiation-induced laryngeal edema is a common and expected side effect. Progressive edema and associated fibrosis105 can lead to long-term problems with phonation as well as swallowing. Tumor infiltration,

Late Effects After Radiation

299

particularly with locally advanced cancers, can cause voice and swallowing symptoms and may exacerbate radiation toxicities. To minimize risks of laryngeal edema, a larynx V50 ≤ 27% and the mean laryngeal dose ≤ 44 Gy are recommended.

Dose-Volume Data: Swallowing Several studies have investigated dose-volume metrics predictive of swallowing dysfunction, with many studies published after the QUANTEC report. In a study from the University of Michigan, mean dose to the pharyngeal constrictors was correlated to risk of aspiration.106 The risk of aspiration increased with a mean dose of > 60 Gy to the pharyngeal constrictors, and with a V40 > 90%, V50 > 80%, V60 > 70%, and V65 > 50%, and with a V50 > 50% for the larynx. Three patients who developed strictures had a pharyngeal constrictor V70 > 50%. In a study from Aarhus University, several significant correlations were found between both subjective and objective swallowing problems and DVH parameters of the base of tongue, pharyngeal constrictors, supraglottic larynx, esophageal sphincter, and glottic larynx.107 Doses < 60 Gy to the supraglottic region, larynx, and upper esophageal sphincter resulted in a low risk of swallowing difficulties and aspiration. In a study from the University of Iowa, point doses to the false vocal cords, lateral pharyngeal walls, and upper esophageal sphincter were correlated with dietary restrictions.103 As an example, the dose to the left lower pharyngeal wall for patients who had no oral intake 1 year after treatment was 79.7 Gy versus 65.1 Gy for those with an unrestricted diet. A greater radiation dose to the aryepiglottic folds was associated with greater weight loss, and a great radiation dose to the false vocal cords was associated with gastrostomy-tube use. In a study from Rotterdam, doses > 50 Gy to the middle and superior pharyngeal constrictors resulted in a 20% probability of dysphagia, with an incremental 19% risk for each additional 10 Gy.108 Another study (39 patients) suggested that the dose (V60-V65 and mean) to the inferior pharyngeal constrictors is most predictive of gastrostomy-tube dependence,109 while in two other studies (50 and 53 patients),110,111 the V50 (one study) and mean dose (both studies) of the middle pharyngeal constrictors were most predictive of dysphagia, along with mean supraglottic larynx dose (one study).111 In an analysis of 96 patients from the Dana-Farber Cancer Institute, the inferior pharyngeal constrictor V50 and larynx V50 were significantly associated with aspiration and stricture risk.112 MDACC recommends a V30 < 65% and V35 < 35% for anterior oral cavity and V55 < 80% and V65 < 30% for superior pharyngeal constrictors, which was predictive for swallowing dysfunction in 31 patients.113 UAB recommends V60 < 24% to the larynx and < 12% to the inferior pharyngeal constrictors to reduce risk of aspiration and gastrostomy-tube dependence, V65 < 75% to the middle pharyngeal constrictors, and < 33% to the superior pharyngeal constrictor to reduce risk of stricture requiring dilation.114 In a Nordic study of 354 patients,115 mean dose to the superior pharyngeal constrictor and supraglottic larynx were most predictive of radiation-induced swallowing dysfunction; different models (resulting in different significant dosimetric variables) were developed specifically for dysphagia to liquids, soft foods, or solids. An analysis based on 53 of 189 patients who developed grade ≥ 3 dysphagia designed a predictive model by analyzing clinicopathological, treatment, and dosimetric parameters (dose to pharyngeal constrictor and esophageal structures) as well as genetic polymorphisms. The best model incorporated concurrent chemotherapy, dose to 2% of the pharyngeal constrictors and the XRCC1 polymorphism.116

Summary and Other Key Points From QUANTEC Review104 Because swallowing is complex, involving voluntary and involuntary stages coordinated through several cranial nerves and muscles, defining

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the most important anatomic structures whose dose-volume parameters have a major impact on dysphagia has been challenging. Emerging data has demonstrated significant correlations between pharyngeal constrictor doses and dysphagia. With limited available data, it is recommended to limit the volume (to the extent possible without compromising target coverage) of the pharyngeal constrictors and larynx receiving ≥ 60 Gy, and reducing when possible the volume receiving ≥ 50 Gy. From data published after the QUANTEC review, it is readily apparent that mean dose and dose in excess of 50 to 60 Gy to the larynx and pharyngeal constrictor muscles are predictive of swallowing difficulties, though it is unclear which of the pharyngeal constrictor muscles and which component(s) of the larynx are most critical.

LUNG Organ Function and Clinical Significance The lung’s main function is gas exchange—of oxygen and carbon dioxide. Radiation damage to the lung can result in symptomatic pneumonitis and fibrosis. Symptomatic radiation pneumonitis is characterized by dyspnea, cough, and sometimes a low-grade fever, typically occurring several weeks to months after radiation. More long-term lung fibrosis can lead to respiratory insufficiency. It is often challenging to distinguish radiation-related pulmonary symptoms from comorbid illnesses (e.g. exacerbation of COPD, infection, cardiac events).117 Objective reductions in the lung’s ability to move and exchange gas can be measured by formal pulmonary function tests (PFTs). Recent systematic reviews, pooled analyses, and meta-analyses have shown that patient-related adverse risk factors for radiation pneumonitis among non–small cell lung carcinoma (NSCLC) and breast cancer118 patients include older age,118–120 history of chronic lung disease or diabetes,121 and low preradiotherapy lung function.121 Smoking was an adverse risk factor in one meta-analysis,121 while not being an active or prior smoker was an adverse risk factor in others,118,119 a discrepancy which is attributed to the complexity of the relationship between smoking, chronic lung disease, and pneumonitis.121 Chemotherapy concurrent

TABLE 18.2

Lung Toxicity

with radiation therapy,121 particularly carboplatin/paclitaxel chemotherapy,120 has been reported to increase the pneumonitis risk. A 2014 study of 369 NSCLC patients also demonstrated increased risk of pneumonitis with cisplatin/docetaxel versus cisplatin/vinorelbine.122 Cytokines appear to play a role (at least perhaps as a marker and maybe as a mediator) in the development of clinical radiation pneumonitis. Seminal work implicates transforming growth factor-β (TGFβ).123,124 A powerful association between native circulating interleukin-1 (IL-1) and IL-6 levels and radiation pneumonitis have been reported by the University of Rochester.125 A French study has also shown a correlation between circulating levels of IL-10 and IL-6 and the development of radiation pneumonitis.126 Nevertheless, the literature reports in this area are not totally consistent. Cytokines may not be important for pulmonary fibrosis.127 More recent data have also demonstrated pneumonitis risks correlated with polymorphisms of DNA repair128–130 and TGF-β131 genes correlating with pneumonitis risks. Positron emission tomography (PET) avidity of lung tissue after radiation has also been correlated with pneumonitis risk.132

Dose-Volume Data: Pneumonitis and Fibrosis Several dosimetric parameters have been shown to be associated with the risk of radiation pneumonitis, including V5 to V70, mean lung dose (MLD), and model-based parameters.133–137 These variables are correlated with each other, accounting for the fact that in most studies examining a range of Vx variables, many/most are significant.138–152 The dosimetric parameters predictive of pneumonitis can also be used to predict fibrosis risks.127 How normal lung is defined (i.e., lung minus gross target volume [GTV] or planning target volume [PTV]) will affect the magnitude of the calculated dose-volume metrics.153 Table 18.2 summarizes select studies discussed later. Most of the published dose-volume data describes pneumonitis risks in lung cancer patients, though data also exists for breast cancer141,154,155 and Hodgkin lymphoma patients.156,157 In Hodgkin lymphoma patients, pneumonitis risks appear to be lower for given dose-volume metrics that may relate to the younger age of this patient population. From a 2015 study of

Summary of Selected Studies Analyzing Dose-Volume Parameters Predictive of

Author, Year (Center)

Patient Population

Endpoint

Subgroup

Seppenwoolde et al., 2003 (van Leeuwenhoek Hospital)141

Breast cancer, lymphoma Non–small cell lung cancer

Radiation pneumonitis

MLD = 31.8 Gy

50% (NTCP)

V13 = 77%

50% (NTCP)

V20 = 65%

50% (NTCP)

MLD = 25 Gy

50% (NTCP)

Yorke et al., 2002 (MSKCC)139

Non–small cell lung cancer

Acute grade ≥ 3 pulmonary toxicity

Toxicity Rate

MLD = 12 Gy

5% (NTCP)

V13 = 42%

20% (NTCP)

V13 (ipsilateral lung) = 80%

50% (NTCP)

V13 (ipsilateral lung) = 62%

20% (NTCP)

V13 (ipsilateral lung) = 40%

Armstrong et al., 1997 (MSKCC)160

Non–small cell lung cancer

Graham et al., 1999 (Washington University)133

Non–small cell lung cancer

Acute grade ≥ 3 pulmonary toxicity Grade ≥ 3 radiation pneumonitis

5% (NTCP)

V40 (lower lung) = 32%

50% (NTCP)

V13 (lower lung) = 36%

20% (NTCP)

V25 > 30%

38%

V25 < 30%

4%

V20 > 40%

36%

V20 = 32%-40%

13%

V20 = 22%-31%

7%

V20 < 22%

0

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CHAPTER 18

301

Late Effects After Radiation

Summary of Selected Studies Analyzing Dose-Volume Parameters Predictive of Lung Toxicity—cont’d

TABLE 18.2

Author, Year (Center) Hernando et al., 2001 (Duke University)138

Tsujino et al., 2003 (Hyogo Medical Center)161

Patient Population Non–small cell lung cancer Small cell lung cancer

Non–small cell lung cancer

Endpoint Grade ≥1 radiation pneumonitis

Grade ≥ 2 radiation pneumonitis

Non–small cell lung cancer

Wang et al., 2006 (MDACC)146

Non–small cell lung cancer

Grade ≥ 3 radiation pneumonitis

Koh et al., 2006 (Princess Margaret Hospital)156

Hodgkin lymphoma

Grade ≥ 2 radiation pneumonitis

Schallenkamp et al., 2007 (Mayo Clinic)151

Non–small cell lung cancer Small cell lung cancer

Mazeron et al., 2010 (University of Lyon)127

Ramella et al., 2010a (Rome, Italy)152

Non–small cell lung cancer

Non–small cell lung cancer

Toxicity Rate 24%

V30 < 18%

Kong et al., 2006 (University of Michigan)162

a

Subgroup V30 > 18%

Grade 2 radiation pneumonitis

Grade ≥ 2 radiation pneumonitis

Radiation fibrosis

Grade ≥ 2 radiation pneumonitis

6%

MLD < 10 Gy

10%

MLD 10-20 Gy

16%

MLD 21-30 Gy

27%

MLD > 30 Gy

44%

V20 ≤ 20%

9%

V20 = 21%-25%

18%

V20 = 26%-30%

51%

V20 ≥ 31%

85%

V20 > 30%

10%

MLD > 20 Gy

10%

V5 ≤ 42%

3%

V5 > 42%

38%

V20 > 40%

25%

V20 ≤ 40%

0%

V10 = 32%-43%

10%-20%

V13 = 29%-39%

10%-20%

V15 = 27%-34%

10%-20%

V20 = 21%-31%

10%-20%

V10 < 33%

11%

V20 < 18%

13%

V30 < 13%

14%

V40 < 10%

14%

V50 < 5%

13%

V10 > 33%

26%

V20 > 18%

24%

V30 > 13%

23%

V40 > 10%

23%

V50 > 5%

24%

Ipsilateral V20 ≤ 52%

9%

Ipsilateral V30 ≤ 39%

8%

Ipsilateral MLD ≤ 22 Gy

a

Fox et al., 2012 (Brigham and Women’s Hospital)157 Palma et al., 2013 (Meta-analysis)120

a

Hodgkin lymphoma

Grade ≥ 2 radiation pneumonitis

7%

Ipsilateral V20 > 52%

46%

Ipsilateral V30 > 39%

38%

Ipsilateral MLD > 22 Gy

23%

V20 ≥ 33.5%

21%

V20 < 33.5%

Non–small cell lung cancer

Non–small cell lung cancer

Grade ≥ 2 radiation pneumonitis

Fatal (grade 5) radiation pneumonitis

2%

MLD > 13.5 Gy

19%

MLD < 13.5 Gy

4%

V20 < 20%

18.4%

V20 = 20% to < 30%

30.3%

V20 = 30% to < 40%

32.6%

V20 > 40

35.9%

V20 < 20%

0%

V20 = 20% to < 30%

1.0%

V20 = 30% to < 40%

2.9%

V20 > 40

3.5% Continued

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Summary of Selected Studies Analyzing Dose-Volume Parameters Predictive of Lung Toxicity—cont’d

TABLE 18.2

Author, Year (Center) Pinnix et al., 2015a (MDACC)158

Patient Population Hodgkin lymphoma, non-Hodgkin lymphoma

Endpoint Grade ≥ 1 radiation pneumonitis

Subgroup V5 < 55%

Toxicity Rate 20%

V10 < 40%

26%

V15 < 35%

18%

V20 < 30%

12%

V25 < 23%

22%

MLD < 13.5 Gy

7%

V5 > 55%

67%

V10 > 40%

62%

V15 > 35%

52%

V20 > 30%

38%

V25 > 23%

57%

MLD > 13.5 Gy

43%

a

Published after QUANTEC review. MDACC, M. D. Anderson Cancer Center; MLD, mean lung dose; MSKCC, Memorial Sloan Kettering Cancer Center; NTCP, normal tissue complication probability modeling.

150 Hodgkin and non-Hodgkin lymphoma patients, mean lung dose of > 13.5 Gy, V20 > 30%, V15 > 35%, V10 > 40%, and V5 > 55% were significantly correlated with grade 1 to grade 3 pneumonitis risks.158 An NTCP analysis from the Netherlands, in collaboration with the University of Michigan, suggests that using the MLD (linear function) is more predictive than using VX (step function).141 However, V13 tended to be more predictive in situations in which the MLD exceeded 20 Gy or V13 exceeded 50%. The TD50 values in this study were MLD 30.8 Gy, V13 > 77% and V20 > 65%, similar to the MLD of 31.8 Gy reported in an earlier multi-institutional study.159 From an NTCP analysis from the Memorial Sloan Kettering Cancer Center (MSKCC),139 a mean lung dose of ~ 26 Gy, V13 > 80% to the ipsilateral lung or V40 > 32% to the lower lung results in a 50% risk of developing late complications. A mean lung dose of ~ 12 Gy or a V13 > 40% to the ipsilateral lung results in a 5% late complication risk. A V13 of 36% of the lower lung, 42% of the total lung, or 62% of the ipsilateral lung results in a 20% risk of developing late grade ≥ 3 complications. In a 1997 study from MSKCC, of patients treated with radiation alone, they showed a significantly increased risk of grade ≥ 3 pulmonary toxicity, 38% with V25 > 30% versus 4% with V25 < 30% (p = 0.04).160 In subsequent studies from this same group, significant variables for predicting grade ≥ 3 pulmonary toxicity include mean lung dose, the range of V5 to V40 of total lung, V5 to 40 of the ipsilateral lung, and V5 to V50 of the lower lung.139,144 The range V5 to V20 for the ipsilateral lung was most predictive. Investigators at Washington University also showed that the risk of pneumonitis significantly correlated with the V20; the 2-year incidence of grade ≥ 2 radiation was 36% versus 13% versus 7% versus 0% with V20 > 40%, 32% to 40%, 22% to 31%, and < 22% (p = 0.0013), respectively.133 In another study from Washington University, radiation pneumonitis was significantly correlated with V5 to V80, with peak significance in the V5 to V15 and V70 to V75 ranges. Radiation pneumonitis was also significantly correlated, with the dose delivered to 5% to 100% of the lung (D5-D100), with peak significance in the D30 to D40 and V90 to V95 ranges.147 In a 2001 study from Duke (in which 18% of patients received concurrent chemoradiotherapy), V30 > 18% versus < 18% was associated with a risk of grade ≥ 1 radiation pneumonitis of 24% versus 6%

(p = 0.0003).138 MLDs < 10 Gy, 10 to 20 Gy, 21 to 30 Gy, and > 30 Gy were associated with risks of 10%, 16%, 27%, and 44%, respectively. A Japanese study of patients treated with platinum-based chemoradiotherapy found a 6-month risk of grade ≥ 2 radiation pneumonitis to be 85%, 51%, 18.3%, and 8.7% (p < 0.0001) with V20 ≥ 31%, 26% to 30%, 21% to 25%, and ≤ 20%, respectively.161 In a University of Michigan study, a 10% risk for grade ≥ 2 pneumonitis and fibrosis was associated with V20 > 30% and MLD > 20 Gy. These thresholds provided a positive predictive value of 50% to 71% and a negative predictive value of 85% to 89%.162 In a study from MDACC, the mean lung dose and V5 to V65 were highly correlated with risk of pneumonitis, and V5 was the most significant factor in a multivariate analysis.146 For a V5 ≤ 42% versus > 42%, the risk of grade ≥ 3 pneumonitis at 1 year was 3% versus 38% (p = 0.001). In a Mayo Clinic study, V10 to V13 were most predictive of radiation pneumonitis; a V10 = 32% to 43%, V13 = 29% to 39%, V15 = 27% to 34%, and V20 = 21% to 31% resulted in a 10% to 20% risk of pneumonitis.151 From a meta-analysis of 836 patients, lung V20 < 20%, 20% to < 30%, 30% to < 40%, and > 40% were associated with symptomatic pneumonitis risks of 18.4%, 30.3%, 32.6%, and 35.9%, respectively, and fatal pneumonitis risks of 0%, 1.0%, 2.9%, and 3.5%, respectively.120 Several dose escalation studies have used V20, Veff, and/or NTCP to allocate patients into given dose levels.163–166 In the RTOG 93-11 doseescalation study, patients with a V20 < 25% experienced a 7% to 16% 18-month actuarial rate of grade ≥ 3 late lung toxicity with prescribed doses of 70.9 to 90.3 Gy; the absolute risk of grade ≥ 2 late lung toxicity was 30% to 45%, with one fatal lung complication at the 90.3-Gy dose level. Patients with a V20 of 25% to 36% treated to doses of 70.9 to 77.4 Gy experienced 15% grade ≥ 3 late toxicity at 18 months and an absolute risk of grade ≥ 2 late lung toxicity of 40% to 60%.163 D15 was the most predictive variable for radiation pneumonitis.150 In a Dutch study, the effect of a regional dose on the lung was investigated, with the lung divided into central and peripheral, ipsilateral and contralateral, caudal and cranial, and anterior and posterior subvolumes.167 The mean regional dose to the posterior, caudal, ipsilateral, central, and peripheral lung subvolumes significantly correlated with the incidence of steroid-requiring radiation pneumonitis; caudal location was correlated with greater pneumonitis risks, while no statistical

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CHAPTER 18 difference in risks was observed between anterior and posterior locations or central and peripheral locations. In a similar study from MSKCC, the risk of radiation pneumonitis was better correlated with the radiation dose to the inferior aspect of the lung rather than the superior aspect.139 Tumor location in the lower lung also appears to be an adverse factor affecting risk of pneumonitis in lung cancer patients.119–121 In the study from Washington University discussed earlier,147 inferior tumor location was the most significant predictor of radiation pneumonitis. Tumor location was not a strong correlate to radiation pneumonitis in a study from patients treated in the RTOG 93-11 trial, perhaps attributable, in part, to differences in treatment (with RTOG 93-11 designed to treat smaller volumes to higher doses) and differences in tumor size and location (the RTOG 93-11 tumors tended to be smaller and more superiorly located).150 Using a combined data set of patients from RTOG 93-11 and Washington University, tumor location, in addition to MLD, was significant. In a Washington University study of 209 patients, cardiac dose, specifically V65 and D10, was more predictive of radiation pneumonitis than lung dose-volume metrics; the reason is unknown and the authors demonstrate that heart variables are not simply surrogates for lung variables.168 For some patients with advanced stage NSCLC, IMRT yields unique dose distributions, with improved target conformality and increased (albeit modest) target heterogeneity.169 The IMRT-based dose distributions appear to reduce the risk of normal tissue injury in patients with NSCLC. Investigators at MDACC compared their rates of lung toxicity in patients treated with IMRT versus 3D planning and noted a reduction in toxicity with the IMRT approach.170 Investigators at MSKCC noted a similarly low rate of clinical lung injury in patients with NSCLC treated with IMRT.171 In the MDACC study, a V5 > 70% was associated with a 21% risk of grade ≥ 3 pneumonitis versus a 2% risk with a V5 ≤ 70% (p = 0.017). Proton therapy also allows for reduction of lung volume receiving a given dose, and data are emerging on its utility. IMRT has also been used to treat patients with mesothelioma. In a study from the Dana-Farber Cancer Institute, in which patients received thoracic IMRT after pneumonectomy for mesothelioma, 6 of 13 patients developed fatal pneumonitis.172 The median V20, V5, and MLD for patients who developed pneumonitis was 17.6%, 98.6%, and 15.2 Gy, respectively, versus 10.9%, 90%, and 12.9 Gy for those who did not develop pneumonitis. While these differences were not significant, the severity of the toxicities merits caution in treating patients to large volumes after a pneumonectomy. In a study from Duke, 1 of 13 patients treated with IMRT for mesothelioma died from pneumonitis, and 2 others developed symptomatic pneumonitis.173 The median V20, V5, and MLD for patients who developed pneumonitis was 2.3%, 92%, and 7.9 Gy, respectively, versus 0.2%, 66%, and 7.5 Gy for those who did not develop pneumonitis, versus 6.9%, 92%, and 11.4 Gy for the patient who developed fatal pneumonitis. In a study of mesothelioma patients from MDACC, 6 of 63 patients died from pulmonary-related causes (including 2 patients with fatal pneumonitis).174 The V20 was significant on univariate and multivariate analyses (p = 0.017), with a V20 > 7% corresponding to a 42-fold increase in the risk of pulmonary death.

Summary and Other Key Points From the QUANTEC Review175 A variety of studies note a dose-response relationship for a variety of metrics predictive of radiation pneumonitis. The QUANTEC review pooled the data from many centers. This shows that there is no specific threshold for pneumonitis, with risks increasing gradually with increased dose. Since many dose/volume parameters of the lung (i.e., V5 through V30, MLD) are correlated with each other, there likely is not an “optimal” parameter. For patients with NSCLC, it is prudent to limit the V20 to

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< 30% to 35%, and the mean lung dose to < 20 to 23 Gy in order to limit the risk of pneumonitis to < 20%. In patients irradiated postpneumonectomy for mesothelioma, it is prudent to limit the V5 to < 60%, the V20 to < 4% to 10%, and the mean lung dose to < 8 Gy. Radiation-induced pneumonitis appears more commonly in patients with lower- versus upper-lobe tumors and may be better correlated with radiation doses to the lower versus upper lung. The cause of this correlation is presently unknown and requires further investigation. Perhaps it is related to differences in ventilation and perfusion of different lung regions.

Dose-Volume Data: Pulmonary Function The majority of studies have considered shortness of breath as the relevant endpoint. This is what is typically recorded in patient records and, from the patient’s perspective, is perhaps the most meaningful endpoint. However, symptoms can be nonspecific and difficult to quantify. Therefore, investigators have also considered more specific and objective endpoints, such as changes in PFTs and imaging. Changes in PFTs following thoracic radiation reflect a combination of improvements due to tumor shrinkage (typically acutely) and declines due to radiation-induced injury (both acute and chronic).176 Several studies have noted long-term declines in PFTs following thoracic radiation,177–179 although changes can be transient.180 The association between shortness of breath following radiation and declines in PFTs is complex.181 Duke University has shown a correlation between V30 and NTCP with changes in FEV1 (forced expiratory volume) and DLCO (diffusing capacity of the lungs for carbon monoxide).182 The University of Michigan, however, did not find any correlation of V20, MLD, or Veff with changes in FEV1 or DLCO.183 Attempts have been made to model the risk of changes in PFTs,184,185 though certainly this is a complicated area of study. Data from MDACC suggest that severity of pneumonitis is correlated with reduction in DLCO.186 Similarly, imaging tests provide clear objective metrics. Several studies have noted an association between regional radiation doses and changes in regional imaging tests (computed tomography [CT]-defined density or single-photon emission computed tomography [SPECT]-defined perfusion/ventilation).187–190 The extent/severity of these imaging changes is related to changes in global lung function (assessed as either symptoms or changes in PFTs), but the correlations are relatively weak.176,184,185,190

Summary and Other Key Points From the QUANTEC Review175 For pulmonary function, it appears that minimizing the V30 minimizes risk of decline in PFT parameters. However, as is the case with pneumonitis, other dose-volume measures may be predictive as well. The study of radiation-induced lung injury is confounded by the use of ambiguous endpoints as well as toxic exposures (e.g., smoking) and treatment with chemotherapy (e.g., bleomycin and cisplatinum). Many toxicity scoring systems combine radiological, functional, and symptomatic criteria in their grading system. However, each pulmonary toxicity endpoint may have different dose/volume dependence, and future studies should be explicit in defining endpoints.

HEART Organ Function and Clinical Significance The heart is the muscular organ, located in the left hemithorax (with the rare exception of dextrocardia) that, via continuous rhythmic contraction, pumps blood throughout the blood vessels. The functional and structural complexity of the heart places it at risk for a spectrum of radiation and chemotherapy injuries that can manifest months to years following therapy. All components of the heart and the surrounding

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pericardium are susceptible to radiation damage. Radiation-induced cardiac injury includes pericarditis, congestive heart failure, restrictive cardiomyopathy, valvular insufficiency and stenosis, coronary artery disease, ischemia, and infarction. A history of anthracycline chemotherapy can exacerbate radiation-related cardiac toxicity.

Dose-Volume Data Abundant studies have demonstrated an increased risk of cardiac morbidity following left-sided thoracic radiation versus right-sided thoracic radiation in patients irradiated for breast cancer. It is well accepted that reducing the dose prescribed to the mediastinum and reducing the volume of heart in the radiation field reduces the risk of late toxicity.191–193 Studies from Duke University demonstrated that an increased percentage of the left ventricle irradiated correlates with a greater risk of cardiac perfusion defects.194–196 Even over the range of low-dose exposure (~ 8-20 Gy) to small volumes of the cardiac apex, an increased risk of heart disease has been reported.197 A study from Stockholm used normal tissue complication probability modeling to predict the risk of late heart toxicity in women treated for breast cancer.198 In their models, the TD50 was optimized to a value of 52 Gy to the myocardium. A 5% risk of excess cardiac mortality at 15 years was associated with a myocardial dose of ~ 30 Gy, a V33 of > 60%, V38 of > 33% or a V42 of > 20%. Calculations using the whole heart volume (as opposed to myocardium) yielded similar values. The same group from Stockholm used a similar analysis to assess cardiac risk in Hodgkin disease patients.199 Patients were stratified into 2 risk groups: those with a V38 of > 35% and those with a V38 of < 35%. The excess mortality risk at 15 years was 7.9% and 4.7%, respectively. The TD50 was calculated to be 70 Gy. A heart dose of 42 Gy resulted in a 5% normal tissue complication probability, while a heart dose of 53 Gy resulted in a 10% normal tissue complication probability. The corresponding values in the breast cancer patients were 37 Gy and 44 Gy, respectively (lower threshold doses and steeper gradient). The differences in complication probabilities and TD50 between the breast and Hodgkin disease cohorts suggest that radiation exposure to different portions of the heart results in differences in cardiac risk,199 though there may be other confounding variables not easily identified (e.g., patient age at treatment, similar risk factors between breast cancer and cardiac disease, and so on). Mean heart dose to the left ventricle, both ventricles, or whole heart were not predictive for cardiac toxicity in a study of 328 NSCLC survivors.200 A Wayne State study of 102 esophageal cancer survivors demonstrated thresholds for symptomatic cardiac toxicity to be heart V20, V30, and V40 above 70%, 65%, and 60%, respectively.201 A landmark Swedish/Danish study analyzed 960 breast cancer survivors who experienced major coronary events and 1205 controls treated from 1958 to 2001.202 The authors showed a linear relationship with mean heart dose and coronary events, with the risk being increased by 7.4% per Gy with no apparent threshold and persisting decades after treatment. A similarly linear relationship (4.2% per Gy) was reported in a study of 2617 Hodgkin lymphoma survivors.203 The concept of no-threshold dose conflicts with our historical understanding (that “low doses” are likely inconsequential) as well as a University of Michigan study looking at myocardial perfusion scans after low-dose exposure (average heart mean dose < 5 Gy) in breast cancer patients; the authors found no correlations between cardiac doses and assessed cardiac function.204 The lack of a dose threshold might be related, in part, to the techniques used and potential differences between the planned and delivered doses (which are affected by inter- and intrafraction variations due to daily setup and motion from breathing).205 A potential criticism of the Swedish/Danish study is that radiation fields were reconstructed using a CT scan of a “typical woman” to generate DVH information, as most patients were treated in the pre-3D-planning era.

The findings from Darby et al. may not be necessarily applicable to women treated with modern radiation planning and delivery methods since the cardiac doses are far lower and the setup techniques more robust. In fact, the lead author previously showed no increase in cardiac mortality among women treated with radiotherapy after 1992 in the United States.206 Cardiac V5 was found to correlate with overall survival (OS) in the RTOG 0617 study of dose escalation (60 vs. 74 Gy) for definitive chemoradiation of stage III NSCLC, though this dose metric was not analyzed with respect to cardiac toxicity and may represent a surrogate for disease burden. Cardiac V5 was not found to correlate with survival in a European study randomizing 161 patients to definitive vs. neoadjuvant chemoradiation for stage III NSCLC.207 In a retrospective study of 416 patients treated with radiotherapy for locally advanced NSCLC, the median heart V50 was significantly higher (20.8% vs. 13.9%, p < 0.0001) for patients who developed Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 1 cardiac toxicity.208 In another single-institution retrospective analysis,209 the dose-exposure to the whole heart, left ventricle, right atrium, and left atrium in 112 patients with stage III NSCLC were analyzed; cardiac toxicity, grouped by pericardial (symptomatic effusion and pericarditis), ischemic, and arrhythmia events were correlated to distinct cardiac subvolumes, suggestive of distinct etiologies for different types of radiation-associated cardiotoxicity. A University of Michigan study investigated mean cardiac dose, and cardiac V5, V30, and V50 among 125 stage II to stage III NSCLC patients enrolled in 1 of 4 prospective studies.210 The mean cardiac dose (hazard ratio [HR], 1.07 per Gy; 95% CI, 1.02-1.13; p = 0.01) as well as cardiac V5 (HR 1.03 per Gy, 95% CI = 1.01-1.05; p < 0.01) and cardiac V30 (HR 1.03 per Gy, 95% CI = 1.01-1.06; p < 0.01) were correlated with cardiac toxicity risks, with greater risks among those with preexisting cardiac disease (HR, 2.96; 95% CI, 1.07-8.21; p = 0.04). These dose metrics did not correlate with survival. Whether mean heart dose or other cardiac dose metrics are a surrogate for dose-volume exposure to specific cardiac substructures such as left-ventricular muscle and coronary arteries is debated.205 Several studies have described reduced perfusion in irradiated cardiac regions that do not correspond to a coronary artery’s territory,194 thus implicating microvascular injury as a potential mechanism for radiation-associated heart injury and an endpoint more plausibly associated with mean dose. In the Darby study, the mean heart dose was as good (or better) a predictor of risk than doses to the coronary arteries. Yet, this observation may be due to uncertainties in their estimation of coronary artery doses. A patient-specific dosimetric analysis of 910 breast cancer patients treated at the University of Groningen confirmed mean heart dose as a risk factor for cardiac toxicity, though the volume of the left ventricle receiving 5 Gy was the most prognostic dose-volume parameter.211 A 2017 study of Hodgkin lymphoma survivors (whose treatment fields often encompass a large volume of the heart) showed minimally increased risk of late heart failure with mean heart doses < 25 Gy versus markedly increased risks after > 25 Gy; for the left ventricle, risks appreciably rose after mean doses > 15 Gy.212 In another Swedish study, which correlated angiography findings with coronary artery dose-exposure extrapolated from the radiation treatment fields, an ~ 2-fold increased risk in high-grade coronary artery stenosis was found in women who received high-risk radiotherapy (i.e., specific coronary arteries were exposed to the highest radiation doses during breast cancer radiotherapy).213 Furthermore, stenosis in these high-risk patients was more likely to occur in irradiated regions, specifically the right coronary artery (not accounted for214 in the Swedish/ Danish study) and distal left anterior descending artery. Risk relative to dose-volume exposure of cardiac substructures (i.e., right and

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CHAPTER 18 left ventricles and coronary arteries) will be investigated in the PatientCentered Outcomes Research Institute–funded Radiotherapy Comparative Effectiveness (RADCOMP) Consortium randomized trial of proton therapy versus photon therapy for patients with nonmetastatic breast cancer receiving comprehensive nodal radiation, including the internal mammary nodes (NCT02603341); the planned accrual is 1,716 patients.215 There are few data correlating heart dose-volume metrics with subsequent ejection fraction. In a study of patients with esophageal cancer treated with chemoradiation at the Roswell Park Cancer Institute, the radiation dose to the heart, left ventricle, and left anterior descending artery (quantified as V20-V40) were not clinically or statistically associated with changes in the ejection fraction (albeit in a small study, with limited follow-up).216 The aforementioned University of Michigan study likewise did not show a dose correlation with ejection fraction.200 A study from MDACC described the risk of pericardial effusions in patients treated for esophageal cancer.217 A mean dose > 26 Gy and relative volumes of the pericardium treated with doses > 3 to 50 Gy (rV3-50) was associated with effusions, with the strongest association being rV30. At 18 months postradiation, for an rV30 of > 46% versus < 46%, the rate of pericardial effusion was 73% versus 13% (p = 0.001); for a mean pericardium dose > 26 Gy versus < 26 Gy, the rate of pericardial effusion was 73% versus 13% (p = 0.001). A study from the University of Michigan also demonstrated that a mean dose > 27 Gy and maximum dose of 47 Gy correlated with risk of pericardial effusion; however, only patients treated with 3.5 Gy fractions developed pericardial effusions.218 Radiotherapy has been associated with valvular heart disease.219 The incidence has been related to mediastinal radiation doses > 30 Gy and younger age at irradiation. Subclinical valvular disease has been detected at 2 to > 20 years postradiation,219 but it appears to take much longer for clinical symptoms to become apparent (median interval, 22 years from radiation to symptoms). For patients receiving radiation for Hodgkin lymphoma, at a median of > 10 years after radiation, aortic valvular disease usually consists of mixed stenosis and regurgitation and is more common than mitral and right-sided valvular disease.219,220 From NTCP modeling of radiation-induced asymptomatic heart valvular defects, among 20 of 56 Hodgkin lymphoma survivors, the cardiac chamber (left ventricle and left atrium) V30, cardiac chamber volume and lung volume were predictive.221 A 2015 study of 89 Hodgkin lymphoma survivors estimated “affected valve” dose and demonstrated a dose-dependent increased risk of valvular disease for doses > 30 Gy (and minimal increase for doses below 30 Gy) with actuarial risks increasing over time, particularly beyond 20 years.222

Anthracyclines and Other Risk Factors In Hodgkin disease patients, radiation exposure in conjunction with anthracyclines may impair ejection fraction and increase risk of myocardial infarction, congestive heart failure, and valvular disorders. Data on the combined effects of anthracycline and radiation remain sparse. A report of 1474 Hodgkin lymphoma survivors younger than 41 years at treatment and followed for a median of 18.7 years has shed some light.223 Risks of myocardial infarction and congestive heart failure were significantly increased, with standard incidence ratios of 3.6 and 4.9, respectively, for Hodgkin lymphoma survivors versus the general Dutch population. Mediastinal radiation alone increases the risks of myocardial infarction, angina pectoris, congestive heart failure, and valvular disorders (2- to 7-fold). The addition of anthracyclines further elevated the risks of congestive heart failure and valvular disorders from mediastinal radiation, with hazard ratios of 2.81 (95% CI, 1.44-5.49) and 2.10 (95% CI, 1.27-3.48), respectively. The 25-year cumulative incidence of congestive heart failure following combined radiation and anthracycline chemotherapy was 7.9%.

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Other risk factors for cardiac disease, particularly coronary artery disease, must be considered. For example, data from the University of Rochester assessed the risk of coronary artery disease in survivors of Hodgkin lymphoma as well as the prevalence of cardiac risk factors. The relative risk of cardiac death was 3.1 for males versus 1.8 for females. Other risk factors were more common than in the general population; among patients with Hodgkin lymphoma experiencing morbid cardiac events, 72% smoked, 72% were male, 78% had hypercholesterolemia, 61% were obese, 28% had a positive family history, 33% had hypertension, and 6% had diabetes.224

Summary and Other Key Points From the QUANTEC Review225 The substructures of the heart, as well as the intersection of the heart and great vessels, can be challenging to differentiate with axial CT imaging, and the heart border is often difficult to differentiate from the adjacent liver and diaphragm. The heart moves with the respiratory and cardiac cycles, with different regions moving to different degrees. Several clinical factors—such as increasing age, comorbidities, and anthracycline exposure—appear to increase the risk of radiation-induced injury. While based on limited data, there appears to be a dose and/ or volume dependence for pericardial disease, cardiac mortality, and perfusion abnormalities. A heart V30 of > 45% and a mean cardiac dose of > 26 Gy are associated with a higher risk of pericarditis. A heart V30 to V40 of ~ 30% to 35% is associated with an ~ 5% excess risk of cardiac death at ~ 15 years. These dose-volume metrics likely oversimplify risk estimates related to coronary artery disease, which are probably best correlated with high dose (> 50 Gy) to small volumes of coronary artery.214 In patients with breast and lung cancer, it is recommended that the irradiated heart volume be minimized as much as possible without compromising target coverage. In patients with lymphoma, the whole heart should be limited to < 30 Gy if the patient is treated with radiation alone and 15 Gy for those also receiving anthracycline chemotherapy.

GASTROINTESTINAL SYSTEM: ESOPHAGUS Organ Function and Clinical Significance The esophagus is the muscle-lined organ that allows and facilitates the transit of solids and liquids from the mouth to the stomach. The esophagus is a moveable (slightly), hollow, distensible organ. On CT images, the cross-sectional esophageal area/volume is highly variable. This may not accurately reflect the true anatomy of the organ. In gross esophageal specimens, the cross-sectional area of the esophagus is fairly uniform at all axial levels.226 Acute esophagitis is very common and is often severe in patients receiving radiation for thoracic malignancies (i.e., esophageal cancer and primary lung cancer). Some patients may require a feeding tube and/or treatment interruptions owing to acute esophagitis. Since most patients with thoracic cancers have a poor prognosis, acute toxicity may be considered more clinically relevant than late injury. Late esophageal complications include dysphagia, stricture, dysmotility, odynophagia, and, rarely, necrosis or fistula.

Dose-Volume Data In a series from Washington University, grade 3 to grade 5 esophageal toxicity (acute and late) was associated with a maximal dose (Dmax) of > 58 Gy, a mean dose of > 34 Gy, and the administration of concurrent chemotherapy.227 The V55 was not significant. A Chinese study reported that Dmax > 60 Gy and the use of concurrent chemotherapy were significant factors for esophageal toxicity (acute and late).228 In a series from Duke University, the V50, the surface dose receiving ≥ 50 Gy (S50), the length of esophagus receiving > 50 to 60 Gy, and a circumferential

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Dmax > 80 Gy were significant predictors of late esophageal toxicity.229 A V50 of > 32% or an S50 of > 32% resulted in crude rates of ~ 30% late esophageal toxicity versus 7% below these thresholds (p = 0.02 and 0.04, respectively). With > 3.2 cm of the esophagus receiving > 50 Gy, late toxicity occurred in ~ 30% versus 4% in those with < 3.2 cm receiving > 50 Gy (p = 0.008). In another series from Duke University, late grade ≥ 1 toxicity was correlated with several dose parameters: the entire circumference receiving ≥ 50 Gy and ≥ 55 Gy, 75% of the circumference receiving ≥ 70 Gy, and maximal percentage of circumference receiving ≥ 60 to 80 Gy.230 The rate of grade ≥ 1 late toxicity was ~ 5% in patients with a V50 to V70 of 0% to 30% versus ~ 25% in those with a V70 of 31% to 64% and ~ 10% in those with a V50 > 60% (nonsignificant). Acute esophageal toxicity was the greatest predictor of late toxicity. In two studies, most of the patients who developed late grade ≥ 3 toxicity had developed acute grade ≥ 3, though roughly 25% to 40% of patients who developed grade ≥ 3 late toxicity had only grade 0 to grade 2 acute esophageal toxicity.227,228 From the data analyzed for QUANTEC, several studies noted an increased risk with increasing dose/volume parameters. However, since different studies considered different variables, optimal dose/volume predictors were considered elusive. Further, since different dose/volume parameters are correlated to each other, it may be that there are no true “optimal” parameters and that alternative predictive models will be equally useful. From a 2013 meta-analysis of 1082 patients treated with chemoradiation for NSCLC, esophageal V5 to V70 parameters (in 5-Gy increments) were all significant predictors of grade ≥ 2 esophagitis. On multivariate analyses, V60 proved to be the most significant predictor of grade ≥ 2 to grade 3 esophagitis.231 Recursive partitioning identified 3 risk groups: low (29% and 4% risk of grade ≥ 2 and ≥ grade 3 esophagitis with V60 < 0.07%), intermediate (41% and 10% risk of grade ≥ 2 and ≥ grade 3 esophagitis with V60 0.07%-17%), and high (59% and 22% risk of grade ≥ 2 and ≥ grade 3 esophagitis with V60 ≥ 17%). These authors did not consider dose-surface metrics or esophageal length or circumference.

Summary and Other Key Points From the QUANTEC Review232 The esophagus can be difficult to differentiate from surrounding soft tissues. Acute esophageal injury is much more common; thus, most studies have explicitly analyzed acute toxicity (which was not explicitly reviewed earlier). For acute and late injury, there is a dose-response for a variety of threshold volumes (V20–V70). A Dmax > 55 to 60 Gy as well as esophageal surface, volume, length, and circumference receiving > 50 to 60 Gy appear to correlate with toxicity. Acute esophageal toxicity can result in late toxicity. It was not possible to identify a single best threshold volumetric parameter for esophageal irradiation, since a wide range of dose-volume parameters correlate with toxicity. Based on the RTOG 0617 dose escalation study for NSCLC, it was suggested that the mean dose to the esophagus be kept to < 34 Gy; in that study, the esophageal V60 will also be reported. A meta-analysis suggests that V60 is most predictive for esophagitis.

GASTROINTESTINAL SYSTEM: STOMACH AND SMALL BOWEL Organ Function and Clinical Significance The stomach and small bowel aid in the digestion and absorption of food and nutrients. Symptoms from radiation-related late toxicities include dyspepsia; gastric ulceration; diarrhea; bowl obstruction; and bowel ulceration, fistula, or perforation. The primary long-term endpoint considered for the small bowel is stricture and diarrhea. For the stomach, perforation and ulceration are commonly considered.

Several patient-related variables—such as history of diabetes, age, race, body habitus, and prior surgery—are also likely to impact the risk of late toxicity.233 Because the stomach and small bowel are mobile and distensible, determining accurate dose-volume (or dose-surface) constraints is challenging. Factors affecting risk of late toxicity include total dose (with doses in excess of 40-50 Gy increasing the risk of late complications), fractional dose, prior abdominal surgery (which increases the risk of bowel obstruction), and concurrent chemotherapy use.

Dose-Volume Data Dose

Late radiation-induced stomach injury has been reported to occur with increasing frequency with increasing doses. In the study from the Walter Reed National Military Medical Center, the rates of gastric ulceration were 4% and 16% after treatment of < 50 versus > 50 Gy. Similarly, the rates of perforation were 2% and 14% in the same dose cohorts. Overall, the dose of ~ 50 Gy to the stomach is associated with about a 2% to 6% incidence of severe late injury. The volume effect for late stomach injury is not well defined. For late small-bowel toxicity, a dose of ~ 50 Gy is associated with obstruction/perforation rates that are ~ 2% to 9%. Prior abdominal surgery appears to increase the risk of late small-bowel injury following radiation. In the EORTC study, the rate of complications was 3% without prior abdominal surgery versus 12% with prior abdominal surgery.234

Dose Volume There is a paucity of good quantitative data on dose-volume metrics that predict for gastric or bowel late toxicity. Nevertheless, there are data that demonstrate a volume effect. The risk of bowel obstruction among patients with rectal cancer whose fields extended to L1 or L2 was 30% versus 9% in those treated with pelvis-only fields.235 The University of Michigan investigated gastric and duodenal bleeding after radiation of patients with liver tumors.236 Normal tissue complication modeling was consistent with a dose threshold (~ 60 Gy) for bleeding without a large volume effect. A few studies published after QUANTEC correlated small-bowel toxicity risks with dose-volume metrics. In a study of 46 locally advanced pancreatic cancer patients treated with concurrent gemcitabine and radiotherapy, duodenal V35 > 20% was associated with a 41% risk of grade ≥ 3 small-bowel toxicity (acute or late) versus 0% for a V35 < 20%.237 In another study of locally advanced pancreatic cancer patients (n = 106) in which duodenal V40 to V60 was analyzed, a V55 ≥ 1 mL versus < 1 mL was significantly correlated with grade ≥ 2 toxicity (47% vs. 9%, p = 0.0003).238 In a study of 46 women treated with extended field radiation for gynecological malignancies, up to 65 Gy, only 3 patients experienced acute grade ≥ 3 gastrointestinal (GI) toxicity and 3 patients experienced late grade ≥ 3 GI toxicity (none of which was duodenal toxicity); V5 to V65 did not correlate with toxicity risks.239 From a systematic review of women undergoing extended field radiation, a point maximum of 55 Gy to the small bowel was estimated to yield a 10% toxicity risk within 5 years.240 In a study of 84 women undergoing posthysterectomy IMRT, the V40/small-bowel volume ratio (optimal threshold of 28%) and maximal dose (optimal threshold of 55.9 Gy) were significant prognostic factors for chronic grade 1 to grade 2 toxicity.241 In a study of 45 rectal cancer patients, grade 2 to grade 3 diarrhea was significantly (p < 0.0001) associated with a small bowel V5 > 292 cc (82% vs. 29% if below this threshold).242

Summary and Other Key Points From the QUANTEC Review243 The stomach and the intestines are mobile structures with definite inter- and intrafraction motion. This makes some of the doses/volumes/

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CHAPTER 18 outcomes data less certain. Two different approaches have been considered when defining small-bowel volumes. Either the entire potential space of small bowel–containing volume (i.e., incorporating all regions where bowel can be situated)244 or the actual visualized loops of bowel on the planning CT245 can be considered as an organ at risk. Using the entire potential small-bowel space, it is suggested that the small bowel exposed to V45 to V50 should be less than 195 cc to reduce acute toxicity (not discussed earlier)244; while using the visualized loops of bowel, it is recommended that the V15 should be less than 120 cc.245 A study (with neoadjuvant radiation for rectal cancer) published after QUANTEC predicts a 10% risk of grade ≥ 3 small-bowel toxicity with a V15 < 275 cc for contoured bowel loops and < 830 cc for the peritoneal space.246 While these dose constraints were derived from acute toxicity data, they provide guidelines that should help minimize risk of late toxicity as well. For the stomach, it is recommended to maintain the dose to the whole stomach to < 45 Gy; a maximum point dose might be an important predictor of toxicity, but more data are needed to confirm this hypothesis.

GASTROINTESTINAL SYSTEM: RECTUM Organ Function and Clinical Significance The rectum is the terminal portion of the large intestines, which functions as a temporary storage for feces, as well as providing the urge to defecate.

TABLE 18.3

Rectal Toxicity

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The most common late radiation–related rectal complication is bleeding. Rectal ulceration and fistula are much less common. Other late injuries include stricture and decreased rectal compliance, which can result in frequent small stool. The anus is also at risk of late complications, including stricture and laxity, leading to fecal incontinence. Patients are at a higher risk of late rectal sequelae—including gastrointestinal bleeding, proctitis, diarrhea, and tenesmus—with higher maximal and mean rectal doses. Several patient-related variables—such as history of diabetes and/or vascular disease, inflammatory disease, and age—may impact the risk of late toxicity.233,247–249 Acute bowel toxicity appears to be correlated with late proctitis and increased stool frquency.249 Prior abdominal surgery is also relevant.250 The XRCC1 polymorphism has also been implicated as a risk factor for late rectal toxicity.251

Dose-Volume Data Abundant dosimetric data has shown a correlation of risk with rectal volume and surface/rectal wall doses.252–267 Table 18.3 summarizes many of these studies, also discussed later. MSKCC has shown a significant difference in the DVHs between patients who developed rectal bleeding versus those who did not after conformal radiation for prostate cancer.252 The percent rectum exposed to 62% and 102% of the prescription dose (70.2 or 75.6 Gy) was significant; the rectal wall being encompassed by the 50% isodose line, higher maximal dose to the rectum, and smaller rectal volume were

Summary of Selected Studies Analyzing Dose-Volume Parameters Predictive of

Author, Year (Center)

Patient Population

Endpoint

Wachter et al., 2001 (University Hospital Vienna)255

Prostate cancer

Grade 2 rectal toxicity

Fiorino et al., 2002, 2003 (L’Ospedale San Raffaele)256, 257

Prostate cancer

Cozzarini et al., 2003 (Hosp. San Raffaele)258

Prostate cancer s/p prostatectomy

Huang et al., 2002 (MDACC)260

Prostate cancer

Peeters et al., 2006 (van Leeuwenhoek Hospital)261

Prostate cancer

Grade 2 rectal toxicity

Late rectal bleeding

Grade ≥ 2 rectal toxicity Rectal bleeding requiring laser treatment or packed red blood cells

Use of incontinence pads

Subgroup

Toxicity Rate

V59 ≥ 57%

31%

V59 < 57%

11%

V50 ≤ 60%-65%

4%-8%

V60 ≤ 45%-50%

4%-8%

V70 ≤ 25%-30%

4%-8%

V50 > 65%

20%-30%

V60 > 50%

20%-30%

V70 > 30%

20%-30%

Mean rectal dose ≥ 54 Gy

7%

V50 ≥ 63%

7%

V55 ≥ 57%

7%

V60 ≥ 50%

7%

Mean rectal dose < 54 Gy

22%

V50 < 63%

21%

V55 < 57%

21%

V60 < 50%

19%

V70 ≥ 26%

54%

V70 < 26%

13%

V65 = 7-23%

< 1%

V65 = 23-29%

4%

V65 = 29-36%

11%

V65 > 36%

10%

Anal mean < 28 Gy

< 5%

Anal mean 28-38 Gy

7%

Anal mean 38-46 Gy

9%

Anal mean > 46 Gy

> 20% Continued

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Summary of Selected Studies Analyzing Dose-Volume Parameters Predictive of Rectal Toxicity—cont’d

TABLE 18.3

Author, Year (Center) Boersma et al., 1998 (Netherlands Cancer Institute)264

Patient Population Prostate cancer

Prostate cancer

Kupelian et al., 2002 (Cleveland Clinic)265

Vargas et al., 2005 (William Beaumont Hospital)262

a

Pederson et al., 2012 (University of Chicago)266

Prostate cancer

Prostate cancer

Endpoint Rectal bleeding

Rectal bleeding

Grade ≥ 2 rectal toxicity

4-year grade ≥ 2 GI toxicity

Subgroup Rectal wall V65 < 40%

Toxicity Rate 0%

Rectal wall V70 < 30%

0%

Rectal wall V75 < 5%

0%

Rectal wall V65 > 40%

10%

Rectal wall V70 > 30%

9%

Rectal wall V75 > 5%

9%

Rectal wall V70-V78 < 15 mL

5%

Rectal wall V70-V78 > 15 mL

22%

V70 < 25%

9%

V70 = 25%-40%

19%

V70 > 40%

24%

Rectal wall V70 < 5 mL

8%

Rectal wall V70 5-15 mL

13%

Rectal wall V70 > 15 mL

32%

Rectal wall V70 < 25%

9%

Rectal wall V70 = 25%-40%

18%

Rectal wall V70 > 40%

25%

V70 ≤ 10%

0%

V65 ≤ 20%

0%

V40 ≤ 40%

0%

V70 ≤ 20%

8%

V65 ≤ 40%

8%

V40 ≤ 80%

8%

V70 > 20%

15%

V65 > 40%

15%

V40 > 80%

15%

a

Published after QUANTEC review. GI, Gastrointestinal; MDACC, M. D. Anderson Cancer Center.

also significantly adverse risk factors.252,253 In a study of 1571 patients treated at MSKCC, the use of IMRT and the lack of acute rectal toxicity predicted for lower risk of late rectal toxicity.254 An Austrian study found that a V59 of ≥ 57% resulted in increased grade 2 rectal toxicity (31 vs. 11%, p = 0.003).255 Two Italian multicenter studies found a significant dose volume effect from V50 to V70, with suggested cutoff values of V50 ≤ 60% to 65%, V60 ≤ 45% to 50%, and V70 ≤ 25% to 30%; the risk of grade ≥ 2 rectal complications was ~ 4% to 8% versus ~ 20% to 30% risk above and below the cutoff values.256,257 A rectal volume < 55 mL was also a significant risk factor for late bleeding. In the postprostatectomy setting, this Italian group demonstrated that a mean rectal dose ≥ 54 Gy, V50 ≥ 63%, V55 ≥ 57%, V60 ≥ 50%, and rectal volume < 60 mL were predictive of late bleeding.258 In a randomized trial of 70 Gy versus 78 Gy from MDACC in the treatment of early- to intermediate-risk early-stage prostate cancer, the risk of late grade ≥ 2 rectal complications was significantly greater with a rectal V70 ≥ 25% versus V70 < 25% (46% vs. 16%, p = 0.001).259 A retrospective analysis from MDACC showed that the risk is a continuous function of dose and volume, with suggested cutoff points for lowering the complication risk: V60 ≤ 41%, V70 ≤ 26%, V76 ≤ 16% or 3.8 mL

and V78 ≤ 5% or 1.4 mL.260 At 6 years, the risk of late grade ≥ 2 rectal complications was 54% for patients with a rectal V70 ≥ 26% versus 13% for a V70 < 26%. Among patients treated in the Dutch randomized trial of 68 versus 78 Gy,248 the mean anal dose (as well as V5-V60) significantly predicted the rate of grade ≥ 2 gastrointestinal toxicity (at 4 years, 16% vs. 31% for a mean dose < 19 Gy vs. > 52 Gy).261 The mean dose (as well as V5-V70) also predicted the risk for use of incontinence pads (at 5 years, < 5% vs. > 20% for a mean dose < 28 Gy vs. > 46 Gy). The anorectal V65 (as well as V55-V60) was significantly predictive of rectal bleeding (4-year risk < 1% and > 10% for a V65 < 23% vs. > 29%).261 In analysis of 748 patients randomized to the 79.2-Gy arm of the RTOG 0126 protocol, rectal V70 ≥ 15% was associated with grade 2+ rectal toxicity (p = 0.034 on multivariate analysis). At 3 years, V70 ≥ 15% was associated with an ~ 24% risk of late gastrointestinal toxicity versus 12% for V70 < 15%. Similar risks were seen with a rectal V75 ≥ 10% versus < 10%.268 The percentage of rectum or rectal wall receiving a given dose can be somewhat subjective (based on how much of the rectum is segmented); using the absolute volume of rectum265 or rectal wall is less subjective, though defining the rectal wall is not standardized. The rectum extends

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CHAPTER 18 from the rectosigmoid junction to the anus, with the inferior extent generally defined as the level of the anal verge, above the anus, the ischial tuberosities or 2 cm below the ischial tuberosities. Dosimetric parameters of the rectal wall or rectal surface may be more predictive of some late toxicities.269 William Beaumont Hospital demonstrated that the rectal volume as well as rectal wall V50 to V70 values predict late toxicity, with the rectal wall being more predictive of grade 2 to grade 3 late effects; acute toxicity is also predictive of late toxicity.262 MDACC has also shown the rectal wall to be better predictive of late rectal bleeding.263 From a 1998 Dutch study, recommendations for the volume of rectal wall exceeding 65 Gy, 70 Gy, and 75 Gy are < 40%, < 30%, and < 5%, respectively.264 Data from the Cleveland Clinic265 and William Beaumont Hospital262 showed a significantly increased risk of grade ≥ 2 rectal toxicity with rectal or rectal wall V70 to V78 of ≥ 15 mL versus < 15 mL (~ 20% to > 30% vs. ~5%-10%). In a study of 1285 prostate cancer patients who received proton therapy, the rectal (p = 0.010) and rectal wall (p = 0.0017) V75 were significant for risk of rectal bleeding on multivariate analysis.270

Summary and Other Key Points From the QUANTEC Review271 The rectum is mobile and distensible; therefore, its position and volume can vary between and during radiation fractions. The superior and inferior borders of the rectum are not always easy to define on CT imaging. Most of the published studies of rectal toxicity address late rectal bleeding. However, most toxicity scoring systems are nonspecific in that a patient can be considered as having a grade 2 or grade 3 event on the basis of diarrhea, stool frequency, rectal mucus, or bleeding. For patients undergoing radiation therapy for prostate cancer, it is recommended to limit the V50, V60, V65, V70, and V75 to less than 50%, 35%, 25%, 20%, and 15%, respectively. From a Phase I/II RTOG study published after the QUANTEC review,272 in which 1009 men received 68.4 to 79.2 Gy in 1.8- to 2.0-Gy fractions, rectal doses < 60 Gy had no detectable impact on the fit of the NTCP model, and multivariate modeling showed only V75 to be significantly associated with late rectal toxicity.273

GASTROINTESTINAL SYSTEM: LIVER Organ Function and Clinical Significance The liver is a vital organ, with a breadth of metabolic functions, including metabolism of ingested nutrients, detoxification, protein synthesis, bile production, glycogen storage, and red blood cell decomposition. Sequelae of radiation-induced liver damage include elevation of liver enzymes, ascites, jaundice, asterixis (tremor), encephalopathy, or coma. One of the most important patient-related predictors of susceptibility to liver damage is the baseline liver function, which is characterized by the Child-Pugh scoring system and accounts for serum bilirubin, albumin, coagulation times, the presence of ascites, and encephalopathy. The risk of radiation toxicity also appears to be greater in the patient population with primary liver malignancies as opposed to liver metastases.

Dose-Volume Data In the RTOG 84-05 Phase I study, in which patients with liver metastases received whole-liver radiation with 1.5-Gy twice-daily fractions, none of the 122 patients who received 27 to 30 Gy developed biochemical evidence of liver toxicity compared with 5 of 51 who received 33 Gy.274 In a study of 79 patients treated with liver radiotherapy at the University of Michigan, only those patients who received whole-liver radiotherapy (1.5-1.65 Gy BID, with or without a boost) developed late radiation toxicity (crude risk of 9/33 vs. 0/46 treated with partial liver radiation). Those who received a mean dose of

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309

> 37 Gy (delivered twice daily with infusional fluorodeoxyuridine) and less sparing of normal liver had greater risk of late radiation toxicity (crude risk of 9/34 vs. 0/45).275 Several studies have explored partial-liver radiation in more detail, many of which used mean liver dose as a dose-volume metric. In a later study from the University of Michigan, no late liver toxicity was observed with a mean liver dose < 31 Gy, with normal tissue complication probability models being optimized with a TD50 of 43 Gy and TD5 of 31 Gy for whole-liver radiation; the risk of complications was strongly dependent on the volume of liver irradiated.276 Other risk factors for late toxicity included primary hepatobiliary carcinoma (as opposed to metastatic disease), use of bromodeoxyuridine chemotherapy (as opposed to fluorodeoxyuridine), and male gender. The normal tissue complication probability models predict a TD5 in excess of 80 Gy if < 1/3 of the liver is irradiated. With irradiation of 2/3 of the liver, the TD5 is on the order of 50 Gy and TD50 on the order of 60 Gy. In a series from Taipei, patients with irradiated hepatocellular carcinoma who developed late liver toxicity had received a mean hepatic dose of 25 Gy (vs. 20 Gy in patients without toxicity, p = 0.02).277 The TD50 for whole liver, 2/3 liver, and 1/3 liver radiation were modeled to be approximately 43 Gy, 50 Gy, and 67 Gy, respectively. The TD5 for whole liver, 2/3 liver, and 1/3 liver radiation were modeled to be approximately 25 Gy, 28 Gy, and 38 Gy, respectively. The volume effect of liver radiation was less in this series. In another study from the same group, the mean liver dose and hepatitis B virus positivity were significant predictors of radiation toxicity; with NTCP modeling, the TD50 was ~ 50 Gy.278 In a Korean study of 105 patients with hepatocellular carcinoma, the mean dose and V20 to V40 parameters to total liver and normal liver (total liver minus GTV) were investigated.279 The total liver V30 was the only significant parameter (p < 0.001). Grade ≥ 2 liver toxicity was observed in only 2.4% of patients with a total liver V30 ≤ 60% and 55% of patients with a total liver V30 > 60% (p < 0.001). Another Korean study demonstrated a correlation of V15 with reduction in Child-Pugh score and recommends a V15 cutoff of < 43.2%.280 The data from Asia differs from Western data, perhaps reflecting differences in the treated malignancy (mostly metastases in the West versus primary liver cancer in Asia, which often occurs in the setting of liver cirrhosis), radiation fractionation, and/or concurrent therapies delivered with radiation.

Summary and Other Key Points From the QUANTEC Review281 An understanding of radiation-induced liver toxicity necessitates an appreciation of liver motion. Extensive work has described liver motion due to breathing, which can displace the liver in excess of 2 cm. Preexisting liver dysfunction secondary to comorbid conditions such as hepatitis B or C infection and cirrhosis appears to increase the susceptibility to radiation-induced liver injury. For patients with liver metastases undergoing partial volume liver radiation, the risk of radiation-induced liver toxicity appears to be more dependent on the volume of liver irradiated. Partial volumes of liver can tolerate relatively high doses. However, tolerances are lower for patients with primary liver cancer (who are more apt to have underlying liver disease). For whole-liver radiation, doses ≤ 28 to 30 Gy in 2-Gy fractions (28 Gy for liver metastases and 30 Gy for primary liver cancer) and ≤ 21 Gy in 3-Gy fractions are recommended. For partial liver radiation, treated with standard fractionation, the mean dose to normal liver (liver minus GTV) is suggested to be < 30 Gy for liver metastases and < 28 Gy for primary liver cancer.

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GENITOURINARY SYSTEM: KIDNEY Organ Function and Clinical Significance The kidney functions to remove wastes; regulate electrolytes; produce erythropoietin, which stimulates red blood cell production; and modulate blood pressure through the renin-angiotensin pathway as well as through fluid/electrolyte balance. Perhaps late kidney toxicity is underreported owing to its long latency as well as toxicity being attributed to more common causes. Late renal complications include decreased kidney function, azotemia, hypertension, and kidney atrophy. Chronic radiation nephropathy in its mildest forms may not be diagnosed until years after therapy. Clinically silent abnormalities may include only proteinuria and azotemia with urinary casts and mild or no hypertension. Certainly, patients with only one functioning kidney or poor baseline renal function are more vulnerable to damage (with or without symptoms) for any given volume of renal irradiation. Platinum- and ifosfamide-based chemotherapeutics can also impact renal function. Ifosfamide can cause glomerular and tubular toxicity, with renal tubular acidosis, or Fanconi syndrome. A study examining grade 3 to grade 4 ifosfamide-induced nephrotoxicity among adult and pediatric patients found a prevalence of 17% in both, and neither age nor cumulative ifosfamide dose were risk factors.282

Dose-Volume Data Several studies have investigated whole-kidney dose tolerance, either after whole abdominal radiation or total body irradiation (generally delivered with lower fractional doses). Renal toxicity can occur after bilateral kidney doses ≥ 10 Gy, and the risk is quite high (50%-80%) after 20 Gy. Thus, the kidneys have a relatively low threshold for damage. The dose-volume effect on the kidneys has been long recognized, even prior to the planning CT era, since kidneys are well visualized on plain simulation films. From these studies, when greater than half of the kidney receives doses > 20 to 30 Gy, or greater than one-third receives > 30 to 40 Gy, patients are at increased risk of developing renal atrophy, decreased kidney function, and hypertension.2,283–285 There is little published on dose-volume parameters to predict late renal toxicity, in part because clinicians make an effort to minimize the volume of kidney exceeding the accepted tolerance dose. Low doses, 10 to 15 Gy to large volumes of kidney, increase the risk of nephrotoxicity,286–288 while smaller volumes of kidney exceeding ~ 20 to 25 Gy can result in late renal toxicity.286,288–290 In a series from Heidelberg, normal tissue complication modeling was used to estimate the risk of late complications.289 A median dose of ~ 17.5 to 21.5 Gy and 22 to 26 Gy corresponded to a 5% and 50% late complication risk (anemia, azotemia, hypertension, and edema), respectively. In another German study, reduced kidney function, as measured by scintigraphy changes, was analyzed as a function of dose and volume.286 After irradiation of 10% to 30%, 30% to 60%, and 60% to 100% of the kidney volume to 20 Gy, the incidence of reduced activity was < 10%, ~ 40%, and > 70%. After irradiation of 10% to 30%, 30% to 60%, and 60% to 100% of the kidney volume to 30 Gy, the incidence of reduced activity was ~ 35%, > 90%, and > 98%. In a Dutch study of patients with gastric cancer (treated with concurrent radiation and cisplatin or capecitabine), the left kidney V20 ≥ 64% and mean left kidney dose of ≥ 30 Gy was associated with a significant decrease in left kidney function as compared with the right.290 In a study of 125 patients with upper GI malignancies, kidney V5 to V20 and mean kidney dose were significantly correlated with reduction in creatinine clearance.291 A 15% to 20% decrease in creatinine clearance was associated with a V5 > 50%, V10 > 30%, V20 > 30% (or > 100 mL), and mean kidney dose > 10 Gy.

Summary and Other Key Points From the QUANTEC Review292 Radiation-associated kidney injury has a poorly understood pathophysiology and is likely underreported due to its long latency. For whole (bilateral) kidney radiation (not discussed earlier), recommendations are for doses < 10 Gy delivered over 5 to 6 fractions (at < 6 cGy/min dose rate) and < 15 to 18 Gy for radiation delivered over ≥ 5 weeks. For partial kidney radiation, the volume of kidneys receiving > 20 Gy predicts risk of renal toxicity. The recommendation for partial-kidney radiation is to maximally spare the kidneys, and maintain a mean dose of < 18 Gy to both kidneys, or maintain a V6 < 30% if one kidney cannot be adequately spared.

GENITOURINARY SYSTEM: BLADDER Organ Function and Clinical Significance The bladder is a highly distensible organ that collects urine. Symptoms from late radiation-related toxicities include increased urinary frequency, hematuria, and dysuria. Necrosis, contracted bladder, and hemorrhage are less common, severe effects. Perhaps late bladder toxicity is underreported owing to its long latency as well as toxicity being attributed to more common causes. Because the bladder is mobile and distensible, determining accurate dose-volume (or dose-surface) constraints are challenging. Endpoints for bladder injury can reflect focal damage (e.g., bleeding) or more global injury (reduce bladder capacity with secondary urinary frequency). Recent data suggests that acute toxicity is predictive of late toxicity (particularly urinary frequency and hematuria) risks, and pretreatment bladder dysfunction is predictive of late urinary symptoms (particularly urinary frequency, incontinence, and slow stream).249

Dose-Volume Data Dose-volume (or dose-surface) analyses are impacted by the complexities of assigning dose-volume metrics to a mobile, distensible structure. For whole-bladder irradiation, doses in excess of 60 Gy, particularly with fraction sizes > 2 Gy and/or accelerated radiation regimens, result in a significant risk of late grade ≥ 3 toxicity. Risks are lower when the whole bladder receives 45 to 55 Gy, followed by a boost to > 60 Gy to a portion of the bladder, though toxicity risk has not been correlated to dose-volume metrics. A Fox Chase Cancer Center study of 503 prostate cancer patients examined urinary bladder V60 to V70 and area under the DVH, with bladder defined as just the bladder wall (“hollow: structure) or entire bladder and contents (“solid” structure). With multivariate analyses, the mean bladder dose and area under the DVH were significant predictors of grade ≥ 2 genitourinary toxicity.293 In a University of Chicago study of 296 prostate cancer patients (in which the bladder was contoured as whole organ after drainage and infusion of 120 mL of saline), no bladder dosevolume relationships were associated with the risk of grade ≥ 2 genitourinary toxicity.266 With prostate cancer treated with high doses (≥ 72 Gy), the inferior portion of the bladder (e.g., trigone area) also receives ≥ 70 Gy. This tends to be well tolerated with respect to bladder toxicity. Arguably, the urinary toxicity that does develop after radiation is due in part to the prostatic urethra receiving suprathreshold doses. In a study of 345 patients treated with chemoradiotherapy for locally advanced rectal cancer, models using the bladder (entire structure) mean dose, equivalent uniform dose, and optimal Vx were analyzed. The model with V35 was superior to the other models in predicting acute cystitis.294

Summary and Other Key Points From the QUANTEC Review295 The primary limitations of deriving strict dose-volume guidelines for the urinary bladder include the lack of robust 3D dose/volume data as

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CHAPTER 18 well as the complicating factor that the bladder is a mobile structure of variable volumes/position. For whole-bladder radiation, the reported risks of grade ≥ 3 toxicity in doses of 50 to 60 Gy range from ≤ 5% to 40%. This variation is likely attributable to the challenges of correlating toxicity with dose delivered to a mobile structure, which is even more problematic when correlating partial volume exposures to toxicity. With the caveat of these issues, bladder constraints of ≤ 15%, ≤ 25%, ≤ 35%, and ≤ 50% receiving ≥ 80 Gy, ≥ 75 Gy, ≥ 70 Gy, and ≥ 65 Gy, respectively, as recommended in the RTOG 0415 study of prostate cancer, are suggested. The protocol advises an empty bladder at the time of simulation and treatment; the bladder is segmented from the base to the dome.

GENITOURINARY SYSTEM: PENILE BULB Organ Function and Clinical Significance The penile bulb is located at the base of the penis, caudal to the prostate.296,297 Radiation dose to the penile bulb can affect erectile function, either as a direct result of damage to this structure (less likely) or damage to surrounding structures, whose radiation-induced damage is correlated with the dose exposure of the penile bulb. The most common scenario in which the penile bulb is irradiated is in the treatment of prostate cancer. IMRT is often used to minimize the dose to the penile bulb.298,299 Interpretation of erectile dysfunction and the effect of penile bulb dose are complicated by preexisting function, comorbid conditions, and other therapies that may hinder (i.e., hormonal therapy) or help (i.e., drugs used to treat erectile dysfunction) erectile function. Also, determining which patients experience erectile dysfunction, a toxicity with varying severity, also complicates data interpretation.

Dose-Volume Data Several studies have investigated dose-volume parameters to predict risk of erectile dysfunction. In several studies, no correlation was discerned for penile bulb dose and erectile function.299–301 In one study, attempts were made to reduce the dose to the penile bulb (mean dose of 25 Gy), and thus few patients received a high dose to the penile bulb.299 In another study of 70 patients, no correlation was found for mean dose or maximal dose to the penile bulb, penile crura, or superiormost 1 cm of the penile crura; DVHs were also compared and found to be similar.300 In a small (21 patients), early study from University of California, San Francisco, patients receiving a D70 of < 40%, 40% to 70%, and > 70% to the penile bulb had a 0%, 80%, and 100% risk, respectively, of experiencing radiation-induced impotence.302 In a study (29 patients) from Thomas Jefferson University, several dose-volume metrics were analyzed; a D30 > 67 Gy, D45 > 63 Gy, D60 > 42 Gy, and D75 > 20 Gy to the proximal penis were correlated with increased erectile dysfunction as well as ejaculatory dysfunction.303 In a study from Royal Marsden Hospital, a D90 > 50 Gy to the penile bulb was associated with significantly worse erectile function, while D15, D30, and D50 showed a similar (albeit not significant) trend toward increased doses in impotent versus intermediate potency vs. potent patients.304 Another small (19 patients) study found that mean dose < 50 Gy was predictive of erectile potency.305 The largest study (158 patients) to date to investigate penile bulb dose is an analysis of the RTOG 9406 dose-escalation study.306 A median dose of ≥ 52.5 Gy was associated with a greater risk of impotence (50% vs. 25% at 5 years).

Summary and Other Key Points From the QUANTEC Review307 There is some uncertainty regarding the critical anatomic structures for radiation-induced erectile dysfunction. Several studies from different academic centers have correlated the dose-volume exposure to the penile

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bulb with erectile dysfunction and, impressively, have had similar results. Based on published data, it is recommended to keep the mean dose to 95% of the penile bulb < 50 Gy and to limit the D70 and D90 to 70 Gy and 50 Gy, respectively.

CONCLUSIONS The study of radiation-associated normal tissue injury has interested investigators for decades. Much progress has been made over the last 20 years. Additional technologies (e.g., gating, image-guided therapy) will provide some refinements in these physical advances. The emergence of novel technologies such as stereotactic body radiotherapy/stereotactic ablative radiotherapy, IGRT, IMRT, charged particle therapy, and 4-dimensional planning have resulted in the increasing use of hypofractionated radiation, more conformal radiation delivery, and heterogeneous dose distributions (i.e., dose painting). Thus, future studies should account for fraction size and small-volume high-dose exposures. Eventually, models predicting dose/volume injury will likely more consistently consider the underlying physiology and substructures of organs, potential interactions between organs, and differences in regional physiological importance (e.g., different regions of the kidney being more important, such as the cortex vs. the medulla, and different regions of the heart being more important, such as the coronary arteries or the left ventricle). There is a need to gain further understanding of the biological underpinnings of radiation-associated normal tissue damage. It is hoped that this will improve our abilities to predict, prevent, and treat radiation-associated normal tissue injury. As we employ more advanced technologies to further limit normal tissue exposure to lessen the risk of radiotherapy-associated injury, we need to be careful not to compromise target coverage. Missing the tumor to avoid a grade 2 (or even grade 3 injury) might not be a reasonable trade-off, as a local tumor recurrence can be morbid. There are several published data sets that demonstrate that this is not a theoretical concern. In patients with orbital tumors and prostate cancer, more conformal techniques (applied to reduce normal tissue risks) have been associated with poorer clinical control outcomes.308,309 Radiation oncology is a dynamic field with constantly emerging technological advances. In tandem with these advances is the critical need for radiation oncologists to build their understanding of the normal tissue consequences of radiation administration. Not only do we need to explore associations of normal tissue damage with volume, dose, fraction size, and particle type, but we need to integrate this with the equally rapid evolution of novel systemic therapies and our pursuit of the pathophysiological (including molecular genetics) basis of normal tissue injury.

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44. Mayo C, Yorke ED, Merchant TE. Radiation-associated brainstem injury. Int J Radiat Oncol Biol Phys. 2010;76:S36–S41. 49. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys. 2010;76:S42–S49. 59. Mayo CS, Martel MK, Marks LB, et al. Tolerance of the optic nerves and chiasm to radiation. Int J Radiat Oncol Biol Phys. 2010;76:S28–S35. 104. Rancati T, Schwarz M, Allen AM, et al. Radiation dose volume effects in the larynx and pharynx. Int J Radiat Oncol Biol Phys. 2010;76:S64–S69. 120. Palma DA, Senan S, Tsujino K, et al. Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2013;85:444–450. 134. Ten Haken RK, Martel MK, Kessler ML, et al. Use of Veff and iso-NTCP in the implementation of dose escalation protocols. Int J Radiat Oncol Biol Phys. 1993;27:689–695. 175. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose volume effects in the lung. Int J Radiat Oncol Biol Phys. 2010;76:S70–S76. 202. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987–998. 209. Wang K, Pearlstein KA, Patchett ND, et al. Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for stage III non-small-cell lung cancer. Radiother Oncol. 2017;125:293–300. 210. Dess RT, Sun Y, Matuszak MM, et al. Cardiac events after radiation therapy: combined analysis of prospective multicenter trials for locally advanced non-small-cell lung cancer. J Clin Oncol. 2017;35:1395–1402. 225. Gagliardi G, Constine LS, Moiseenko W, et al. Radiation-associated heart injury. Int J Radiat Oncol Biol Phys. 2010;76:S77–S85.

231. Palma DA, Senan S, Oberije C, et al. Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2013;87:690–696. 232. Werner-Wasik M, Yorke ED, Deasy JO, et al. Radiation-associated esophageal toxicity. Int J Radiat Oncol Biol Phys. 2010;76:S86–S93. 243. Kavanagh B, Pan CC, Dawson LA, et al. Radiation dose volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys. 2010;76:S101–S107. 271. Michalski JM, Gay H, Jackson A, et al. Radiation induced rectal injury. Int J Radiat Oncol Biol Phys. 2010;76:S123–S129. 273. Tucker SL, Dong L, Michalski JM, et al. Do intermediate radiation doses contribute to late rectal toxicity? An analysis of data from radiation therapy oncology group protocol 94-06. Int J Radiat Oncol Biol Phys. 2012;84:390–395. 281. Pan CC, Kavanagh B, Dawson LA, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys. 2010;76:S94–S100. 292. Dawson LA, Kavanagh BD, Paulino AC, et al. Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys. 2010;76:S108–S115. 295. Viswanathan AN, Yorke ED, Marks LB, et al. Radiation-associated bladder injury. Int J Radiat Oncol Biol Phys. 2010;76:S116–S122. 307. Roach M, Nam J, Gagliardi G, et al. Radiation dose volume effects and the penile bulb. Int J Radiat Oncol Biol Phys. 2010;76:S130–S134.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 18

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21. Lee AW, Foo W, Chappell R, et al. Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1998;40:35–42. 22. Lee AW, Kwong DL, Leung SF, et al. Factors affecting risk of symptomatic temporal lobe necrosis: significance of fractional dose and treatment time. Int J Radiat Oncol Biol Phys. 2002;53:75–85. 23. Teo PM, Leung SF, Chan AT, et al. Final report of a randomized trial on altered-fractionated radiotherapy in nasopharyngeal carcinoma prematurely terminated by significant increase in neurologic complications. Int J Radiat Oncol Biol Phys. 2000;48:1311–1322. 24. Jen YM, Hsu WL, Chen CY, et al. Different risks of symptomatic brain necrosis in NPC patients treated with different altered fractionated radiotherapy techniques. Int J Radiat Oncol Biol Phys. 2001;51:344–348. 25. Shaw E, Arusell R, Scheithauer B, et al. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a north central cancer treatment group/radiation therapy oncology group/eastern cooperative oncology group study. J Clin Oncol. 2002;20:2267–2276. 26. Corn BW, Yousem DM, Scott CB, et al. White matter changes are correlated significantly with radiation dose. Observations from a randomized dose-escalation trial for malignant glioma (Radiation Therapy Oncology Group 83-02). Cancer. 1994;74:2828–2835. 27. Ruben JD, Dally M, Bailey M, et al. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65:499–508. 28. Sause WT, Scott C, Krisch R, et al. Phase I/II trial of accelerated fractionation in brain metastases RTOG 85-28. Int J Radiat Oncol Biol Phys. 1993;26:653–657. 29. Murray KJ, Scott C, Greenberg HM, et al. A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys. 1997;39:571–574. 30. Lawrence RY, Li AX, Naqa IE, et al. Radiation dose volume effects in the brain. Int J Radiat Oncol Biol Phys. 2010;76:S20–S27. 31. Gentile MS, Yeap BY, Paganetti H, et al. Brainstem injury in pediatric patients with posterior fossa tumors treated with proton beam therapy and associated dosimetric factors. Int J Radiat Oncol Biol Phys. 2018;100:719–729. 32. Haas-Kogan D, Indelicato D, Paganetti H, et al. National Cancer Institute Workshop on proton therapy for children: considerations regarding brainstem injury. Int J Radiat Oncol Biol Phys. 2018;101:152–168. 33. Jian JJ, Cheng SH, Tsai SY, et al. Improvement of local control of T3 and T4 nasopharyngeal carcinoma by hyperfractionated radiotherapy and concomitant chemotherapy. Int J Radiat Oncol Biol Phys. 2002;53:344–352. 34. Schoenfeld GO, Amdur RJ, Morris CG, et al. Patterns of failure and toxicity after intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys. 2008;71:377–385. 35. Daly ME, Chen AM, Bucci MK, et al. Intensity-modulated radiation therapy for malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys. 2007;67:151–157. 36. Hoppe BS, Wolden SL, Zelefsky MJ, et al. Postoperative intensitymodulated radiation therapy for cancers of the paranasal sinuses, nasal cavity, and lacrimal glands: technique, early outcomes, and toxicity. Head Neck. 2008;30:925–932. 37. Nishimura H, Ogino T, Kawashima M, et al. Proton-beam therapy for olfactory neuroblastoma. Int J Radiat Oncol Biol Phys. 2007;68:758–762. 38. Noel G, Habrand JL, Mammar H, et al. Combination of photon and proton radiation therapy for chordomas and chondrosarcomas of the skull base: the Centre de Protontherapie D’Orsay experience. Int J Radiat Oncol Biol Phys. 2001;51:392–398. 39. Weber DC, Rutz HP, Pedroni ES, et al. Results of spot-scanning proton radiation therapy for chordoma and chondrosarcoma of the skull base: the Paul Scherrer Institut experience. Int J Radiat Oncol Biol Phys. 2005;63:401–409. 40. Wenkel E, Thornton AF, Finkelstein D, et al. Benign meningioma: partially resected, biopsied, and recurrent intracranial tumors treated

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SECTION I

Scientific Foundations of Radiation Oncology

with combined proton and photon radiotherapy. Int J Radiat Oncol Biol Phys. 2000;48:1363–1370. 41. Debus J, Hug EB, Liebsch NJ, et al. Brainstem tolerance to conformal radiotherapy of skull base tumors. Int J Radiat Oncol Biol Phys. 1997;39:967–975. 42. Debus J, Hug EB, Liebsch NJ, et al. Dose-volume tolerance of the brainstem after high-dose radiotherapy. Front Radiat Ther Oncol. 1999;33:305–314. 43. Uy NW, Woo SY, Teh BS, et al. Intensity-modulated radiation therapy (IMRT) for meningioma. Int J Radiat Oncol Biol Phys. 2002;53:1265–1270. 44. Mayo C, Yorke ED, Merchant TE. Radiation-associated brainstem injury. Int J Radiat Oncol Biol Phys. 2010;76:S36–S41. 45. Schultheiss TE. The radiation dose-response of the human spinal cord. Int J Radiat Oncol Biol Phys. 2008;71:1455–1459. 46. Marucci L, Niemierko A, Liebsch NJ, et al. Spinal cord tolerance to high-dose fractionated 3D conformal proton-photon irradiation as evaluated by equivalent uniform dose and dose volume histogram analysis. Int J Radiat Oncol Biol Phys. 2004;59:551–555. 47. Mul VE, de Jong JM, Murrer LH, et al. Lhermitte sign and myelopathy after irradiation of the cervical spinal cord in radiotherapy treatment of head and neck cancer. Strahlenther Onkol. 2012;188:71–76. 48. Lim DC, Gagnon PJ, Meranvil S, et al. Lhermitte’s sign developing after IMRT for head and neck cancer. Int J Otolaryngol. 2010;2010:907960. 49. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys. 2010;76:S42–S49. 50. van den Bergh AC, Schoorl MA, Dullaart RP, et al. Lack of radiation optic neuropathy in 72 patients treated for pituitary adenoma. J Neuroophthalmol. 2004;24:200–205. 51. Harris JR, Levene MB. Visual complications following irradiation for pituitary adenomas and craniopharyngiomas. Radiology. 1976;120:167–171. 52. Jiang GL, Tucker SL, Guttenberger R, et al. Radiation-induced injury to the visual pathway. Radiother Oncol. 1994;30:17–25. 53. Aristizabal S, Caldwell WL, Avila J. The relationship of time-dose fractionation factors to complications in the treatment of pituitary tumors by irradiation. Int J Radiat Oncol Biol Phys. 1977;2:667–673. 54. Parsons JT, Bova FJ, Fitzgerald CR, et al. Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys. 1994;30:755–763. 55. Kline LB, Kim JY, Ceballos R. Radiation optic neuropathy. Ophthalmology. 1985;92:1118–1126. 56. Bhandare N, Monroe AT, Morris CG, et al. Does altered fractionation influence the risk of radiation-induced optic neuropathy? Int J Radiat Oncol Biol Phys. 2005;62:1070–1077. 57. Martel MK, Sandler HM, Cornblath WT, et al. Dose-volume complication analysis for visual pathway structures of patients with advanced paranasal sinus tumors. Int J Radiat Oncol Biol Phys. 1997;38:273–284. 58. Mackley HB, Reddy CA, Lee SY, et al. Intensity-modulated radiotherapy for pituitary adenomas: the preliminary report of the cleveland clinic experience. Int J Radiat Oncol Biol Phys. 2007;67:232–239. 59. Mayo CS, Martel MK, Marks LB, et al. Tolerance of the optic nerves and chiasm to radiation. Int J Radiat Oncol Biol Phys. 2010;76:S28–S35. 60. Bhandare N, Antonelli PJ, Morris CG, et al. Ototoxicity after radiotherapy for head and neck tumors. Int J Radiat Oncol Biol Phys. 2007;67:469–479. 61. Oh YT, Kim CH, Choi JH, et al. Sensory neural hearing loss after concurrent cisplatin and radiation therapy for nasopharyngeal carcinoma. Radiother Oncol. 2004;72:79–82. 62. Pan CC, Eisbruch A, Lee JS, et al. Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys. 2005;61:1393–1402. 63. Honore HB, Bentzen SM, Moller K, et al. Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: individualized risk estimation. Radiother Oncol. 2002;65:9–16. 64. Chen WC, Jackson A, Budnick AS, et al. Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma. Cancer. 2006;106:820–829.

65. van der Putten L, de Bree R, Plukker JT, et al. Permanent unilateral hearing loss after radiotherapy for parotid gland tumors. Head Neck. 2006;28:902–908. 66. Herrmann F, Dorr W, Muller R, et al. A prospective study on radiationinduced changes in hearing function. Int J Radiat Oncol Biol Phys. 2006;65:1338–1344. 67. Chan SH, Ng WT, Kam KL, et al. Sensorineural hearing loss after treatment of nasopharyngeal carcinoma: a longitudinal analysis. Int J Radiat Oncol Biol Phys. 2009;73:1335–1342. 68. Hitchcock YJ, Tward JD, Szabo A, et al. Relative contributions of radiation and cisplatin-based chemotherapy to sensorineural hearing loss in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys. 2009;73:779–788. 69. Walker GV, Ahmed S, Allen P, et al. Radiation-induced middle ear and mastoid opacification in skull base tumors treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2011;81:e819–e823. 70. Bhandare N, Jackson A, Eisbruch A, et al. Radiotherapy; sensorineural hearing loss; ototoxicity. Int J Radiat Oncol Biol Phys. 2010;76:S50–S57. 71. Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys. 1999;45:577–587. 72. Eisbruch A, Kim HM, Terrell JE, et al. Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;50:695–704. 73. Eisbruch A, Ship JA, Dawson LA, et al. Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer. World J Surg. 2003;27:832–837. 74. Chao KS. Protection of salivary function by intensity-modulated radiation therapy in patients with head and neck cancer. Semin Radiat Oncol. 2002;12:20–25. 75. Chao KS, Deasy JO, Markman J, et al. A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results. Int J Radiat Oncol Biol Phys. 2001;49:907–916. 76. Blanco AI, Chao KS, El Naqa I, et al. Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62:1055–1069. 77. Amosson CM, Teh BS, Van TJ, et al. Dosimetric predictors of xerostomia for head-and-neck cancer patients treated with the smart (simultaneous modulated accelerated radiation therapy) boost technique. Int J Radiat Oncol Biol Phys. 2003;56:136–144. 78. Maes A, Weltens C, Flamen P, et al. Preservation of parotid function with uncomplicated conformal radiotherapy. Radiother Oncol. 2002;63:203–211. 79. Munter MW, Karger CP, Hoffner SG, et al. Evaluation of salivary gland function after treatment of head-and-neck tumors with intensitymodulated radiotherapy by quantitative pertechnetate scintigraphy. Int J Radiat Oncol Biol Phys. 2004;58:175–184. 80. Pacholke HD, Amdur RJ, Morris CG, et al. Late xerostomia after intensity-modulated radiation therapy versus conventional radiotherapy. Am J Clin Oncol. 2005;28:351–358. 81. Roesink JM, Schipper M, Busschers W, et al. A comparison of mean parotid gland dose with measures of parotid gland function after radiotherapy for head-and-neck cancer: implications for future trials. Int J Radiat Oncol Biol Phys. 2005;63:1006–1009. 82. Portaluri M, Fucilli FI, Castagna R, et al. Three-dimensional conformal radiotherapy for locally advanced (stage II and worse) head-and-neck cancer: dosimetric and clinical evaluation. Int J Radiat Oncol Biol Phys. 2006;66:1036–1043. 83. Bussels B, Maes A, Flamen P, et al. Dose-response relationships within the parotid gland after radiotherapy for head and neck cancer. Radiother Oncol. 2004;73:297–306. 84. Braam PM, Roesink JM, Moerland MA, et al. Long-term parotid gland function after radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62:659–664. 85. Roesink JM, Moerland MA, Battermann JJ, et al. Quantitative dosevolume response analysis of changes in parotid gland function after

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CHAPTER 18 radiotherapy in the head-and-neck region. Int J Radiat Oncol Biol Phys. 2001;51:938–946. 86. Li Y, Taylor JM, Ten Haken RK, et al. The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy. Int J Radiat Oncol Biol Phys. 2007;67:660–669. 87. Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2011;12:127–136. 88. Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol. 2007;25:4873–4879. 89. Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. Conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys. 2006;66:981–991. 90. Tribius S, Sommer J, Prosch C, et al. Xerostomia after radiotherapy. What matters–mean total dose or dose to each parotid gland? Strahlenther Onkol. 2013;189:216–222. 91. Mendenhall WM, Mendenhall CM, Mendenhall NP. Submandibular gland-sparing intensity-modulated radiotherapy. Am J Clin Oncol. 2012. 92. Saarilahti K, Kouri M, Collan J, et al. Sparing of the submandibular glands by intensity modulated radiotherapy in the treatment of head and neck cancer. Radiother Oncol. 2006;78:270–275. 93. Wang ZH, Yan C, Zhang ZY, et al. Impact of salivary gland dosimetry on post-IMRT recovery of saliva output and xerostomia grade for head-and-neck cancer patients treated with or without contralateral submandibular gland sparing: a longitudinal study. Int J Radiat Oncol Biol Phys. 2011;81:1479–1487. 94. Jellema AP, Doornaert P, Slotman BJ, et al. Does radiation dose to the salivary glands and oral cavity predict patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with curative radiotherapy? Radiother Oncol. 2005;77:164–171. 95. Little M, Schipper M, Feng FY, et al. Reducing xerostomia after chemo-IMRT for head-and-neck cancer: beyond sparing the parotid glands. Int J Radiat Oncol Biol Phys. 2012;83:1007–1014. 96. Jha N, Harris J, Seikaly H, et al. A phase II study of submandibular gland transfer prior to radiation for prevention of radiation-induced xerostomia in head-and-neck cancer (RTOG 0244). Int J Radiat Oncol Biol Phys. 2012;84:437–442. 97. Beetz I, Schilstra C, Burlage FR, et al. Development of ntcp models for head and neck cancer patients treated with three-dimensional conformal radiotherapy for xerostomia and sticky saliva: the role of dosimetric and clinical factors. Radiother Oncol. 2012;105:86–93. 98. Beetz I, Schilstra C, van der Schaaf A, et al. Ntcp models for patientrated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: the role of dosimetric and clinical factors. Radiother Oncol. 2012;105:101–106. 99. Deasy JO, Moiseenko W, Marks LB, et al. Radiation therapy dose-volume effects on salivary gland function. Int J Radiat Oncol Biol Phys. 2010;76:S58–S63. 100. Moiseenko V, Wu J, Hovan A, et al. Treatment planning constraints to avoid xerostomia in head-and-neck radiotherapy: an independent test of quantec criteria using a prospectively collected dataset. Int J Radiat Oncol Biol Phys. 2012;82:1108–1114. 101. Eisbruch A, Schwartz M, Rasch C, et al. Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys. 2004;60:1425–1439. 102. Sanguineti G, Adapala P, Endres EJ, et al. Dosimetric predictors of laryngeal edema. Int J Radiat Oncol Biol Phys. 2007;68:741–749. 103. Dornfeld K, Simmons JR, Karnell L, et al. Radiation doses to structures within and adjacent to the larynx are correlated with long-term diet- and speech-related quality of life. Int J Radiat Oncol Biol Phys. 2007;68:750–757. 104. Rancati T, Schwarz M, Allen AM, et al. Radiation dose volume effects in the larynx and pharynx. Int J Radiat Oncol Biol Phys. 2010;76:S64–S69.

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105. Johns MM, Kolachala V, Berg E, et al. Radiation fibrosis of the vocal fold: from man to mouse. Laryngoscope. 2012;122(suppl 5):S107–S125. 106. Feng FY, Kim HM, Lyden TH, et al. Intensity-modulated radiotherapy of head and neck cancer aiming to reduce dysphagia: early dose-effect relationships for the swallowing structures. Int J Radiat Oncol Biol Phys. 2007;68:1289–1298. 107. Jensen K, Lambertsen K, Grau C. Late swallowing dysfunction and dysphagia after radiotherapy for pharynx cancer: frequency, intensity and correlation with dose and volume parameters. Radiother Oncol. 2007;85:74–82. 108. Levendag PC, Teguh DN, Voet P, et al. Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a doseeffect relationship. Radiother Oncol. 2007;85:64–73. 109. Li B, Li D, Lau DH, et al. Clinical-dosimetric analysis of measures of dysphagia including gastrostomy-tube dependence among head and neck cancer patients treated definitively by intensity-modulated radiotherapy with concurrent chemotherapy. Radiat Oncol. 2009;4:52. 110. Deantonio L, Masini L, Brambilla M, et al. Dysphagia after definitive radiotherapy for head and neck cancer. Correlation of dose-volume parameters of the pharyngeal constrictor muscles. Strahlenther Onkol. 2013;189:230–236. 111. Dirix P, Abbeel S, Vanstraelen B, et al. Dysphagia after chemoradiotherapy for head-and-neck squamous cell carcinoma: Dose-effect relationships for the swallowing structures. Int J Radiat Oncol Biol Phys. 2009;75:385–392. 112. Caglar HB, Tishler RB, Othus M, et al. Dose to larynx predicts for swallowing complications after intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72:1110–1118. 113. Schwartz DL, Hutcheson K, Barringer D, et al. Candidate dosimetric predictors of long-term swallowing dysfunction after oropharyngeal intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2010;78:1356–1365. 114. Caudell JJ, Schaner PE, Desmond RA, et al. Dosimetric factors associated with long-term dysphagia after definitive radiotherapy for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2010;76:403–409. 115. Christianen ME, Schilstra C, Beetz I, et al. Predictive modelling for swallowing dysfunction after primary (chemo)radiation: results of a prospective observational study. Radiother Oncol. 2012;105:107–114. 116. Kim DR, Duprez F, Werbrouck J, et al. A predictive model for dysphagia following IMRT for head and neck cancer: introduction of the emlasso technique. Radiother Oncol. 2013. 117. Kocak Z, Evans ES, Zhou SM, et al. Challenges in defining radiation pneumonitis in patients with lung cancer. Int J Radiat Oncol Biol Phys. 2005;62:635–638. 118. Gokula K, Earnest A, Wong LC. Meta-analysis of incidence of early lung toxicity in 3-dimensional conformal irradiation of breast carcinomas. Radiat Oncol. 2013;8:268. 119. Vogelius IR, Bentzen SM. A literature-based meta-analysis of clinical risk factors for development of radiation induced pneumonitis. Acta Oncol. 2012;51:975–983. 120. Palma DA, Senan S, Tsujino K, et al. Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2013;85:444–450. 121. Zhang XJ, Sun JG, Sun J, et al. Prediction of radiation pneumonitis in lung cancer patients: a systematic review. J Cancer Res Clin Oncol. 2012;138:2103–2116. 122. Dang J, Li G, Ma L, et al. Predictors of grade ≥ 2 and grade ≥ 3 radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with three-dimensional conformal radiotherapy. Acta Oncol. 2013;52:1175–1180. 123. Anscher MS, Marks LB, Shafman TD, et al. Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy. Int J Radiat Oncol Biol Phys. 2003;56:988–995. 124. Anscher MS, Thrasher B, Zgonjanin L, et al. Small molecular inhibitor of transforming growth factor-beta protects against development of

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radiation-induced lung injury. Int J Radiat Oncol Biol Phys. 2008;71:829–837. 125. Chen Y, Williams J, Ding I, et al. Radiation pneumonitis and early circulatory cytokine markers. Semin Radiat Oncol. 2002;12:26–33. 126. Arpin D, Perol D, Blay JY, et al. Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis. J Clin Oncol. 2005;23:8748–8756. 127. Mazeron R, Etienne-Mastroianni B, Perol D, et al. Predictive factors of late radiation fibrosis: a prospective study in non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2010;77:38–43. 128. Yin M, Liao Z, Liu Z, et al. Functional polymorphisms of base excision repair genes xrcc1 and apex1 predict risk of radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys. 2011;81:e67–e73. 129. Yang M, Zhang L, Bi N, et al. Association of p53 and atm polymorphisms with risk of radiation-induced pneumonitis in lung cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2011;79:1402–1407. 130. Zhang L, Yang M, Bi N, et al. Atm polymorphisms are associated with risk of radiation-induced pneumonitis. Int J Radiat Oncol Biol Phys. 2010;77:1360–1368. 131. Yuan X, Liao Z, Liu Z, et al. Single nucleotide polymorphism at rs1982073:T869c of the tgfbeta 1 gene is associated with the risk of radiation pneumonitis in patients with non-small-cell lung cancer treated with definitive radiotherapy. J Clin Oncol. 2009;27:3370–3378. 132. Mac Manus MP, Ding Z, Hogg A, et al. Association between pulmonary uptake of fluorodeoxyglucose detected by positron emission tomography scanning after radiation therapy for non-small-cell lung cancer and radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2011;80:1365–1371. 133. Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3d treatment for non-small cell lung cancer (nsclc). Int J Radiat Oncol Biol Phys. 1999;45:323–329. 134. Ten Haken RK, Martel MK, Kessler ML, et al. Use of veff and iso-ntcp in the implementation of dose escalation protocols. Int J Radiat Oncol Biol Phys. 1993;27:689–695. 135. Tucker SL, Mohan R, Liengsawangwong R, et al. Predicting pneumonitis risk: a dosimetric alternative to mean lung dose. Int J Radiat Oncol Biol Phys. 2013;85:522–527. 136. Liu F, Yorke ED, Belderbos JS, et al. Using generalized equivalent uniform dose atlases to combine and analyze prospective dosimetric and radiation pneumonitis data from 2 non-small cell lung cancer dose escalation protocols. Int J Radiat Oncol Biol Phys. 2013;85:182–189. 137. Jenkins P, Watts J. An improved model for predicting radiation pneumonitis incorporating clinical and dosimetric variables. Int J Radiat Oncol Biol Phys. 2011;80:1023–1029. 138. Hernando ML, Marks LB, Bentel GC, et al. Radiation-induced pulmonary toxicity: a dose-volume histogram analysis in 201 patients with lung cancer. Int J Radiat Oncol Biol Phys. 2001;51:650–659. 139. Yorke ED, Jackson A, Rosenzweig KE, et al. Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys. 2002;54:329–339. 140. Willner J, Jost A, Baier K, et al. A little to a lot or a lot to a little? An analysis of pneumonitis risk from dose-volume histogram parameters of the lung in patients with lung cancer treated with 3-d conformal radiotherapy. Strahlenther Onkol. 2003;179:548–556. 141. Seppenwoolde Y, Lebesque JV, de Jaeger K, et al. Comparing different ntcp models that predict the incidence of radiation pneumonitis. Normal tissue complication probability. Int J Radiat Oncol Biol Phys. 2003;55:724–735. 142. Kim TH, Cho KH, Pyo HR, et al. Dose-volumetric parameters for predicting severe radiation pneumonitis after three-dimensional conformal radiation therapy for lung cancer. Radiology. 2005;235:208–215. 143. Fay M, Tan A, Fisher R, et al. Dose-volume histogram analysis as predictor of radiation pneumonitis in primary lung cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2005;61:1355–1363.

144. Yorke ED, Jackson A, Rosenzweig KE, et al. Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study. Int J Radiat Oncol Biol Phys. 2005;63:672–682. 145. Piotrowski T, Matecka-Nowak M, Milecki P. Prediction of radiation pneumonitis: Dose-volume histogram analysis in 62 patients with non-small cell lung cancer after three-dimensional conformal radiotherapy. Neoplasma. 2005;52:56–62. 146. Wang S, Liao Z, Wei X, et al. Analysis of clinical and dosimetric factors associated with treatment-related pneumonitis (trp) in patients with non-small-cell lung cancer (nsclc) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3d-crt). Int J Radiat Oncol Biol Phys. 2006;66:1399–1407. 147. Hope AJ, Lindsay PE, El Naqa I, et al. Modeling radiation pneumonitis risk with clinical, dosimetric, and spatial parameters. Int J Radiat Oncol Biol Phys. 2006;65:112–124. 148. Tsujino K, Hirota S, Kotani Y, et al. Radiation pneumonitis following concurrent accelerated hyperfractionated radiotherapy and chemotherapy for limited-stage small-cell lung cancer: Dose-volume histogram analysis and comparison with conventional chemoradiation. Int J Radiat Oncol Biol Phys. 2006;64:1100–1105. 149. Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2007;68:94–102. 150. Bradley JD, Hope A, El Naqa I, et al. A nomogram to predict radiation pneumonitis, derived from a combined analysis of RTOG 9311 and institutional data. Int J Radiat Oncol Biol Phys. 2007;69:985–992. 151. Schallenkamp JM, Miller RC, Brinkmann DH, et al. Incidence of radiation pneumonitis after thoracic irradiation: Dose-volume correlates. Int J Radiat Oncol Biol Phys. 2007;67:410–416. 152. Ramella S, Trodella L, Mineo TC, et al. Adding ipsilateral v20 and v30 to conventional dosimetric constraints predicts radiation pneumonitis in stage iiia-b nsclc treated with combined-modality therapy. Int J Radiat Oncol Biol Phys. 2010;76:110–115. 153. Wang W, Xu Y, Schipper M, et al. Effect of normal lung definition on lung dosimetry and lung toxicity prediction in radiation therapy treatment planning. Int J Radiat Oncol Biol Phys. 2013;86:956–963. 154. Blom Goldman U, Wennberg B, Svane G, et al. Reduction of radiation pneumonitis by v20-constraints in breast cancer. Radiat Oncol. 2010;5:99. 155. Lind PA, Wennberg B, Gagliardi G, et al. Roc curves and evaluation of radiation-induced pulmonary toxicity in breast cancer. Int J Radiat Oncol Biol Phys. 2006;64:765–770. 156. Koh ES, Sun A, Tran TH, et al. Clinical dose-volume histogram analysis in predicting radiation pneumonitis in Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys. 2006;66:223–228. 157. Fox AM, Dosoretz AP, Mauch PM, et al. Predictive factors for radiation pneumonitis in Hodgkin lymphoma patients receiving combinedmodality therapy. Int J Radiat Oncol Biol Phys. 2012;83:277–283. 158. Pinnix CC, Smith GL, Milgrom S, et al. Predictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2015;92:175–182. 159. Kwa SL, Lebesque JV, Theuws JC, et al. Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys. 1998;42:1–9. 160. Armstrong J, Raben A, Zelefsky M, et al. Promising survival with three-dimensional conformal radiation therapy for non-small cell lung cancer. Radiother Oncol. 1997;44:17–22. 161. Tsujino K, Hirota S, Endo M, et al. Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys. 2003;55:110–115. 162. Kong FM, Hayman JA, Griffith KA, et al. Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (nsclc): predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys. 2006;65:1075–1086.

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CHAPTER 18 163. Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of RTOG 9311: a phase I–II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2005;61:318–328. 164. Hayman JA, Martel MK, Ten Haken RK, et al. Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase i trial. J Clin Oncol. 2001;19:127–136. 165. Narayan S, Henning GT, Ten Haken RK, et al. Results following treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer. Lung Cancer. 2004;44:79–88. 166. Rosenzweig KE, Mychalczak B, Fuks Z, et al. Final report of the 70.2-Gy and 75.6-Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer. Cancer J. 2000;6:82–87. 167. Seppenwoolde Y, De Jaeger K, Boersma LJ, et al. Regional differences in lung radiosensitivity after radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;60:748–758. 168. Huang EX, Hope AJ, Lindsay PE, et al. Heart irradiation as a risk factor for radiation pneumonitis. Acta Oncol. 2011;50:51–60. 169. Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;58:1258–1267. 170. Liao ZX, Komaki RR, Thames HD Jr, et al. Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2009. 171. Sura S, Gupta V, Yorke E, et al. Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol. 2008;87:17–23. 172. Allen AM, Czerminska M, Janne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys. 2006;65:640–645. 173. Miles EF, Larrier NA, Kelsey CR, et al. Intensity-modulated radiotherapy for resected mesothelioma: the duke experience. Int J Radiat Oncol Biol Phys. 2008;71:1143–1150. 174. Rice DC, Smythe WR, Liao Z, et al. Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys. 2007;69:350–357. 175. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose volume effects in the lung. Int J Radiat Oncol Biol Phys. 2010;76:S70–S76. 176. De Jaeger K, Seppenwoolde Y, Boersma LJ, et al. Pulmonary function following high-dose radiotherapy of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2003;55:1331–1340. 177. Choi NC, Kanarek DJ. Toxicity of thoracic radiotherapy on pulmonary function in lung cancer. Lung Cancer. 1994;10(suppl 1):S219–S230. 178. Miller KL, Zhou SM, Barrier RC Jr, et al. Long-term changes in pulmonary function tests after definitive radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys. 2003;56:611–615. 179. Abratt RP, Willcox PA. The effect of irradiation on lung function and perfusion in patients with lung cancer. Int J Radiat Oncol Biol Phys. 1995;31:915–919. 180. Jaen J, Vazquez G, Alonso E, et al. Long-term changes in pulmonary function after incidental lung irradiation for breast cancer: a prospective study with 7-year follow-up. Int J Radiat Oncol Biol Phys. 2012;84:e565–e570. 181. Marks LB, Fan M, Clough R, et al. Radiation-induced pulmonary injury: symptomatic versus subclinical endpoints. Int J Radiat Biol. 2000;76:469–475. 182. Marks LB, Munley MT, Bentel GC, et al. Physical and biological predictors of changes in whole-lung function following thoracic irradiation. Int J Radiat Oncol Biol Phys. 1997;39:563–570. 183. Allen AM, Henning GT, Ten Haken RK, et al. Do dose-volume metrics predict pulmonary function changes in lung irradiation? Int J Radiat Oncol Biol Phys. 2003;55:921–929. 184. Fan M, Marks LB, Hollis D, et al. Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction? J Clin Oncol. 2001;19:543–550.

Late Effects After Radiation

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185. Fan M, Marks LB, Lind P, et al. Relating radiation-induced regional lung injury to changes in pulmonary function tests. Int J Radiat Oncol Biol Phys. 2001;51:311–317. 186. Lopez Guerra JL, Gomez D, Zhuang Y, et al. Change in diffusing capacity after radiation as an objective measure for grading radiation pneumonitis in patients treated for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2012;83:1573–1579. 187. Mah K, Van Dyk J. Quantitative measurement of changes in human lung density following irradiation. Radiother Oncol. 1988;11:169–179. 188. Marks LB, Munley MT, Spencer DP, et al. Quantification of radiationinduced regional lung injury with perfusion imaging. Int J Radiat Oncol Biol Phys. 1997;38:399–409. 189. Ghobadi G, Hogeweg LE, Faber H, et al. Quantifying local radiationinduced lung damage from computed tomography. Int J Radiat Oncol Biol Phys. 2010;76:548–556. 190. Borst GR, De Jaeger K, Belderbos JS, et al. Pulmonary function changes after radiotherapy in non-small-cell lung cancer patients with long-term disease-free survival. Int J Radiat Oncol Biol Phys. 2005;62:639–644. 191. Gagliardi G, Lax I, Rutqvist LE. Partial irradiation of the heart. Semin Radiat Oncol. 2001;11:224–233. 192. Adams MJ, Hardenbergh PH, Constine LS, et al. Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol. 2003;45:55–75. 193. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA. 1993;270:1949–1955. 194. Marks LB, Yu X, Prosnitz RG, et al. The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys. 2005;63:214–223. 195. Evans ES, Prosnitz RG, Yu X, et al. Impact of patient-specific factors, irradiated left ventricular volume, and treatment set-up errors on the development of myocardial perfusion defects after radiation therapy for left-sided breast cancer. Int J Radiat Oncol Biol Phys. 2006;66: 1125–1134. 196. Das SK, Baydush AH, Zhou S, et al. Predicting radiotherapy-induced cardiac perfusion defects. Med Phys. 2005;32:19–27. 197. Carr ZA, Land CE, Kleinerman RA, et al. Coronary heart disease after radiotherapy for peptic ulcer disease. Int J Radiat Oncol Biol Phys. 2005;61:842–850. 198. Gagliardi G, Lax I, Ottolenghi A, et al. Long-term cardiac mortality after radiotherapy of breast cancer–application of the relative seriality model. Br J Radiol. 1996;69:839–846. 199. Eriksson F, Gagliardi G, Liedberg A, et al. Long-term cardiac mortality following radiation therapy for Hodgkin’s disease: analysis with the relative seriality model. Radiother Oncol. 2000;55:153–162. 200. Schytte T, Hansen O, Stolberg-Rohr T, et al. Cardiac toxicity and radiation dose to the heart in definitive treated non-small cell lung cancer. Acta Oncol. 2010;49:1058–1060. 201. Konski A, Li T, Christensen M, et al. Symptomatic cardiac toxicity is predicted by dosimetric and patient factors rather than changes in 18F-FDG pet determination of myocardial activity after chemoradiotherapy for esophageal cancer. Radiother Oncol. 2012;104:72–77. 202. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987–998. 203. van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation doseresponse relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol. 2016;34:235–243. 204. Chung E, Corbett JR, Moran JM, et al. Is there a dose-response relationship for heart disease with low-dose radiation therapy? Int J Radiat Oncol Biol Phys. 2013;85:959–964. 205. Zagar TM, Marks LB. Breast cancer: risk of heart disease after radiotherapy-cause for concern. Nat Rev Clin Oncol. 2013;10:310–312. 206. Henson KE, McGale P, Taylor C, et al. Radiation-related mortality from heart disease and lung cancer more than 20 years after radiotherapy for breast cancer. Br J Cancer. 2013;108:179–182. 207. Guberina M, Eberhardt W, Stuschke M, et al. Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B

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Scientific Foundations of Radiation Oncology

non-small-cell lung cancer: secondary analysis of a randomized trial. Ann Oncol. 2017;28:1084–1089. 208. Speirs CK, DeWees TA, Rehman S, et al. Heart dose is an independent dosimetric predictor of overall survival in locally advanced non-small cell lung cancer. J Thorac Oncol. 2017;12:293–301. 209. Wang K, Pearlstein KA, Patchett ND, et al. Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for stage III non-small-cell lung cancer. Radiother Oncol. 2017;125:293–300. 210. Dess RT, Sun Y, Matuszak MM, et al. Cardiac events after radiation therapy: combined analysis of prospective multicenter trials for locally advanced non-small-cell lung cancer. J Clin Oncol. 2017;35:1395–1402. 211. van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures. J Clin Oncol. 2017;35:1171–1178. 212. van Nimwegen FA, Ntentas G, Darby SC, et al. Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines. Blood. 2017;129:2257–2265. 213. Nilsson G, Holmberg L, Garmo H, et al. Distribution of coronary artery stenosis after radiation for breast cancer. J Clin Oncol. 2012;30: 380–386. 214. Pezner RD. Coronary artery disease and breast radiation therapy. Int J Radiat Oncol Biol Phys. 2013;86:816–818. 215. MacDonald SM. Proton therapy for breast cancer: getting to the heart of the matter. Int J Radiat Oncol Biol Phys. 2016;95:46–48. 216. Tripp P, Malhotra HK, Javle M, et al. Cardiac function after chemoradiation for esophageal cancer: comparison of heart dose-volume histogram parameters to multiple gated acquisition scan changes. Dis Esophagus. 2005;18:400–405. 217. Wei X, Liu HH, Tucker SL, et al. Risk factors for pericardial effusion in inoperable esophageal cancer patients treated with definitive chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2008;70:707–714. 218. Martel MK, Sahijdak WM, Ten Haken RK, et al. Fraction size and dose parameters related to the incidence of pericardial effusions. Int J Radiat Oncol Biol Phys. 1998;40:155–161. 219. Heidenreich PA, Hancock SL, Lee BK, et al. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol. 2003;42:743–749. 220. Hull MC, Morris CG, Pepine CJ, et al. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA. 2003;290:2831–2837. 221. Cella L, Liuzzi R, Conson M, et al. Multivariate normal tissue complication probability modeling of heart valve dysfunction in Hodgkin lymphoma survivors. Int J Radiat Oncol Biol Phys. 2013;87:304–310. 222. Cutter DJ, Schaapveld M, Darby SC, et al. Risk of valvular heart disease after treatment for Hodgkin lymphoma. J Natl Cancer Inst. 2015;107. 223. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007;109:1878–1886. 224. King V, Constine LS, Clark D, et al. Symptomatic coronary artery disease after mantle irradiation for Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 1996;36:881–889. 225. Gagliardi G, Constine LS, Moiseenko W, et al. Radiation-associated heart injury. Int J Radiat Oncol Biol Phys. 2010;76:S77–S85. 226. Kahn D, Zhou S, Ahn SJ, et al. “Anatomically-correct” dosimetric parameters may be better predictors for esophageal toxicity than are traditional CT-based metrics. Int J Radiat Oncol Biol Phys. 2005;62:645–651. 227. Singh AK, Lockett MA, Bradley JD. Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2003;55:337–341. 228. Qiao WB, Zhao YH, Zhao YB, et al. Clinical and dosimetric factors of radiation-induced esophageal injury: radiation-induced esophageal toxicity. World J Gastroenterol. 2005;11:2626–2629.

229. Maguire PD, Sibley GS, Zhou SM, et al. Clinical and dosimetric predictors of radiation-induced esophageal toxicity. Int J Radiat Oncol Biol Phys. 1999;45:97–103. 230. Ahn SJ, Kahn D, Zhou S, et al. Dosimetric and clinical predictors for radiation-induced esophageal injury. Int J Radiat Oncol Biol Phys. 2005;61:335–347. 231. Palma DA, Senan S, Oberije C, et al. Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2013;87:690–696. 232. Werner-Wasik M, Yorke ED, Deasy JO, et al. Radiation-associated esophageal toxicity. Int J Radiat Oncol Biol Phys. 2010;73: S86–S93. 233. Eifel PJ, Levenback C, Wharton JT, et al. Time course and incidence of late complications in patients treated with radiation therapy for FIGO Stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 1995;32:1289–1300. 234. Cosset JM, Henry-Amar M, Burgers JM, et al. Late radiation injuries of the gastrointestinal tract in the H2 and H5 EORTC Hodgkin’s disease trials: emphasis on the role of exploratory laparotomy and fractionation. Radiother Oncol. 1988;13:61–68. 235. Mak AC, Rich TA, Schultheiss TE, et al. Late complications of postoperative radiation therapy for cancer of the rectum and rectosigmoid. Int J Radiat Oncol Biol Phys. 1994;28:597–603. 236. Pan CC, Dawson LA, McGinn CJ, et al. Analysis of radiation-induced gastric and duodenal bleeds using the Lyman-Kutcher-Burman model. Int J Radiat Oncol Biol Phys. 2003;57:S217. 237. Huang J, Robertson JM, Ye H, et al. Dose-volume analysis of predictors for gastrointestinal toxicity after concurrent full-dose gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2012;83:1120–1125. 238. Kelly P, Das P, Pinnix CC, et al. Duodenal toxicity after fractionated chemoradiation for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2013;85:e143–e149. 239. Poorvu PD, Sadow CA, Townamchai K, et al. Duodenal and other gastrointestinal toxicity in cervical and endometrial cancer treated with extended-field intensity modulated radiation therapy to paraaortic lymph nodes. Int J Radiat Oncol Biol Phys. 2013;85:1262–1268. 240. Stanic S, Mayadev JS. Tolerance of the small bowel to therapeutic irradiation: a focus on late toxicity in patients receiving para-aortic nodal irradiation for gynecologic malignancies. Int J Gynecol Cancer. 2013;23:592–597. 241. Chen Z, Zhu L, Zhang B, et al. Dose-volume histogram predictors of chronic gastrointestinal complications after radical hysterectomy and postoperative intensity modulated radiotherapy for early-stage cervical cancer. BMC Cancer. 2014;14:789. 242. Reis T, Khazzaka E, Welzel G, et al. Acute small-bowel toxicity during neoadjuvant combined radiochemotherapy in locally advanced rectal cancer: determination of optimal dose-volume cut-off value predicting grade 2-3 diarrhoea. Radiat Oncol. 2015;10:30. 243. Kavanagh B, Pan CC, Dawson LA, et al. Radiation dose volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys. 2010;76:S101–S107. 244. Roeske JC, Bonta D, Mell LK, et al. A dosimetric analysis of acute gastrointestinal toxicity in women receiving intensity-modulated whole-pelvic radiation therapy. Radiother Oncol. 2003;69:201–207. 245. Baglan KL, Frazier RC, Yan D, et al. The dose-volume relationship of acute small bowel toxicity from concurrent 5-FU-based chemotherapy and radiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys. 2002;52:176–183. 246. Banerjee R, Chakraborty S, Nygren I, et al. Small bowel dose parameters predicting grade ≥ 3 acute toxicity in rectal cancer patients treated with neoadjuvant chemoradiation: an independent validation study comparing peritoneal space versus small bowel loop contouring techniques. Int J Radiat Oncol Biol Phys. 2013;85:1225–1231. 247. Schultheiss TE, Lee WR, Hunt MA, et al. Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys. 1997;37:3–11.

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CHAPTER 18 248. Peeters ST, Heemsbergen WD, van Putten WL, et al. Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys. 2005;61:1019–1034. 249. Barnett GC, De Meerleer G, Gulliford SL, et al. The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397). Clin Oncol (R Coll Radiol). 2011;23:613–624. 250. Peeters ST, Hoogeman MS, Heemsbergen WD, et al. Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: normal tissue complication probability modeling. Int J Radiat Oncol Biol Phys. 2006;66:11–19. 251. Langsenlehner T, Renner W, Gerger A, et al. Association between single nucleotide polymorphisms in the gene for XRCC1 and radiationinduced late toxicity in prostate cancer patients. Radiother Oncol. 2011;98:387–393. 252. Jackson A, Skwarchuk MW, Zelefsky MJ, et al. Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys. 2001;49:685–698. 253. Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys. 2000;47:103–113. 254. Zelefsky MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensitymodulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:1124–1129. 255. Wachter S, Gerstner N, Goldner G, et al. Rectal sequelae after conformal radiotherapy of prostate cancer: Dose-volume histograms as predictive factors. Radiother Oncol. 2001;59:65–70. 256. Fiorino C, Sanguineti G, Cozzarini C, et al. Rectal dose-volume constraints in high-dose radiotherapy of localized prostate cancer. Int J Radiat Oncol Biol Phys. 2003;57:953–962. 257. Fiorino C, Cozzarini C, Vavassori V, et al. Relationships between dvhs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions. Radiother Oncol. 2002;64:1–12. 258. Cozzarini C, Fiorino C, Ceresoli GL, et al. Significant correlation between rectal dvh and late bleeding in patients treated after radical prostatectomy with conformal or conventional radiotherapy (66.6-70.2 Gy). Int J Radiat Oncol Biol Phys. 2003;55:688–694. 259. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys. 2002;53:1097–1105. 260. Huang EH, Pollack A, Levy L, et al. Late rectal toxicity: Dose-volume effects of conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2002;54:1314–1321. 261. Peeters ST, Lebesque JV, Heemsbergen WD, et al. Localized volume effects for late rectal and anal toxicity after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2006;64:1151–1161. 262. Vargas C, Martinez A, Kestin LL, et al. Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62:1297–1308. 263. Tucker SL, Dong L, Cheung R, et al. Comparison of rectal dose-wall histogram versus dose-volume histogram for modeling the incidence of late rectal bleeding after radiotherapy. Int J Radiat Oncol Biol Phys. 2004;60:1589–1601. 264. Boersma LJ, van den Brink M, Bruce AM, et al. Estimation of the incidence of late bladder and rectum complications after high-dose (70–78 Gy) conformal radiotherapy for prostate cancer, using dosevolume histograms. Int J Radiat Oncol Biol Phys. 1998;41:83–92. 265. Kupelian PA, Reddy CA, Carlson TP, et al. Dose/volume relationship of late rectal bleeding after external beam radiotherapy for localized prostate cancer: absolute or relative rectal volume? Cancer J. 2002;8:62–66. 266. Pederson AW, Fricano J, Correa D, et al. Late toxicity after intensitymodulated radiation therapy for localized prostate cancer: an exploration of dose-volume histogram parameters to limit genitourinary

Late Effects After Radiation

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and gastrointestinal toxicity. Int J Radiat Oncol Biol Phys. 2012;82:235–241. 267. Tomita N, Soga N, Ogura Y, et al. Preliminary analysis of risk factors for late rectal toxicity after helical tomotherapy for prostate cancer. J Radiat Res. 2013. 268. Michalski JM, Yan Y, Watkins-Bruner D, et al. Preliminary toxicity analysis of 3-dimensional conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial. Int J Radiat Oncol Biol Phys. 2013;87:932–938. 269. Buettner F, Gulliford SL, Webb S, et al. Assessing correlations between the spatial distribution of the dose to the rectal wall and late rectal toxicity after prostate radiotherapy: an analysis of data from the MRC RT01 trial (ISRCTN 47772397). Phys Med Biol. 2009;54:6535–6548. 270. Colaco RJ, Hoppe BS, Flampouri S, et al. Rectal toxicity after proton therapy for prostate cancer: an analysis of outcomes of prospective studies conducted at the University of Florida proton therapy institute. Int J Radiat Oncol Biol Phys. 2015;91:172–181. 271. Michalski JM, Gay H, Jackson A, et al. Radiation induced rectal injury. Int J Radiat Oncol Biol Phys. 2010;76:S123–S129. 272. Michalski JM, Bae K, Roach M, et al. Long-term toxicity following 3D conformal radiation therapy for prostate cancer from the RTOG 9406 phase I/II dose escalation study. Int J Radiat Oncol Biol Phys. 2010;76:14–22. 273. Tucker SL, Dong L, Michalski JM, et al. Do intermediate radiation doses contribute to late rectal toxicity? An analysis of data from Radiation Therapy Oncology Group protocol 94-06. Int J Radiat Oncol Biol Phys. 2012;84:390–395. 274. Russell AH, Clyde C, Wasserman TH, et al. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol. Int J Radiat Oncol Biol Phys. 1993;27:117–123. 275. Lawrence TS, Ten Haken RK, Kessler ML, et al. The use of 3-D dose volume analysis to predict radiation hepatitis. Int J Radiat Oncol Biol Phys. 1992;23:781–788. 276. Dawson LA, Normolle D, Balter JM, et al. Analysis of radiation-induced liver disease using the Lyman NTCP model. Int J Radiat Oncol Biol Phys. 2002;53:810–821. 277. Cheng JC, Wu JK, Huang CM, et al. Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication. Int J Radiat Oncol Biol Phys. 2002;54:156–162. 278. Cheng JC, Wu JK, Lee PC, et al. Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease. Int J Radiat Oncol Biol Phys. 2004;60:1502–1509. 279. Kim TH, Kim DY, Park JW, et al. Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2007;67:225–231. 280. Son SH, Kay CS, Song JH, et al. Dosimetric parameter predicting the deterioration of hepatic function after helical tomotherapy in patients with unresectable locally advanced hepatocellular carcinoma. Radiat Oncol. 2013;8:11. 281. Pan CC, Kavanagh B, Dawson LA, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys. 2010;76:S94–S100. 282. McCune JS, Friedman DL, Schuetze S, et al. Influence of age upon ifosfamide-induced nephrotoxicity. Pediatr Blood Cancer. 2004;42:427–432. 283. Dewit L, Verheij M, Valdes Olmos RA, et al. Compensatory renal response after unilateral partial and whole volume high-dose irradiation of the human kidney. Eur J Cancer. 1993;29A:2239–2243. 284. Kim TH, Somerville PJ, Freeman CR. Unilateral radiation nephropathy– the long-term significance. Int J Radiat Oncol Biol Phys. 1984;10:2053–2059. 285. Willett CG, Tepper JE, Orlow EL, et al. Renal complications secondary to radiation treatment of upper abdominal malignancies. Int J Radiat Oncol Biol Phys. 1986;12:1601–1604. 286. Kost S, Dorr W, Keinert K, et al. Effect of dose and dose-distribution in damage to the kidney following abdominal radiotherapy. Int J Radiat Biol. 2002;78:695–702.

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SECTION I

Scientific Foundations of Radiation Oncology

287. Welz S, Hehr T, Kollmannsberger C, et al. Renal toxicity of adjuvant chemoradiotherapy with cisplatin in gastric cancer. Int J Radiat Oncol Biol Phys. 2007;69:1429–1435. 288. Varlotto JM, Gerszten K, Heron DE, et al. The potential nephrotoxic effects of intensity modulated radiotherapy delivered to the para-aortic area of women with gynecologic malignancies: preliminary results. Am J Clin Oncol. 2006;29:281–289. 289. Flentje M, Hensley F, Gademann G, et al. Renal tolerance to nonhomogenous irradiation: comparison of observed effects to predictions of normal tissue complication probability from different biophysical models. Int J Radiat Oncol Biol Phys. 1993;27:25–30. 290. Jansen EP, Saunders MP, Boot H, et al. Prospective study on late renal toxicity following postoperative chemoradiotherapy in gastric cancer. Int J Radiat Oncol Biol Phys. 2007;67:781–785. 291. Diavolitsis VM, Rademaker A, Boyle J, et al. Change in creatinine clearance over time following upper abdominal irradiation: a dosevolume histogram multivariate analysis. Am J Clin Oncol. 2011;34:53–57. 292. Dawson LA, Kavanagh BD, Paulino AC, et al. Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys. 2010;76:S108–S115. 293. Ahmed AA, Egleston B, Alcantara P, et al. A novel method for predicting late genitourinary toxicity after prostate radiation therapy and the need for age-based risk-adapted dose constraints. Int J Radiat Oncol Biol Phys. 2013. 294. Appelt AL, Bentzen SM, Jakobsen A, et al. Dose-response of acute urinary toxicity of long-course preoperative chemoradiotherapy for rectal cancer. Acta Oncol. 2015;54:179–186. 295. Viswanathan AN, Yorke ED, Marks LB, et al. Radiation-associated bladder injury. Int J Radiat Oncol Biol Phys. 2010;76:S116–S122. 296. Wallner KE, Merrick GS, Benson ML, et al. Penile bulb imaging. Int J Radiat Oncol Biol Phys. 2002;53:928–933. 297. Gay HA, Barthold HJ, O’Meara E, et al. Pelvic normal tissue contouring guidelines for radiation therapy: a radiation therapy oncology group consensus panel atlas. Int J Radiat Oncol Biol Phys. 2012;83:e353–e362. 298. Kao J, Turian J, Meyers A, et al. Sparing of the penile bulb and proximal penile structures with intensity-modulated radiation therapy for prostate cancer. Br J Radiol. 2004;77:129–136. 299. Brown MW, Brooks JP, Albert PS, et al. An analysis of erectile function after intensity modulated radiation therapy for localized prostate carcinoma. Prostate Cancer Prostatic Dis. 2007;10:189–193.

300. van der Wielen GJ, Hoogeman MS, Dohle GR, et al. Dose-volume parameters of the corpora cavernosa do not correlate with erectile dysfunction after external beam radiotherapy for prostate cancer: results from a dose-escalation trial. Int J Radiat Oncol Biol Phys. 2008;71:795–800. 301. Selek U, Cheung R, Lii M, et al. Erectile dysfunction and radiation dose to penile base structures: a lack of correlation. Int J Radiat Oncol Biol Phys. 2004;59:1039–1046. 302. Fisch BM, Pickett B, Weinberg V, et al. Dose of radiation received by the bulb of the penis correlates with risk of impotence after threedimensional conformal radiotherapy for prostate cancer. Urology. 2001;57:955–959. 303. Wernicke AG, Valicenti R, Dieva K, et al. Radiation dose delivered to the proximal penis as a predictor of the risk of erectile dysfunction after three-dimensional conformal radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004;60:1357–1363. 304. Mangar SA, Sydes MR, Tucker HL, et al. Evaluating the relationship between erectile dysfunction and dose received by the penile bulb: using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397). Radiother Oncol. 2006;80:355–362. 305. Magli A, Giangreco M, Crespi M, et al. Erectile dysfunction after prostate three-dimensional conformal radiation therapy. Correlation with the dose to the penile bulb. Strahlenther Onkol. 2012;188:997–1002. 306. Roach M, Winter K, Michalski JM, et al. Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: findings from a prospective, multi-institutional, phase I/II dose-escalation study. Int J Radiat Oncol Biol Phys. 2004;60:1351–1356. 307. Roach M, Nam J, Gagliardi G, et al. Radiation dose volume effects and the penile bulb. Int J Radiat Oncol Biol Phys. 2010;76:S130–S134. 308. Engels B, Soete G, Verellen D, et al. Conformal arc radiotherapy for prostate cancer: increased biochemical failure in patients with distended rectum on the planning computed tomogram despite image guidance by implanted markers. Int J Radiat Oncol Biol Phys. 2009;74:388–391. 309. Pfeffer MR, Rabin T, Tsvang L, et al. Orbital lymphoma: is it necessary to treat the entire orbit? Int J Radiat Oncol Biol Phys. 2004;60:527–530.

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19 Quality and Safety in Radiation Oncology Louis Potters, Suzanne B. Evans, and Todd Pawlicki

INTRODUCTION The Relationship Between Safety and Quality Health care is replete with examples of errors culminating in adverse events that compromise the quality and value of care.1 It comes as no surprise that optimum oncological outcomes depend on excellent execution and design of a radiotherapy plan. In the clinical trial setting, there are numerous reports of the association of protocol variations with inferior survival,2,3 or worse, toxicity.4 Considering that the protocol violations are classically related to inappropriate dosing or inappropriate targeting, which is the same ultimate outcome in the setting of error, it is no stretch to understand that error can profoundly affect outcome, and optimum quality depends on optimum safe practice. It is only surprising that this relationship is not seen in every post-hoc analysis of protocol deviations. Imagine, if you will, the complex relationship between the importance of safety in quality care throughout a varied spectrum of patients seen in any clinic. There is an idealized survival rate for any cancer. We then must adjust this for a variety of factors: current medical knowledge, safe and accurate execution of that medical knowledge, competing morbidities of the patient, and the ability and desire of the patient to tolerate and adhere to recommended therapy. The survival rate for any disease can never be higher than what the most limiting factor allows (Fig. 19.1). It is likely that this interplay explains why protocol variation and errors in radiotherapy do not always exhibit measurable decrements in outcome. Despite this, we recognize the unfortunate truth that the capacity for error is intrinsically human and, wherever humans exist, the capacity for error will exist. Historically, there has been an overarching tendency to look for a scapegoat and to blame a single individual or group of “bad apples” for the incident in question. Apart from reckless (defined here as deliberately risk-taking) behavior on the part of the individual, the majority of adverse events are attributed instead to any number of error-permeable conditions prevalent at the system level. There can be individual factors that prevent the interception of the error from its origin to the “sharp end”5 of patient care, but usually these occurs with a much greater number of system factors to carry the weight of culpability. This has led to the popularity of the approach of “systems thinking,” which refers to the need for solutions that address systems weaknesses behind the error. Indeed, the very bottom of the hierarchy of effectiveness6 (Fig. 19.2) is personal vigilance, underlying exactly why exhortation should be an uncommon corrective action.7

The Nature of Error It is important to recognize that there are several categories of error, which center around whether the failure occurred at the planning stage or execution stage.8 Execution failures—in which an appropriate

intervention is performed, but performed poorly—are called slips or lapses. Slips typically involve failure of attention: confused perception, misordering of events, or reversing events. Lapses tend to involve memory failures: omission of steps, performing tasks without appropriate intentionality. In contrast, planning failures involve rule-based and knowledge-based mistakes. In rule-based mistakes, the agent misapplies a rule that is good and appropriate or applies a rule that is inappropriate or poorly made. With knowledge-based mistakes, the causes are various: there can be confirmation bias, one can engage in encysting (also referred to as situational unawareness, in which one pays attention to small details, overlooking the broader picture), one can experience search satisfying, or any number of other biases that we will discuss shortly. Such behavior has also been classified under the broad term “unsafe acts,”9 which can be errors or violations. Errors can be skill based, decisional, or perceptual; whereas violations can be routine (normalization of deviance in failure to follow an ill-regarded policy) or exceptional (intoxication at work). Additionally, one can think of “latent” or “active” failures.10 Active errors occur at the point of interaction between the health care provider and some aspect of a larger system. Latent errors are more subtle failures of organization or workflow design that contributed to the error. For instance, an active failure would be an inappropriate manual override of the table tolerance for an incorrectly shifted patient. The latent failure behind this may be a complicated simulation procedure that inadvertently encourages error in the calculation of a shift. The reader should be advised that there are many ways to classify error. The important piece of this discussion is to comprehend the many pathways for error, most of which are distinct from negligent or reckless behavior. In the majority of the aforementioned pathways to error, there is no malice or deviation from professionalism. The role of cognitive bias in both the failure to recognize error and in the commission of error is profound. The Joint Commission has recognized cognitive bias as a major issue in patient safety.11 The world of health care is a complex system, fraught with person factors, system factors, and patient factors that make cognitive bias more likely (Table 19.1). One can easily imagine a scenario in which a normally highly proficient health care provider, overloaded with patients, working through illness and little sleep, might be treating a complex admitted patient with spinal cord compression under great time pressure across several different electronic medical record systems amid a busy clinic day, with an error resulting from this convergence of factors. The field of cognitive bias has more than 150 different recognized human biases that can cloud judgment and result in poor decisions or actions. Readers are directed to the work of Croskerry12–16 for a comprehensive view of these biases. Anyone who has ever been in chart rounds understands sunk cost fallacy: the reluctance to change one’s course of action when there is a lot of time and effort already expended

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CHAPTER 19 100

Quality and Safety in Radiation Oncology

315

Factors Associated With Higher Prevalence of Cognitive Bias11

TABLE 19.1

80 60

Execution Knowledge Adherence/tolerance Competing morbidity

40 20 0

Patient “A” Patient “B” Patient “C” Fig. 19.1 In this figure, the limitations on the maximum attainable survival rate for three patients is given. For Patient “A,” there is a huge rate of competing morbidity; thus, the major factors impacting potential for survival are death from other causes and tolerance to treatment. The effectiveness of treatment based on our medical knowledge and safe and accurate execution play a minor role. For Patient “B,” the knowledge of the disease and available medical treatments are extremely poor; thus, the adherence to this therapy and its execution have essentially no import. The main factor impacting survival is the disease itself and competing morbidity. Finally, for Patient “C,” there is very little competing morbidity, and tolerance to treatment is certain. For this patient, the proper application of medical knowledge through treatment and appropriate execution of this treatment is of critical value.

Person Factors

Patient Factors

Fatigue

Complex patient presentation

Workflow design (task complexity, reliance on memory, multiple hand-offs)

Cognitive loading

Elevated number of comorbidities

Insufficient time to procure, integrate, and make sense of information

Affective bias

Lack of complete history

Inadequate processes to acquire information (e.g., transfer)

System Factors

Poorly designed/integrated or inaccessible health information technology Poorly designed environment (e.g., distractions, interruptions, noise, poor lighting) Poor teamwork, collaboration, and communication Inadequate culture to support decision-making (e.g., lack of resources, time, rigid hierarchical structure) Adapted from Ford EC, Evans SB. Incident learning in radiation oncology: a review. Med Phys. 2018;45(5):e100-e119.

Forcing functions Automation, computerization, and technology Standardization and protocols Staffing organization Policies, rules, and expectations Checklists & double-checks Risk assessment and communication errors Education and information Personal initiative—vigilance Fig. 19.2 The hierarchy of effectiveness—the top of the pyramid has the most effective strategies and the bottom has the least effective strategies for error prevention. (Adapted from Woods DM, Holl JL, Angst D, et al. Improving clinical communication and patient safety: clinicianrecommended solutions. In: Henriksen K, Battles BJ, Keyes MA, et al., eds. Advances in Patient Safety: New Directions and Alternative Approaches Vol. 3: Performance and Tools. Rockville, MD: Agency for Healthcare Research and Quality; 2008.

in the current course of action. Likewise, posterior probability error is common in diagnostic error, in which one assumes that because the prior cause of a headache was a migraine three times in the past that this headache must be a migraine and not brain metastases despite new concerning features in the presentation. Gambler’s fallacy refers to the reluctance to believe that a certain event cannot be repeated multiple times in a row, such as 3 patients with leg swelling in one clinic day all having deep venous thrombosis, when the truth is that the patients have no relationship to each other and each likelihood must be considered

in isolation from the other. Confirmation bias is present during chart checks of a skilled dosimetrist’s plan when it is erroneously judged that the plan is perfect because that is what one subconsciously expects from a normally excellent team member. Availability bias is assigning a cause based more on what readily comes to mind rather than a rigorous consideration of all reasonable possibilities. Anchoring is the tendency to hold on to one’s initial thought about a situation despite subsequent disconfirming evidence. In the investigation of the Lisa Norris Glasgow incident, in which a young woman being treated for CNS malignancy received an ultimately fatal dose of radiation to her brain, an error was found in her spine plan. The investigators postulated that search-satisfying bias contributed to the miss of the second error in the whole-brain plan that caused her demise,17 such that those performing the plan check subconsciously stopped looking once they found a single error despite the presence of two errors. It is important to note that cognitive biases are also referred to as failed heuristics (failed rules of thumb) because these mental shortcuts can be quite useful in everyday life. For instance, hearing hoofbeats, one can use posterior probability error to correctly conclude that there are horses approaching; however, sometimes zebras appear. Additional work in radiation medicine has been done regarding the NASA task load index, which is helpful for understanding the environment in which error occurs. In this schema, each task is given a certain “load” based on mental and physical demands.18 In this data, it becomes apparent that mistakes happen at very low and very high task-load indices.19 One might postulate that in the low-load time period, one “goes on autopilot” and inattention prevails, leaving one open to a slip. At high workloads, there is cognitive overload, predisposing one to rely on cognitive biases and subsequent error. This work has also shown that cross-coverage is associated with higher workloads, which is another vulnerable clinical situation for error.20 A multitude of other factors may impact our decision-making quality and task performance, including

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316

SECTION II

Techniques and Modalities

rudeness (from patients, families, or team members),21,22 clinician attitudes,23,24 group gender composition and collective intelligence,25,26 and group dynamics.27 The clear understanding that all clinicians are vulnerable to error and the recognition of the scenarios that increase its likelihood are essential to the foundation of a safety culture and a compassionate department.

The Role of Safety Culture System weaknesses also tend to be pronounced in systems with complex interactions,5,10,28–34 for which a normal rate of accidents may be expected.35 Thus, the opportunity to improve quality and safety in radiation oncology must originate at the system level. This creates a culture that drives high reliability to minimize adverse events despite the intrinsically complex and hazardous work associated with the delivery of high-energy ionizing radiation. The commitment to safety at all levels of the department and system, from frontline providers to managers and executives, establishes a culture of safety that forms the foundation of “Safety is No Accident,” issued by the American Society for Radiation Oncology (ASTRO).36 That cultural foundation acknowledges the risk associated in the treatment of patients. It requires a just culture,37 in which reporting of errors is without fear of recrimination, with encouragement of collaboration across the spectrum of job descriptions. The goal is to seek solutions to safety problems; thus, leadership is committed to resources to address safety concerns. Improving the culture of safety serves as a foundation for everyone in health care in general, specifically in radiation oncology in preventing or reducing errors and improving overall health care quality. The importance of creating this culture is as or more important than any specific disease-related treatment covered in this book, as outcomes are directly related to the quality of care that our patients receive. Participating in the safety culture is paramount to everything we do every day in ensuring that our patients receive the best care possible.

The Impact of Error Clearly, the occurrence of medical error is truly devastating38 for the patients and families affected by it. Medical error is also devastating to clinicians who are involved in error, leading to the use of the term “second victim.”39 It should be noted that this term is controversial in some circles: it can be seen to detract from the patient experience or, alternatively, can be valued for the degree of urgency that it conveys.40 For the purposes of this chapter, the term second victim will be used for health care providers, with no intention of detracting from the patient experience of error. Involvement in medical error has been linked to physician burnout,41–46 suicidal ideation,47 and loss of physicians to the profession of medicine. There is an increasing movement to provide support to clinicians following error, including removing them from clinical care to process the event, if possible,48 providing support from peers,49,50 or just a simple intervention of a small gift to show concern for the individual.51 Hospital-wide programs in peer support to clinicians in times of adverse events have been found to be highly valued and highly cost-effective.52 Readers are directed to learn more about what helps clinicians in times of error53; establishing a moral context, teaching others about the error, and becoming an expert are strategies that can help individuals thrive after an error experience.

SYSTEMS ENGINEERING Health care quality is defined by the Institute of Medicine (IOM) as “the degree to which health care services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge.”54 Six goals for defining quality care have been identified: that care is safe, effective, timely, efficient, equitable,

and patient centered.55 Although patient-centered care is somewhat ambiguous, the reader should consider it to be timely, dignity promoting, respectful of privacy, quality-of-life focused, culturally respectful, and inclusive of shared decision-making.56 The conceptual work of Donabedian forms the basis for the IOM framework,57–60 which established seven pillars for quality: efficacy, efficiency, optimality, acceptability, legitimacy, equity, and efficiency (Table 19.2). This framework also required that the connections and links between the dimensions of structures, processes, and outcomes must be understood before quality can be assessed. Radiation medicine standards have been profoundly impacted by Donabedian’s work. This framework is the basis for patterns-of-care studies in radiation medicine61 and the dimensional triad of structure, process, and outcome associated with 10% of over 400 global standards in radiation medicine.62 Structural aspects upstream of processes are easiest to measure, especially by accreditation organizations.57 Such structural aspects include physician or physicist board certification, therapist certification, hospital joint commission status, or patient volumes treated. Process measures are easier for health care providers to relate to, proximal to errors, can be relatively easily benchmarked using policies and medical records, require less follow-up, and provide direct feedback, but must be linked to outcomes.57 Process indicators include the appropriate use of chemotherapy and/or radiation for a given disease stage, margin status or completeness of surgical nodal evaluation, pain control, or adequacy of dose prescriptions. Multiple process measures are considered to reflect the multidisciplinary nature of oncology care and the variation in quality that might occur across disciplines but within a given patient’s treatment course. Although some might defend such variations as “the art of medicine,” deviations from radiotherapy treatment protocols built on firm structural and process bases have been linked with poorer patient outcomes.2 All dimensions should be collectively considered along with understanding causes for deviation and variation to assess quality in an “environment of watchful concern.”63 The International Council on Systems Engineering (INCOSE) defines system engineering as “an interdisciplinary approach and means to enable the realization of successful systems,”64 designed to allow for excellent functioning over the lifespan of the system. Although this

TABLE 19.2

The Seven Pillars of Quality

Quality Pillar

Definition

Efficacy

The ability of care, at its best, to improve health

Effectiveness

The degree to which attainable health improvements are realized

Efficiency

The ability to obtain the greatest health improvement at the lowest cost

Optimality

The most advantageous balancing of costs and benefits

Acceptability

Conformity to patient preferences regarding accessibility, the patient-practitioner relation, the amenities, the effects of care, and the cost of care

Legitimacy

Conformity to social preferences concerning all of the above

Equity

Fairness in the distribution of care and its effects on health

Defined

Adapted from Donabedian A. The seven pillars of quality. Arch Pathol Lab Med. 1990;114(11):1115-1118.

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CHAPTER 19 science began in the 1930s,65 systems engineering focuses on the system with particular emphasis on maintenance of communication and management of uncertainty and complexity in the interaction of its components—including human-machine interface. It facilitates the translation of qualitative customer demands into concrete quantitative product/process design features through discovery, learning, diagnosis, and iterative conversations. Six Sigma methods (introduced by Motorola in the 1980s) are statistically driven methods that strive to achieve high-quality process performance that compares favorably to client expectations. Quantitatively, the aim is to minimize defect (or error) rates to fewer than 3.4 per million opportunities. The sigma level is a measure of the ability of a process to achieve a desired mean value, centered within a tolerance range. Ideally, the variability in the process itself (standard deviation) is much smaller than the difference between the mean value and the limits of the tolerance range. A defective process is one that is not contained by the tolerance range. Thus, a Six Sigma process is one in which the standard deviation is one-sixth of that difference (between the mean value and the limits of the tolerance range) and corresponds to a long-term defect-free rate of 99.99966% (Fig. 19.3). Despite repeated testing, such processes are more resistant to variation and are exceedingly reliable. Reaching this level of nearly defect-free performance requires a dedicated system with excellent understanding of the factors that affect the process, their variations, and effective strategies to facilitate process control.

PROCESS ENGINEERING AND RADIATION MEDICINE Quality function deployment (QFD) is a hierarchical, iterative systems engineering approach to quality, which can also be referred to as customer-driven engineering. The success, or quality, of QFD is thought to be based on the customer’s satisfaction with the service or product. QFD is inclusive of the customer’s desires, along with the desires of company stakeholders. This input from both sources is sought along the continuum of product design stages, including parts requirements, manufacturing processes, and quality control.66 Management, technical, and business elements are considered integratively, correlations between key enabling factors are made transparent, and prioritization of efforts is established to ensure that quality efforts are directed at key control parameters (KCP) and key noise parameters (KNP). The process starts with obtaining key customer requirements, also known as critical-to-quality (CTQ) characteristics, or “Ys.” These are colloquially termed customer “wows, wants, and musts” to reflect the

Quality and Safety in Radiation Oncology

desirability of each item and where it lies within customer expectations. The relative importance of each CTQ characteristic is ranked by the customer, and industry benchmarks are sought by the team. Next, technical product characteristics, also known as “Xs,” required for each of the CTQ characteristics are established. The magnitude of correlation (high, medium, low, or numerical ranks) between each X and all Ys, along with the direction (increase, decrease) determines their overall relationships. The Pareto principle maintains that 80% of the output in a given system is produced by 20% of the input. The Xs are Pareto sorted in order of their overall impact on all Ys using the weighted rank sum. For an example of how such charting is useful, see Fig. 19.4. In radiation medicine, QFDs aid in the selection and prioritization of Lean Six Sigma projects,67 or risk mitigation.68 Alternatively, this approach may help us achieve a more patient-centered practice by helping our departments align with patients’ needs and increasing patient satisfaction.

RETROSPECTIVE AND PROSPECTIVE ERROR ANALYSIS The safety pillar of the IOM framework is part of the imperative that leads us to pursue risk mitigation in radiation medicine. Both predictable errors and prior errors are appropriate foci for analysis; incorporating both analyses is optimal for surveillance.69,70 Root cause analysis (RCA, a retrospective tool) and failure mode and effects analysis (FMEA, a prospective tool) are useful systems and safety engineering tools that can also be of value in Six Sigma projects.71 A key point about these tools is that a single individual cannot perform them successfully: they must be performed with a multidisciplinary team, ideally representing all of the professions involved in a given workflow. RCA is usually done when errors of significance come to the attention of the multidisciplinary team. The goal is to identify and ultimately improve or eliminate contributory factors that lead to unsafe conditions, near misses, or incidents that reach the patient. The taxonomy of contributing factors deployed in the Radiation Oncology Incident Learning System (RO-ILS) for radiation medicine is based on the principles of RCA.71 FMEA is most useful when contemplating a process change or implementing new technology in the clinic.70–72 Team members identify potential weak points in the process steps in which errors may occur, how they may appear, what causes them, and what existing controls may restrain them. Three risk assessments are assigned on an ordinal scale corresponding to potential severity of errors, their likelihood of occurrence, and their likelihood of detection if they do occur. It may help to think of detectability as a scale of “undetectability”—as this scale ranks something that would not be seen by any existing

Process average

Lower limit

Upper limit

99.7% 95% 68% –6σ

–5σ

–4σ

–3σ

–2σ

–1σ Mean

317

1σ

2σ

3σ

4σ

5σ

6σ

Fig. 19.3 A schematic of the definition of Six Sigma. (From Lean Manufacturing and Six Sigma Definitions 2018: http://leansixsigmadefinition.com/glossary/six-sigma/.)

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100 90 80 70 60 50 40 30 20 10 0

200 150 100 50

Number of complaints Cumulative percentage

ai

W

Po

or

pa

rk in tt ga W im va ai t t e fo ilab im r ili t In ad e fo rea ty eq r p tm ua hy en U na t s t va In e e icia ila ad xp ns eq ec bl e t ap uat atio po e p n in r tm iva c St ent y af t im fr ud e en es s

0

Fig. 19.4 An example Pareto Chart for radiotherapy patient complaints. Through this Pareto chart, you can see that 80% of the complaints in this department relate to issues with parking and waiting times for treatment. Therefore, quality management efforts would be best focused on these two issues.

Six Sigma Design-Measure-Analyze-Improve-Control for Quality Improvement Design-Measure-Analyze-Improve-Control (DMAIC) is a data-driven Six Sigma approach widely used in quality management. This approach conceptualizes the process as five sequential phases.73 The first three phases concentrate on identifying and understanding the problem, while the last two focus on developing solutions. DMAIC requires that measurable performance metrics be identified. For the efficient use of a DMAIC process, the scope of the problem must be fairly contained and well understood. Full completion of the cycle is necessary to realize the benefit of a DMAIC process. The IOM framework’s six domains of quality are all amenable to improvement through a DMAIC approach. It has been used productively in many health care settings73 as well as in improving safety processes within radiation medicine.68

Lean Six Sigma While Six Sigma methodologies focus on reducing defects and promoting process standardization, Lean methodologies target performance improvement through the reduction of nonvalue-added steps. A valueadded step moves the process toward completion, is not a rework step, and is valued by the “customer.” Nonvalue-added steps are inefficient and can potentially cause higher error rates (e.g., replanning of an intensity-modulated radiation therapy [IMRT] plan that was found to be nondeliverable owing to collision). Similarly, high defect (error) rates can potentially add wasteful steps. Consider the example of physician approval of a problematic plan: the problematic plan is identified by some control, such as physics check or chart rounds, which then leads to a series of nonvalue-added steps (such as repeat segmentation, replanning, repeat quality assurance checks, and patient delay). Lean Six Sigma combines the two approaches to accomplish both goals using

High JEWELS

HIGH HARDS

LOW HANGING FRUIT

DROP

BENEFIT

control—with a top score of 10. The other two scales rank logically according to their name (very severe = 10, happens a lot = 10). The product of these three risk factors represents the composite risk, the risk priority number (RPN), which will later be used to help identify the order in which these process weaknesses may be addressed. When ranking severity, many advise that the worst possible outcome of a failure should be considered at that level. A complete FMEA process would then mean reperforming the process analysis after the new controls are devised such that any new inadvertent pathways for error are identified and assessed for control procedures.

Low

Easy

EFFORT

Difficult

Fig. 19.5 Lean Six Sigma process map. (From Kim CS, Hayman JA, Billi JE, Lash K, Lawrence TS. The application of lean thinking to the care of patients with bone and brain metastasis with radiation therapy. J Oncol Pract. 2007;3(4):189-193.)

a similar DMAIC approach but adding Lean tools. These tools include value stream mapping, Kaizen (Quality Improvement), Kanban (a Pull system of regulating the flow of goods), Muda (Waste) and 5S (Sort, Set in Order, Shine, Standardize, Sustain).73,74 In a Lean approach, a multidisciplinary team delineates the process from its origin. The process map is divided into value-added and nonvalueadded steps by value stream mapping. The Muda tool (Muda means waste) encourages the use of the acronym “DOWNTIME” to conceptualize these nonvalue-added steps. These letters signify: Defects, Overproduction, Waiting, Nonvalue-added extra processing, Transportation, Inventory, Motion, or Eschewed Talents. These wasteful activities are then cast into a 2 × 2 matrix to segregate those steps that would require little effort to fix but that would yield high benefits (Fig. 19.5). Improvement strategies are implemented and evaluated. Successful strategies will be sustained. These approaches can yield rapid results that retain statistical rigor, and they have been implemented in radiation medicine.67,75,76

Engineering Summary Systems engineering and Six Sigma methodologies hold much promise for enhancing quality of care and improving outcomes in radiation medicine. These principles are universal; the process improvements

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CHAPTER 19 achieved through these methodologies are adoptable by others, enhancing their value to the field.

INCIDENT LEARNING SYSTEMS An incident learning system (ILS) can be described as a method to capture and analyze safety-related information and to address safety-related issues in a department. A successful ILS is never used in isolation as a stand-alone safety improvement tool but rather should be part of a safety management program. True incidents that reached the patient (whether or not they caused harm) are entered into an ILS along with other factors, such as near misses, unsafe conditions, and operational recommendations from frontline staff. All of these are collectively referred to as an “event.” As part of a safety management program, all entries into an ILS must be reviewed and addressed by a competent multidisciplinary team. Department leaders with disciplinary authority should not be part of the multidisciplinary review team, as this could discourage reporting or entering the information into the reports for fear of retribution. There are two implementations of ILSs: mandatory and voluntary reporting. Mandatory reporting is typically required at the governmental level when an actual incident occurs that reaches the patient and has a certain level of magnitude. While the definition of magnitude can vary from location to location, it is generally considered as an event in which the wrong body part was treated or the wrong dose was delivered in excess of 20%. Voluntary reporting is when there is no requirement or threshold for reporting and all events are encouraged to be reported. Voluntary reporting systems also tend to be associated with anonymity so that the person reporting is not required to provide one’s name or job function with the report. This section of the chapter is focused on anonymous voluntary ILSs and provides a high-level overview with an emphasis on a United States-based ILS. Comprehensive reviews of incident learning in radiation oncology are available.77,78

Introduction to Reporting Reporting is a systematic approach to gathering information related to departmental events. The first layer of information is that an event occurred. The second layer of information provides all available details related to the event. The actual method of gathering information (e.g., paper-based, computer-based, and so on) is not a critical aspect of reporting. Effective reporting can be accomplished with any informationgathering approach. The main advantage of computer-based systems is that they facilitate data aggregation and analysis. This becomes particularly important when analyzing reporting trends. As previously mentioned, it is important that all safety-related issues should be reported, especially near misses. While there is no single definition for incidents and near misses, incidents generally refer to something that went wrong and reached a patient or patients, whereas a near miss refers to something that went wrong but was caught and addressed before it reached the patient. A clear distinction between these two terms is not important for effective reporting except perhaps for incidents that reach a regulatory level and reporting is required. An example of a near miss is a physicist checking a patient’s chart before starting treatment who identifies incorrectly documented setup information that is immediately corrected before the patient is treated. Other events are more clearly in a gray zone, for example, if a computed tomography (CT) simulation is completed on the patient, but the dosimetrist realizes that the CT scan does not encompass the entire treatment area, thus, the patient is rescanned. In this case, the patient was never treated incorrectly, but the patient did require an additional diagnostic imaging dose, suffer inconvenience, and possibly treatment delay. Other issues that should also be reported are process deviations and unsafe or unexpected

Quality and Safety in Radiation Oncology

319

conditions. Examples of these are delays in the course of treatment or improperly functioning equipment. Some safety management programs ask that only “unnecessary” process deviations are reported, for example, an unnecessary treatment delay. However, from the appropriate perspective, knowing that a patient was delayed for any reason is valuable information. Rather than the person reporting, the multidisciplinary review team is in a better position to decide what is unnecessary when taken in context of all the reports over time. It can also be helpful for the review team to have an appreciation for the difference between a systematic event and a sporadic event. A systematic event is one that, given the same set of circumstances, is very likely to occur again. This case can arise with out-of-date policies or operating procedures as well as when equipment has been upgraded with new functionality but the old procedures are still being used. A sporadic event is one that occurs apparently at random. An example is forgetting to place a bolus on the patient when the prescription and treatment plan require it. It is not unusual for a therapist to forget to use a bolus from time to time. Analyzing and categorizing the number of similarly reported events will help highlight when a recurring random event occurs with greater frequency than historical data suggests is normal and needs to be addressed. Events that occur with a human contributing factor are likely not random. As previously discussed in this chapter, there are well-understood human biases that will lead to events given the right set of circumstances. Even when human biases are considered, it can be very difficult to truly understand exactly which human biases were at play when an event occurred. Therefore, it is acceptable to design mitigation strategies as though the human contribution were occurring randomly. There are no hypothesis-driven studies on the effectiveness of reporting and ILSs in radiation oncology. There are, however, several qualitative benefits of reporting and ILSs, such as encouraging and sustaining a departmental culture of safety.79–81 There is some research showing that a higher number of reports in an ILS is associated with a lower rate of patient safety indicators and a robust departmental culture of safety.82 The appropriate use of an ILS can be an important component of operating a department as a high-reliability organization.83 In radiation oncology, ILSs have been shown to capture a majority of safety-related issues that were identified in a prospective risk assessment effort as well as a number that were not identified.84 An ILS requires that data is collected immediately after an event is discovered. The information entered is typically the minimum necessary to understand the essence of the event, and speculation about unclear details is not encouraged. At a later time, the review team can then work to understand all of the details surrounding the event and propose corrective actions (i.e., perform a causal analysis). In some ILSs, only a narrative is required to capture an event.85 In other ILSs, some key information is required to help categorize the event, for example, the step in the process in which the event was identified. Events collected need to be analyzed in a timely manner and feedback provided to the department. The follow-up of the reported events will require different responses from immediate action necessary to monitor for future similar events. The former is typically required when an actual incident occurs, whereas the latter is used for seemingly benign process deviations that may be addressed by operational improvements. Explicit support from departmental leadership for the use of an ILS is essential but not sufficient for successful incident learning. A multidisciplinary review team should manage the ILS within a broader departmental safety management program. The review team should meet at regular intervals. For example, if a departmental ILS is receiving 10 reports per week, then a weekly committee meeting will likely be necessary to appropriately address the workload. The review team should also have the authority to make or recommend process changes. Other

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useful strategies for establishing and maintaining a successful ILS are to create an in-house workshop around incident reporting to explain the goals, methods, and benefits of the ILS. It can also be helpful to include a way for staff members to recognize their colleague in a positive way, e.g., one employee can give another a “gold star” or other accolade for a job well done. To maintain reporting, staff members need to see that their reports are being used to affect positive departmental change; otherwise, they will not go through the hassle of reporting. A safety culture is an important aspect of an effective patient safety management program and consists of both a reporting culture and a just culture. A reporting culture encourages the capture of information in an ILS related to any event. Staff should have the understanding that there will not be any retribution for entering reports into the ILS. Department leadership should encourage reports to be entered from all professional groups, and it should be clear that the ILS will not be used punitively. However, entering a report into an ILS cannot be used as a way for staff to avoid punitive action when it is appropriate. To achieve this seemingly contradictory function, a just culture should be implemented. A just culture requires that performance expectations are clearly defined for the different professional groups within a department. All members of the department must be held to those performance expectations whether or not a report is entered into an ILS. The key to a successful just culture is to hold people accountable only for actions over which they have complete control. Examples of these include arriving to work on time, collegial behavior with colleagues, and understanding departmental policies and procedures. Making the wrong decision that leads to an accident is almost never a punishable issue unless there is negligent or reckless behavior that leads to this bad decision (e.g., purposefully omitting a time-out procedure for no reason or intoxication at work).

ASTRO’s Radiation Oncology Incident Learning System The RO-ILS is a web-based national radiation oncology–specific incident learning system for the United States. The development of the RO-ILS started in 2011 when it was approved by the Board of Directors of ASTRO. ASTRO partnered with the American Association of Physicists in Medicine (AAPM) to develop the RO-ILS and began beta testing in September 2013. In 2005, the US Congress passed the Patient Safety and Quality Improvement Act (PSQIA), which defines and authorizes the creation

of patient safety organizations (PSOs). A PSO is an entity that health care providers in the United States can contract with to report, investigate, and conduct analysis of patient safety events within a confidential and privileged environment that also contains some protections against litigation. The RO-ILS was released for general use on June 19, 2014 and has rapidly gained a user base. It is free to use for all ASTRO and AAPM members but requires that a contract be signed between the radiation oncology department and the ASTRO-PSO.86 The “consensus recommendations for incident learning database structures in radiation oncology” guided the framework for developing the data elements within RO-ILS.87 The structure provides a causality table that can be used to help identify contributing factors related to an event, which also provides a common way to share information about events. The operational infrastructure and processes of the RO-ILS are shown schematically in Fig. 19.6. Users of the RO-ILS can access and enter data as if it were their own departmental ILS. The RO-ILS can also be used by the department for event investigation and follow-up. Some key data elements are required for any event submission, such as event classification (e.g., radiation overdose or underdose, nonradiation accident, near miss, and so on), workflow step in which the event was first discovered, workflow step(s) in which the event occurred, dose deviation for the course of treatment between the planned total prescription and the delivered dose, and contributing factors. These are partly consistent with the Agency for Healthcare Research on Quality (AHRQ) common data elements. Only if the department decides to send the information to the national database will it be accessible by the PSO and the Radiation Oncology Healthcare Advisory Council (RO-HAC), which will be described in the next section. The Patient Safety Work Product (PSWP) constitutes all of the information (data, reports, records, memoranda, and analysis) created by the department for reporting to the PSO. The RO-ILS is considered a Patient Safety Evaluation System (PSES) and includes the collection, management, and analysis of information for the purpose of reporting to the PSO. Most importantly, the protections afforded to the provider by the PSQIA apply only when an event is submitted to the national PSO database. Original sources of information that contribute to data elements, such as medical records, are not protected under the PSQIA. In the RO-ILS, all reporting is encouraged, including major rare events, minor frequent events, near misses, and unsafe or unexpected conditions.

Radiation oncology department (PSES)

Patient safety organization (PSES)

Event Private PSWP Dept PSWP

National DB Yes Submit?

Portal to PSO

RO-HAC PSWP

National safety alerts and reports

Department DB

Fig. 19.6 Schematic of Radiation Oncology Incident Learning System (RO-ILS) setup between a radiation oncology department and the Patient Safety Organization. The department decides whether or not it wants to submit an event from the department’s DB to the national DB. DB, Database; PSES, Patient Safety Evaluation System; PSO, patient safety organization; PSWP, Patient Safety Work Product; RO-HAC, Radiation Oncology Healthcare Advisory Committee.

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CHAPTER 19

ASTRO Radiation Oncology Healthcare Advisory Council Examples The ASTRO RO-HAC is a multidisciplinary review team of radiation oncology professionals that provides clinical expertise when evaluating the events submitted to the national RO-ILS database. The RO-HAC includes, but is not limited to, radiation oncologists, medical physicists, radiation therapists, dosimetrists, nurses, and administrators. Each member is required to have a demonstrated knowledge of quality and safety tools and techniques, that is, they must have more than just an interest in the topic. The members of the RO-HAC are appointed by the leadership of ASTRO’s Clinical Affairs and Quality Council and AAPM’s Working Group on the Prevention of Errors. The RO-HAC functions as part of the PSO’s PSES but its operation, results, and conclusions are otherwise completely independent of both ASTRO’s and AAPM’s leadership. Since the inception of the RO-ILS in 2014, the RO-HAC and PSO have provided a number of reports on submitted events, including three annual reports. The following is a high-level summary of the information gathered and the analysis from the annual reports to date,88–90 covering three categories: risky processes, areas for improvement, and effective mitigation strategies.

Risky Processes Any changes to a planned or intended course of treatment increases the chance for an error. Examples of changes are replans, changes in the radiation prescription, or changes in the number of fractions, such as finishing the course of therapy early. Changes in the intended course of therapy frequently lead to rushing processes, which is another risky behavior and is a documented contributing factor in accidents. An example of the dangers of rushing processes is the well-known 2005 incident reported in the lay press in which a case was urgently replanned and a problem with the delivery occurred, leading to a massive overdose and subsequent death of the patient.91 Communication of the radiation prescription, especially from the radiation oncologist to the dosimetrist, is also a risky process. Even though this occurs daily in all departments, it is an error-prone step in the radiation therapy process. There is a process in place for a nonprocedural time-out, termed critical conversations to allow for special mindfulness in the communication of such critical information,92 although this has not been broadly adopted by the field of radiation medicine.

Areas for Improvement There are several areas for improvement that have been identified by the RO-HAC based on the reports entered into the RO-ILS. While the specifics of each incident are not available, general areas are noted based in part on the frequency of the assignable causes. The areas for improvement are communication, training and education, following policies and procedures, treatment prescription, and contouring. Communication is a general issue that includes hand-offs and verbal requests. Manual entry of data is also a problem that falls within the communication

Quality and Safety in Radiation Oncology

area. The training and education area is related to students and trainees who may have made missteps that were not readily identified and corrected by staff. The inability of staff to follow policies and procedures is a recurring issue leading to events entered into the RO-ILS. It is important to understand the reason that a policy or procedure is not being followed before an appropriate mitigation strategy can be selected and applied. In some cases, training is warranted, but in other cases, the policy or procedure must be amended. An inaccurate, incorrect, or incomplete treatment prescription has led to a number of events. To remedy this, an industry-wide proposal to standardize the dose prescription (Fig. 19.7) has been developed and published by ASTRO to help address treatment prescription errors.93 Lastly, contouring has been identified as an area for improvement. Both accuracy of contouring (targets in particular) and unambiguous contour names are issues that need to be improved. AAPM Task Group 263—entitled “American Association of Physicists in Medicine Task Group 263: Standardizing Nomenclatures in Radiation Oncology”—will help in achieving standardized structure naming.94

Effective Mitigation Strategies There are a number of mitigation strategies that have been identified from the RO-ILS data to be particularly effective. Not all error mitigation strategies are applicable in all situations, but the following list can be considered as a good starting point for safety improvement: checklists, no interruption zones, procedures for emergencies, and peer review. Multiple near-miss events are caught by the use of checklists. Optimal checklists can come in different forms and can be applied at different steps in the radiation therapy process. The AAPM Medical Physics Practice Guideline—entitled “Medical Physics Practice Guideline 4.a: Development, implementation, use and maintenance of safety checklists”—provides an excellent discussion about building checklists and how to use them effectively.95 Interruptions and distractions frequently lead to near misses and accidents. It can be a productive departmental safety improvement exercise to identify sources of interruptions for different professional groups in the department. An effective mitigation strategy to reduce interruptions is to create no-interruption zones. A no-interruption zone is simply a protected space or time when someone is performing a critical job function and should not be bothered by anyone. For example, therapists at the treatment console or a radiation oncologist contouring a tumor volume fall into this category. Protocols for emergencies are important for a coordinated and thoughtful response to a potentially stressful situation. While not every emergency can be anticipated, departments should consider defining what constitutes an emergency and then outline how best to handle it, including a determination of the appropriate staffing level and experience. Lastly, peer review is an important error mitigation strategy that should be a routine department function. Peer review should be performed by true peers; for example, trainees cannot be expected to provide effective peer review of experienced staff without special training and education. While peer review is typically thought of as an exercise for physicians,

Standard prescription Key elements

Treatment site

Delivery method

321

Dose per fraction

Fraction number

Total dose

Fig. 19.7 Standardized dose prescription as proposed by the American Society for Radiation Oncology. The treatment site nomenclature should be standardized. At a minimum, the delivery method should specify brachytherapy and external beam. The dose per fraction and the total dose should be specified in units of cGy. The fraction number is the total number of fractions. (From Evans SB, Fraass BA, Berner P, et al. Standardizing dose prescriptions: An ASTRO white paper. Pract Radiat Oncol. 2016;6(6):e369-e381.)

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it can be equally effective for all professional groups of the department. An excellent reference when considering peer review is the ASTRO white paper entitled “Enhancing the role of case-oriented peer review to improve quality and safety in radiation oncology.”96

QUALITY MANAGEMENT As we discussed in other sections of this chapter, the process of continuous learning, evaluations, and rotations of plan-do-study-act is essential to organizational improvement. Equally important to the question of what to change is the question of how to effect and implement change within your organization. Change management is the major object of struggle for organizations. Fortunately, there is much known about the proper steps and considerations to effecting change. Although there are many theories of change, we will limit our consideration to a few. It is felt that the fitness of an organization for change depends on the ability of leadership to respond to and recognize internal tensions; failure to do so results in a 70% failure rate for change initiatives.97 Organizational characteristics considered to be change’s “silent killers” are the presence of a hierarchical senior management style; unclear strategic vision, particularly when accompanied by conflicting priorities; ineffective upper level management; poor vertical communication; poor coordination of efforts between and across teams; and inadequate leadership development in rising management positions.98,99 Change management theories can be based on financial incentives and increasing profitability or based on increasing human capabilities, maximizing internal dynamics, and capitalizing on individual and organizational learning.99,100 Too often, organizations focus on the “what” of change first rather than the “why” of change. Basic foundations of change management are described by Davidson,101 inclusive of clear visions for the future state, stakeholder priorities, and measures of success (Table 19.3).

Basic Foundations of Change Management101

TABLE 19.3 Critical Element for Change

Description

Rationale

Why is the status quo not an option? Why do we need this change? What is the evidence that supports this?

Future state

Why and how will the future state be better? Be specific.

Stakeholder input

Seek engagement of stakeholders in a meaningful way and not just to say that you did. You might learn that your proposed change is actually foolhardy.

Early involvement of the principals

Involve the stakeholders early on so that they can develop ownership of the change.

Target dates

Set realistic dates for implementation of change. Adjust them as needed with clear communication as to why this adjusted time course is necessary.

Specific measures of change

Establish metrics and outcomes to track for the success of your change, and assign responsible parties for these elements.

Allowance for change fatigue

We often change more than one thing at once. Be mindful of what is changing in the realms of your department, and sequence changes temporally if necessary.

Humility to learn from failure

You will not have a 100% change initiative success rate. Accept this and learn from your failures with critical examination.

Adapted from Davidson J. What’s all the buzz about change management? Healthc Manage Forum. 2015;28(3):118-120.

FUTURE DIRECTIONS Improving quality and safety for patient care requires additional effort beyond implementing well-established tools and techniques. New technologies are constantly being developed, and the field is continually learning how best to adapt the well-established tools to the radiation oncology environment. In this section, future possibilities for improving quality and safety are discussed.

Artificial Intelligence, Machine Learning, Deep Learning Machine learning and deep learning can be thought of as subsets of artificial intelligence (AI).102 These approaches are computer algorithms that use very large data sets—“big data”—to make decisions about other data (e.g., tumor contours on a set of images) or provide answers to clinical questions (e.g., What is the life expectancy of this patient?). While different approaches have different strengths and weaknesses, the objective of this section is to simply discuss the possibilities afforded by AI and its derivatives without getting into the details of any one approach or methodology. A systems approach to using big data in radiation oncology has previously been presented that contains several ideas, including an evidence-based approach to quality and safety in radiation oncology, data aggregation, automation in quality and safety areas, standardization of processes and equipment use, and defining the value of safety and quality in radiation oncology.103 Big data and AI may improve the quality of radiotherapy by facilitating comparative effectiveness research for all relevant outcomes, such as disease-free survival, recurrence, and complications. This can be applied

within a system of health care that is continually learning as new data is acquired. Such a healthcare system would accelerate discovery and hypothesis derivation, provide decision support, and leverage both genomics and radiomics to create fully personalized radiotherapy.104,105 Furthermore, AI has been shown to be valuable in radiation oncology contouring for head and neck cases.106 AI may also play a significant role in revolutionizing conventional equipment quality assurance. In this scenario, similar machines around the world can be compared and evaluated for functionality defects or degradation, thus reducing the conventional quality assurance burden on the medical physicist. Once data is being collected, then predictive monitoring algorithms can be developed and deployed to anticipate machine down events. This is directly related to improved safety because workflow disruptions can be minimized. Real-time localization systems (RTLSs) for patient, staff, and equipment tracking107,108 can improve safety. This data can be used to understand workflow for the purpose of safety monitoring and predicting when accidents are likely to occur. Retrospectively, the RO-ILS data can be used to guide a better understanding of events in conjunction with the RTLS data. Lastly, it is important to remember that AI is only as good as the data collected. Therefore, a number of principles have been proposed that would optimally allow learning from and using the data collected.109 To be optimally useful, data needs to be findable, accessible, interoperable, and reusable (FAIR). Distributing learning techniques that send the AI algorithms to FAIR data stores around the world would be ideal so that there is no need for centralizing all the data collected.

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Examples of Automation

Possible Workflow Changes

Automation has the potential to impact the following areas: cost reduction, productivity, availability, reliability, and performance.110 Increasing productivity by automating manual tasks will subsequently reduce labor costs because fewer people are needed to do the work. The ubiquitous availability of information will improve quality and safety by improving decision-making.106 Automating manual tasks will also improve reliability because human error will become a greatly reduced failure mode. Overall, the performance of radiation oncology facilities will be enhanced. The following are some areas that may be impacted in the near future.

The discussions on AI and automation possibilities will likely facilitate some workflow changes in the radiation oncology department of tomorrow. Real-time adaptive radiation therapy is a workflow change that is already used to some degree with the MR-Linac.129,130 General availability of real-time adaptive treatments would allow optimal sparing of normal tissue from unnecessary treatment. This advancement would be accompanied by significant changes in workflow. For example, someone would need to review and approve the contours, review and approve the treatment plan of the day, and quality would need to be assured before beaming on. With automated acceptance, commissioning, and QA tools, the medical physicist will have time that can be allocated to other areas. For example, physicists may become more directly involved in patient care —physicists could schedule physicist-patient consults before and during care.131 Medical physicists could familiarize themselves with any underlying concerns that patients (or caregivers) have about radiation or radiotherapy, be the primary resource for all of the technical aspects related to patients’ treatments, as well as provide information about their treatment plans and treatment delivery. This approach has been shown to reduce patient anxiety and increase patient comfort with the technical aspects of treatment.132 Furthermore, the radiation oncologist may have additional time for other patient care activities. Radiation oncologists will also be able to spend more time with patients because the contours and treatment plans will be automated. They will have the time to more fully manage a patient’s care, perhaps even being the lead physician directing a patient’s cancer care. Additionally, this may counterbalance the inefficiency introduced by the electronic medical record: the use of the EMR is estimated to cost physicians 4 hours a week.133 Radiation oncologists of the future will be experts in aggregating and using multiple data types and sources, functions that are already a core skill set in radiation oncology. Similarly, radiation therapists and dosimetrists will likely have a new role in this paradigm that is focused on synthesizing data—for example, dose, serial CBCT, and so forth—or otherwise making treatment decisions in an adaptive manner.129,130

Treatment Planning Historically, arriving at an acceptable treatment plan to meet the prescription is a trial-and-error process that depends on the knowledge and experience of the dosimetrist. It has been documented that large variation in treatment plan quality exists even for dosimetrists in the same department.111,112 Knowledge-based treatment planning is an approach to automating the process of optimization so that plan quality is largely assured and independent of the dosimetrist.113,114 The process of treatment planning is accelerated and made more consistent with knowledge-based treatment plan automation.

Contouring and Image Matching Treatment plans are designed based on contouring the target(s) and normal tissues. This requires a significant amount of expertise and training; case-by-case contouring can be a time-consuming process leading to interphysician (radiation oncologist) contour variation.115,116 Therefore, automating the process of contouring (automated segmentation) would be a significant benefit in radiation oncology. There are many approaches to achieving autosegmentation, such as atlas-based and AI approaches, including deep learning. While this technology requires further development, it is making strides into clinical use.117,118 Image matching (registrations or fusions) is another frequently performed task in radiotherapy. For example, this occurs when combining the CT simulation scan with secondary imaging from magnetic resonance, positron emission tomography, or diagnostic CT scan, as well as at the treatment console when matching a CT simulation scan to the cone beam computed tomography scan of the day or planar kV images to the digitally reconstructed radiographs from the treatment planning system.119,120 There are existing software tools in clinical use to facilitate these tasks, but full and robust automation is still an area of research, particularly for deformable image fusion, in which automation is being developed for the purpose of assessment of the quality of the fusion.121,122

Equipment Commissioning and Quality Assurance Equipment for radiotherapy is complex and expensive. Bringing a linear accelerator into clinical service, for example, can require several weeks of coordinated work between the vendor and medical physicist. Equipment performance must be assessed and characterized, and the radiation beams in the associated treatment planning system must be accurately modeled. Similar to treatment planning, the preparation of the device for clinical use depends on the knowledge and expertise of the medical physicist. There are examples in which this has gone terribly wrong and negatively impacted patients.123 Automating the acceptance and commission process can significantly reduce the time to bring these machines into clinical service and also ensure that it is done with minimal risk.124–126 Similarly, patient-specific quality assurance (QA) will be impacted by combining large data sets127 as well as using AI techniques to understand and predict QA results.128 These approaches will more robustly catch true errors while freeing up time for more important work that is ideally suited for human intervention.

A Call for Research As noted throughout this chapter, defining metrics for quality and safety research is not sufficient to determine whether or not we are actually making improvements. An additional level of scientific scrutiny needs to be imposed on quality and safety research so that it is held to the same standard as any other medical research.134 We support this notion and further believe in a like methodology of clinical trials as a framework for quality and safety research. A proposed system of phases, similar to that of clinical trials, was suggested135 and outlined as follows. Phase I: Researchers propose a quality and safety intervention, implement it locally at their institution (or test it on retrospective data) to evaluate its perceived value and determine potential roadblocks to a broad implementation and ongoing use. At this phase, the intervention would be a proof of concept and hypothesis-driven research would not be required. Phase II: The quality and safety intervention is tested over time at the institution that performed the Phase I study to see if it is longitudinally effective and to further evaluate its value and roadblocks to implementation and ongoing use at other institutions. A hypothesis-driven approach and appropriate statistical analysis of the data before and after the intervention would be required at this phase. Phase III: The quality and safety intervention is given to a group of institutions outside the institution that performed the Phase I study to confirm its effectiveness, monitor ways that the intervention goes

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awry, compare it to other related quality and safety interventions, and collect information that will allow other institutions to implement and sustain the intervention. Phase IV: Studies are done after the quality and safety intervention has been widely implemented to gather information on the intervention’s effect in various environments (e.g., large versus small institutions, developed versus developing countries, and so on) and any untoward effects associated with long-term use of the intervention. Our collective view is that quality and safety are paramount to patient outcomes, yet the research associated with safety remains undervalued and that simply producing more process-based or consensus-driven research will not produce safer and more consistent quality care. Improving safety and quality in radiation oncology depends on the availability of the best research possible and on our ability to deliver the results of that research into the hands of providers, policy makers, and consumers. Ultimately, we believe that the result of establishing a research hierarchy will improve health care, safety practices, and patient outcomes that will continue to drive the value of radiation oncology.

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A complete reference list can be found online at ExpertConsult.com.

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54. Lohr KN, ed. Medicare: A Strategy for Quality Assurance: Volume II Sources and Methods. Washington, DC: National Academy of Sciences; 1990. 55. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy of Sciences; 2001. 56. Stewart M, Brown JB, Donner A, et al. The impact of patient-centered care on outcomes. J Fam Pract. 2000;49(9):796–804. 57. Albert JM, Das P. Quality assessment in oncology. Int J Radiat Oncol Biol Phys. 2012;83(3):773–781. 58. Donabedian A. Evaluating the Quality of Medical Care. Milbank Q. 2005;83(4):691–729. 59. A. D. Explorations in Quality Assessment and Monitoring. Vol. I-III. Ann Arbor: Health Administration Press; 1985. 60. Donabedian A. The quality of care. How can it be assessed? JAMA. 1988;260(12):1743–1748. 61. Hayman JA. Measuring the quality of care in radiation oncology. Semin Radiat Oncol. 2008;18(3):201–206. 62. Donaldson H, Cao J, French J, et al. Quality standards in radiation medicine. Pract Radiat Oncol. 2014;4(4):208–214. 63. Earle CC, Emanuel EJ. Patterns of care studies: creating “an environment of watchful concern”. J Clin Oncol. 2003;21(24):4479–4480. 64. Haskins C, Forsberg K, Krueger M, et al Systems engineering handbook. A guide for system life cycle processes and activities. International Council on Systems Engineering Handbook. 4th ed: Wiley; 2015. 65. Hughes TP. Rescuing Prometheus. New York: Pantheon Books; 1998. 66. Akao Y. Development history of quality function deployment. In: Mizuno S, Akao Y, eds. QFD, the Customer-Driven Approach to Quality Planning and Deployment. Tokyo, Japan.: Asian Productivity Organization; 1994:339–351. 67. Bonilla C, Pawlicki T, Perry L, Wesselink B. Radiation oncology Lean Six Sigma project selection based on patient and staff input into a modified quality function deployment. Int J Six Sigma Comp Adv. 2008;4(3):196–208. 68. Kapur A, Potters L. Six sigma tools for a patient safety-oriented, quality-checklist driven radiation medicine department. Pract Radiat Oncol. 2012;2(2):86–96. 69. Senders JW. FMEA and RCA: the mantras of modern risk management. Qual Saf Health Care. 2004;13(4):249–250. 70. Kapur A, Goode G, Riehl C, et al. Incident learning and Failure-Modeand-Effects-analysis guided safety initiatives in radiation medicine. Front Oncol. 2013;3:305. 71. Ford EC, Gaudette R, Myers L, et al. Evaluation of safety in a radiation oncology setting using failure mode and effects analysis. Int J Radiat Oncol Biol Phys. 2009;74(3):852–858. 72. Huq MS, Fraass BA, Dunscombe PB, et al. A method for evaluating quality assurance needs in radiation therapy. Int J Radiat Oncol Biol Phys. 2008;71(1 suppl):S170–S173. 73. Trusko BE, Pexton C, Harrington J, Gupta PK. Improving Healthcare Quality and Cost With Six Sigma. Upper Saddle River, NJ: FT Press; 2007. 74. George ML. Lean Six Sigma: Combining Six Sigma Quality With Lean Production Speed. New York: McGraw-Hill Education; 2002. 75. Kim CS, Hayman JA, Billi JE, et al. The application of lean thinking to the care of patients with bone and brain metastasis with radiation therapy. J Oncol Pract. 2007;3(4):189–193. 76. Kapur A, Riebling N, Galli B, et al. Streamlining the head and neck treatment process in radiation medicine using a kaizen approach. Int J Radiat Oncol Biol Phys. 2012;84(3):S151. 77. Ford EC, Evans SB. Incident learning in radiation oncology: a review. Med Phys. 2018;45(5):e100–e119. 78. Pawlicki T, Coffey M, Milosevic M. Incident learning systems for radiation oncology: development and value at the local, national and international level. Clin Oncol (R Coll Radiol). 2017;29(9):562–567. 79. Kusano AS, Nyflot MJ, Zeng J, et al. Measurable improvement in patient safety culture: a departmental experience with incident learning. Pract Radiat Oncol. 2015;5(3):e229–e237. 80. Mazur L, Chera B, Mosaly P, et al. The association between event learning and continuous quality improvement programs and culture of patient safety. Pract Radiat Oncol. 2015;5(5):286–294.

81. Woodhouse KD, Volz E, Bellerive M, et al. The implementation and assessment of a quality and safety culture education program in a large radiation oncology department. Pract Radiat Oncol. 2016;6(4):e127–e134. 82. Mardon RE, Khanna K, Sorra J, et al. Exploring relationships between hospital patient safety culture and adverse events. J Patient Saf. 2010;6(4):226–232. 83. Yang F, Cao N, Young L, et al. Validating FMEA output against incident learning data: a study in stereotactic body radiation therapy. Med Phys. 2015;42(6):2777–2785. 84. Carroll JS, Rudolph JW. Design of high reliability organizations in health care. Qual Saf Health Care. 2006;15(suppl 1):i4–i9. 85. Rahn DA 3rd, Kim GY, Mundt AJ, Pawlicki T. A real-time safety and quality reporting system: assessment of clinical data and staff participation. Int J Radiat Oncol Biol Phys. 2014;90(5):1202–1207. 86. Patient Safety: RO-ILS FAQS. 2018. Accessed August 1, 2018. 87. Ford EC, Fong de Los Santos L, Pawlicki T, et al. Consensus recommendations for incident learning database structures in radiation oncology. Med Phys. 2012;39(12):7272–7290. 88. Year in Review 2015. 2015. Accessed August 1, 2018. 89. Year in Review 2016. 2016. Accessed August 1, 2018. 90. Year in Review 2017. 2017. Accessed August 1, 2018. 91. Bogdanich W. Radiation offers new cures, and ways to do harm. New York Times. 2010;1. 92. Sehgal NL, Fox M, Sharpe BA, et al. Critical conversations: a call for a nonprocedural “time out.” J Hosp Med. 2011;6(4):225–230. 93. Evans SB, Fraass BA, Berner P, et al. Standardizing dose prescriptions: an ASTRO white paper. Pract Radiat Oncol. 2016;6(6):e369–e381. 94. Mayo C, Moran JM, Xiao Y, et al. AAPM Task Group 263: tackling standardization of nomenclature for radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):E383–E384. 95. Fong de Los Santos LE, Evans S, Ford EC, et al. Medical Physics Practice Guideline 4.a: development, implementation, use and maintenance of safety checklists. J Appl Clin Med Phys. 2015;16(3):5431. 96. Marks LB, Adams RD, Pawlicki T, et al. Enhancing the role of caseoriented peer review to improve quality and safety in radiation oncology: executive summary. Pract Radiat Oncol. 2013;3(3):149–156. 97. Kotter J. Leading Change. Boston, MA: Harvard Business School Press; 1996. 98. Beer M. The silent killers of strategy implementation and learning. Sloan Manage Rev. 2000;41(4):29–40. 99. Beer M, Nohria N. Cracking the code of change. Harv Bus Rev. 2000;78(3):133–141, 216. 100. Steinke C, Dastmalchian A, Blyton P, Hasselback P. Organizational change strategies within healthcare. Healthc Manage Forum. 2013;26(3):127–135. 101. Davidson J. What’s all the buzz about change management? Healthc Manage Forum. 2015;28(3):118–120. 102. Meyer P, Noblet V, Mazzara C, Lallement A. Survey on deep learning for radiotherapy. Comput Biol Med. 2018;98:126–146. 103. Potters L, Ford E, Evans S, et al. A systems approach using big data to improve safety and quality in radiation oncology. Int J Radiat Oncol Biol Phys. 2016;95(3):885–889. 104. Sanders JC, Showalter TN. How big data, comparative effectiveness research, and Rapid-Learning Health-Care systems can transform patient care in radiation oncology. Front Oncol. 2018;8:155. 105. McNutt TR, Benedict SH, Low DA, et al. Using big data analytics to advance precision radiation oncology. Int J Radiat Oncol Biol Phys. 2018;101(2):285–291. 106. Cardenas CE, McCarroll RE, Court LE, et al. Deep learning algorithm for Auto-Delineation of High-Risk oropharyngeal clinical target volumes with Built-In dice similarity coefficient parameter optimization function. Int J Radiat Oncol Biol Phys. 2018;101(2):468–478. 107. Harry T, Taylor M, Fletcher RL, et al. Passive tracking of linac clinical flow using radiofrequency identification technology. Pract Radiat Oncol. 2014;4(1):e85–e90. 108. Conley K, Chambers C, Elnahal S, et al. Using a real-time location system to measure patient flow in a radiation oncology outpatient clinic. Pract Radiat Oncol. 2018;8(5):317–323.

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CHAPTER 19 109. Lustberg T, van Soest J, Jochems A, et al. Big Data in radiation therapy: challenges and opportunities. Br J Radiol. 2017;90(1069):20160689. 110. Moore KL, Kagadis GC, McNutt TR, et al. Vision 20/20: automation and advanced computing in clinical radiation oncology. Med Phys. 2014;41(1):010901. 111. Nelms BE, Robinson G, Markham J, et al. Variation in external beam treatment plan quality: an inter-institutional study of planners and planning systems. Pract Radiat Oncol. 2012;2(4):296–305. 112. Das IJ, Cheng CW, Chopra KL, et al. Intensity-modulated radiation therapy dose prescription, recording, and delivery: patterns of variability among institutions and treatment planning systems. J Natl Cancer Inst. 2008;100(5):300–307. 113. Shiraishi S, Moore KL. Knowledge-based prediction of threedimensional dose distributions for external beam radiotherapy. Med Phys. 2016;43(1):378. 114. Wu B, Ricchetti F, Sanguineti G, et al. Data-driven approach to generating achievable dose-volume histogram objectives in intensitymodulated radiotherapy planning. Int J Radiat Oncol Biol Phys. 2011;79(4):1241–1247. 115. Stanley J, Dunscombe P, Lau H, et al. The effect of contouring variability on dosimetric parameters for brain metastases treated with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2013;87(5):924–931. 116. Eminowicz G, McCormack M. Variability of clinical target volume delineation for definitive radiotherapy in cervix cancer. Radiother Oncol. 2015;117(3):542–547. 117. Lustberg T, van Soest J, Gooding M, et al. Clinical evaluation of atlas and deep learning based automatic contouring for lung cancer. Radiother Oncol. 2018;126(2):312–317. 118. Sharp G, Fritscher KD, Pekar V, et al. Vision 20/20: perspectives on automated image segmentation for radiotherapy. Med Phys. 2014;41(5):050902. 119. Robar JL, Clark BG, Schella JW, Kim CS. Analysis of patient repositioning accuracy in precision radiation therapy using automated image fusion. J Appl Clin Med Phys. 2005;6(1):71–83. 120. Brock KK, Mutic S, McNutt TR, et al. Use of image registration and fusion algorithms and techniques in radiotherapy: report of the AAPM Radiation Therapy Committee Task Group No. 132. Med Phys. 2017;44(7):e43–e76. 121. Neylon J, Min Y, Low DA, Santhanam A. A neural network approach for fast, automated quantification of DIR performance. Med Phys. 2017;44(8):4126–4138. 122. Kierkels RGJ, den Otter LA, Korevaar EW, et al. An automated, quantitative, and case-specific evaluation of deformable image registration in computed tomography images. Phys Med Biol. 2018;63(4):045026.

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123. Bogdanich W, Ruiz RR. Radiation errors reported in Missouri. New York Times. 2010;2010:A17. 124. Yaddanapudi S, Cai B, Harry T, et al. Rapid acceptance testing of modern linac using on-board MV and kV imaging systems. Med Phys. 2017;44(7):3393–3406. 125. Harry T, Yaddanapudi S, Cai B, et al. Risk assessment of a new acceptance testing procedure for conventional linear accelerators. Med Phys. 2017;44(11):5610–5616. 126. Wexler A, Gu B, Goddu S, et al. FMEA of manual and automated methods for commissioning a radiotherapy treatment planning system. Med Phys. 2017;44(9):4415–4425. 127. Dong L, Antolak J, Salehpour M, et al. Patient-specific point dose measurement for IMRT monitor unit verification. Int J Radiat Oncol Biol Phys. 2003;56(3):867–877. 128. Interian Y, Rideout V, Kearney VP, et al. Deep nets vs expert designed features in medical physics: an IMRT QA case study. Med Phys. 2018;45(6):2672–2680. 129. Acharya S, Fischer-Valuck BW, Kashani R, et al. Online magnetic resonance image guided adaptive radiation therapy: first clinical applications. Int J Radiat Oncol Biol Phys. 2016;94(2):394–403. 130. Lamb J, Cao M, Kishan A, et al. Online adaptive radiation therapy: implementation of a new process of care. Cureus. 2017;9(8):e1618. 131. Atwood TF, Brown DW, Murphy JD, et al. Care for patients, not for charts: a future for clinical medical physics. Int J Radiat Oncol Biol Phys. 2018;100(1):21–22. 132. Atwood TF, Brown DW, Murphy JD, et al. Establishing a new clinical role for medical physicists: a prospective phase II trial. Int J Radiat Oncol Biol Phys. 2018;102(3):635–641. 133. McDonald CJ, Callaghan FM, Weissman A, et al. Use of internist’s free time by ambulatory care Electronic Medical Record systems. JAMA Intern Med. 2014;174(11):1860–1863. 134. Ibrahim JE. Translating quality into research: do we need more research into quality or should quality activities be conducted using the principles and methodological rigour of scientific research? Australasian Association for Quality in Health Care. J Qual Clin Pract. 2000;20(2–3):63–64. 135. Pawlicki T, Potters L. Research on quality and safety: what are we missing? Int J Radiat Oncol Biol Phys. 2015;91(1):17–19. 136. Donabedian A. The seven pillars of quality. Arch Pathol Lab Med. 1990;114(11):1115–1118. 137. Lean Manufacturing and Six Sigma Definitions; 2018. Accessed August 1, 2018.

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20 Brachytherapy Sophie J. Otter, Caroline L. Holloway, Desmond A. O’Farrell, Phillip M. Devlin, and Alexandra J. Stewart

GENERAL PRINCIPLES Brachytherapy is arguably the most conformal of all the modes of radiotherapy. Accurate placement of sources directly in the target area allows for precise dose delivery to the target with unparalleled sparing of normal adjacent tissue. Although a conformal therapy, it is by nature inhomogenous in dose delivery, with the advantage that much of the central regions of the target get a greater dose than the minimum prescribed dose covering the target volume. The physics and radiobiology of brachytherapy are areas of great breadth and scholarship and are described elsewhere. In this chapter, our aim is to provide the reader with a set of up-to-date references and, more importantly, an experience-based guide to the initiation and development of a brachytherapy program. Brachytherapy takes advantage of the physical process of radioactive decay; an exponential phenomenon represented in general terms by the equation A = A0 e-λt, where A0 is the initial activity, t is the elapsed time, and λ is the decay constant (ln2/half-life). This decay releases energy, which is deposited as dose to the target structure. The primary clinical isotopes currently in use are shown in Table 20.1. Generally, photon-emitting beta, gamma, and x-ray emitters are employed. High linear energy transfer (LET) emitters such as neutron and alpha sources are seldom encountered clinically in brachytherapy. The dose rates of treatment delivery vary and are detailed in Table 20.2. Isotope selection is based on the emission type, energy of the emission, and half-life of the isotope. Cost and availability of the isotope are also a practical consideration. Developing a brachytherapy physics treatment program can seem daunting at first. However, the fundamentals of any program can be reduced to the following:

dose to staff or patients. Finally, the use of appropriate afterloading personnel from the radioactive sources. In the United States, the Nuclear Regulatory Commission has a guidance and compliance document (10CFR35),2 of radioactive by-products, license requirements, equipment specifications, and the reportage of medical events. Some states—agreement states—have local regulations that meet or exceed these federal requirements. Essential to a brachytherapy program is the ability to independently verify the stated activity of any received radioisotope before administration. The physics unit should have a variety of appropriately calibrated and traceable well-chambers and electrometers with seed-specific seed holders.

Planning Central to good brachytherapy planning practice is the importance of good implant geometry. The spacing of sources or catheters in regular arrays and patterns mitigates the later need to overmodulate the source dwell times or position. The historical planning techniques of the 4 Paterson-Parker,3 and Paris5 systems serve as safe starting principles from which minor planning modifications can be made.6 Brachytherapy practitioners may use three principal planning approaches. A single disease site example, Iodine-125 (125I) seed placement for prostate cancer, is used here as an illustration.

Preplanning

Practitioners are referred to American Association of Physicists in Medicine (AAPM) Task Group (TG) 431 tion of dose calculation.

The prostate volume is assessed using three-dimensional (3D) imaging: ultrasound, magnetic resonance imaging (MRI), or computed tomography (CT). An initial plan is run to evaluate pubic arch interference, volume of target and the number, and activity of sources required. With experience, each institution can make an accurate determination of the number and activity of seeds to be ordered based on target volume. The configuration of needles, seeds, and spacers is determined and prepared before the procedure and brought into the operating room (Fig. 20.1).

Time, Distance, and Shielding

Real-Time/Dynamic Planning

Good practice allows the practitioner to use the aforementioned physical

In this scenario, the plan is developed during the operative procedure. Some preparation is needed to ensure that adequate supplies are available for any eventualities. Advantages include the ability to compensate dynamically for any needle or seed misdirection that may occur during insertion with adjustments to subsequent needle or seed insertion. Second, the practitioner can compensate for edema secondary to needle insertion during the brachytherapy procedure.

distance, because of the inverse square relationship with dose, can be most useful in reducing dose to staff. The use of long-handled implements for source handling is recommended. Planned choreography and rehearsal of source loading and unloading and thoughtful layout of sources and equipment can reduce the time of exposure and, hence,

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A

B

Fig. 20.1 (A) Volumes drawn on prostate transrectal ultrasound for preplanning. (B) Preplanned dose distribution and seed location for treatment of prostate cancer with very-low-dose-rate permanent seeds.

Radioisotopes in Common Clinical Use With Their Relevant Physical Properties and Radium-226 for Comparison

TABLE 20.1

Mean Therapeutic Energy

Half Value Layer mm of Lead

for initial, near maximum edema, and steady-state seed configurations, respectively.

Planning Systems Brachytherapy planning systems are commonly license add-ons to external

Isotope

HalfLife

Emission Type

Radium-226

1626 y

Alpha, beta, and gamma

830 keV

16

Iodine-125

59.6 d

Gamma

28 keV

0.025

Palladium-103

17 d

Gamma

21 keV

0.013

Cesium-131

9.6 d

Gamma

29 keV

0.030

Cesium-137

30 yr

Gamma

662 keV

3.28

CLINICAL SCENARIOS

Iridium-192

74.2 d

Gamma

380 keV

6

Strontium-90/ Yttrium-90

28.8 y/ 2.7 d

Beta

2.27 MeV

12 Gy/h delivered over multiple pulses/d

Gynecological, head and neck, skin

Definition

Postplanning (Postoperative Dosimetry) This is used as a treatment quality assessment following the implant. This technique is best practiced by experienced users who will position seeds or catheters a priori with a good idea of the likely dosimetric outcome. Manual or automated seed finding is employed, usually using CT imaging. Postsurgical edema and its resolution may be tracked at intervals; day 0, day 1, and day 30 may be used as proxies

and 3D display dose volume analytics. The AAPM TG 537 strategy to ensure contour quality, positional fidelity, and accurate dose calculation in the system. Commercial isotopes have been evaluated using the TG 431 protocols, and quality systems will have standard seed configurations preloaded and accommodate manual entry of new seed data.

Cervical Cancer Cervical cancer was one of the first tumors to be treated with brachytherapy, with initial reports of cervical low-dose-rate (LDR) brachytherapy using radium published in 1903. The original principles of treatment with a central tandem and ovoids placed against the cervix have remained. Fortunately, though, we have moved away from the use of wine corks as applicators. For many years, a fixed dosimetry technique based on the Manchester principles was used to deliver a defined dose to point A: 2-cm superior and lateral to the external os. This was then enhanced by the use of the International Commission on Radiation Units (ICRU) However, the advent of 3D imaging moved cervical cancer brachytherapy dosing and precise determination of maximal dose received. This has resulted in fewer toxicities and the ability to deliver higher doses, which results in higher cure rates.8,9 It has also moved treatment in general away from LDR and toward high-dose-rate (HDR) or pulsed-dose-rate

LDR to HDR with the possibility of lower toxicity with HDR.10 There are data indicate that they are likely to be comparable. The brachytherapy applicator is generally placed operatively. A preoperative MRI close to the time of brachytherapy improves applicator selection and target definition.11 The patient may receive general anesthesia or regional anesthesia. Analgesia can be maintained throughout the length of a PDR implant or a single-insertion fractionated HDR implant using a spinal catheter.12 Spinal anesthesia does not cause tumor hypoxia during an HDR implant.13 Examination under anesthesia

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CHAPTER 20

A

Brachytherapy

327

B

Fig. 20.2 Sagittal planning computed tomograpy image demonstrating placement of uterine tandem without ultrasound guidance (A), causing a posterior myometrial perforation (not penetrating serosa), and with ultrasound guidance (B), showing the tandem within the uterine cavity.

Fig. 20.3 Illustration of tandem and ring with interstitial needles allowing additional dose coverage to tumor.

confirms the preoperative imaging findings. The cervix is dilated and a uterine tandem is placed, preferably using ultrasound guidance (Fig. 20.2).14 A variety of applicators are available for intracavitary brachytherapy. For tumors greater than 5 cm, the addition of interstitial needles 15,16 is becoming more common because it has brought the ability to deliver interstitial brachytherapy to a wider group (Fig. 20.3). Interstitial template applicators, such as the MUPIT17 or the Syed-Neblett18 applicator, should be used to treat disease with marked lateral or vaginal extension, although it is important to maintain a degree of central dose heterogeneity (in contrast to the heterogeneity preferred in interstitial implants in other areas of the body) to maintain the central cervix doses needed for cure.19 Studies of intensity-modulated radiotherapy (IMRT) versus brachytherapy show that external beam radiotherapy (EBRT) techniques cannot deliver the high-dose regions that are required for tumor eradication. Thus, brachytherapy remains a necessary component of treatment.20

Because of the anatomy of the pelvis, the bladder and rectum always receive a proportion of the radiation dose. This dose varies according to physiological variations (e.g., the bladder dose may vary according to the extent of bladder filling, which may also affect the amount of small bowel in the field).21 The traditional ICRU reference points22 have been widely used in gynecological brachytherapy since their inception. However, in the era of CT- and MRI-based gynecological brachytherapy treatment planning, it has been shown in cervical cancer brachytherapy that the ICRU reference points do not provide a good surrogate for normal tissue dose evaluation in the pelvis.23 Européen de Curiethérapie/European Society for Therapeutic Radiation (ABS) recommendations for normal tissue dose evaluation in cervical cancer based on CT- or MRI-based treatment planning allow a much more accurate determination of the doses received by the bladder and the rectum during cervical tandem and ring brachytherapy.24 This allows not only better prediction

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328

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Techniques and Modalities

Fig. 20.4 Single-channel cylinder to deliver vaginal brachytherapy. Axial and sagittal images show relation to the rectum and bladder.

26,35

tissue irradiation. Although devised for cervical brachytherapy dosimetry, these recommendations are generally used for evaluation of treatment plans in all areas of gynecological brachytherapy.

Endometrial Cancer Brachytherapy for the management of endometrial carcinoma was first described by Heyman in 1935, before the routine use of hysterectomy for uterine cancer.25 Endometrial cancer is the most common gynecological malignancy in the United States and the incidence is predicted to rise as obesity rates increase. Fortunately, the majority of patients with endometrial cancer are caught at an early stage because of vaginal discharge and bleeding. The use of radiation alone has now evolved; the primary treatment for endometrial cancer is surgery, total abdominal Vaginal cylinder brachytherapy can be used in the treatment of selected gynecological malignancies.26–28 It may be indicated as adjuvant treatment following hysterectomy or for vaginal recurrence of gynecological cancer in selected patients. The majority of patients receiving adjuvant radiotherapy will have EBRT to the whole pelvis followed by a fractionated course of brachytherapy. The use of pelvic radiotherapy in selected 29–31 and a 32 30,31 Cochrane meta-analysis. 33 showed that the addition of pelvic radiotherapy to surgery resulted in significantly lower rates of local relapse but no be because these patients already have a low risk of relapse and the in view of high rates of intercurrent illness in this patient population. Also, salvage radiotherapy to the vagina in the event of relapse is generally successful. The Cochrane meta-analysis found that the number of patients needed to treat to prevent one local recurrence was 16.7.32 In patients with pelvic radiotherapy. The most common site of relapse in early-stage endometrial cancer following surgery alone is the vaginal vault.34 Adjuvant primary vaginal vault irradiation has been shown to decrease the incidence of vaginal apex recurrence in endometrial cancer from 12% to 15% to as low as

Selected patients may have adjuvant vaginal cylinder brachytherapy monotherapy (e.g., patients with a well-differentiated adenocarcinoma of the endometrium with myometrial invasion greater than 50%, which gives similar regional control rates to pelvic EBRT with significantly less toxicity).26,35 The use of HDR vaginal cylinder brachytherapy is well established.36–38 The role of pelvic lymphadenectomy and postoperative radiotherapy in that setting is a controversial and less well-defined area.39,40 Vaginal vault brachytherapy can be administered using many different applicators. The most commonly used applicator is a single-channel cylinder that comes in a variety of diameters chosen according to patient anatomy and comfort (Fig. 20.4). HDR afterloading has become increasingly common for vaginal cylinder brachytherapy, with no increase in morbidity or local control rates seen in retrospective analysis.38 The target for vaginal vault brachytherapy is the vaginal mucosa and operative scar. Ninety percent of recurrences occur at the vaginal vault and 10% in the distal vagina; therefore, in the majority of cases, the upper third to half of the vagina is treated. This decreases the morbidity associated with treating the whole vagina, such as vaginal dryness or shortening.41 Brachytherapy can be prescribed at the cylinder surface or at 5 mm into tissue, a depth that approximates the vaginal lymphatics. The calculated conversion of LDR dose to fractionated HDR dose is an area of considerable variation between investigators, with fractionation schemes chosen as much because of the availability of local resources as radiobiological parameters. For HDR to be radiobiologically equivalent to LDR, the dose per fraction should be kept as low as is practically possible, usually requiring the total dose to be split into several fractions. The most common endometrial cancer HDR postoperative vaginal vault brachytherapy fractionation schedule in the United States in 2014 was 15 Gy in three fractions when given with EBRT and 21 Gy in three fractions when brachytherapy alone was used, both prescribed at 0.5 cm from the cylinder surface.37 The dose and fractionation of HDR administered is closely correlated with local control and late complications in gynecological brachytherapy.42,43 Sorbe et al. showed equivalent locoregional recurrence rates when treating the vaginal 15 Gy in 6 fractions or 30 Gy in 6 fractions at 0.5 cm deep from the cylinder surface over 8 days.44 However, there were much lower rates

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CHAPTER 20

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Fig. 20.5 Interstitial brachytherapy treatment for endometrial cancer recurrence at the vaginal vault. A central obturator is placed into the vagina with sources allowing for central vaginal dose. A template is placed over the obturator to allow placement of interstitial needles, facilitating coverage of disease.

of late vaginal morbidity in the lower-dose-per-fraction group. The biological effects increase faster with an increasing dose per fraction in late-reacting than in early-reacting normal tissue.44,45 Therefore, a small dose per fraction in HDR may be associated with a lower risk of late complications and a better therapeutic ratio provided that overall treatment time is not overly protracted. Vaginal vault brachytherapy can also be used to treat other gynecological malignancies, such as postoperative early-stage cervical cancer28 or early-stage vaginal cancer. For patients with greater than 1-cm residual disease at the vaginal vault at the time of brachytherapy, an interstitial applicator should be used for the boost treatment. There are commercially available vaginal cylinders with interstitial needles integrated within them; alternatively, a full interstitial template should be used. The central dose heterogeneity associated with interstitial cervical cancer implants is not as easily achieved in this situation because of the lack of a uterus (Fig. 20.5). As endometrial carcinoma is linked to obesity and hypertension, some patients have medical comorbidities that preclude surgery; for those, radiotherapy may be the definitive treatment of choice. In this group, treatment is delivered via intracavitary uterine brachytherapy applicators with or without EBRT. A variety of brachytherapy techniques have been described, including Heyman capsules and double-lumen patients with high levels of intercurrent illness. Initial experiences used LDR brachytherapy46,47 with applicator insertion under anesthesia and or uterine perforation, but the risk of morbidity—such as deep venous thrombosis and decubitus ulcers—increases. Retrospective analysis has shown similar disease control comparing LDR and HDR remote afterloading brachytherapy in inoperable disease.28 HDR carries the advantage over LDR in patients with significant comorbidities with greatly reduced treatment times, from several days to multiple fractions lasting several minutes. Various series have reported the use of different applicators, showing that multiple channels are generally preferable to a single tandem channel and that 3D planning achieves better target

coverage while still sparing the surrounding normal structures, particularly the rectum, to tolerable doses.48,49

Genitourinary Cancers Prostate

Brachytherapy for prostate cancer is evolving. In the past, brachytherapy was most commonly used for men with low-risk prostate cancer. The use of prostate brachytherapy has widened recently and now incorporates both permanent implants of very-low-dose-rate (vLDR) sources and temporary implants of HDR sources (Video 20.1). Both techniques are now used as monotherapy for patients of low- or intermediate-risk disease or as a boost for patients with high-risk disease. Prostate brachytherapy is also being evaluated as a salvage treatment option after previous EBRT. Image guidance is the principle factor that guides both vLDR and HDR prostate brachytherapy. The most common technique for vLDR brachytherapy is with transrectal ultrasound (TRUS) guidance using preoperative or intraoperative planning techniques (see Fig. 20.1). HDR brachytherapy for prostate cancer also involves image guidance, using ultrasound or CT, with placement of catheters into the prostate (Fig. 20.6). Relative contraindications for vLDR brachytherapy include high International Prostate Symptom Score (IPSS), prior pelvic radiotherapy, than 60 cc, and inflammatory bowel disease.50 Different loading techniques can be used to achieve dose coverage to the CTV and protect 51 Pre- and postprocedure dose evaluation should include reporting of dose to 90% of the CTV (D90), volume receiving 100% of the dose (V100), volume receiving 150% of prescription dose (V150), rectal D2cc, and urethral volume receiving 150% of dose (UV150).52 Three radioactive isotopes are used in vLDR prostate brachytherapy: Iodine (125I), Palladium-103 (103Pd), and Cesium-131 (131Cs). There are no differences in clinical outcomes between 125I or 103Pd seeds.53,54 Radiation proctitis has been reported to be more intense in the first month with 103Pd, as would be expected because of its shorter half-life.55 131 Cs is

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330

SECTION II

Techniques and Modalities

A

B

Fig. 20.6 (A) High-dose-rate (HDR) prostate axial image showing placement of HDR catheters and dose distribution around the prostate. (B) Three-dimensional rendering of the prostate with catheters and relation to the bladder and rectum.

being evaluated as an alternative isotope.56 The dose characteristics and half-life are listed in Table 20.1. HDR brachytherapy, on the other hand, uses high-activity Iridium-192 (192Ir). An advantage of HDR includes remote afterloading of the source

advantage of the potentially low alpha-to-beta ratio of prostate cancer cells.57 The advantages of HDR brachytherapy include the ability to implant patients with large prostates (> 60 cc), patients with extracapsular extension, and patients who have had previous transurethral resection of the prostate (TURP).58,59 There are no established normal tissue dose constraints for HDR prostate brachytherapy secondary to the variety of dose schedule options. The urethral dose range has been reported at less than 110% of prescription dose to less than 125% of prescription dose depending on the dose and fractionation. The rectal doses range from D2cc less than 70% of prescription dose or volumes receiving 80% of the prescription dose less than 0.5 cc.60 Indications for monotherapy. Patients with low-risk prostate cancer are appropriate for vLDR monotherapy and have shown good outcomes in the literature.61,62 The use of vLDR monotherapy has also been evaluated in patients with intermediate-risk prostate cancer with or without the use of androgen deprivation with good results.63 The initial have not shown a benefit in progression-free survival (PFS) with the use of EBRT and LDR brachytherapy compared with brachytherapy alone in intermediate-risk patients.64 Acute side effects were similar in both groups, but the EBRT and brachytherapy group experienced more late side effects (particularly urinary side effects) compared with brachytherapy alone. The patients included in this trial had T1c-T2b disease and either Gleason score 6 with prostate specific antigen (PSA) 10 to 20 or Gleason 7 with PSA less than 10. However, more recently, a favorable and unfavorable intermediate-risk classification has been proposed.65 Patients with unfavorable intermediate-risk disease may benefit from EBRT in addition to brachytherapy, whereas favorable 0232 trial. Evidence for the use of HDR monotherapy in favorable intermediaterisk prostate cancers has increased markedly recently from the results of large single-institution cohorts. The 10-year biochemical relapse-free survival (bRFS) following HDR prostate brachytherapy (43.5 Gy in 6 fractions) for low-risk or intermediate-risk prostate cancer is 97.8% 66 HDR brachytherapy has also been used as monotherapy for high-risk disease (45.5-54 Gy in 7-9 fractions over

4-5 days).67 The majority of high-risk patients also received neoadjuvant hormone therapy with or with adjuvant hormones. The 8-year cancerspecific survival was 93%, metastasis-free survival was 74% and the biochemical failure–free survival was 77%. However, further investigation, is safe to omit EBRT in these high-risk patients. The disadvantage of HDR monotherapy is the potential need for multiple implant procedures to attain an effective dose. However, in a single-institution study, there was equivalence in terms of acute and late toxicity and clinical outcomes between 38 Gy in 4, 24 Gy in 2, and 27 Gy in 2 fractions.68 Schedules comprising two fractions can be delivered on the same day; therefore, only one operative procedure is required to place the catheters. More recently, a single fraction of 19 or 20 Gy is being explored and may have similar rates of late morbidity and bRFS compared with 2- to 3-fraction schedules, albeit with very limited follow-up.69 Several other groups are exploring single 19-Gy fractions, but this approach should not be done outside a clinical trial.70–72 The American College of Radiology (ACR) appropriateness paper published in 2012 did not support the more hypofractionated monotherapy regimens (more than 9.5 Gy for 4 fractions) and felt that the more fractionated regimens had longer follow-up and support for use.57 Indications for boost. There is increasing evidence that increased radiation dose in high-risk patients results in improved local control (LC) and prostate cancer metastasis-free survival.60,73–77 Dose escalation can be achieved with EBRT alone or using brachytherapy as a boost. The dose for both LDR and HDR must be adjusted to account for the addition of EBRT (Table 20.3). Sequencing of brachytherapy can be before or after EBRT or, in the case of HDR, sandwiched between. Evidence supporting EBRT in combination with an LDR brachytherapy boost for intermediate- and high-risk disease comes from the ASCENDE-RT trial, which treated men with 12 months of androgendeprivation therapy (ADT) and pelvic radiotherapy to 46 Gy.78 Patients brachytherapy boost. Men who received the EBRT boost were twice as likely to experience biochemical failure as those receiving the brachytherapy boost. This benefit was seen in both intermediate- and high-risk disease. There was no differences in overall, prostate cancer-specific, or metastasis-free survivals. However, the improvement in biochemical control with trimodality therapy was associated with an increased risk of late morbidity. The cumulative incidence of grade 3 genitourinary (GU) events was 18% for the brachytherapy boost arm and 5% for the EBRT boost (p < 0.01).79 The prevalence of grade 3 GU toxicity was lower at 9% and 2%, respectively (p = 0.058). There was also a trend

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CHAPTER 20

Brachytherapy

331

Dose Ranges Reported for HDR and vLDR Prostate Brachytherapy

TABLE 20.3 Dose Range a

HDR

vLDR Iodine-125 Palladium-103 Cesium-131

Monotherapy 12–13.5 Gy × 2 10.5 Gy × 3 9.5 Gy × 4 6.5 Gy × 6 7.25 Gy × 6

Boost 15 Gy × 1 10.5 Gy × 2 7 Gy × 3 6 Gy × 4

140–160 Gy 110–125 Gy 115 Gy

108–110 Gy 90–100 Gy 80–85 Gy

a

No particular dose fractionation can be recommended because of heterogeneity of reported doses in the literature. HDR, High dose rate; vLDR, very low dose rate. Adapted from ABS consensus guidelines.

for worsening grade 3 gastrointestinal (GI toxicity), which did not reach significance. A large retrospective review using the US National Cancer Database included more than 25,000 men with intermediate- or high-risk disease who were treated between 2004 and 2012 with either an LDR brachytherapy boost or EBRT boost.80 It showed that during this time, use of LDR brachytherapy decreased from 29% to 14%. However, the patients of 0.74 (95% confidence interval [CI], 0.66-0.89). Similarly, a multicenter retrospective review of patients with Gleason 9-10 disease showed improved 5-year prostate cancer–specific mortality of 12% for radical prostatectomy, 13% for EBRT, and 3% for EBRT and brachytherapy boost.81 and 38% had HDR. There were no differences in outcome between those receiving LDR and HDR. Support for the use of an HDR brachytherapy boost in combination with EBRT began with the experience of single institutions.82,83 et al. prospectively assessed an HDR boost in a variety of dose and fractionation schedules in combination with 46 Gy in 23 fractions EBRT to the pelvis for intermediate- and high-risk patients. It was demonstrated that patients receiving a cumulative biologically effective dose (BED) of over 268 Gy had a 10-year biochemical failure rate of 19% compared with 43% for patients receiving a BED below this level.84 Hoskin et al. examined the role of an HDR brachytherapy boost when using hypoto EBRT alone using 55 Gy in 20 fractions or EBRT 35.75 Gy in 13 fractions followed by an HDR boost of 17 Gy in 2 fractions. The HDR boost group had improved bRFS.76 Late urinary and GI toxicity were similar between the two arms. Brachytherapy is also being evaluated as salvage treatment in patients with recurrence after previous radiation. Salvage brachytherapy has been reported in the LDR, HDR, and PDR literature.85–87 Initial results 0526) have shown acceptable rates of late grade 3 GI/GU adverse events of 14% for LDR salvage brachytherapy.88 The clinical efficacy outcomes are awaited. In a Phase II study by Yamada et al., HDR brachytherapy salvage was used in 42 patients (32 Gy in 4 fractions over 30 hours with a single insertion).86 The 5-year bRFS was 68.5% and cause-specific survival (CSS) was 90%. There was only 7% grade 2 late urinary toxicity and 1 patient with grade 3 urinary incontinence. Rectal toxicity was minimal. These findings are in keeping with the long-term follow-up results of salvage treatment of 37 men who underwent brachytherapy

Fig. 20.7 Interstitial brachytherapy implant of a urethral cancer in a female patient.

for salvage treatment by Burri et al., in which the 10-year bRFS was 54% and CSS was 96%.85 No statistically significant differences in efficacy or toxicity have been seen between LDR or HDR in this clinical scenario.89

Penile Cancer Squamous cell carcinoma of the penis is a rare cancer accounting for only 1% of male cancers. Brachytherapy is an alternative to penectomy in T1 and T2 tumors confined to the glans that are less than 4 cm in 90 An interstitial implant is the most common technique, either template or freehand. LDR, PDR, and HDR treatments have been described.91,92 The treatment volume includes the gross disease and a wide margin (1 cm). A multiplanar implant is recommended for most procedures to ensure dose coverage at depth. The implantation technique has been described in detail in the literature.93 The spacing between needles for LDR and PDR is recommended to be between 1.4 and 1.6 cm, but closer spacing (1.0–1.2 cm) is recommended for HDR techniques. The typical dose for LDR and PDR is 60 Gy at 0.5 to 0.6 Gy/ hour over 5 days (assuming hourly fractions for PDR). ABS guidelines recommend 38.4 Gy in 3.2-Gy fractions twice daily over 6 days for HDR.92 The 5-year LC is 70% to 87% with penile preservation in 70% to 88% of the cases.92,94–98 The rate of soft-tissue necrosis ranges between 0% and 26% and increases with doses over 60 Gy and large-volume disease. The rate of urethral stenosis ranges between 9% and 45% and relates to the proximity of the needles to the urethra.92

Urethral Cancer Brachytherapy alone or with EBRT can be part of the treatment in urethral cancers in women or men. For any tumor greater than 5 mm, an interstitial technique (Fig. 20.7) is required; for higher-stage disease, multimodality treatment is recommended.99 The doses are similar to that described for penile brachytherapy. In the treatment of female urethral cancers, the entire length of the urethra can be implanted. The dose for LDR monotherapy is 60 to 65 Gy in 3 to 5 days or 20 to 25 Gy if prescribed as a boost.100 In a review by Milosevic et al.,101 the outcomes of 34 women treated with EBRT alone (14 patients), EBRT with

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332

SECTION II

TABLE 20.4

Techniques and Modalities

Recommendations on Patient Selection for Accelerated Partial Breast Irradiation GEC/ESTRO106

Good Candidate (Low Risk)

Possible Candidate (Intermediate Risk)

ASTRO107 Contraindication for APBI (High Risk)

Suitable Candidate

Cautionary Candidate

Unsuitable Candidate

ABS105 Acceptable Candidate

Age (y)

> 50

> 40-50

≤ 40

≥ 50

40-49

< 40

≥ 45

Histology

IDCa

IDCa

—

IDCa

IDCa

—

IDCa

ILC

Absent

Allowed

—

Absent

Allowed

—

Allowed

LCIS

Allowed

—

—

Allowed

—

—

—

DCIS

Absent

Allowed

—

Absent

≤ 3 cm

> 3 cm

Allowed

Grade

Any

—

—

Any

—

—

Any

Tumor size

pT1-2 (≤ 3 cm)

pT1-2 (≤ 3 cm)

pT2 ≥ (3 cm), pT3-4

pT1 ≤ 2 cm

pT0-2 (2.1-3.0 cm)

> 3 cm

≤ 3 cm

Margins

≥ 0.2 cm

< 0.2 cm

Positive

≥ 0.2 cm

< 0.2 cm

Positive

Negative

Multicentric

Unicentric

Unicentric

Present

Unicentric

Unicentric

Present

—

Multifocal

Unifocal

Multifocal within 2 cm of index lesion

Multifocal > 2 cm of index lesion

Clinically unifocal (≤ 2 cm)

Clinically unifocal (2.1-3.0 cm)

Clinically multifocal or microscopically > 3 cm of index lesion

—

EIC

Absent

Absent

Present

Absent

≤ 3 cm

> 3 cm

—

LVI

Absent

Absent

Present

Absent

Limited/focal

Extensive

Not allowed

ER/PR

Any

—

—

Positive

Any

—

Any

Lymph node status

pN0

pN1mi, pN1a

pNx; ≥ pN2a

pN0 (I, i )

pN0 (I, i )

pN1, pN2, pN3, or pNx

Negative

BRCA1/2 mutation

—

—

—

Absent

Absent

Present

—

+

+

a

Subtypes include mucinous, tubular, and colloid. ABS, American Brachytherapy Society; APBI, accelerated partial breast irradiation; ASTRO, American Society for Radiation Oncology; DCIS, ductal carcinoma in situ; EIC, extensive intraductal component; ER/PR, estrogen receptor/progesterone receptor; GEC/ESTRO, Groupe Européen de Curiethérapie/European Society for Therapeutic Radiation Oncology; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; LCIS, lobular carcinoma in situ; LVI, lymph-vascular invasion.

brachytherapy (15 patients), or brachytherapy alone (5 patients) were evaluated. Brachytherapy led to an improved LC of 77% versus 32% to other reports in the literature. Fistula formation was reported in 15% of patients.

Breast Cancer Breast-conserving surgery followed by whole-breast irradiation (WBI) is a standard of care for many early breast cancers. The rationale for partial breast irradiation comes from reports of in-breast failure patterns following partial mastectomy versus partial mastectomy and WBI, in which the location of failure was most often in the region of the primary lesion or the surgical bed.102,103 Accelerated partial breast irradiation (APBI) has similar ipsilateral breast recurrence and survival rates to whole-breast IMRT but lower acute and late toxicities and better cosmetic outcome.104 Patient selection remains uncertain, with consensus statements from 105–107 Factors that are considered when contemmargin status, histology, lymphovascular space invasion, and nodal status (Table 20.4). There are many techniques for APBI. Interstitial multicatheter techniques using LDR were the first reported (Fig. 20.8); this technique has now evolved for HDR and PDR treatment. HDR is the more typical

cavity, commonly in the postoperative setting under image guidance using a template. Typically, the CTV is the lumpectomy cavity plus an additional 1- to 2-cm margin. Multiplanar implants are required to cover the CTV with catheter spacing between 1 and 1.5 cm.108 to ABPI with multicatheter interstitial brachytherapy or WBI with EBRT with an EBRT boost. The doses used were 32 Gy in 8 fractions or 30.1 Gy in 7 fractions for HDR brachytherapy or 50 Gy in 0.6- to 0.8-Gy pulses for PDR. For EBRT, a dose of 50 to 50.4 Gy in 25 to 28 fractions was prescribed to the whole breast with a boost of 10 Gy in 5 fractions. The trial demonstrated that APBI was noninferior to WBI 109 Early toxicity data demonstrated significantly higher acute grade 3 skin toxicity (radiation dermatitis) in the WBI group (7% vs. 0.2%, p < 0.0001). However, hematoma rates were increased in the APBI arm (20% vs 2%, p < 0.001).110 The cumulative incidence of grades 2-3 late skin toxicity was lower in the APBI arm (6.9% vs. 10.7%, p = 0.02).111 Polgar et al. published the 10-year results of their single-institution therapy (36.4 Gy in 7 fractions) or electrons (50 Gy in 25 fractions) versus WBI. The 10-year local recurrence (LR) results between APBI and WBI were similar (5.9% vs. 5.1%), with superior cosmesis in the APBI cohort.112 APBI. A total of 100 patients with either stage I or II breast cancer less

Multiple catheters are placed percutaneously through the lumpectomy

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CHAPTER 20

A

Brachytherapy

333

B Fig. 20.8 (A) Clinical photograph of a patient with interstitial high-dose-rate catheters placed to give coverage to the tumor bed and margin. (B) Dosimetry images of an interstitial breast treatment plan.

Fig. 20.9 Single-lumen catheter within the breast seroma. The treatment planning images illustrate uniform radiation dose delivery.

extracapsular extension) were eligible. Brachytherapy treatments consisted of either LDR 45 Gy in 3.5 to 5 days (33 patients) or HDR 34 Gy in 10 fractions twice daily over 5 days (66 patients). The trial was not designed to compare the 2 brachytherapy arms, but similar rates of in-breast failure (3%–6%) were seen at 6 years using the 2 brachytherapy techniques.113 Cosmesis was rated excellent/good in 66% of patients. However, fibrosis was reported in 45%, skin catheter marks in 54%, and symptomatic fat necrosis in 15%.114 of outcomes predicting for suboptimal cosmetic outcome and toxicity. The factors associated with increased toxicity were number of source dwell positions, V150, volume receiving 200% of the dose (V200), and the dose homogeneity index (DHI). Large V150 hotspots were associated with symptomatic fat necrosis.115

Balloon-Based Intracavitary Technique MammoSite (Hologic Inc, Bedford, MA) was developed and marketed as an accessible way to perform APBI. This single-lumen catheter can either be placed into the surgical cavity at the time of surgery or postoperatively cal bed, a balloon around the catheter is inflated to fill the cavity and compress the adjacent breast tissue. The limitation of this technique is that it had only a single dwell position; hence, the dose distribution was volumes or to avoid chest wall or skin (Fig. 20.9). The distance of the catheter to the chest wall or skin was found to relate to toxicity, leading to recommendations of skin spacing greater than or equal to 7 mm.116,117

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334

SECTION II

Techniques and Modalities

A

B

Fig. 20.10 (A) Axial image of an interstitial breast implant with permanent seeds showing dose distribution and (B) three-dimensional rendering of the breast with the clinical target volume and seed strands.

The final analysis of the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial has been published. In this trial, 1449 women were treated with 34 Gy in 3.4-Gy fractions, the majority (87%) of whom had invasive breast cancer. The median follow-up was 63.1 months. The 5-year actuarial recurrence rate for in-breast recurrences was 3.8% (3.7% invasive breast cancer, 4.1% ductal carcinoma in situ). associated with in-breast recurrence. There was a trend toward increased in-breast recurrence in the case of positive margins and American Society p = 0.06 and p = 0.07), but these were not statistically significant.118 The rate of seroma at any time in this trial was 13.4%, symptomatic fat necrosis 2.5%, infection 9.6%, and telangiectasia 13%. At 84 months, 90.6% of patients were rated with excellent/good cosmesis. Further enhancements of intracavitary techniques led to multichannel balloon–based catheters and a multichannel strut-adjusted volume implant (SAVI) applicator. The multichannel catheters allow for multiple dwell positions and were found to be dosimetrically superior to the single lumen/single dwell MammoSite with improved target coverage and decreased dose to the chest wall and skin even in cases in which the skin and chest wall were less than or equal to 7 mm.119–122 The Contura catheter (SenoRx, Inc., Aliso Viejo, CA) is a multichannel balloon catheter with 1 central catheter and 4 peripheral catheters offset from the center by 5 mm. The MammoSite Multi-Lumen has one central catheter surrounded by three peripheral catheters. The SAVI applicator has a central catheter surrounded by 6, 8, or 10 peripheral catheters. The peripheral catheters, once placed into the surgical cavity, are expanded to fill the cavity. The dosimetry of the SAVI applicator is more similar to the multichannel interstitial implants in terms of dose inhomogeneity of multiple dwell positions. The SAVI applicator has been found to be 123

Electronic balloon brachytherapy (Xoft Axxent, San Jose, CA) differs from other balloon-based treatments because the radiation source is an electronic x-ray tube that produces a 50-kVp photon range as opposed to the average of 380 keV for Iridium-192. The advantage of this technique includes increased access, as a specially shielded treatment room is not required and rapid dose fall-off results in decreased dose to normal tissues. Dosimetry to a planning target volume (PTV) with electronic brachytherapy and HDR implants are comparable, but the electronic brachytherapy has a higher balloon surface dose and decreased dose to the heart and ipsilateral lung.124,125 Further follow-up of this technique is required to evaluate outcomes and toxicity, especially given that the radiobiological effective dose with low-energy photons may differ from standard HDR treatments.

Interstitial permanent vLDR 103Pd seeds are being evaluated for partial breast irradiation (PBI) in the low-risk population with the potential advantage of a reduction in treatment time and decreased dose to critical normal structures because of the low energy of the isotope.126,127 Patient selection for this technique is limited by general ≤ 2.5 cm) and anticipated implant volume (≤ 120 cc). Imaging of the tumor bed using ultrasound or CT is performed and, similarly to permanent prostate brachytherapy, a preplan with the desired placement of needles and seeds is made (Fig. 20.10). A vLDR dose of 90 Gy to the tumor bed plus margin is planned, keeping the dose to the skin less than or equal to 90% of the prescription.128 The implant is performed under image guidance using local anesthetic and conscious sedation. A report on the outcomes of 134 patients treated with a permanent breast seed implant showed a local recurrence rate of 1.2%, similar to that with WBI.129 A dosimetry study of 131Cs versus 103Pd has shown a potential advantage to using 131Cs with decreased V200 but this may not be clinically significant.130 Breast brachytherapy is also being evaluated as a boost technique with conventional HDR or using a noninvasive breast brachytherapy (NIBB) technique with Accuboost (Billerica, MA). NIBB uses image

centered on the target124 for directed photons at the cavity without the usual PTV margin required for standard EBRT boost, resulting in comparatively smaller treatment volumes with the potential for decreased toxicity. A 2 : 1 matched control study of NIBB versus EBRT boost showed that there is less combined skin and subcutaneous toxicity in patients treated with NIBB (2% NIBB vs. 9.5% EBRT boost, p = 0.046).131 APBI has been used as salvage treatment for in-breast tumor recurthat interstitial multicatheter brachytherapy was feasible and effective mastectomy.132 Kauer-Dorner et al. reported on a prospective trial of interstitial PDR brachytherapy in 29 patients with local tumor control comparable to mastectomy with greater than or equal to grade 3 late side effects in 16%.133 partial breast radiation in 1 fraction with either electrons or 50 kV versus WBI have reported increased IBTR in the APBI arms.134,135 The increased IBTR may be related to poor patient selection.136 guidelines state that patients should be counseled regarding the increased

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CHAPTER 20

Brachytherapy

335

Fig. 20.11 Endobronchial catheter with computed tomography planning allowing for evaluation of the placement of the catheter and relation to clinical target volume and organs at risk, including a pulmonary vein, which is in close proximity to the implant.

107

For low-energy

Lung–Endobronchial Brachytherapy In 1922, Yankauer described the use of radium placed endobronchially to treat lung cancer.137 Brachytherapy continues to be used to deliver radical or palliative endoluminal therapy to the bronchus. Local treatment can be important to improve the quality of life for lung cancer patients. A narrow-bore brachytherapy tube is placed under bronchoscopic guidance, extending at least 2 cm past the tumor and firmly secured at the nostril. The dose is delivered, usually using HDR, as a single or multiple fractions. The 2016 ABS guidelines recommend dose prescription at 1 cm.138 However, in the era of CT planning, the orientation of the catheter within the bronchus has been identified as an area of concern delivered when the catheter position is offset against the luminal wall.138 138 catheter centrally139,140 This is important, since fatal hemoptysis rates range from 7% to 22% in 141–143

ABS guidelines recommended the use of endobronchial brachytherapy for palliation, particularly for endobronchial lesions not amenable to laser or stenting. A range of doses are recommended: using 10 to 24 Gy in 1 to 4 fractions as sole treatment or 10 to 15 Gy in 2 to 3 fractions following EBRT.138 A 2012 Cochrane meta-analysis144 examined 14 or in combination with other therapies such as EBRT, chemotherapy, or laser. A variety of dose and fractionation schedules were used that for improved LC and less hemoptysis over 15.2 Gy in 4 fractions. There appears to be no advantage to adding endobronchial brachytherapy to an EBRT treatment course, either palliative or radical. When used for palliation as sole therapy, 50% of brachytherapy-only cases proceeded to receive EBRT with a median time to treatment of 4 months compared with under one-third requiring brachytherapy following EBRT with a median time to treatment of 10 months.141 Secondary analysis

Fig. 20.12 Permanent interstitial seeds placed in a single-plane mesh.

subsequently showed a survival advantage to EBRT with a relative risk reduction of 61%. The Cochrane review concluded that endobronchial brachytherapy can be considered for palliation in patients previously treated with EBRT for symptoms resulting from central obstruction. ACR guidelines from 2013 recommend that it can be used for palliation of patients with symptomatic endobronchial tumors.145

Thoracic Seed Brachytherapy Interstitial seeds formed into a single-plane mesh implant can be placed intraoperatively in areas at high risk of relapse (Fig. 20.12). These are commonly used within the thorax but are also described in other anatomic sites, particularly in sarcoma resections. Most institutions describe the use of 125I but the use of 103Pd and 131Cs is also described.146–148 The use of a planar 125I implant placed along the suture line following sublobar resection decreased recurrence rates over those expected with sublobar resection alone.149 However, results from the Phase III prospec-

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336

SECTION II

Techniques and Modalities

Fig. 20.13 Esophageal brachytherapy prescribed 1 cm from the source axis demonstrating simple line source dose distribution.

Z4032 have not demonstrated a difference in 5-year local recurrence with the addition of brachytherapy (17% with brachytherapy vs. 14% without, p = Better than expected rates of negative margins were achieved; thus, the trial may have been underpowered to detect a small difference.150,151 Therefore, the ABS guidelines do not recommend seed implantation following sublobar resection outside of the confines of a clinical trial.137 Placement of mesh implants following close or positive surgical margins has shown lower rates of recurrence than would otherwise be expected in thoracic and paraspinal tumor resections.149,152

Gastrointestinal

Esophageal Cancer Esophageal brachytherapy can be administered in the radical and palliative settings. A brachytherapy catheter is placed over a guide wire under endoscopic guidance traversing the tumor and firmly secured at the nose. The treatment volume should extend 2 cm superior and inferior to all macroscopic disease to encompass any microscopic tumor foci. Treatment is generally prescribed at 1 cm from the source axis, though 3D planning can be used for complex cases and the dose received by the use of an array of inflatable peripheral balloons. If a stent is present, around the stent, 5% higher at 0.5 mm and up to 245% in the immediate vicinity of the stent.153 As part of the radical treatment of esophageal cancer, brachytherapy The ABS recommends 10 Gy prescribed at 1 cm from the source train in 2 fractions 1 week apart following chemoradiation 45 to 50 Gy or radiotherapy alone up to 60 Gy154 (Fig. 20.13). This dose/fractionation

49% but used a dose of 10 Gy in 2 fractions following unacceptable rates of toxicity using 15 Gy in 3 fractions.155 A thicker applicator fistulas.

For palliation, brachytherapy delivers improvement of swallowing in the majority of cases, with maintenance of swallowing in most of the remainder. A range of doses for HDR esophageal brachytherapy is considered acceptable. The ABS recommends palliative doses of 14 Gy in 1 to 2 fractions following EBRT of 30 Gy in 10 fractions and, for sole treatment, 15 to 20 Gy in 1 to 2 fractions.154 A dose comparison study of 18 Gy in 3 fractions versus 16 Gy in 2 fractions by the International Atomic Energy Agency (IAEA)156 showed no difference in efficacy or toxicity with an overall 11% stricture rate and 10% fistula rate. It is not known how much brachytherapy may have contributed to fistula formation, but it was noted that all fistulae occurred in the presence of disease progression. therapy (12 Gy in 1 fraction) over stenting157 with improved quality of life, longer duration of palliation, and equivalent overall health care costs.158 Because there is a slight delay in onset of symptom palliation with brachytherapy, it was recommended that brachytherapy should be used instead of stenting in patients with a predicted survival over 2 months. If the predicted survival is under 2 months, stenting should be used. A trial of fractionated treatment using 21 Gy in 3 fractions versus stenting did not show any evidence of benefit, though the number of patients in the trial may have been too small to draw definitive conclusions.159 A Cochrane meta-analysis in 2009 showed that brachytherapy has a longer duration of palliation than stenting, with significantly better quality of life and lower complications (33% vs. 47%)160 and may even provide a survival advantage. Brachytherapy was comparable to laser for palliation and may improve the dysphagia-free interval when EBRT is added to showed that the addition of EBRT 30 Gy in 10 fractions to 16 Gy in 2 fractions brachytherapy resulted in significantly better symptom relief than brachytherapy alone.161 two groups. Thus, patients with a greater predicted survival (e.g., over 6 months) may benefit from the addition of EBRT to brachytherapy. A

compared to 144 days with a similar side effect profile.162

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CHAPTER 20

Rectal Brachytherapy can be considered in two situations for rectal cancer: attempting to avoid colostomy as organ preservation in early rectal cancer or for palliation in surgically unfit patients, either as a boost following EBRT or as monotherapy. Two methods of treatment are available: contact radiotherapy or HDR brachytherapy. A consensus statement on rectal cancer treatment described rectal brachytherapy as an option to downstage tumors and facilitate resection but that it requires further assessment.163 Contact x-ray brachytherapy (CXB), often called Papillon radiotherapy after its original proponent, uses a 50-kVp source to deliver highly advent of dedicated modern machines, contact brachytherapy for rectal cancer is enjoying a renaissance. Following sigmoidoscopic assessment, a fixed diameter applicator is placed into the rectum and the radiation delivered under direct vision to the tumor. Generally, a dose of 110 Gy in 4 fractions delivered at 2 weekly intervals is used for sole treatment of T1 tumors; for T2 and above, 85 to 90 Gy in 3 fractions is used in patients unwilling to have surgical excision, those assigned to 39 Gy in 13 fractions EBRT alone had a 63% rate of colostomy at 10 years compared with 29% in the group receiving 85 Gy in 3 fractions contact brachytherapy in addition to the EBRT.164 Because CXB has a higher recurrence rate than surgery, patients who are surgically eligible must be counseled accordingly and accept the requirement for increased sigmoidoscopic and MRI follow-up evaluations for the first 2 years. is unchanged.165 addition of an EBRT boost versus a CXB boost to chemoradiotherapy 45 Gy in 25 fractions with oral capecitabine in surgically fit patients (NCT02505750). Modern HDR brachytherapy uses a flexible silicone applicator with multiple channels to provide a conformal dose that can treat larger fields with deeper penetration than contact radiotherapy (Fig. 20.14). Before applicator placement, the superior and inferior extents of the tumor are marked with fiducial markers or clips. The applicator is then inserted and the treatment field defined, preferably using CT or MRI planning. A dose of 26 Gy in 4 daily fractions is used for radical treatment or up to 30 Gy in 3 fractions for palliation, usually following pelvic EBRT. A Phase II study of neoadjuvant HDR brachytherapy has shown recurrence rates of 5% with low rates of toxicity. Matched-pair analysis has shown lower

A

Brachytherapy

337

rates of reoperation within 30 days with preoperative HDR brachytherapy (in Canada) compared to short-course radiotherapy or no preoperative treatment (in Sweden), although different surgical techniques in the two countries may have contributed to this difference.166 even if they are not fit for surgery. For those with smaller tumors, contact brachytherapy may be a useful option. For institutions without access to contact brachytherapy or for patients with larger, more bulky tumors, HDR endorectal brachytherapy is an option. This is usually given after EBRT—either a long course with or without chemotherapy or a short course of 25 Gy in 5 fractions or 39 Gy in 13 fractions. A variety of dose/fractionation schemes have been described, with up to 36 Gy in 6 fractions following EBRT167,168 showing good tumor control with acceptable late toxicity. The HERBERT study was a dose escalation study that determined there was good efficacy with acceptable toxicity when using pelvic EBRT 39 Gy in 13 fractions with an HDR boost of 21 Gy in 3 fractions (prescribed to the outer aspect of the tumor volume) in patients unfit for surgery.169

Anal Cancer Squamous cell carcinoma of the anus is a rare cancer that is usually treated with concurrent chemoradiation with good rates of sphincter radical surgery required to achieve cure. Therefore, methods of local dose escalation for primary treatment have been explored. EBRT plus concurrent chemotherapy is used to treat the tumor and wider nodal area and the tumor boost can be delivered using EBRT, electrons, or brachytherapy.170 Interstitial implants typically target the volume of interest using a horseshoe-shaped perineal template curved around the anus. Improved catheter placement may be achieved by the use of advanced imaging techniques such as 3D endoluminal ultrasound.171,172 Papillon et al. described an LDR boost using 192Ir to deliver 20 to 30 Gy in 221 patients 2 months after completing EBRT. LC rates were comparable to surgical techniques.173 A split-course technique for anal cancer is no longer recommended. A brachytherapy boost may provide better LC than EBRT if treatment delays occur because of toxicity or illness between the first phase of EBRT and the boost.174 PDR techniques have been described with similar rates of disease control and toxicity to those of LDR.175–177 HDR brachytherapy has been described but is rarely used. In a retrospective review, an HDR dose of 14 Gy in 7 fractions over 3 days gave equivalent control to an EBRT boost with lower skin toxicity.178

B

Fig. 20.14 Axial (A) and sagittal (B) images of a flexible silicone rectal applicator in place. A high-dose-rate plan has been created to cover the gross tumor volume (blue) with a 2-mm expansion to the planning target volume (red). Note low doses received by the contralateral bowel wall.

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Head and Neck Cancers Head and neck brachytherapy was one of the first reported uses of radiotherapy. The early methods simply involved the placement of radium sources in or on tumors for various amounts of time to look for resolution of the tumor. The development of afterloading techniques both in Europe and the United States led to several parallel methods that have inspired modern practice. The enhancement of modern tion of dose has made the conformality and utility of this surgical type of brachytherapy more attractive. A myriad of techniques have been described, including the gutter guide Pierquin technique, plastic tube technique of Henschke, through and through technique, loop technique, sealed end technique, hypodermic technique, thread techniques, and direct implantation. However, the combined innovations of IMRT and of many of these implant techniques. tumors as either monotherapy or as a boost to EBRT for lip, buccal mucosa, oral tongue, floor of mouth, base of tongue and pharyngeal recommendations for the use of head and neck brachytherapy,179,180 with a particular focus on dose, treatment selection, and quality assurance. The ABS also recently updated guidelines for head and neck brachytherapy, focusing on treatment selection in the era of advanced EBRT techniques.181 brachytherapy, has been described for recurrent nodal disease in the neck.182 A base-of-tongue implant serves as an illustrative example of complex head and neck brachytherapy. Human papillomavirus (HPV)–associated oropharyngeal tumors often present in younger patients and require a definitive approach. The greatest challenge in this setting is delivering a sufficiently high dose to a target between the angles of the mandible and in close proximity to the pharyngeal constrictors and muscles of mastication. An implant provides a highly conformal boost that will This technique is of significant importance in the setting of recurrent disease after previous radiotherapy. Harrison et al. reported the Memorial Sloan Kettering Cancer Center (MSKCC) series in which largely nodepositive disease had high rates of local and distant control of disease.183

Karakoyun-Celik et al. reported the Massachusetts General Hospital series deploying the blind-ended HDR catheter technique with excellent local and distant control.184 Cano et al. also reported reduced dose after concomitant chemotherapy and EBRT, again showing excellent results in a largely locally advanced and node-positive cohort.185 The use of base-of-tongue implants in the IMRT era is also worth considering, as it may have less negative effect on swallowing function. Teguh et al.186 and Al-Mamgani et al.187 reported significantly more dysphagia, trismus, and dry mouth after an IMRT boost than an interstitial boost. Although a full review of each technique is beyond the scope of this chapter, a comprehensive review of head and neck brachytherapy applications and techniques is available.188

Skin/Superficial Brachytherapy has been described for superficial treatments of both benign and malignant skin neoplasms. The most common cutaneous malignancies are nonmelanoma skin cancers (squamous cell carcinoma and basal cell carcinoma). There are a variety of treatment options with radiation for these lesions, including EBRT, electrons, orthovoltage, and brachytherapy. Brachytherapy techniques can include LDR, PDR, HDR, and—more recently—electronic brachytherapy.189 Brachytherapy has advantages over the other radiation treatments in areas of the body with complex superficial targets (Fig. 20.15) and allows for shorter treatment courses. Both interstitial and surface techniques have been described. Single-plane interstitial implants can often be placed under local anesthetic; for thicker lesions, multiple planes may be required to get adequate deep coverage. Ducassou et al. reported their experience in 132 patients treated with LDR interstitial treatments for squamous cell and basal cell carcinomas. The 5-year local relapse-free survival (LRFS) was 87.3%. Patients who were treated with primary brachytherapy had better LRFS compared to patients treated at time of recurrence (HR, 2.91; 95% CI, 1.06–8.03; p = 0.039), the LRFS was superior in patients treated for basal cell compared with squamous cell carcinoma (90.4% vs. 70.8%, p = 0.03).190 Superficial techniques can be performed with custom molds, surface applicator (Nucletron, an Elekta company, Veenendaal, the Netherlands). Superficial applicators are limited to surface tumors. Electronic brachyand rapid dose fall-off after 3 mm.191

Fig. 20.15 Custom surface mold with high-dose-rate applicator with an optimized treatment plan to a complex superficial target showing equivalent dose penetration despite multiple contours of the face.

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CHAPTER 20 using molds or flaps have the ability to treat larger volumes and slightly deeper, but a high surface dose has to be considered. Gauden et al. at 3 to 4 mm daily in 3 Gy fractions (36 Gy/12 fractions). They reported 98% LC and 88% excellent/good cosmesis.192 Similarly, Guix et al. therapy with 192Ir with doses between 60 and 65 Gy/30 to 33 fractions. Tumors larger than 4 cm were boosted after a treatment break to 75 to 80 Gy.193 Bhatnagar and Loper reported their experience using electronic brachytherapy in 122 patients treated to 40 Gy in 8 fractions given twice weekly.191 LC at 1 year is 100%; no grade 3 or above adverse events were noted. Success has also been reported for palliative treatments of Kaposi sarcoma, cutaneous metastatic melanoma, angiosarcoma, Merkel cell metastases, and T-cell and B-cell lymphomas.194–197 Doses and fractionation for these treatments differ significantly. Superficial treatments using brachytherapy in the postoperative setting are also described to prevent keloid scarring, with dose ranges between 15 and 20 Gy in 3 to 10 fractions.198–200

Sarcoma Soft-tissue sarcomas (STSs) are rare tumors that can occur throughout the body. The majority of the literature for STS brachytherapy managed primary tumors of the trunk or extremities. Brachytherapy for STS can be used as a monotherapy postoperatively to improve LC or in combination with EBRT. Although much of the initial literature for brachytherapy in STS used LDR brachytherapy, there is now sufficient evidence to support the use of both HDR and PDR brachytherapy in the treatment of STS as described in the ABS guidelines.201 The Phase III MSKCC study evaluating LDR brachytherapy in STS lowing R0/R1 (no residual/microscopic residual) resection to surgery alone versus surgery and brachytherapy. LC at 5 years was observed in 82% of brachytherapy patients versus 69% with surgery alone (p = 0.04). The LC difference was limited to patients with high-grade lesions (5-year LC 89% vs. 66%, p = 0.0025), whereas brachytherapy had no impact on LC in patients with low-grade lesions.202 There was and depth had no impact on LC. Whether brachytherapy monotherapy is sufficient for tumors with positive margins is uncertain. In early MSKCC analyses, patients with high-grade STS and positive resection margins had trends for improved LC when treated with EBRT plus brachytherapy compared with brachytherapy alone (LC in 90% [9/10] vs. 59% [10/17], p = 0.08).203 However, in subsequent publications, that difference was not sustained (LC 75% for brachytherapy vs. 74% for EBRT with brachytherapy, p = 0.9).204 Factors that may influence consideration of EBRT with tumor, and prior surgeries.205 The prescribed doses for brachytherapy monotherapy and boost are presented in Table 20.5. The implant techniques for LDR, PDR, and HDR interstitial STS brachytherapy are the same. At the time of surgical resection, the radiation oncologist and surgeon define the CTV and arrange a series of brachytherapy catheters to cover the CTV plus a margin of 1 cm to 2 cm. The catheters can be placed perpendicular to the scar or parallel with equal distance between the catheters. Typically, the scar and drain sites are not included in the CTV. Single-plane implants are the most common, but multiplanar implants have also been described. The catheters may be secured within the tumor bed and to the skin with sutures. CT planning allows for 3D evaluation of the CTV and normal tissues, including the skin (Fig. 20.16). Source loading of the implant typically occurs at least 5 days postoperatively because this has been found to

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Recommended Brachytherapy Prescription Doses for Soft-Tissue Sarcoma

TABLE 20.5

Modality

Monotherapy

Boosta

Dose Per Fraction or Dose Rate

LDR

45–50 Gy

15–25 Gy

0.45–0.5 Gy/h

DOSE

PDR

45–50 Gy

15–25 Gy

0.45–0.5 Gy/h

HDR

30–50 Gy

12–20 Gy

2–4 Gy/fraction

a

Brachytherapy boost dose based on delivery of 45 to 50 Gy with external-beam radiotherapy. HDR, High dose rate; LDR, low dose rate; PDR, pulsed dose rate. Modified from Naghavi A, Fernandez N, Mosko A, et al. American Brachytherapy Society (ABS) consensus statement for soft tissue sarcoma brachytherapy. Brachytherapy. 2017;16:466-489.

decrease wound complications.206 LC for brachytherapy monotherapy ranges from 55% to 100% and EBRT with brachytherapy from 71% to 100%.207 In a prospective cohort comparison, the treatment outcomes of patients treated with brachytherapy monotherapy were compared with IMRT. The IMRT cohort had more adverse features, including positive therapy monotherapy (91% vs. 81%). The LC of the IMRT group was, however, comparable to other studies of brachytherapy monotherapy or brachytherapy boost, as mentioned previously. Therefore, the ABS recommends using brachytherapy alone for sarcomas at low risk of recurrence and brachytherapy as a boost to EBRT for sarcomas at high risk of recurrence.201 The most common acute toxicity is delayed wound healing, with reoperation reported between 2.3% and 13.8% in the literature.208 Bone fractures and neuropathy are reported, but the incidence does not appear to be increased by brachytherapy.207 There are no trials to evaluate toxicity outcomes based on dose rate. Brachytherapy has also been described as a boost for retroperitoneal sarcomas with mixed results. In a Princess Margaret Hospital study, investigators initially reported EBRT plus brachytherapy to be well tolerated acutely except in the upper abdomen. In a subsequent analysis with longer follow-up, EBRT plus brachytherapy was associated with increased toxicity with no difference in disease control compared with EBRT alone.209

Central Nervous System Primary central nervous system (CNS) tumors continue to be among the most aggressive and resistant of all human tumors. Despite the potential for higher tumor control through dose escalation, the results have continued to disappoint. Whereas CNS brachytherapy at initial surgery is not practiced, it is reasonable to consider brachytherapy in treating recurrences in younger and high performance status patients when all EBRT options have been exhausted. The most common form of CNS brachytherapy is the intraoperative placement of 125I seeds along the walls of the resection cavity, held in place by various methods. Individual case series show a reasonable level of LC with a tolerable level of radionecrosis. Another method uses an intracavitary balloon connected to a subcutaneous reservoir/port that is then filled with 125I colloid for up to a week to deliver a therapeutic dose. The Brain Metastasis Study Group reported a Phase II study in which this device was used as a perioperative boost of 60 Gy with survival and recurrence similar to other published series of resection followed by EBRT.210

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Fig. 20.16 Single-plane implant for sarcoma brachytherapy delivery. The catheters are placed at the time of surgery.

for CNS brachytherapy. Brain Tumor Cooperative Group 87-01 trial (GBM) to temporary 125I brachytherapy as an addition to the regimen of EBRT and carmustine (BCNU) chemotherapy; 270 patients were evaluated, 137 with EBRT alone and 133 EBRT with brachytherapy. A 10-week survival advantage favored the addition of brachytherapy, but this did not reach statistical significance.211 The University of Toronto 125 I boost after EBRT also showed no survival advantage.212 Age, performance status, and the use of chemotherapy were associated with relative improved survival. Brachytherapy has been explored in other CNS histologies, especially atypical meningioma, in which small case series demonstrate the potential for brachytherapy in the recurrent setting.213 Spinal CNS brachytherapy with permanent radioactive 125I seeds placed in the region of the tumor and close margin at the dura at the time of partial or total vertebrectomy and reconstruction for various diseases has been reported.210 An innovative approach deploys the temporary intraoperative use of a dural plaque coated with a beta-emitting foil such as Yttrium-90 (90Y).214

Pediatrics Brachytherapy is seldom considered a part of first-line therapy for children with cancer. However, the broad use of this modality in the adult population combined with its inherent tissue-sparing abilities continues to stimulate pediatric radiation oncologists to develop innovative uses of brachytherapy as a part of modern multimodality care. Case series for many solid tumor sites—including Wilms tumor, neuroblastoma, hepatoblastoma, Ewing sarcoma, osteosarcoma, STS, rhabdomyosarcoma, retinoblastoma, and craniopharyngioma—demonstrate the reasonableness of such approaches. Such series involve rare tumors, spread over many centers in different parts of the world with heterogeneous equipment and training. These case series demonstrate the reasonable use of 192Ir HDR afterloading brachytherapy with computer graphics 125 I-based 125 extremity therapy, and sophisticated uses of I eye plaques or radioactive colloids. Patients considered for brachytherapy should be referred to

a pediatric cancer program with the necessary equipment, experience, and expertise. Special considerations include room shielding, sedation, and training for staff and family members about radiation protection. A comprehensive review of the applications and techniques in modern pediatric brachytherapy can be found elsewhere.215

Ophthalmic junctiva or the sclera. Brachytherapy can be used for benign disorders such as pterygium and macular degeneration or for the treatment of primary malignant conjunctival tumors such as melanoma, squamous cell carcinoma, and lymphoma or for palliation of metastatic disease.216 The choice of isotope used determines the type of applicator. Curved solid isotope applicators use Strontium-90 (90Sr) with a fixed-diameter applicator (typically 12 mm; Fig. 20.17) or Ruthenium-106 (106Ru) in a range of diameters. These can be held in place for short applications or sutured directly to the sclera for longer applications. Alternatively, usually 125I, although the use of 103Pd and 131Cs seeds has also been investigated with promising dosimetry.217,218 anesthetic eye drops. The applicator is applied directly to the area of bare sclera, adjacent limbus, and affected cornea and either held in place by the operator for short applications or sutured to the sclera for longer applications. Following brachytherapy, the patient must wear The use of natural spacers, such as amniotic membrane, has been described and may help to decrease pain during the procedure and reduce late toxicity.219 Following treatment, mild conjunctivitis is common and long-term dose increase. Scleral ulceration is the most common complication. Maculopathy may occur and is significantly associated with larger tumor 220 Retinal detachment is a rare late complication, with a reported rate of 1.48% up to 10 years after 106Ru treatment of ocular melanoma221 responding well to surgical management. Radiation-induced cataracts

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melanoma using a 90Sr applicator administering doses of 450 to 800 Gy at the sclera.229 There were a proportion of recurrences at the edge of was a 45% preservation of vision, which was generally dependent on tumor position rather than dose delivered.

Vascular Endovascular brachytherapy in the treatment of peripheral vascular stenosis following angioplasty is used with decreasing frequency owing control trials of percutaneous transluminal angioplasty (PTA) alone compared with PTA and brachytherapy in the femoropopliteal artery did not find sufficient evidence to support widespread use of endovascular brachytherapy.230 Several trials comparing drug-eluting stents versus brachytherapy for bare metal stent in-stent restenosis (ISR) of coronary vessels have shown brachytherapy to be associated with an increased incidence of target vessel failure.231,232 In the TAXUS V-ISR trial, 396 paclitaxel or beta source brachytherapy. At 24 months, the freedom from clinical restenosis was worse for the brachytherapy cohort, but there were similar rates of death and myocardial infarction and target vessel thrombosis.233 nary brachytherapy for de novo lesions also failed to show benefit beyond 6 months with delayed and progressive restenosis.234 Nonetheless, in the setting of patients with multiple drug-eluting stent ISR failures for whom there is not a surgical bypass option, coronary vessel brachytherapy can be attempted to achieve suppression of refractory intimal hyperplasia. outflow stenosis in patients who undergo dialysis following angioplasty of a thrombosed graft. This trial closed early but did not show benefit to endovascular brachytherapy.235

Fig. 20.17 Strontium applicator being held in position to deliver radiation to the sclera.

are rare, occurring after higher doses and responding well to surgery. Radiation exposure to the surgeon’s hands and fingers during implantation is low.222 Pterygium is a benign proliferation of the conjunctiva over the cornea. Locally applied 90Sr decreases the rate of recurrence following surgery to as low as 0.5%,223 using doses varying from 20 to 60 Gy in 1 to 6 fractions. Late scleral complications are decreased with fractionated treatment (4.5% vs. 1%). However, alternative perioperative treatments, such as topical chemotherapy and conjunctival autografting, are replacing ophthalmic plaque brachytherapy.224,225 90 Sr has also been used in the treatment of age-related macular of the retina. However, a Phase III trial comparing patients with active AMD who were already on a vascular endothelial growth factor (VEGF) inhibitor to either vitrectomy followed by 24-Gy brachytherapy (and continuing prn anti-VEGF treatment) or to anti-VEGF treatment on an 226

125

I for choroidal melanoma. The prescribed dose was 85 Gy delivered at a dose rate between 0.42 to 1.05 Gy/h. When the use of 125I brachytherapy was compared with enucleation for tumors of 3- to 8-mm depth, there was no difference in survival and similar rates of toxicity.227,228 Van Ginderdeuren et al. demonstrated a 90% 15-year tumor control for sclera

SUMMARY AND FUTURE POSSIBILITIES Brachytherapy is a fundamental part of any radiation oncology program. There are now more techniques and sources than ever before to use the unique physics and radiobiology of brachytherapy. Clinical research must continue to evaluate brachytherapy techniques, allowing for more normal tissues. These further studies will also help guide dose and fractionation and define dose constraints and parameters. treatment through the use of image guidance and the ability to choose the best applicators and dose rate to fit the clinical scenario. Brachytherapy is particularly suited to subvolume dose escalation because of the ability rounding tissue. New biological and functional imaging modalities, such as magnetic resonance spectroscopy (MRS) or positron emission repopulation that may allow dose escalation using brachytherapy. The delivery systems for brachytherapy are also likely to evolve and improve in the future. The move from multiple catheter interstitial partial breast irradiation to single-channel catheters is an example of this type of innovation. Delivery systems could be made more versatile with the capability to deliver different treatment modalities through the same applicator (e.g., brachytherapy and hyperthermia or chemotherapy). Brachytherapy delivery systems are not restricted to applicators. The use of injectable radioisotopes bound to delivery agents such as tagged antibodies or annealed spheres is likely to increase with future developments in antibody technology. Future indications for brachytherapy are ever increasing, but it must be remembered that recommendations for the use of resource-intense

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treatment and planning modalities such as CT-guided implant placement or MRI brachytherapy planning may create treatment paradigms that are unsustainable in many health care systems around the world. When international guidelines are devised, emphasis should be placed on the use of available and accessible technology.

Acknowledgments We thank Drs. F. Bachand, F. Hussain, H. Kader, A-G Martin, T. Neal, and Mrs Melanie Cunningham for images appearing in this chapter.

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for non–small cell lung cancer. Cochrane Database Syst Rev. 2012;(12):CD004284. Gaspar LE, Nag S, Herskovic A, et al. American brachytherapy society (ABS) consensus guidelines for brachytherapy of esophageal cancer. Int J Radiat Oncol Biol Phys. 1997;38:127–132. Homs MY, Steyerberg EW, Eijkenboom WM, et al. Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial. Lancet. 2004;364:1497–1504. Lukens JL, Hu KJ, Levendag PC. Head and neck brachytherapy. In: Devlin PM, ed. Brachytherapy Applications and Techniques. 2nd ed. Baltimore MD: Wolters Kluwer Publishers; 2015. Pisters PW, Harrison LB, Leung KHY, et al. Long-term results of a

sarcoma. J Clin Oncol. 1996;14:859–868. 207. Holloway CL, Delaney TF, Alektiar KM, et al. American brachytherapy society (ABS) consensus statement for sarcoma brachytherapy. Brachytherapy. 2013;12:179–190. 215. Krasin MJ, Merchant TE. The role of brachytherapy in pediatrics. In: Devlin PM, ed. Brachytherapy Applications and Techniques. 2nd ed. New York: Demos Medical Publishing, LLC; 2015. I-125 brachytherapy. Clin Trials. 2011;8:661–673.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 20

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41. Potter R, Gerbaulet A, Haie-Meder C. Endometrial cancer. In: Gerbaulet The GEC ESTRO Handbook of Brachytherapy 42. Hama Y, Uematsu M, Nagata I, et al. Carcinoma of the uterine cervix: twice versus once-weekly high dose rate brachytherapy. Radiology. 2001;219:207–212. 43. Stitt JA, Fowler JF, Thomadsen BR, et al. High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: i. clinical and radiobiological consideration. Int J Radiat Oncol Biol Phys. 1992;24:335–348. 44. Sorbe B, Straumits A, Karlsson L. Intravaginal high-dose-rate two dose-per-fraction levels. Int J Radiat Oncol Biol Phys. 2005;62:1385–1389. 45. Fertil B, Malaise EP. Intrinsic radiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors: analysis of 101 published cell curves. Int J Radiat Oncol Biol Phys. 1985;11:1699–1707. 46. Taghian A, Pernot M, Hoffstetter S, et al. Radiation therapy alone for medically inoperable patients with adenocarcinoma of the endometrium. Int J Radiat Oncol Biol Phys. 1988;15:1135–1140. 47. Fishman DA, Roberts KB, Chambers JT, et al. Radiation therapy as exclusive treatment for medically inoperable patients with stage I and II endometrioid carcinoma with endometrium. Gynecol Oncol. 1996;61:189–196. 48. Beriwal S, Kim H, Heron DE, et al. Comparison of 2D vs. 3D

61. Bowes D, Crook J. A critical analysis of the long-term impact of brachytherapy for prostate cancer: a review of the recent literature. Curr Opin Urol. 2011;21:219–224. 62. Grimm PD, Blasko JC, Sylvester JE, et al. 10-year biochemical (prostate-specific antigen) control of prostate cancer with (125)I brachytherapy. [see comment]. Int J Radiat Oncol Biol Phys. 2001;51:31–40. brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: a population-based cohort study. Radiother Oncol. 2012;103:228–232. 64. Prestidge BR, Winter K, Sanda MG, et al. Initial report of NRG beam radiation and transperineal interstitial permanent brachytherapy with brachytherapy alone for selected patients with Intermediate-Risk prostatic carcinoma. Int J Radiat Oncol Biol Phys. 2016;96:S4. 65. Zumsteg ZS, Zelefsky MJ. Short-term androgen deprivation therapy for patients with intermediate-risk prostate cancer undergoing doseescalated radiotherapy: the standard of care? Lancet Oncol. 2012;13:e259–e269. 66. Hauswald H, Kamrava MR, Fallon JM, et al. High-Dose rate Int J Radiat Oncol Biol. 2016;94:667–674. monotherapy for Intermediate- and High-Risk prostate cancer: clinical results for a median 8-Year Follow-Up. Int J Radiat Oncol Biol. 2016;94:675–682.

medically inoperable endometrial cancer. Technol Cancer Res Treat. 2005;5:1–6. 49. Mock M, Knocke T, Fellner C, et al. Analysis of different application systems and CT-controlled planning variants in treatment of primary endometrial carcinomas. Is brachytherapy treatment to the entire uterus technically possible? Strahlenther Onkol. 1998;174:320–328. consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy. 2012;11:6–19. 51. Rosenthal SA, Bittner NH, Beyer DC, et al. American society for

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permanent prostate brachytherapy with (131)Cs: a consensus report from the cesium advisory group. Brachytherapy. 2008;7:290–296. 57. Hsu IC, Yamada Y, Assimos DG, et al. ACR appropriateness criteria high-dose-rate brachytherapy for prostate cancer. Brachytherapy. 2014;13:27–31. for large prostate volumes (> or = 50 cc)-uncompromised dosimetric coverage and acceptable toxicity. Brachytherapy. 2008;7:7–11. dose rate brachytherapy in the setting of prior transurethral prostate resection. J Urol. 2007;178:1963–1967. 60. Yamada Y, Rogers L, Demanes DJ, et al. American brachytherapy society consensus guidelines for high-dose-rate prostate brachytherapy. Brachytherapy. 2012;11:20–32.

treatment schedules of High-Dose rate brachytherapy monotherapy for Favorable-Risk prostate cancer. Int J Radiat Oncol Biol Phys. 2016;94:657–666. brachytherapy compared to two and three fractions for locally advanced prostate cancer. Radiother Oncol. 2017;124:56–60. men with Low-and Intermediate-risk prostate cancer treated with 19-Gy Single-fraction High-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. 2017;97:98–106. 71. Prada P, Cardenal J, Blanco AG, et al. High-dose-rate brachytherapy as monotherapy in one fraction for the treatment of favorable stage prostate cancer: toxicity and long-term biochemical results. Radiother Oncol. 2016;119:411–416. 72. Morton G, Chung H, McGuffin M, et al. Prostate high dose-rate brachytherapy as monotherapy for low and intermediate risk prostate II clinical trial of one fraction of 19 Gy or two fractions of 13.5 Gy. Radiother Oncol. 2017;122:87–92.

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CHAPTER 20 78. Morris WJ, Tyldesley S, Rodda S, et al. Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the trial comparing a Low-Dose-Rate brachytherapy boost to a DoseEscalated external beam boost for High- and Intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2017;98:275–285. 79. Rodda S, Tyldesley S, Morris WJ, et al. ASCENDE-RT: an analysis of Low-Dose-Rate brachytherapy boost with a Dose-Escalated external beam boost for High- and Intermediate-Risk prostate cancer. Int J Radiat Oncol Biol Phys. 2017;98:286–295. 80. Johnson SB, Lester-Coll NH, Kelly JR, et al. Brachytherapy boost Eur Urol. 2017;72:738–744. radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with gleason score 9-10 prostate cancer. JAMA. 2018;9:896–905. 82. Yaxley JW, Lah K, Yaxley JP, et al. Long-term outcomes of high-dose-rate brachytherapy for intermediate- and high-risk prostate cancer with a median follow-up of 10 years. BJU Int. 2017;120:56–60. 83. Vigneault E, Mbodi K, Magnan S, et al. High-dose-rate brachytherapy boost for prostate cancer treatment: different combinations of hypofractionated regimens and clinical outcomes. Radiother Oncol. 2017;124:49–55.

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Cancer-Related events at 10 years for Intermediate- and High-Risk prostate cancer patients treated with hypofractionated High-Dose-Rate boost and external beam radiotherapy. Int J Radiat Oncol Biol Phys. 2011;79:363–370. Burri RJ, Stone NN, Unger P, et al. Long-term outcome and toxicity of salvage brachytherapy for local failure after initial radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010;77:1338–1344. Yamada Y, Kollmeier MA, Pei X, et al. A phase II study of salvage high-dose-rate brachytherapy for the treatment of locally recurrent prostate cancer after definitive external beam radiotherapy. Brachytherapy. 2014;13(2):111–116. Lahmer G, Lotter M, Kreppner S, et al. Protocol-based image-guided salvage brachytherapy. early results in patients with local failure of prostate cancer after radiation therapy. Strahlenther Onkol. 2013;189:668–674. Crook J, Zhang P, Pisansky T, et al. A prospective phase II trial of transperineal Ultra-sound-guided brachytherpay for locally recurrent

Brachytherapy. 2017;16:S37. 89. Kollmeir MA, McBride S, Taggar A, et al. Salvage brachytherapy for recurrent prostate cancer after definitive radiation therapy: a comparison of low-dose-rate and high-dose-rate brachytherapy and the importance of prostate-specific antigen doubling time. Brachytherapy. 2017;16:1091–1098. 90. Crook J. Radiation therapy for cancer of the penis. Urol Clin North Am. 2010;37:435–443. 91. Petera J, Sirak I, Kasaova L, et al. High-dose rate brachytherapy in the treatment of penile carcinoma–first experience. Brachytherapy. 2011;10:136–140. 92. Crook JM, Haie-Meder C, Demanes DJ, et al. American Brachytherapy Society-Groupe Européen de Curiethérapie-European Society of statement for penile brachytherapy. Brachytherapy. 2013;12:191–198.

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therapy for squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys. 1992;24:479–483. Eng TY, Naguib M, Galang T, et al. Retrospective study of the treatment of urethral cancer. Am J Clin Oncol. 2003;26:558–562. Gerbaulet A, Haie-Meder C, Marsiglia H, et al. Brachytherapy in cancer of the urethra. Ann Urol (Paris). 1994;28:312–317. Milosevic MF, Warde PR, Banerjee D, et al. Urethral carcinoma in women: results of treatment with primary radiotherapy. Radiother Oncol. 2000;56:29–35. Liljegren G, Holmberg L, Bergh J, et al. 10-year results after sector resection with or without postoperative radiotherapy for stage I breast J Clin Oncol. 1999;17:2326–2333. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a mastectomy for early breast cancer. N Eng J Med. 2002;347:1227–1232.

using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer. 2015;51:451–463. 105. Shah C, Vicini F, Shaitelman S, et al. The American brachytherapy society consensus statement for accelerated partial-breast irradiation. Brachytherapy. 2018;17:154–170. 106. Polgar C, Van Limbergen E, Potter R, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the groupe Europeen de curietherapiebreast cancer working group based on clinical evidence (2009). Radiother Oncol. 2010;94:264–273. 107. Correa C, Harris E, Leonardi MC, et al. Accelerated partial breast Based consensus statement. Pract Radiat Oncol. 2017;7:73–79. partial breast irradiation. Brachytherapy. 2012;11:163–175. partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet. 2016;387:229–238. 3-trial: accelerated partial breast irradiation with interstitial multicatheter brachytherapy versus external beam whole breast irradiation: Early toxicity and patient compliance. Radiother Oncol. 2016;120:119–123. 111. Polgar C, et al. Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18:259–268. 112. Polgar C, Fodor J, Major T, et al. Breast-conserving therapy with partial trial. Radiother Oncol. 2013;108(2):197–202. 113. Arthur DW, Winter K, Kuske RR, et al. A phase II trial of brachytherapy alone after lumpectomy for select breast cancer: tumor control and Int J Radiat Oncol Biol Phys. 2008;72:467–473.

and postimplant issues. Brachytherapy. 2010;9:151–158. 94. de Crevoisier R, Slimane K, Sanfilippo N, et al. Long-term results of brachytherapy for carcinoma of the penis confined to the glans (N- or NX). Int J Radiat Oncol Biol Phys. 2009;74:1150–1156.

evaluate brachytherapy as the sole method of radiation therapy for stage I and II breast carcinoma-year-5 toxicity and cosmesis. Brachytherapy. 2014;13(1):17–22.

for 49 patients. Int J Radiat Oncol Biol Phys. 2005;62:460–467. 96. Chaudhary AJ, Ghosh S, Bhalavat RL, et al. Interstitial brachytherapy in carcinoma of the penis. Strahlenther Onkol. 1999;175:17–20.

irradiation: an analysis of variables associated with late toxicity and long-term cosmetic outcome after high-dose-rate interstitial brachytherapy. Int J Radiat Oncol Biol Phys. 2006;64:489–495.

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116. Chao KK, Vicini FA, Wallace M, et al. Analysis of treatment efficacy, cosmesis, and toxicity using the MammoSite breast brachytherapy catheter to deliver accelerated partial-breast irradiation: the William Beaumont hospital experience. Int J Radiat Oncol Biol Phys. 2007;69:32–40. trial of MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast cancer. Am J Surg. 2007;194:456–462. 118. Shah C, Badiyan S, Ben Wilkinson J, et al. Treatment efficacy with accelerated partial breast irradiation (APBI): final analysis of the American Society of Breast Surgeons MammoSite((R)) breast brachytherapy registry trial. Ann Surg Oncol. 2013;20:3279–3285. multilumen brachytherapy catheters for accelerated partial breast irradiation. Brachytherapy. 2012;11:369–373. outcome in patients treated with multilumen balloon brachytherapy with skin spacing 100% to contoured OARs). However, for a patient with rectal cancer, this could consist of 5 to 10 criteria, with included priorities for each listed goal to guide the planner in making trade-offs when not all criteria can be satisfied simultaneously. A typical set of 3D conformal therapy planning goals may include the following: 1. PTV coverage conform to the PTV (target volume) shape; thus, the minimum dose to the PTV will be 95% of the plan normalization point dose. Note that for IMRT plans, although the coverage goals can be more restrictive (e.g., 99% of the PTV receiving 99% of the plan normalization point dose), this should be done carefully and after discussions between physicians and planners because it also can escalate hot spots as minimum coverage is escalated. ± 5%), which will determine the maximum dose allowed in the PTV (in this example, 105%). 2. OAR limits (typically, 45-50 Gy).

tissue limits for the planner. For example, one can specify that the mean dose to the normal lung stay below some given value because it is known that mean dose can be used to predict the chances that pneumonitis will develop or that max dose to the bowel stay below certain limits. The physician should also specify any other goals, constraints, or evaluation expectations that will be used for final plan evaluation. One of the primary causes of additional planning iterations and frustrated planners is a physician who chooses to use a plan evaluation criterion or rule that was not described to the planner as a goal or expectation. Thus, close collaboration between physicians and planners is very important, both before the planning stage to ensure that expectations are clear and after the plan has been completed to discuss challenges or areas for improvement. Ideally, this information would then become part of an enhanced version of the treatment planning directive to continue to improve safety and efficiency.

Iterative Planning Shaping beams is an important part of the iterative planning process. Typically, a BEV margin of 6 to 7 mm is a good starting point for

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CHAPTER 21

Intensity-Modulated and Image-Guided Radiotherapy

conformal beam shaping, but the shape of each field will then need to be modified to improve the conformality of the calculated dose distribution, as discussed previously. This is the part of the iterative forward planning process that is potentially most time-consuming because, in principle, one needs to optimize the location of each leaf of the MLC for each beam and there are 50 to 100 involved MLC leaves in each field. However, the changes in shape that are needed are somewhat predictable because larger MLC margins are needed in regions where there are no other beams (e.g., the superior and inferior aspects of the PTV for a plan with axial-only fields), whereas the margins can be much smaller if there are other beams that are transiting from an orthogonal direction. In the end, many iterations of the shapes may be necessary to get reasonably close to the optimal shaping. This is the part of forward planning that is often time limited by clinical needs and potentially could be significantly improved by the application of computerized optimization methods to perform this shaping automatically.89 Beam weights, use of wedges, and collimator angle rotation followed by revised beam shaping can also be part of the iterative planning process.

Plan Evaluation for Forward Planning Evaluations of plans resulting from forward planning are typically based on isodose line display and DVH plots for target (PTV) and normal tissues. The physician evaluates the plan using these tools and decides whether the plan is adequate for clinical use and whether the plan has the potential to be improved through plan technique changes (e.g., adding beams and changing energies) or by the physician modifying the dosimetric planning goals that were specified initially for the planning. In forward planning, most clinical trade-off decisions are made in a qualitative way by inspection of the displayed dose distribution and the DVHs in contrast to more quantitative trade-offs possible in inverse planning. After the physician agrees that the plan meets his or her intent in terms of target and OAR doses, a prescription must be written or approved if drafted prior to planning. Although the strategy for prescriptions would ideally be uniform across our field, currently there is substantial variability across clinics104 and sometimes across physicians. A recent white paper has started the standardization process for our field. For now, at the very least, there should be a clinic-level standard for prescriptions. Some common methods are to prescribe the dose to the plan normalization point and accept ±5% uniformity throughout the target, or to prescribe the minimum dose to the target volume, and accept that the dose in the target may be as much as, for example, 10% higher or prescribe to a volume like the PTV.

Inverse Planning Rather than trying plans and seeing what kind of dose distribution can be achieved, as in forward planning, the basic concept of inverse planning is to decide up front what the dose distribution should look like and to then “invert” the problem to solve for the beams (and beam intensities) that will give the desired doses. This inverse problem, which is the inverse of the CT back-projection process, would be acceptable except for two small problems: (1) Because there are no negative radiation intensities, it is not possible to invert the problem; and (2) planners probably do not know what the best “achievable” dose distribution would be to use as a goal. Planners do know that the goal of full dose to the target and zero dose to the normal tissues is not possible. To get around these problems, inverse planning makes use of computerized optimization techniques to search for the best plan among all possible candidate plans, using an objective or cost function to drive the optimization toward the plan that is “optimal.” This kind of inverse planning or plan optimization process could be performed in principle for any kind of radiotherapy plan. In practice, however, the plan needs to have many adjustable (optimizable) parameters so that

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there is enough flexibility in the plan to allow the optimization search to find a good solution to the planning problem. This is the reason that, up to this point, most inverse planning and optimization efforts have been applied to IMRT plans created with many separate beamlets or intensity “bixels” per beam because there are a large number of degrees of freedom in the plan that make it possible for the optimization process to work effectively. A typical inverse planning process can be summarized as follows: 1. Define the anatomy. The planner and physician must define (contour) all target and normal tissue structures of interest. Whereas with forward planning one is not “forced” to delineate all important structures, with inverse planning, one must define all anatomic objects that are to be considered by the optimization to prevent unplanned dose from being deposited in unintended regions. One must also define how calculation points are to be distributed throughout the involved objects. 2. Communicate the treatment intent. As discussed earlier, the clinician must define dose goals for targets and OARs and set priorities for assistance in trade-offs in planning. 3. Create the plan. The planner will typically define the beam energies and directions, and choose the intensity-modulated technique such as static beam IMRT or VMAT. 4. Prepare the optimization algorithm parameters. Based on the planning directive, one must define the cost function (and possibly the optimization search algorithm if more than one is available) to be used for the inverse plan. The cost (or objective) function definition is crucial because it will be used to direct the optimization search and to drive the solution toward the desired dose distribution. The cost function can use a body site and situation-dependent template as a starting point but then is defined individually for each patient and is likely to be the most crucial decision involved in determining what kind of plan will result from the optimization process. 5. Iterative plan optimization. Inverse planning uses the optimization search algorithm, driven by the evaluation of the chosen cost function, to perform iterative plan optimization, with the search algorithm determining how the plans are modified and the cost function serving as the judge of plan quality. In most current inverse planning, only the beamlet intensities are varied. Thus, to recalculate the change in the plan dose distribution and cost function, one only needs to resum the dose contributions from the changed beamlets, a calculation that can be performed quickly. The optimization search will continue until predefined stopping criteria are achieved. 6. Plan evaluation and reoptimization. Once the optimization process is complete, the physician and planner must evaluate the plan, dose distribution, cost function results and metrics, and any other relevant information to decide whether the plan is acceptable. If it is not, then the plan optimization process must be rerun. However, it is necessary to make changes in the cost function to drive the plan toward a different result because running the optimization again using the same cost function should result in approximately the same plan result as the first time. For segmental IMRT and VMAT planning, the optimization variables are aperture shapes and intensities. 7. Plan completion. Once the plan is judged acceptable or complete by the planner and physician, the plan is prepared for use. For a beamletoptimized IMRT plan, this completion step includes leaf sequencing, which is the preparation of the MLC leaf trajectories (DMLC delivery) or MLC segment shapes (SMLC delivery) that will create the desired beamlet distribution. Leaf sequencing issues are described in more detail later. Other preparation steps include calculation of MUs for treatment (usually included in leaf sequencing for IMRT), calculation of DRRs or preparation of anatomic information to be used for

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patient localization and IGRT, and transfer of the plan to the treatment delivery system. Comparison of this process for inverse planning with the previously described forward planning process (see Forward Planning section) shows that only two steps are really different; most of the planning process is approximately the same. However, for inverse planning, most interactions aimed at improving the plan must be made by modifying the cost function used for the optimization, a much more indirect type of control on the plan parameters than when modifying a beam shape while performing forward planning.

Setting Planning Goals for Inverse Plans As with forward planning, it is critical for the physician and planner to decide the overall goals for the inverse plan and to prioritize the various clinical issues. Goals for inverse planned IMRT may include the following: be specified: typically, this is the minimum dose, mean dose, or dose to a specific point inside the targets. or absolute dose, depending on published dose-volume-toxicity data or models. methods to force dose reduction based on distance from the PTV. The physician should also define and specify any other constraints or evaluation expectations that will be used for the cost function because there is no other way to specify to the optimization method what it should do or should not do.

Optimization Method The most important issue affecting the quality of the final IMRT plan is typically the type of cost function used and, in particular, how the different parts of the cost function are defined for each relevant organ or other anatomic object. In some systems, there is limited flexibility in the type of cost function available because the cost function is limited to a simple method (often, a quadratic function of dose) to allow the gradient descent-based optimization search method to easily calculate the derivative of the cost function for each variable. However, other cost function methods can be quite general, allowing the use of dose, dose-volume, biological model, or other types of costlets that can be combined into an overall cost function.61 In any event, it is the relationship of the different costlets (individual pieces of the cost function) that determines how important the various parts of the plan evaluation are. Thus, by changing one or more parameters in a costlet or costlets, one can drive the solution of the plan toward a different type of solution. Learning how to modify the cost function to enhance the kind of solution achieved for the plan is one of the most important aspects of inverse planning and may take a significant amount of effort to master. Regardless of the type of inverse planning system or cost function used for inverse planning, one of the easiest ways to choose the appropriate cost function parameters for the plan is to first make sure that the clinical goals for the plan have been prioritized. Then, the cost function is constructed using the highest weights (or power or importance) for the high-priority issues and decreasing weights for the lower-priority issues. How this works in detail is specific for each type of inverse planning system, search method, and clinical site, but the general concept holds true for most inverse planning methods. A number of different types of search algorithms are used for IMRT optimization; these different methods can have specific characteristics that are useful to know. Many current inverse planning systems, however, make use of only one search method; therefore, many planners will not

be able to choose different methods for specific patients or plans. Many inverse planning systems use gradient descent-based search methods because they are fast, but this forces their cost functions to be limited to easily differentiable functions, typically quadratic dose penalties that take the form wi(D – Di)2 where wi is the weight of the penalty and Di is the dosimetric goal for the ith object. This type of cost function tends to lead to tails on the DVHs because a small volume of the object can go higher than the desired dose without causing too much of a penalty. Another common concern about gradient-descent algorithms is the possibility of local minima in the cost function. For simple cost functions this is not a problem, but use of many costlets or complex functions can potentially lead to local minima that may trap the optimization search at a solution that is not the “global” minimum (the optimal solution). To avoid the possibility of being trapped in such local minima, stochastic search algorithms such as simulated annealing51 and others can be used. These algorithms can perform a global search that is more certain to achieve the global minimum of the cost function, but they often are quite slow and can also be sensitive to the search parameters used (as, in fact, are all of the search algorithms).

Plan Evaluation for Inverse Planning When evaluating a complex radiotherapy plan, it is important to have a standard process to ensure that all items are reviewed, particularly in today’s increasingly complex environment that requires multitasking and hand-offs by physicians, planners, and physicists. The beam arrangement/arcs, dose distributions, DVHs, and other available metrics should all be reviewed. One common system popularized by Washington University is “The Good, the Bad, and the Ugly.” The Good. PTV coverage: Is minimum coverage adequate? Is it as homogenous (or heterogeneous if you requested a hot spot) as requested? The Bad. OAR doses: Do they match the goals listed in the planning directive? The Ugly. Hot spot: Where is it? Also look at relative hot spots. Zoom out during evaluation to view entrance doses for each beam. Are there any clinically significant relative hot spots in unexpected and unacceptable locations such as the contralateral chest wall for a lung SBRT case or the groins for a bilateral hip replacement prostate case? Another system first coined by Dr. Stanley Liauw at the University of Chicago is: “Hot Chocolate, Glazed Donuts, and Cookies.” Tumor: Heterogeneity/homogeneity of dose in PTV Coverage of the PTV by 100% isodose surface Normal Tissues: Gradient of dose (is it steep where it matters?) DVH goals (and, can you do better?) Conformality of coverage (irradiated vs. target volume) A more recent addition (not substitution) to this manual evaluation is an automated one, comparing the intended doses to those achieved. Several commercial planning systems have the ability to create templates of these with color coded (e.g., Green = achieved and yellow or orange for not achieved) at-a-glance dashboards. For a complex plan with multiple levels of prioritized dose goals, it is perfectly acceptable for items with lower priorities to be yellow, as this would be expected in situations in which competing goals cannot all be simultaneously achieved (e.g., PTV underdosed next to the spinal cord in order to achieve nonnegotiable spinal cord limits). Often, review of this dashboard is the first step in plan review, for an overall assessment of intended versus achieved doses. This is then followed by a detailed DVH and dose distribution review as discussed earlier.

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CHAPTER 21

Intensity-Modulated and Image-Guided Radiotherapy

If planners knew exactly how to define the cost function so that it correctly summarized all of the physician’s goals and desires for the treatment plan, then if the optimization method worked correctly and achieved the global minimum (rather than a local minimum), they would know that the best plan had been found, which would complete the plan evaluation. However, this presently is not the case. Most clinical inverse planning is still limited by many factors; therefore, many IMRT plans still involve some “forward” iterative plan optimization. Often, when an inverse plan is performed and the plan is evaluated by the physician or planner, the cost function is modified. Then, the plan is reoptimized as the planner or physician attempts to push the plan toward some goal believed to be a better clinical result than what the inverse plan yielded on the first attempt. As cost functions and search methods become more sophisticated, we can expect that this iterative forward planning use of inverse planning technology will become less necessary. If the physician provides the planner information on clinical trade-offs (e.g., prioritize achieving max dose to 0.1 cc of the spinal cord 8 mm to 2.3 mm for liver patients).128 Daily IGRT also provides detailed information about the stability of patients and their positioning, enabling adaptive treatment changes that allow individualization of the margins and setup techniques used for each patient. This is a rapidly developing area that promises improvements in patient treatment precision and in improving our ability to image129 and respond to changes in the patient, tumor, or normal tissue behavior through the course of therapy. In the last decade, major progress has been made in taking account of motion and patient respiration throughout the patient imaging, planning, and delivery processes. 4D CT130,131 is now regularly available in most clinics, giving the physician and planner the ability to visualize, to a limited degree, the motion that occurs as a result of respiration or other such internal motions. Planning strategies that take into account respiratory motion have been described,132 including the definition of an ITV or iGTV, which describes the extra margin required to keep the CTV or GTV in the high-dose region of the dose distribution. Respiration management systems71,72 are routinely used to minimize respiratory motion, leading to a significant decrease in the additional margins that need to be left to keep the target in the high-dose volume in the face of motion as a result of respiration. Using deep inspiration breath hold (DIBH) methods for patients with left-sided breast cancers has helped significantly decrease cardiac dose from the usual tangent-like fields used for those patients.133,134 Finally, real-time monitoring of motion in the target can be accomplished with radiofrequency beacons, video surface imaging, and other realtime methods that can give direct information about motion during treatment.

CLINICAL CONSIDERATIONS To this point, the technical process of conformal therapy planning and delivery has been described. This final section describes some of

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the clinical considerations involved in the application of conformal therapy techniques.

Immobilization and Setup Uncertainties Patient positioning and immobilization should be reproducible and comfortable enough to be maintained for the duration of the treatment, whether it is 5 or 50 minutes. Because position reproducibility and PTV (or PRV) margin are necessarily linked, careful consideration must be given to both. For example, if a target intended for high doses is near a critical structure, such as the spinal cord, a small PTV margin is desired; thus, careful immobilization is required, even if less comfortable. Without nearby critical structures, immobilization can be less restrictive. PTV margins also vary per site, depending on specific immobilization devices or techniques. The clinically measured range of motion and setup uncertainties for each clinical site should be known, as those uncertainties will determine the margins required for the PTVs and PRVs (if used) during treatment planning. Additional margin information can be obtained from the literature, as margins for a sample of patient populations using commercial, widely available immobilization systems have been determined and published; for example, the setup error standard deviation when using a commercial thermoplastic mask for head and neck immobilization has been determined to be 3 to 4 mm if patient-specific information is obtained and daily patient repositioning protocols using portal imaging are enacted.72 Although weekly verification is considered the standard method for conventional radiotherapy and 3D radiotherapy, daily imaging of the skeletal anatomy or implanted fiducial markers using an EPID has reduced systematic and random variations. Systematic setup error can be established from imaging during the first three to five treatments80 and can then be corrected, leaving only the random deviation to be accounted for by adequate PTV margins. Daily patient imaging and correction of setup deviations can reduce it even further, making it possible to minimize the PTV margin, thereby increasing the sparing of adjacent noninvolved tissue. Considerations of patient setup and immobilization approaches are complex. For example, in prostate cancer, the prone patient position can improve the separation between the prostate and the rectum compared with the supine position, potentially improving sparing of the rectum. However, prone positioning also can increase breathingrelated motion of the prostate,72,135 which may increase the required margin in the superior-inferior dimension, actually increasing the length of rectum within or close to the PTV. In breast cancer, prone positioning is gaining popularity for patients with large or pendulous breasts. However, with prone positioning, the heart can fall closer to the chest wall and potentially into the tangential fields for a left-sided breast cancer.136 Thus, careful evaluation of how immobilization position impacts not only target, but also normal tissue geometry, is crucial.

Patient and Organ Motion Individual measurements of motion and setup uncertainties, and their corrections, are especially important in sites where breathing or internal motion is significant, such as the thorax and abdomen. Techniques for dealing with this motion can be separated into two basic categories: eliminating motion or including motion in planning and delivery. Methods to eliminate motion include forced or voluntary breath hold. With these methods, assessment of tumor position can be performed using CBCT or orthogonal imaging of implanted fiducials on the chest wall, and setup variation can be reduced to a few millimeters.128,137 Methods to confirm position of external surrogates138 are popular and user friendly but rely on the assumption that there is a consistent relationship between external surrogates and specific internal anatomy, which is not always the case.139 Not all patients can tolerate breath-hold

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treatments. In addition, they increase time on the treatment machine and patient discomfort. Thus, methods to include motion in planning and delivery are important to avoid treating a PTV that is too small and risking a marginal tumor failure, or treating one too large and risking increased toxicity. Most free-breathing motion management strategies start with a 4D CT to understand the trajectory of tumor motion, which can be quite complex and variable.72 The apparent tumor (if identifiable without optimal intravenous contrast enhancement) is contoured on all phases to include the GTV with motion envelope, also known as the iGTV. Then, a clinical target volume margin is added to include regions of microscopic spread. Last, a margin must still be added for setup uncertainty before arriving at the final PTV. This workflow is most commonly used for lung tumors, in which a CTV is added after the iGTV is defined. If the tumor is apparent only on breath-hold contrast-enhanced CT or MRI, the GTV is still contoured, and a motion envelope for asymmetrical expansions can be created by studying the motion of an internal surrogate in close proximity to the tumor, ideally, implanted fiducials. Adding margins for microscopic spread (if appropriate) and setup uncertainty would also follow. This is most useful for liver tumors. Although most of the focus is on motion of targets, it is important to keep in mind that normal tissues also move, often differently. This can happen during as well as between treatments. During respiration, even different abdominal organs have varying amplitudes of motion.140 Additionally, the shape of and relationship between organs can change, most notably for the stomach, but for other organs such as the colon, duodenum, gallbladder, and bladder as well.141 Thus, a PRV margin and patient instructions on empty versus full stomach and bladder can be helpful to avoid inadvertently high doses to nearby organs. Avoidance instructions can also be given for IGRT guidance. Both breath-hold and free-breathing techniques can be used with treatment gating or tracking. With gating, the beam is on through a prespecified range of positions, within the ITV and PTV margin employed.142 With tracking, the radiation beam follows the motion of the tumor.143 Selection of gating versus tracking is a complex choice, with considerations including practical (which technology is available in a particular center) and theoretical (considerations of duty cycle, margins, and so on).144

Determining the Targets and Normal Tissues For each tumor type and clinical situation, a combination of visible tumor and predicted microscopic extent will be defined and described in detail in subsequent chapters. For 3D conformal and IMRT treatments, uninvolved normal tissues, or OARs, also must be defined. For 3D planning, these OAR contours can assist in beam angle selection, as the angles with the greatest separation of targets and OARs are generally favored. For both, DVHs are calculated, reflecting the achieved doses to absolute or relative volumes, compared with the treatment intent to evaluate plan quality. For IMRT specifically, it is imperative to contour all normal tissues in proximity to the targets, as the optimization system will otherwise skew dose into undefined regions, potentially inadvertently overdosing critical organs. Many normal-tissue atlases have recently been published to standardize delineation and, thus, aid in consistent dose reduction to critical organs.145-149 In addition, inverse planning typically requires the definition of “nonspecified tissue.” This information is usually obtained by subtracting all targets and specified organs at risk from the external contour of the patient in the CT dataset. It allows limits on the maximum doses delivered outside the targets and the OARs, which is necessary to reduce unexpected damage to soft tissue, nerves, blood vessels, and so on. This is particularly important when a new technique is being implemented. For example, in the early days of IMRT, alopecia and dermatitis of the

posterior low scalp were an unanticipated result of using multiple beams without dose limits on the nonspecified normal tissue of the scalp. With the resurgence of arc therapy and the development of new techniques, it is particularly important to carefully set dose limits on normal tissues, often requiring contouring of structures that had traditionally been spared by avoiding beams entering through these regions.

Treatment Goals and Rationale for Highly Conformal Radiotherapy Data from many disease sites suggests that target dose escalation improves local control. At the same time, we are learning more about the doseresponse curves for toxicity after irradiation of OARs. Additionally, as the number of normal tissues with avoidable toxicity increases, often treatment planning becomes similar to avoiding mines in a battlefield. In many situations, this absolutely could not be accomplished without IMRT, newer modes of arc therapy, and, potentially, proton therapy.81 However, this must be balanced against the increased time and cost required for each situation. The clinical considerations for specific sites are described in subsequent chapters.

Target Differential Dosing In many clinical scenarios, several targets are treated with different total doses. Historically, this has been accomplished with “boosts,” which consecutively treated increasingly smaller areas so that the “final boost” resulted in relatively high doses, whereas the initial fields often covered large areas to moderate doses. Examples included 2 Gy daily to the whole breast to 50 Gy followed by a boost of 2 Gy a day to an additional 10 Gy to the lumpectomy cavity, or 1.8 Gy daily to the pelvic nodes to 45 Gy followed by a boost of 1.8 Gy a day to an additional 5.4 Gy to the lower pelvis and rectum. With IMRT, integrated boosts are commonplace as long as the daily dose spread is reasonable, generally, 1.6 to 2.6 Gy. In practice, the most common situation that still uses sequential boosts is prostate cancer when nodal treatment is included due to the large difference in overall doses. In the simultaneous integrated boost (SIB) technique, high-risk targets receive both a higher total dose and a higher daily dose compared with the lower-risk targets and are compared with critical normal structures whose total maximal dose is limited to total doses that are lower than the prescribed target doses. Smaller daily doses reduce the biological effect of the doses delivered to the critical organs (described by the normalized total dose [NTD]); thus, the SIB technique creates the situation in which the maximum critical organ doses usually allowed in standard radiotherapy become much more conservative when used with the SIB IMRT technique if they are treated with lower doses per fraction. Conversely, doses above 2 Gy per fraction should be used with careful consideration because this would deliver a higher biological dose to normal tissues (e.g., mandible) adjacent to these targets. In addition, the maximum doses specified in IMRT or 3D CRT are delivered to smaller (or much smaller) organ volumes compared with conventional radiotherapy. IMRT or highly conformal 3D CRT treatments may be safer than corresponding standard radiotherapy treatments even if nominal maximum critical organ doses are similar. On the other hand, higher-than-standard total target doses, delivered inadvertently as a result of nonuniform dose distributions typical of many IMRT plans or resulting from intentional GTV dose escalation in an effort to increase tumor control rates, are associated with increased daily doses, causing a further increase of the NTD to the tumor. This has the potential to increase toxicity related to tissue embedded within the target. Such toxicity may only be apparent long after therapy and its prevalence is not yet known. Dose escalation relying on the ability of IMRT to restrict the high-dose volume to the GTVs should be conducted only within careful clinical trials.

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CHAPTER 21

Intensity-Modulated and Image-Guided Radiotherapy

When Should the Use of Highly Conformal Radiotherapy/Intensity-Modulated Radiotherapy Be Considered? Planning, delivery, and QA of 3D CRT/IMRT are more complex, costly, and work intensive compared with these factors for previous technologies. The use of 3D CRT/IMRT is justified if it offers apparent clinical advantages. The advantage of dose distributions achieved by IMRT compared with 3D radiotherapy is more flexibility in achieving more complex, conformally shaped dose distributions, including concave, horseshoe-like high-dose distributions (desirable when the target partly encircles a critical involved structure whose tolerance is less than the desired target dose). This includes the following, among many others not listed: and lateral to the spinal cord and are bounded laterally by the major salivary glands and sometimes extends slightly laterally as well, particularly in the postoperative setting nodes) may lay close to the esophagus or the primary tumor may be in close proximity to the spinal cord, brachial plexus, or heart lateral to and posterior to the small bowel the tumor on 3 sides such as the duodenum, stomach, and colon to part of the lung and heart

inner ear IMRT may also be indicated in cases in which minimizing the extent of the tissues receiving a high dose (at the expense of higher volumes receiving low doses) is likely to be beneficial, such as retreatment of recurrent cancer. On the other hand, it is less likely that a dosimetric benefit will be gained from IMRT in cases in which tumors are remote from sensitive tissues or are adjacent to a sensitive tissue but do not (partly) surround it, compared with simpler conformal techniques. Even when dosimetric differences between 3D CRT and IMRT are small—as in prostate cancer, in which the anterior wall of the rectum can protrude somewhat into the posterior prostatic target—these differences still may be translated into a clinically meaningful benefit in reducing rectal complications by IMRT compared with 3D CRT. Patient-related issues include the ability to tolerate treatment times that are longer than those required for less complex treatments—although more rapid methods, such as VMAT, are reducing this problem. Poor immobilization and breathing-related motion increase uncertainties regarding the accurate positions of the targets and adjacent normal tissue in the chest and abdomen and, to a lesser degree, in the pelvis. Daily changes in the shapes of organs such as the rectum and bladder may affect their spatial relationships with the prostate target. Because of the tight dose distributions produced by 3D CRT and IMRT, these uncertainties require the use of techniques that minimize, or take into account, target and OAR internal motion in most sites apart from the brain and head and neck. An additional concern is tumor shrinkage during therapy, which may also change the shape and relative position of adjacent organs. Whether these changes over the course of treatment require modifications of the treatment plans in most patients is the subject of current investigations.150-152

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The high flexibility possible in creating desired dose distributions by IMRT or other highly conformal techniques provides the ability to deliver high doses to parts of tumors judged to be at higher risk than other parts as identified by functional imaging. Clinical accomplishment of this concept, termed dose sculpting, or dose painting, depends on the verification of the reproducibility and reliability of innovative imaging of tumor physiology and early tumor response prediction. IMRT treatment plans are often characterized by nonhomogeneous dose distributions in the targets that produce “hot spots,” receiving substantially more than the prescribed dose. It is imperative that these hot spots are confined to the GTVs but, as with SBRT, these high-dose regions may be associated with higher tumor control. Still, the potential for increased local toxicity as a result of hot spots is not yet clear and may depend on the site irradiated; high doses delivered to the nasopharynx may be well tolerated, as attested by the common use of an intracavitary boost with radioactive sources for nasopharyngeal cancer, but may not be well tolerated by the mucosa in other sites in the head and neck. In any case, heterogeneous dose distributions by IMRT are not a necessity. By strictly limiting maximum doses, homogeneous dose distributions can be created, as for use in breast cancer. The decision regarding whether to deliver homogeneous doses belongs to the physician and planner, who can force more homogeneity by limiting maximum doses allowed by the optimization cost function.

Potentially Negative Aspects of IntensityModulated Radiotherapy Several potential negative aspects of IMRT exist for which there is as yet no clinical validation. Although IMRT reduces the tissue volumes receiving high doses, larger tissue volumes receive low doses compared with standard radiotherapy or 3D CRT. With rotational techniques such as VMAT and tomotherapy, this so-called “low-dose bath” may be even more pronounced. This is primarily a result of the use of many beams, many MUs, and leakage through the MLC leaves. This characteristic may increase the risk of radiotherapy-related second malignancies because the risk of radiotherapy-related mutations and carcinogenesis increases at intermediate rather than at high doses and is also related to volume of irradiated tissues. This risk is especially relevant for young patients. As the risk of radiotherapy-related cancers increases over time, usually beyond 5 to 10 years after therapy, clinical data are not available at this time. Another theoretical concern is the loss of biological effect of radiotherapy when treatment delivery time is prolonged. Prolonged treatment delivery time is characteristic of some IMRT delivery techniques. IMRT delivery modes make a difference in this respect. For example, tomotherapy delivers sequential treatment throughout the target volumes so that the exposure time of each tumor cell to daily radiation is short. In contrast, other systems irradiate all targets simultaneously over a relatively prolonged daily treatment time. Whether the prolonged fraction delivery time translates into a clinical difference is not known. The recent increase in use of VMAT has partially negated these concerns, as the delivery time is typically much faster than static beam IMRT. A last caution for clinics implementing IMRT and other highly conformal techniques: definition of all normal tissues of interest is required because, with inverse planning, beam selection alone cannot limit dose to OARs, as often done in 3D planning. For example, if the small bowel is not specifically contoured for abdominal or pelvic cases, with dose limits specified in optimization, dose may be the same if not higher with IMRT as compared with 3D, wasting the potential to reduce dose. Additionally, IMRT has a tendency to create “horns” of higher dose on the sides of an OAR so that if the OAR geometry changes, even subtly, it can enter a high-dose region. Thus, optimization using PRVs is often helpful.

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Future Efforts To further improve the technical clinical contribution of IMRT to cancer therapy, additional steps need to be taken. They include better understanding of tumor and organ motion and changes during each treatment fraction and during the total course of therapy, along with an improved ability to image the anatomic extent and metabolic activity of tumors. Detailed knowledge of the clinical dose-volume-response relationships for all tissues involved in irradiation, to be gained from careful clinical studies and analyses, will help lead to improved treatments using the tools provided by conformal therapy and IMRT planning and delivery. Adaptive planning workflows will allow more customized radiation plan delivery, which then will need to be evaluated for benefit balanced against the extra effort required.

CONCLUSION Conformal therapy describes a general strategy for conforming the dose distribution to the desired target volume(s) while minimizing the dose to all normal tissues. Many different techniques can be used to accomplish this, ranging from multiple flat conformally shaped fields (3D conformal) to complex intensity-modulated static IMRT or VMAT plans. The key to high-quality conformal therapy is the accuracy and precision with which targets and normal tissues are defined, the optimization of treatment plan(s), and the delivery of treatments using image-guidance methods (IGRT). Any technical improvement that enhances any of those capabilities will potentially improve the outcome of the therapy. Though conformal therapy has now been studied and used for as long as 25 years, the most important remaining task continues to be the clinical study of normal tissue complications and tumor control as a function of dose, volume, fractionation, and other factors so that radiation oncologists have the basic clinical data necessary to further improve the optimization of conformal therapy treatment.

CRITICAL REFERENCES 61. Kessler ML, McShan DL, Epelman MA, et al. Costlets: a generalized approach to cost functions for automated optimization of IMRT treatment plans. Optim Eng. 2005;6(4):421–448. 64. Scaggion A, Fusella M, Roggio A, et al. Reducing inter- and intra-planner variability in radiotherapy plan output with a commercial knowledge-based planning solution. Phys Med. 2018;53:86–93. 67. Jaffray DA, Siewerdsen JH, Wong JW, Martinez AA. Flat-panel cone-beam computed tomography for image-guided radiation therapy. Int J Radiat Oncol Biol Phys. 2002;53(5):1337–1349. 73. Brock KK, Mutic S, McNutt TR, et al. Use of image registration and fusion algorithms and techniques in radiotherapy: report of the AAPM Radiation Therapy Committee Task Group No. 132. Med Phys. 2017;44(7):e43–e76. 76. Guerreiro F, Burgos N, Dunlop A, et al. Evaluation of a multi-atlas CT synthesis approach for MRI-only radiotherapy treatment planning. Phys Med. 2017;35:7–17. 77. Paradis E, Cao Y, Lawrence TS, et al. Assessing the dosimetric accuracy of magnetic resonance-generated synthetic CT images for focal brain VMAT radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(5):1154–1161. 79. Mayo CS, Moran JM, Bosch W, et al. American Association of Physicists in Medicine Task Group 263: standardizing nomenclatures in radiation oncology. Int J Radiat Oncol Biol Phys. 2018;100(4):1057–1066.

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A complete reference list can be found online at ExpertConsult.com.

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Intensity-Modulated and Image-Guided Radiotherapy

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97. Bentzen SM, Constine LS, Deasy JO, et al. Quantitative analyses of normal tissue effects in the clinic (QUANTEC): an introduction to the scientific issues. Int J Radiat Oncol Biol Phys. 2010;76(3):S3–S9. 98. Dawson LA, Normolle D, Balter JM, et al. Analysis of radiation-induced liver disease using the Lyman NTCP model. Int J Radiat Oncol Biol Phys. 2002;53(4):810–821. 99. Hayman JA, Martel MK, Ten Haken RK, et al. Dose escalation in non–small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial. J Clin Oncol. 2001;19(1):127–136. 100. Niemierko A, Goitein M. Implementation of a model for estimating tumor control probability for an inhomogeneously irradiated tumor. Radiother Oncol. 1993;29(2):140–147. 101. Webb S, Nahum AE. A model for calculating tumour control probability in radiotherapy including the effects of inhomogeneous distributions of dose and clonogenic cell density. Phys Med Biol. 1993;38(6):653–666. 102. Niemierko A. Reporting and analyzing dose distributions: a concept of equivalent uniform dose. Med Phys. 1997;24(1):103–110. 103. Qiuwen W, Mohan R, Niemierko A. IMRT optimization based on the generalized equivalent uniform dose (EUD). Proceedings of the 22nd Annual International Conference of the IEEE Engineering in Medicine and Biology Society (Cat. No.00CH37143). 104. Evans SB, Fraass BA, Berner P, et al. Standardizing dose prescriptions: an ASTRO white paper. Pract Radiat Oncol. 2016;6(6):e369–e381. 105. Kessler ML, McShan DL, Fraass BA. A computer-controlled conformal radiotherapy system. III: graphical simulation and monitoring of treatment delivery. Int J Radiat Oncol Biol Phys. 1995;33(5):1173–1180. 106. Siochi RAC. Minimizing static intensity modulation delivery time using an intensity solid paradigm. Int J Radiat Oncol Biol Phys. 1999;43(3):671–680. 107. Boyer AL, Antonuk L, Fenster A, et al. A review of electronic portal imaging devices (EPIDs). Med Phys. 1992;19(1):1–16. 108. Balter J, McShan DL, Lam K, et al. Incorporation of patient setup measurement and adjustment within a computer controlled radiotherapy system. Paper presented at: XIIth international conference on the use of computers in radiation therapy — ICCRT 1997; Madison, WI. 109. van Herk M, Meertens H. A matrix ionisation chamber imaging device for on-line patient setup verification during radiotherapy. Radiother Oncol. 1988;11(4):369–378. 110. Antonuk LE, Boudry J, Huang W, et al. Demonstration of megavoltage and diagnostic x-ray imaging with hydrogenated amorphous silicon arrays. Med Phys. 1992;19(6):1455–1466. 111. Antonuk LE, Boudry J, Weidong H, et al. Thin-film, flat-panel, composite imagers for projection and tomographic imaging. IEEE Trans Med Imaging. 1994;13(3):482–490. 112. Lam KL, Haken RKT, McShan DL, Thornton AF. Automated determination of patient setup errors in radiation therapy using spherical radio-opaque markers. Med Phys. 1993;20(4):1145–1152. 113. Uematsu M, Fukui T, Shioda A, et al. A dual computed tomography linear accelerator unit for stereotactic radiation therapy: a new approach without cranially fixated stereotactic frames. Int J Radiat Oncol Biol Phys. 1996;35(3):587–592. 114. Jaffray DA, Carlone M, Menard C, Breen S. Image-guided radiation therapy: emergence of MR-guided radiation treatment (MRgRT) systems. Medical Imaging 2010: Physics of Medical Imaging; 2010/03/04, 2010. 115. Dempsey JF, Benoit D, Fitzsimmons JR, et al. A device for realtime 3D image-guided IMRT. Int J Radiat Oncol Biol Phys. 2005;63:S202. 116. Raaymakers BW, Lagendijk JJ, Overweg J, et al. Integrating a 1.5 T MRI scanner with a 6 MV accelerator: proof of concept. Phys Med Biol. 2009;54(12):N229–N237. 117. Fallone BG, Murray B, Rathee S, et al. First MR images obtained during megavoltage photon irradiation from a prototype integrated linac-MR system. Med Phys. 2009;36(6Part1):2084–2088. 118. Kolling S, Oborn B, Keall P. Impact of the MLC on the MRI field distortion of a prototype MRI-linac. Med Phys. 2013;40(12):121705. 119. Bert C, Metheany KG, Doppke K, Chen GTY. A phantom evaluation of a stereo-vision surface imaging system for radiotherapy patient setup. Med Phys. 2005;32(9):2753–2762.

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120. Perry H, Mantel J, Lefkofsky MM. A programmable calculator to acquire, verify and record radiation treatment parameters from a linear accelerator. Int J Radiat Oncol Biol Phys. 1976;1(9–10):1023–1026. 121. Sternick ES, Berry JR, Curran B, Loomis SA. Real-time computer verification for radiation therapy treatment machines. Radiology. 1979;131(1):258–262. 122. Fraass BA, McShan DL, Kessler ML, et al. A computer-controlled conformal radiotherapy system I: overview. Int J Radiat Oncol Biol Phys. 1995;33(5):1139–1157. 123. Eisbruch A, Marsh LH, Martel MK, et al. Comprehensive irradiation of head and neck cancer using conformal multisegmental fields: assessment of target coverage and noninvolved tissue sparing. Int J Radiat Oncol Biol Phys. 1998;41(3):559–568. 124. Fraass BA, McShan DL, Matrone GM, et al. A computer-controlled conformal radiotherapy system. IV: electronic chart. Int J Radiat Oncol Biol Phys. 1995;33(5):1181–1194. 125. Boer JC, Heijmen BJM, Pasma KL, Visser AG. Characterization of a high-elbow, fluoroscopic electronic portal imaging device for portal dosimetry. Phys Med Biol. 1999;45(1):197–216. 126. Louwe RJW, McDermott LN, Sonke JJ, et al. The long-term stability of amorphous silicon flat panel imaging devices for dosimetry purposes. Med Phys. 2004;31(11):2989–2995. 127. Litzenberg D, Moran JM, Fraass BA. A semi-automated analysis tool for evaluation of dynamic MLC delivery. J Appl Clin Med Phys. 2002;3:63–72. 128. Balter JM, Brock KK, Litzenberg DW, et al. Daily targeting of intrahepatic tumors for radiotherapy. Int J Radiat Oncol Biol Phys. 2002;52(1):266–271. 129. Sonke J-J, Zijp L, Remeijer P, van Herk M. Respiratory correlated cone beam CT. Med Phys. 2005;32(4):1176–1186. 130. Low DA, Nystrom M, Kalinin E, et al. A method for the reconstruction of four-dimensional synchronized CT scans acquired during free breathing. Med Phys. 2003;30(6):1254–1263. 131. Ford EC, Mageras GS, Yorke E, Ling CC. Respiration-correlated spiral CT: a method of measuring respiratory-induced anatomic motion for radiation treatment planning. Med Phys. 2002;30(1):88–97. 132. Keall PJ, Mageras GS, Balter JM, et al. The management of respiratory motion in radiation oncology report of AAPM Task Group 76a). Med Phys. 2006;33(10):3874–3900. 133. Sixel KE, Aznar MC, Ung YC. Deep inspiration breath hold to reduce irradiated heart volume in breast cancer patients. Int J Radiat Oncol Biol Phys. 2001;49(1):199–204. 134. Hanley J, Debois MM, Mah D, et al. Deep inspiration breath-hold technique for lung tumors: the potential value of target immobilization and reduced lung density in dose escalation. Int J Radiat Oncol Biol Phys. 1999;45(3):603–611. 135. Olsen JR, Parikh PJ, Watts M, et al. Comparison of dose decrement from intrafraction motion for prone and supine prostate radiotherapy. Radiother Oncol. 2012;104(2):199–204. 136. Shah AP, Kupelian PA, Willoughby TR, et al. An evaluation of intrafraction motion of the prostate in the prone and supine positions using electromagnetic tracking. Radiother Oncol. 2011;99(1):37–43. 137. Balter JM, Brock KK, Lam KL, et al. Evaluating the influence of setup uncertainties on treatment planning for focal liver tumors. Int J Radiat Oncol Biol Phys. 2005;63(2):610–614. 138. Peng JL, Kahler D, Li JG, et al. Characterization of a real-time surface image-guided stereotactic positioning system. Med Phys. 2010;37(10):5421–5433. 139. Feng M, Balter JM, Normolle D, et al. Characterization of pancreatic tumor motion using cine MRI: surrogates for tumor position should be used with caution. Int J Radiat Oncol Biol Phys. 2009;74(3):884–891. 140. Bussels B, Goethals L, Feron M, et al. Respiration-induced movement of the upper abdominal organs: a pitfall for the three-dimensional conformal radiation treatment of pancreatic cancer. Radiother Oncol. 2003;68(1):69–74. 141. Watanabe M, Isobe K, Takisima H, et al. Intrafractional gastric motion and interfractional stomach deformity during radiation therapy. Radiother Oncol. 2008;87(3):425–431.

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142. Ge J, Santanam L, Yang D, Parikh PJ. Accuracy and consistency of respiratory gating in abdominal cancer patients. Int J Radiat Oncol Biol Phys. 2013;85(3):854–861. 143. Keall PJ, Joshi S, Vedam SS, et al. Four-dimensional radiotherapy planning for DMLC-based respiratory motion tracking. Med Phys. 2005;32(4):942–951. 144. Sawkey D, Svatos M, Zankowski C. Evaluation of motion management strategies based on required margins. Phys Med Biol. 2012;57(20): 6347–6369. 145. Nielsen MH, Berg M, Pedersen AN, et al. Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: national guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group. Acta Oncol (Madr). 2013;52(4):703–710. 146. Feng M, Moran JM, Koelling T, et al. Development and Validation of a Heart Atlas to Study Cardiac Exposure to Radiation Following Treatment for Breast Cancer. Int J Radiat Oncol Biol Phys. 2011;79(1):10–18. 147. Gay HA, Barthold HJ, O’Meara E, et al. Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group Consensus Panel atlas. Int J Radiat Oncol Biol Phys. 2012;83(3):e353–e362.

148. Hall WH, Guiou M, Lee NY, et al. Development and validation of a standardized method for contouring the brachial plexus: preliminary dosimetric analysis among patients treated with IMRT for head-andneck cancer. Int J Radiat Oncol Biol Phys. 2008;72(5):1362–1367. 149. Kong FM, Ritter T, Quint DJ, et al. Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. Int J Radiat Oncol Biol Phys. 2011;81(5):1442–1457. 150. Hunter KU, Fernandes LL, Vineberg KA, et al. Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2013;87(4):676–682. 151. Koay EJ, Lege D, Mohan R, et al. Adaptive/nonadaptive proton radiation planning and outcomes in a phase II trial for locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2012;84(5):1093–1100. 152. Battista JJ, Johnson C, Turnbull D, et al. Dosimetric and radiobiological consequences of computed tomography–guided adaptive strategies for intensity modulated radiation therapy of the prostate. Int J Radiat Oncol Biol Phys. 2013;87(5):874–880.

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22 Intraoperative Irradiation Brian G. Czito, Felipe A. Calvo, Michael G. Haddock, Rachel Blitzblau, and Christopher G. Willett

Intraoperative radiotherapy (IORT) is the delivery of radiation during surgery (Video 22.1). The rationale is straightforward: escalating radiation dose may enhance local tumor control. In many clinical situations, the dose delivered by external-beam radiation techniques is limited by tolerance of surrounding normal tissues. To overcome this, intraoperative irradiation has been employed as a technique facilitating tumor dose escalation. In the era of precision medicine, IORT is a technical component of radiation dose delivery that optimizes risk-adapted strategies in local cancer therapy, offering a highly individualized approach to improve the therapeutic index.1 Recent Phase III trials have explored IORT, testing noninferiority or equivalence in patients with early breast cancer.2,3 This chapter reviews the rationale and treatment strategies of intraoperative electron radiotherapy (IOERT), intraoperative high-doserate brachytherapy (HDR-IORT), and orthovoltage techniques with surgery. These strategies frequently integrate external-beam radiotherapy (EBRT) and chemotherapy.

EBRT (with or without concomitant chemotherapy) and resection. The rationale is that EBRT fields encompass the primary tumor and surrounding tissues harboring potential microscopic disease. In contrast to a large single fraction of irradiation, fractionated radiation (EBRT) is radiobiologically advantageous in promoting tumor control while minimizing late normal tissue injury. Shrinking-field techniques permit dose escalation. This approach is used in many malignancies—including head and neck cancers, breast cancer, and cervical cancer—with excellent local control and acceptable morbidity to dose-limiting normal tissues. These “boost” fields can be delivered in a multitude of ways, including interstitial and intracavitary techniques as well as superficial electrons. For selected intraabdominal, pelvic, thoracic, and other malignancies, IORT is a technique for localized dose escalation while optimizing normal tissue protection.

HISTORY

When EBRT is fractionated, there is a preferential therapeutic advantage for normal tissues relative to tumor as defined by the 4Rs of classical radiobiology (normal tissue repair, tumor reoxygenation, cell-cycle redistribution, and normal tissue repopulation). With a single large fraction of radiotherapy, these advantages are lost. In addition, large doses per fraction may result in increased risk of late effects. There is evidence that small-vessel injury caused by large doses per fraction may contribute to late effects, and ischemic complications are dose dependent.8 Furthermore, tumor response to single and fractionated radiotherapy depends on the percentage of hypoxic cells within a tumor. This differential sensitivity between hypoxic and well-oxygenated cells increases with increasing dose. Using alpha/beta calculations (α/β), biologically equivalent doses to a fractionated EBRT course using 2 Gy per fraction for varying IORT doses have been estimated (Table 22.1). As shown, there are disadvantages from a late-effects standpoint with IORT. However, many of these disadvantages are mitigated by exclusion of nontarget tissues from the radiation field by direct inspection, mobilization, and shielding.9 When combined with EBRT and resection, IORT doses of 10 to 20 Gy provide local control for most solid tumors, especially in the setting of microscopic residual disease. When combined with EBRT and surgery, there is little reason to exceed IORT doses of 10 to 20 Gy. Late normal-tissue complications are often the limiting sequelae of IORT administration; careful planning and administration with techniques designed to reduce dose to nontarget tissues is of paramount importance. Experimental animal data and clinical studies have documented the tolerance of normal tissues to IOERT, EBRT, or both modalities combined, with detailed description of incidence and characteristics of reported observations and toxic events expected in the clinical practice scenario.10

The use of IORT was first employed almost 100 years ago.4 The contemporary approach to IORT was initiated in the 1960s by Abe et al. in Japan. These investigators advocated resection (where possible) with large, single-dose radiotherapy (25-40 Gy using cobalt-60).5 In the mid- to late 1970s, many institutions in the United States adopted IORT as a treatment approach, primarily as a radiation boost component, using linear accelerator (LINAC)-based electron treatment in the operating room, including Howard University, Massachusetts General Hospital (MGH), the Mayo Clinic, and the National Cancer Institute (NCI). In recent years, National Comprehensive Cancer Network guidelines have included IORT as a treatment option in soft-tissue sarcomas, resected pancreatic cancer, oligo-recurrent intraabdominal disease, T4 rectal cancer, and accelerated partial breast irradiation breast cancer candidates.6 At present, there are about 90 centers in at least 16 countries worldwide with active IORT programs.7

RATIONALE IORT has the potential to improve local control and the therapeutic ratio in many tumor sites by reducing the volume of the irradiation “boost” field by direct tumor/tumor bed visualization and conformal treatment, exclusion of part or all of dose-limiting normal structures by operative mobilization, direct shielding, or varying electron beam energy, and allowing the delivery of high-dose irradiation by the preceding methods. Although early investigators studied this modality separately in the treatment of resected and unresectable malignancies, current approaches frequently employ this technique in combination with fractionated

BIOLOGY OF INTRAOPERATIVE RADIOTHERAPY

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Estimated Biologically Equivalent EBRT Doses (2 Gy Per Day) of Varying IORT Doses

further systemic therapy, followed by resection. Despite this, local recurrence occurs in 30% to 70% of patients.17

IORT Dose

10 Gy

15 Gy

20 Gy

Normal tissue (acute)

20 Gy

37 Gy

60 Gy

17 Gy

31 Gy

50 Gy

30 Gy

65 Gy

120 Gy

For patients with cervical cancer, paraaortic nodal metastases are common. Despite the presence of these “distant” metastases, approximately 15% to 20% of patients are cured by radical radiotherapy techniques employing EBRT doses of 55 to 60 Gy. However, high complication rates have been reported with these doses and techniques.18,19 As in rectal cancer, patients with recurrent cervical cancer in the pelvis or paraaortic region have a poor long-term prognosis, with 5-year overall survival (OS) rates ranging from 5% to 30%. These patients have often been previously irradiated and retreatment with meaningful doses of EBRT is usually not feasible given normal tissue tolerance. When patients have paraaortic or locally recurrent disease, administration of IORT is a feasible method to escalate dose and enhance local control.

TABLE 22.1

(α/β = 7) Tumor (α/β = 10) Normal tissue (late) (α/β = 2) EBRT, External beam radiotherapy; IORT, intraoperative radiotherapy.

LOCAL CONTROL: AN IMPORTANT ENDPOINT For any treatment, a patient is incurable if local control of the tumor is not achieved. If conventional treatment methods of EBRT, chemotherapy, and surgery provided high local control rates, IORT as a component of treatment would be unnecessary. Single-dose irradiation with precise radiotherapy techniques has also emerged as a valid alternative in patients with metastatic disease11 or as a potentially cost-effective technique for patients with tumors in early stages and with a favorable prognosis.12 Although local control rates are satisfactory in many tumor sites using conventional techniques, local failure is problematic in other sites, including abdominal and pelvic malignancies. Treatment of these areas employing standard EBRT techniques is limited by normal tissue tolerance. Examples of such sites are discussed herein.

Pancreatic Cancer EBRT with 5-fluorouracil (5-FU)–based chemotherapy employed in the treatment of unresectable pancreatic cancer results in a doubling of median survival compared with surgical bypass/stenting alone (3-6 months vs. 9-13 months) and an increase in 2-year survival from between 0% to 5% and 10% to 20%.13 Unfortunately, these techniques result in poor local control rates (20%-30%). The use of IORT has been evaluated in patients with both resectable and unresectable pancreatic cancer.

Retroperitoneal Sarcoma When surgery is used as the primary treatment modality for retroperitoneal sarcomas, local failure has been reported to range from 40% to 90%. Despite the addition of EBRT to surgery, local failure rates are 40% to 80%. This is in contrast to extremity sarcomas, where local control rates approach 90%. Because of the limited tolerance of surrounding normal tissue (small intestine, stomach, liver, kidney, and spinal cord), EBRT doses are limited. A randomized NCI trial evaluating IORT in retroperitoneal sarcomas demonstrated that patients receiving IORT with EBRT experienced significantly improved local control and less small-bowel toxicity versus patients treated with EBRT alone (80% in-field relapse; discussed later).14

Colon and Rectal Cancer In patients with locally advanced (T4) or locally recurrent colon and rectal cancers, local control is difficult to achieve despite multimodality therapy. Studies from Princess Margaret Hospital and the Mayo Clinic report local failure rates of 90% or greater in evaluable patients treated with EBRT with or without systemic therapy.15,16 In patients who are radiation naïve, the general approach in locally advanced tumors is preoperative EBRT combined with 5-FU-based chemotherapy, potentially

Cervical Cancer

Oligorecurrences: Miscellaneous Intraabdominal Sites Active follow-up of patients with cancer initially treated for cure has identified new entities, including oligometastatic or oligorecurrent disease still amenable to salvage treatment by combining surgical and radiotherapy components. Analyses of patient cohorts, including varying cancer primary sites and histological subtypes, have reported local control rates of greater than 80% and 5-year survivals of 35% in patients with extrapelvic, oligotopic disease.20 In the case of intrapelvic gynecological oligorecurrences, salvage therapy with extended surgery and IOERT has demonstrated a 10-year locoregional control of 58%, with improved results if EBRT was integrated into this approach.21

LOCAL CONTROL: RADIATION DOSE, COMPLICATIONS, SHRINKING-FIELD TECHNIQUES, AND DISTANT METASTASES Influence of Dose In both animal and human models, the probability of local control of a tumor by radiation is generally proportional to the total dose administered. The dose of radiation to control a tumor locally depends on several factors, including tumor type, clonogen number, and tumor microenvironment. Thus, a given radiation dose may be able to control a small tumor with high probability and acceptable morbidity; however, that same dose may be insufficient against disease of larger volume. Clinical experience has generated a body of data correlating local control by tumor type and radiation dose. Figure 22.1 summarizes in vivo data for a variety of irradiated human tumors of varying sizes and types.22 Fletcher examined local control probability as a function of radiation dose for patients undergoing treatment for breast carcinoma and squamous cell carcinoma of the upper aerodigestive tract (eTable 22.1). For patients with breast cancer, control of subclinical disease was approximately 60% to 70% with 30 to 35 Gy, 85% with 40 Gy, and 95% with 45 to 50 Gy. For larger/palpable tumors, EBRT doses of 46 Gy, 59 Gy, and 76 to 90 Gy result in a local control probability of 20%, 35% to 50%, and 70% to 80%, respectively.23–26 Dose-response data is summarized for patients with squamous cell carcinomas of the upper aerodigestive tract in eTable 22.1. These data suggest that marked improvements in local control can be achieved by escalating radiation doses.

Dose Versus Complications The chief limitation of EBRT to control macroscopic disease in the abdomen and pelvis is normal tissue tolerance. Normal organs such as the stomach, small bowel, and kidney have tolerance levels well below the radiation doses required to eradicate most abdominal and pelvic

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CHAPTER 22

Intraoperative Irradiation

eTABLE 22.1 Tumor Control Probability Correlated With Irradiation Dose and Volume of Cancer Dose (Gy)

Tumor Control Probability

Squamous Cell Carcinoma: Upper Aerodigestive Tract > 90% subclinical 50a ~ 60% T1 lesions of nasopharynx ~ 50% 1-cm to 3-cm neck nodes 60a

~ 90% T1 lesions of pharynx and larynx ~ 50% T3 and T4 lesions of tonsillar fossa ~ 90% 1-cm to 3-cm neck nodes ~ 70% 3-cm to 5-cm neck nodes

70a

~ 90% T2 lesions of tonsillar fossa and supraglottic larynx ~ 80% T3 and T4 lesions of tonsillar fossa

Adenocarcinoma of the Breast > 90% subclinical 50a 60a

90% clinically positive axillary nodes, 2.5-3 cm

70a

65% 2-3 cm primary

70-80 (8-9 wk)

30% >5 cm primary

80-90 (8-10 wk)

56% >5 cm primary

80-100 (10-12 wk)

75% 5-15 cm primary

a

10 Gy in five fractions each week. Modified from Fletcher GH, Shukovsky LJ. The interplay of radiocurability and tolerance in the irradiation of human cancers. J Radiol Electrol. 1975;56:383–400.

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CHAPTER 22 100

Intraoperative Irradiation

373

100

60 Percent

Control (%)

80

40 20 0

0

2000

4000 6000 Dose (cGy)

Complications Tumor control

8000 0

Hodgkin lymphoma Skin Oat cell of lung Cervix Subclinical breast Locally advanced breast Head and neck subclinical Head and neck intermediate Fig. 22.1 Local control versus dose of irradiation. (Modified from Gunderson LL, Tepper JE, Biggs PJ, et al. Intraoperative ± external beam irradiation. Curr Probl Cancer. 1983;7(11):1–69.)

malignancies. Exceeding these, EBRT doses result in prohibitive risk of late normal-tissue damage (eTable 22.2). Because of this, “conventional” tolerable doses of EBRT from 45 to 55 Gy using 1.8 to 2 Gy per fraction are not curative in most abdominal and pelvic malignancies, with resultant local persistence/local recurrence of disease common in patients treated with radiotherapy alone. This often results in tumor-related morbidity and mortality, such as bowel obstruction and perforation, ureteral obstruction, and neuropathy. Although local control is enhanced with increasing doses of radiation, tumor dose-response curves with EBRT closely resemble normal-tissue complication curves. Therefore, efforts to improve local control through escalating EBRT doses may also result in treatment-related complications (Fig. 22.2). In an R1 (microscopic residual) resection, EBRT doses of 60 Gy or higher using conventional fractionation schemes are necessary to achieve a high probability of local control. In an R2 (gross residual) resection, even higher doses are usually required. Such doses often exceed normal-tissue tolerance (see eTable 22.2). Because of the risks associated with dose escalation beyond normaltissue tolerance, an attractive alternative in patients with locally advanced malignancies is to deliver moderate doses of EBRT (i.e., at or below accepted tolerance of surrounding normal tissue). A typical course would range from 45 to 50 Gy at 1.8 to 2 Gy per fraction, followed by surgical exploration. After resection, IORT would be performed, avoiding or minimizing irradiation of surrounding organs by shielding or mobilization. With this approach, an increase in local control with decreased risk of normal-tissue complications (relative to an EBRT-only approach) can be achieved (see Fig. 22.2—local control curve shifts to left with IORT; complication curve shifts to right with increasing EBRT doses).

Shrinking-Field (Boost) Techniques The concept of shrinking-field irradiation, otherwise known as administering “boost” treatments, has been used for decades by radiation oncologists. This strategy entails treating larger fields encompassing the primary/recurrent tumor along with locoregional lymph node basins

Dose Fig. 22.2 Radiation dose versus incidence of tumor control or complications. (Modified from Gunderson LL, Tepper JE, Biggs PJ, et al. Intraoperative ± external beam irradiation. Curr Probl Cancer. 1983;7(11):1–69.)

and other tissues at risk for subclinical disease. These larger fields receive a dose sufficient to control microscopic disease yet respect normal organ tolerance (often 45-50 Gy using 1.8-2 Gy per fraction). Fields are then reduced to encompass gross disease with smaller margins, excluding dose-limiting normal tissues. An additional 20 to 35 Gy may then be administered to these fields using either EBRT or brachytherapy techniques, bringing the cumulative dose to 65 to 80 Gy. These approaches are employed in many tumor sites, including gynecological and head and neck cancers, with excellent long-term outcomes and local control with relatively low and acceptable morbidity levels. The concept of administering IORT in conjunction with EBRT is a logical application of this approach.

Local Control and Development of Distant Metastases Preclinical data suggests that the incidence of distant metastases is related to both tumor size and the development of locally recurrent disease in multiple spontaneous tumor systems.27–29 In fibrosarcoma and squamous cell carcinoma cell lines in rodent models, Ramsay et al. reported increased rates of distant metastases in tumors measuring 12 mm versus 6 mm, as well as recurrent versus primary tumors.27 Additionally, Suit et al. showed that in mouse mammary tumors treated with single-dose irradiation, increasing rates of local failure were associated with increasing rates of distant metastases.29 Specifically, the incidence of metastatic disease was 31% (16 of 52) of mice with local control, 50% (9 of 18) in those with local relapse salvaged by resection, and 80% (12 of 15) in mice with local relapse in whom salvage was not attempted. Similar high rates of metastases associated with local failure have been observed in human malignancies, including cervix,30 prostate,31 head and neck,32 and breast33 cancers. These and other data suggest that metastases may arise from locally recurrent disease.

PATIENT SELECTION AND EVALUATION Patient Selection Criteria Candidates for IORT should be evaluated by the treating surgeon and radiation oncologist in a multidisciplinary setting. This allows for joint decisions regarding the appropriateness of IORT and whether further studies that may influence IORT and EBRT planning are appropriate. Additionally, joint decisions can be made defining the optimal sequencing of surgery/IORT and EBRT. Informed consent should be obtained from both specialties, specifically with regard to potential risks, benefits, and

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CHAPTER 22

eTABLE 22.2

Tolerance

Intraoperative Irradiation

Gastrointestinal Radiation DOSES (IN GY)a

Organ

Injury at 5 yr

TD5/5

TD50/5

Volume or Length

Esophagus

Ulcer, stricture

60-65

75

75 cm3

Stomach

Ulcer, perforation

45-50

55

100 cm3

Intestine (small)

Ulcer, stricture

45-50

55

100 cm3

Colon

Ulcer, stricture

55-60

75

100 cm3

Rectum

Ulcer, stricture

55-60

75

100 cm3

Anus

Ulcer, stricture

60-65

≥75

—

Pancreas

Secretory functions

—

—

—

Liver

Liver failure, ascites

35

45

Whole

Biliary ducts

Stricture, obstruction

50

70b

—

Data based on supervoltage (6/18 MV), 9 Gy/wk (5 × 1.8). External beam radiation to 50.4 Gy ( 28 × 1.8 5 12 weeks) plus 20 Gy at 1-cm radius with iridium 192. TD5/5, 5% chance of severe intolerance within 5 years; TD50/5, 50% chance of severe intolerance within 5 years. Modified from Gunderson LL, Martenson JA. Gastrointestinal tract radiation tolerance. Front Radiat Ther Oncol. 1989;23:277–298. a

b

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Techniques and Modalities

side effects of proposed treatments. Criteria for the appropriate selection of patients for IORT generally include the following: 1. Surgery alone will result in a high probability of incomplete resection (microscopic or gross residual disease) and resultant high probability of failure within the tumor bed. Potential candidates must be appropriate for surgical attempts at gross total resection. IORT administration should be performed at the time of a planned operation. 2. There is no evidence of distant metastases. Rare exceptions include resectable single-organ metastasis, slow progression of systemic disease, excellent chemotherapy options, and patients with oligometastatic disease with slow systemic progression and high probability of symptomatic local failure. 3. EBRT doses required for high probability of local control following subtotal or no resection exceed normal-tissue tolerance (total doses required for eradication in this setting: 60-70 Gy for microscopic disease and 70-90 Gy for gross disease at 1.8-2 Gy per fraction). 4. Surgical displacement or shielding of dose-limiting structures or organs can be accomplished during IORT administration, allowing for acceptable risks of immediate and late effects. Theoretically, EBRT in conjunction with IORT should result in an improved therapeutic ratio between disease eradication and normal-tissue complications.

Patient Evaluation Pretreatment patient evaluation in patients eligible for IORT should include a thorough history and physical examination, with attention to palpable disease and its relationship to anatomically immobile normal structures. Examples include pelvic disease and its relationship to the pelvic sidewall, presacral space, prostate, or vagina. Computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound may aid in identifying adherence to structures (e.g., bony pelvis and large vessels) that may be surgically unresectable for cure. Examination under anesthesia may be helpful in some situations, including locally advanced gynecological and rectal cancers. Routine blood work—including complete blood count (CBC), liver function tests, renal function tests, and tumor-specific serum test (e.g., carcinoembryonic antigen, CA19-9)—should be obtained when appropriate. Patients should be evaluated clinically and radiographically for evidence of distant spread. Positron emission tomography (PET), preferably in conjunction with CT, may facilitate defining local disease extent as well as unsuspected distant metastases. Evaluation of distant metastases is particularly important in the recurrent setting in which concurrent distant failure is common. Biopsy confirmation of disease should usually be obtained before proceeding with resection.

SEQUENCING AND DOSE OF EXTERNAL BEAM RADIOTHERAPY AND INTRAOPERATIVE RADIOTHERAPY Sequencing of External Beam Radiotherapy, Intraoperative Radiotherapy, and Surgery For patients with localized malignancy, the goal of curative oncological surgery is an R0 (margin-negative) resection. Because of the locally advanced and infiltrative nature of many primary tumors (including colorectal, gynecological, upper gastrointestinal [GI] malignancies, sarcomas, among others) and locally recurrent malignancies, surgery may be compromised with close margins or microscopic/gross residual tumors. For patients with locally advanced tumors, preoperative EBRT to doses of 45 to 50 Gy using 1.8 to 2 Gy fractions (with or without chemotherapy) followed by laparotomy, resection, and IORT offers

theoretical and clinical advantages over resection and IORT followed by EBRT. These are listed as follows: 1. By postponing surgical resection until after preoperative therapy is completed, patients with disease that is rapidly progressive may avoid an unnecessary surgical procedure with associated morbidity. 2. Preoperative therapy may allow for tumor downstaging and facilitate resection with curative intent. 3. Preoperative therapy may reduce the risk of tumor seeding/ dissemination at resection. 4. Preoperative therapy allows delivery of treatment to disease with an intact vasculature, potentially improving the delivery of chemotherapy and improving oxygen delivery for EBRT. 5. The morbidity and delayed recovery time associated with extensive surgical procedures may prevent the timely delivery of postoperative therapy in a high percentage of patients.34,35 The role of preoperative versus postoperative therapy has been evaluated in rectal cancer. A large German randomized trial demonstrated that patients undergoing neoadjuvant irradiation and chemotherapy experienced significantly improved local control and less toxicity than patients receiving postoperative irradiation and chemotherapy.36

Radiation Dose and Technique Techniques combining EBRT and IORT have been fairly uniform in the United States and Europe. In previously untreated patients, EBRT doses of 45 to 54 Gy have been employed, delivering 1.8 to 2 Gy per fraction, 5 days per week, over a period of 5 to 6 weeks. Because of the anatomic location of pelvic and abdominal malignancies, high-energy (> 10 MV) photons delivered via LINACs using multifield, shaped techniques are generally appropriate. CT-, PET-, or MRI-based treatment planning permits accurate definition of the target volume. For extrapelvic, unresected, or residual disease following resection, radiation doses of 40 to 45 Gy delivered at 1.8 to 2 Gy per fraction with a 3- to 5-cm margin accounting for microscopic extension and target mobility are sometimes used. Treatments are generally delivered through multifield techniques aided by three-dimensional (3D) or IMRT-based treatment planning. Reduced-field—or “boost”—techniques are often used to bring the total dose to 45 to 54 Gy as dictated by tolerance of surrounding normal tissue (see previous discussion). Concurrent chemotherapy administration during EBRT varies by tumor site. For patients with gastrointestinal malignancies, concurrent 5-FU-based regimens (plus cisplatin or mitomycin C for squamous cell histologies) are frequently implemented, and for patients with gynecological cancers, concurrent cisplatin is frequently given. In carefully selected patients who have received prior irradiation, moderate preoperative EBRT doses of 30 to 36 Gy at 1.8 to 2.0 Gy per fraction (often with concurrent chemotherapy) may be safely employed if all of the previously irradiated small bowel can be excluded.

Dose of Intraoperative Radiotherapy IORT dose should be based on extent of residual disease at resection, the amount of EBRT delivered previously, and the type and volume of normal tissue irradiated. For patients who have received preoperative doses of 45 to 54 Gy (1.8 to 2 Gy per fraction, 5 days per week), IORT doses usually range from 10 to 20 Gy. For patients with microscopic residual or close margins, doses of 10 to 12.5 Gy are often administered. Patients with gross residual disease require higher doses; 15 to 20 Gy is usually administered. In previously irradiated patients, in whom additional EBRT is feasible (30-36 Gy), the dose of IORT generally ranges between 15 Gy and 20 Gy. In patients in whom no or very limited EBRT is planned, IORT doses from 25 to 30 Gy have been administered; however, doses in this range should be judiciously employed, given the risk of normal-tissue damage, specifically peripheral nerve injury.

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CHAPTER 22 The biological effectiveness of single-dose IORT in early responding tissues (tumor) relative to an equivalent total dose of fractionated EBRT has been estimated to be 1.5 to 2.5 times the IORT dose delivered (see Table 22.1).9,37,38 Therefore, the effective tumor dose (when “normalized” to fractionated EBRT doses) of IORT treatment added to 45 to 50 Gy given by EBRT is as follows: 10 Gy IORT dose, 60 to 80 Gy; 15 Gy IORT dose, 75 to 87.5 Gy; 20 Gy IORT dose, 85 to 100 Gy. These figures are not intended to be exact but represent educated estimates. A field-within-a-field technique allows dose escalation within the target using a large field (an applicator in the case of electrons, recommended dose of 10-12.5 Gy) to encompass the tumor bed at risk and a second field to further boost or increase the dose (additional recommended dose of 7.5-10 Gy) to a more limited region known to be involved by residual cancer or close margins (Fig. 22.3).

Technical Aspects The technical aspects of IORT administration are beyond the scope of this chapter and have been discussed in other publications (see reference list). In brief, the implementation of IORT-based treatment is a multidisciplinary effort including one or multiple surgeons, a radiation oncologist, anesthesiologist, operating room nurse, radiation physicist/ dosimetrist, and therapist. In its broadest sense, IORT may be administered with either electrons (IOERT) or HDR photon afterloading techniques (HDR-IORT). Of note, intraoperative electron irradiation represents over 90% of reported clinical results in non–breast cancer indications.39 Electron beams are able to produce homogeneous dose distribution in anatomic targets with R1 or R2 postresection status.40 Each method has potential advantages and disadvantages, which are summarized later.

The development of normal-tissue late effects increases with increasing radiation dose as well as dose delivered per fraction. Therefore, the incidence of late normal-tissue effects in patients receiving IORT plus EBRT would be higher than those receiving EBRT alone.41 However, in this context, the severe morbidity and mortality associated with locally recurrent tumor is often overlooked. As an example, when EBRT alone is used as the primary treatment modality for locally advanced rectal cancer, more than 90% of patients experience local persistence or local recurrence of disease with associated symptomatology. These symptoms include severe pelvic pain and neuropathy, which are difficult to manage

Normal Tissue Tolerance to Intraoperative Electron Irradiation in Animals (Usually Dogs)

TABLE 22.2

Tissue Intact Structure Aorta, vena cava

Maximum Tolerated Dose (Gy) 50

Tissue Effect Fibrosis of wall (patency up to 50 Gy)

Dose (Gy) ≥ 30

Peripheral nerve

15

Neuropathy, sensory motor

≥ 20

Bladder

30

Contraction and ureterovesical narrowing

≥ 25

Fibrosis and stenosis

≥ 30

Atrophy and fibrosis

≥ 20

Fibrosis and stenosis

≥ 30

< 20

Ulceration, fibrosis, stenosis

≥ 20

15

Ulceration, fibrosis, stenosis

≥ 17.5

Ureter

30

Kidney

< 15

Small intestine Large bowel

20

Perforation

50

Esophagus Ulceration, stricture

≥ 30

40

No sequelae at this dose

≥ 40

Muscle (psoas)

23

50% decrement muscle fibers

Heart (right atrium)

20

Fibrosis

≥ 30

Lung

20

Fibrosis

≥ 20

Trachea

30

Submucosal fibrosis

≥ 30

Fibrosis and stenosis

≥ 20

No anastomosis disruption

≤ 45

Full thickness Partial thickness

≤ 20

Surgically Manipulated Aorta anastomosis 20 (end to end)

Fig. 22.3 Field-within-a-field technique in a retroperitoneal soft-tissue sarcoma intraoperative electron radiotherapy procedure.

375

clinically, and the vast majority of patients experience disease-related death within 2 to 3 years. An argument can be made that the tumorrelated morbidity/mortality approaches 100% in these patients.42 IORT tolerance for intact or surgically manipulated organs or structures in animals (primarily canines) is seen in Table 22.2. Much of this information has been derived from studies from the NCI43–48 and Colorado State University (CSU).49–51 Several dose-sensitive structures have been studied in humans receiving IORT, including the ureter and peripheral nerve. These are discussed next.

Bile duct

INTRAOPERATIVE RADIOTHERAPY DOSELIMITING STRUCTURES AND TOLERANCE

Intraoperative Irradiation

38

Aortic prosthetic graft

25

Graft occlusion

25

Portal vein anastomosis

40

Stenosis

>40

Biliary-enteric anastomosis

< 20

Anastomotic breakdown

≥ 20 ≤ 20

Small intestine (defunctionalized)

45

Fibrosis and stenosis No suture line breakdown

≤ 45

Bladder

30

Healing but contraction

≥ 30

Absence of air leak

> 40

Bronchial stump

> 40

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376

SECTION II

Techniques and Modalities

Colorectal IOERT, Mayo Clinic IOERT Dose Versus Neuropathy

TABLE 22.3

Ureter Clinical studies of the effect of IOERT on the ureters of patients with cancer have been undertaken at the Mayo Clinic. Doses of 10 Gy administered intraoperatively resulted in a 50% incidence of ureteral obstruction, increasing to 70% with doses from 15 to 25 Gy. This high complication rate relative to canine models may be as a result of agerelated factors, surgical manipulation, EBRT, or tumor bed effects.52 In an update of this experience, investigators from the Mayo Clinic reported on 146 patients with locally advanced malignancies receiving IORT to one or both ureters of doses between 7.5 Gy and 30 Gy. They reported that the risk of obstruction following IOERT is significant and increases with time and IORT dose. The rates of clinically apparent type 1 obstruction (obstruction from any cause) after IOERT at 2, 5, and 10 years were 47%, 63%, and 79%, respectively. The rates of clinically apparent type 2 obstruction (obstruction occurring at least 1 month after IOERT, excluding obstruction caused by tumor or abscess and patients with stents) at 2, 5, and 10 years were 27%, 47%, and 70%, respectively. Multivariate analysis revealed that the presence of obstruction before IOERT was associated with an increased risk of clinically apparent type 1 obstruction (p < 0.001). Increasing IOERT dose was associated with an increased risk of clinically apparent type 2 obstruction (p < 0.04). Obstruction rates in ureters not receiving IOERT at 2, 5, and 10 years were 19%, 19%, and 51%, respectively, suggesting an underlying risk of ureteral injury from other causes (EBRT, surgical manipulation of ureters resulting in devascularization).53

Peripheral Nerve The peripheral nerve is the principal dose-limiting normal tissue for IORT in the pelvis and retroperitoneum. Data regarding peripheral nerve tolerance and neuropathy comes from canine models as well as clinical analyses from patients treated intraoperatively.44,47,49,52,54–64 The peripheral nerve is often situated adjacent to or is directly involved by tumor in the abdomen and pelvis. Because of this, the relative surgical “immobility” of peripheral nerves and inability to shield the nerve from the IORT field, nerve tissue will often receive full-dose EBRT and IORT. The mechanism of neuropathy following IORT is poorly understood. Peripheral nerve tolerance depends on the volume of nerve irradiated and total dose delivered. In animal models, histomorphological findings following IORT have demonstrated decreased central nerve fiber density, particularly in large nerve fibers receiving greater than 20 Gy. Electron microscopy analysis has demonstrated increased microtubule density and neurofilament accumulation within axons without associated myelin changes, suggesting possible hypoxic injury related to vascular changes.64 A Spanish study evaluated 45 patients with primary or locally recurrent extremity soft-tissue sarcoma undergoing resection with IOERT (10-20 Gy). Nine patients received IOERT alone secondary to prior EBRT or patient refusal. Five patients developed neurotoxicity at a median of 13 months; 4 of 5 showed objective weakness or sensory loss. Most patients developing neuropathy received IOERT doses greater than 15 Gy.65 An analysis from the Mayo Clinic evaluated peripheral-nerve tolerance in 51 patients undergoing IOERT for primary or recurrent pelvic malignancies. Patients received EBRT (median dose, 50.4 Gy), maximal resection where possible, and IOERT boost from 10 to 25 Gy using 9 MeV to 18 MeV electrons. Sixteen patients (32%) experienced grades 1 to 3 peripheral neuropathy as manifested by pelvic/extremity pain, leg weakness, numbness, or tingling. Pain was severe (grade 3) in 3 of 51 patients (6%; eTable 22.3).52 A follow-up study from the Mayo Clinic evaluated 178 patients with locally advanced colorectal cancer receiving IOERT. This study suggested a relationship between increasing doses of IOERT and the incidence of clinically significant neuropathy (Table 22.3). In patients with primary

IOERT DOSE VERSUS GRADE 2 OR 3 NEUROPATHY Disease Presentation 56a

Primary

Recurrent, no prior EBRT55b Primary + recurrent

≤ 12.5 Gy

≥ 15 Gy

1/29

6/28

(3%)

(21%)

2/29

19/101

(7%)

(19%)

3/58

25/129

(5%)

(19%)

p 0.03 0.12 0.01

a

57 IOERT fields in 55 evaluable patients. Incidence of grade 3 neuropathy by dose: ≤12.5 Gy, 0 of 9; 15 Gy or 17.5 Gy, 1 of 19, or 5%; ≥20 Gy, 2 of 9, or 22%. b 130 IOERT fields in 123 patients. EBRT, External beam irradiation; IOERT, intraoperative electron irradiation.

and locally recurrent colorectal cancer, the incidence of severe (grade 3) neuropathy was approximately 5%, and the incidence of any neuropathy was approximately one-third. This is consistent with canine studies suggesting that increasing IOERT doses are related to the incidence of clinical and electrophysiological neuropathy.55,56 A more recent Mayo Clinic analysis of 607 patients with locally recurrent colorectal cancer receiving IORT reported an incidence of grades 1 to 3 neuropathy of 15% (grade 1, 5%; grade 2, 7%; grade 3, 3%). A dose-related increase in grades 2 and 3 neuropathy was seen in patients receiving greater than or equal to 15 Gy compared with less than or equal to 12.5 Gy.57

CONCLUSIONS All patients considered for IORT should undergo thorough pretreatment informed consent, including a discussion regarding neuropathy-related side effects. It should also be remembered that uncontrolled tumor frequently causes symptoms related to neural impingement and, in fact, many potential IORT candidates present with neuropathic symptoms caused by primary or recurrent disease. Based on human and animal data evaluating IORT-induced neuropathy, IORT doses are generally limited to 10 to 20 Gy when a full course of EBRT is administered (45 to 54 Gy using 1.8 to 2 Gy per fraction). Doses exceeding 20 Gy in the intraoperative setting should be used with caution, and it is recommended that administration of higher doses be considered only in the setting of limited EBRT options (i.e., prior EBRT treatment).

INTRAOPERATIVE RADIOTHERAPY RESULTS FOR SELECTED DISEASE SITES A summary of IORT results and future possibilities in selected disease sites (pancreas, breast, colorectal, gynecological cancers, and retroperitoneal/ pelvic sarcomas) is now presented. For a more detailed discussion, the reader is referred to dedicated chapters on each site in an IORT text.66

Pancreas Cancer

External Beam Radiotherapy and Intraoperative Radiotherapy Given local failure rates of 50% to 80%, the use of IORT in the setting of pancreatic cancer is rational. In patients with unresectable and even metastatic pancreatic cancer, autopsy analyses have demonstrated that

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CHAPTER 22

eTABLE 22.3

Intraoperative Irradiation

376.e1

Clinical Peripheral Neuropathy Characteristics With Pelvic IOERT, Mayo Clinic SEVERITY

TIME COURSE (MO FROM IORT)

Characteristic

Incidence

Mild/Moderate

Severe

Onsetsb

Resolution, Range

Pain

16/50 (32%)

13 (26%)

3 (6%)

1/2-18 (15)

6/14 (42%),c 5-32d

8/50 (16%)

6 (12%)

2 (4%)

3-22 (7)

11/50 (22%)

11 (22%)

0 (0%)

3-22 (7)

Motor Sensory

a

1/8 (13%), 20 4/11 (36%), 1, 7, 19, 20

a

One patient excluded who died postoperatively. Values in parentheses represent median. c Two patients excluded who were lost to follow-up. d Median, 15 months. IOERT, Intraoperative electron radiotherapy; IORT, intraoperative radiotherapy. Modified from Shaw E, Gunderson IL, Martin JK, et al. Peripheral nerve and ureteral tolerance of intraoperative radiation therapy: clinical and dose-response analysis. Radiother Oncol. 1990;18:247–255. b

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CHAPTER 22 local tumor progression contributes to significant morbidity and mortality.67 Available data in patients receiving IORT after pancreaticoduodenectomy demonstrates an improvement in local control; however, a clear survival benefit has not been demonstrated. Series of patients with locally advanced pancreatic cancer suggest local control and pain relief, with select studies demonstrating an OS benefit. Intraoperative radiotherapy in resected disease. In the United States, initial feasibility of IORT in conjunction with surgery was demonstrated at the NCI. Thereafter, the NCI reported a series evaluating 24 further patients randomized to receive IORT (20 Gy) versus EBRT. After excluding 7 perioperative deaths, an improvement in local control (67% vs. 0%) and median survival (median OS, 18 vs. 12 months, p = 0.01) was seen in the patients who received IORT.68 Further data on IORT at the time of surgery are limited to single- and multi-institutional retrospective series (Table 22.4). The largest of the single-institution series evaluated 127 patients treated with surgery and IORT compared with a cohort of 26 patients who underwent surgery alone. No additional operative morbidity or mortality was seen with the addition of IORT; however, for patients with stage I/II disease, IORT resulted in lower rates of local failure and significantly longer time to local failure, time to failure, and OS compared with surgery alone. These data suggest possible local control benefit with the use of IORT after resection in select patients.69

TABLE 22.4 Series/Treatment Sindelar and Kinsella

68

These data are corroborated by two multi-institutional series. A Japanese series evaluated 210 patients undergoing surgery and IORT with and without EBRT. Median IORT and EBRT doses were 25 Gy and 45 Gy, respectively. Of these patients, 71% experienced disease relapse, with local failure occurring in 15% of the patients. Median and 2-year OS were 19.1 months and 42%, respectively. The combination of IORT and chemotherapy resulted in improved survival compared with IORT alone. The authors concluded that IORT yields excellent local control rates for pancreatic cancer with a low incidence of toxicity, and IORT combined with chemotherapy confers a survival benefit compared with IORT alone.70 A European multi-institutional series evaluated 270 patients treated at five institutions between 1985 and 2006.71 Neoadjuvant EBRT or concurrent chemoradiotherapy (CRT) was delivered in 24% of cases and median IORT dose was 15 Gy (range, 7.5-25 Gy). Significantly better local control was seen in patients undergoing preoperative radiotherapy with a median time to local relapse not reached and median OS of 30 months compared with 22 months with postoperative EBRT or CRT and 13 months with IORT alone. The authors concluded that preoperative EBRT increases the effect of IORT in terms of local control and survival, with favorable long-term local control rates.71 A recent update of 7 studies analyzed 942 patients postresection, reporting local recurrence rates in the range of 16% to 41% and median survival of

Results of Selected Studies of IORT in Patients With Resected Pancreatic Cancer IORT Dose (Gy)

EBRT (%)

Operative Mortality

Postop Complication

Local Recurrence

Median

100%

27%

71%

—

—

Overall

Overall

100%

12 mo

(1999)

—

12

—

Surgery/IORT/EBRT

12

20 Gy

(1994)

—

36%

—

Surgery alone

47

—

—

Surgery and IORT

43

12.5-20

— 67%

Alfieri et al.166

(2001)

—

Surgery ± EBRT

20

—

Surgery/IORT ± EBRT

26

10

(2001)

—

Surgery ± EBRT

76

Surgery/IORT ± EBRT

127

Reni et al.69

70

SURVIVAL

Year/Pt No.

Surgery/EBRT Zerbi et al.165

18 mo (p = 0.01)

—

—

—

2.1%

23.4%

56.3%

12 mo

16%

2.3%

23.2%

27%a

19 mo

24%

—

—

(5 year)

—

8%

43%

71.2%

10.8 mo

9%

57%

41.6%

14.3 mo

—

—

(median to LR)

—

—

4%

45%

11 mo

12 mo

10-25

3%

39%

14 mo

15.5 mo

28%

(2010)

—

—

—

—

—

—

20-30

30%

—

—

16.3%

19 mo

(2009)

—

—

—

—

—

—

Surgery/IORT ± EBRT

270

7.5-25

64%

2%

24%

(median to LR)

—

Preop EBRT/CRT

63

Not reached

30 mo

Postop EBRT/CRT

106

28 mo

22 mo

IORT/no EBRT

95

8 mo

13 mo

Surgery/IORT ± EBRT Valentini et al.71

Bachireddy et al.167

(2010)

(Ortho)

—

—

—

—

—

23

6-15

78%

—

6%

39%

—

(2013)

—

100%

—

—

(5 y)

20% (5 y)

Surgery + EBRT/CRT

41

—

0%

39%

72%

Surgery/IORT + EBRT

29

10-15

7%

48%

8%

Surgery/IORT ± EBRT Calvo et al.168

2 yr

33%

210

Ogawa et al.

377

Intraoperative Irradiation

42%

27%

p < 0.01. CRT, Chemoradiation; EBRT, external beam irradiation; IORT, intraoperative irradiation; LR, local recurrence; mo., months; Ortho, orthovoltage; Postop, postoperative; Preop, preoperative; Pt No., patient numbers. a

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378

SECTION II

Techniques and Modalities

14 to 19 months, which were superior to cohorts in which patients did not receive an IOERT boost.72 Compared with historical controls, these low rates of local failure and reasonable median survival reflect the possible benefit of IORT in patients with resected pancreatic cancer. Intraoperative radiotherapy in locally unresectable disease. The role of IORT has been more clearly defined in the treatment of patients with locally unresectable pancreatic cancer. Many studies have documented both safety and pain control with IORT, resulting in complete pain resolution in 75% to 90% of cases.73 Table 22.5 shows outcomes of select series using IORT in locally unresectable pancreatic cancer patients. A study from the Mayo Clinic evaluated 159 patients with locally unresectable pancreatic cancer who underwent exploratory laparotomy; 122 had postoperative EBRT alone or EBRT plus 5-FU and 37 received an IOERT boost followed by EBRT alone or EBRT plus 5-FU. One-year local control (LC) with the combination of EBRT and IORT was 82% compared with 48% with EBRT alone (2-year LC was 66% vs. 20%, p = 0.0005). Despite a benefit in LC, there was no difference in median or long-term survival between the groups given the high incidence of liver or peritoneal relapse in both groups (> 50%).74 A Japanese study evaluated the use of IORT in the treatment of 115 patients with locally unresectable pancreatic cancer. Patients received either a combination of EBRT and IORT, EBRT alone, or IORT alone. In the subgroup of patients with a CA19-9 < 1000, the combination of EBRT and IORT produced superior survival compared with EBRT alone.75 Investigators at MGH initially published early results of the use of IORT (15-20 Gy) in patients with locally unresectable pancreatic cancer.76 The publication of updated data on 194 consecutive MGH patients with locally unresectable cancer demonstrated a median survival of 12 months and long-term survival in 6 patients. Patients treated with a smaller-diameter applicator, a surrogate for smaller tumor size, had superior survival rates and the only long-term survivors were within the smaller-applicator-diameter cohort. On multivariate analysis, small applicator size, low comorbidity index, and receipt of

chemotherapy predicted improved OS.77,78 A further report from MGH investigators analyzed 68 patients with locally advanced or borderline resectable pancreatic cancer who received neoadjuvant chemotherapy and CRT followed by exploratory laparotomy. Of 68 patients, 41 (60%) underwent resection, 18 (27%) had unresectable disease, and 9 (13%) had distant metastases. Twenty-two of 41 resectable patients underwent IORT for close or positive margins. Median survival was 26.6 months for patients undergoing resection, 35.1 months for resection and IORT, and 24.5 months for resection alone. Seventeen of 18 unresectable patients received IORT, with a median survival of 24.8 months. The authors concluded that survival rates in patients with close/positive margins and unresectable disease were encouraging.79 Two retrospective studies from Thomas Jefferson University Hospital (TJUH) evaluated the use of IORT in patients with locally unresectable primary disease. In the initial TJUH series, 49 patients were treated with IORT and perioperative chemotherapy followed by concurrent CRT. Median survival was 16 months, with a 4-year OS of 7%.80 In a follow-up series from TJUH, 105 patients received multimodality therapy, including surgery, chemotherapy, and radiotherapy. Patients were subdivided into three groups: IORT via electrons (IOERT), IORT with iodine-125 implant, and no IORT. Median OS in the group receiving IOERT was 18 months with 2-year LC of 70%.81 The median and long-term survival results from these IORT series are significantly longer than outcomes seen in other studies evaluating patients with locally advanced pancreatic cancer treated with conventional combined modality approaches.

Future Possibilities Although slight gains in survival may be achieved by improving LC in patients with pancreatic cancer, the high rate of distant metastases limits significant improvements in long-term survival by IORT approaches. Given the high incidence of failure in the peritoneal cavity and liver, aggressive locoregional therapy should be combined with effective multiagent chemotherapy. Ongoing studies continue to evaluate novel combinations of systemic agents in the treatment of this disease, including

Results of Selected Studies of IORT in Patients With Locally Unresectable Pancreatic Cancer

TABLE 22.5

Author/Reference Institution or Group 74

Roldan et al., Mayo Clinic

IORT Dose (Gy)

SURVIVAL

Year

Pt. No./Type of Treatment

1988

159

—

(2 yr)

—

—

122 EBRT ± 5FU

—

80%

12.6 mo

16.5% 12.0%

Local Recurrence

Median

2 yr

37 IORT/EBRT ± 5FU

20

34%

13.4 mo

Shibamoto et al.75

1996

115 44 EBRT, 16 IORT 55 EBRT and IORT

30-33

—

No difference

Tepper et al.,169 RTOG

1991

51 analyzable EBRT and IORT

20

Not assessable

9 mo

—

Willett et al.,77,78 MGH

2005, 2013

194 EBRT and IORT

15-25

(2 yr) 59%

12 mo

16%

Mohiuddin et al.,80 TJUH

1995

49

—

—

—

—

EBRT and IORT

10-20

29%

16 mo

22%

105

15-20

(2 yr) 30%

—

—

18 mo

17%

43 EBRT and 125I

15 mo

19%

29 EBRT alone

9 mo

NS

Schuricht et al.,81 TJUH

1998

33 EBRT and IOERT

EBRT, External beam irradiation; IORT, intraoperative radiotherapy; MGH, Massachusetts General Hospital; NS, not significant; RTOG, Radiation Therapy Oncology Group; TJUH, Thomas Jefferson University Hospital.

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CHAPTER 22 “targeted” and immunotherapy-based agents, as well as novel combinations of more traditional chemotherapeutics.

Breast Cancer

Intraoperative Radiotherapy Alone Randomized trials have demonstrated equivalent disease-free survival (DFS) and OS in selected patients with breast cancer undergoing either mastectomy or breast-conserving surgery followed by EBRT.82 Local recurrences frequently occur at or adjacent to the original tumor bed following breast-conserving surgery, and the use of boost treatments in this setting has been shown to significantly reduce local recurrence rates (see online supplement). There is increasing interest in the use of IORT as a supplement to or alternative to EBRT in selected cases in both Europe and the United States.83–93 Phase III trials. The Italian ELIOT trial of 1305 patients was a randomized Phase III trial comparing 21 Gy IOERT versus standard EBRT whole-breast/boost therapy.84 IOERT was delivered with a mobile LINAC—the NOVAC 7 (Sit Sordina Vicenza VI, Italy)—while shielding the thoracic wall with a lead plate. Women aged 48 to 75 years with early breast cancer, a maximum tumor diameter of up to 2.5 cm, and suitable for breast-conserving surgery were randomly assigned to the two treatment arms. This was an equivalence trial with a primary endpoint of ipsilateral breast tumor recurrence (IBTR). After a median follow-up of 5.8 years, 35 patients in the IOERT group and 4 patients in the EBRT group had experienced an IBTR (p < 0.0001). The 5-year outcomes for the IOERT compared with the EBRT arms included an IBTR rate of 4.4% compared with 0.4% (hazard ratio [HR], 9.3; 95% confidence interval [CI], 3.3-26.3) and 5-year OS of 96.8% compared with 96.9%. ELIOT patients considered low risk by tumor size, receptor status, nodal positivity, and grade had a 1.5% IBTR at 5 years. Significantly fewer skin side effects occurred in women in the IOERT than in the EBRT arms (p = 0.0002). The authors concluded that the rate of IBTR was significantly greater with IOERT than with EBRT, and OS did not differ between groups, while improved selection of patients could reduce the rate of IBTR with IOERT.94 An approach of targeted IORT using the INTRABEAM system (TARGIT; Carl Zeiss Meditec, Jena, Germany) implements a 50-kV x-ray generator mounted on a flexible floor stand with a set of spherical applicators ranging from 1.5 cm to 5 cm in diameter. Radiotherapy is delivered to the tumor bed by placing the applicator within the tumor cavity and conforming the adjacent breast tissues around the applicator before treatment. A potential disadvantage of this approach is that low-energy x-rays could potentially lead to underdosing of residual tumor cells removed from the tumor cavity. In an international Phase III TARGIT-A trial,95,96 patients were randomized to IORT alone (n = 1721) or a typical course of EBRT (n = 1730). If resected patients were at high risk of local recurrence in other quadrants (extensive intraductal component, extensive lymphovascular invasion, nodal metastases, and so on), then EBRT could be delivered postoperatively. Supplemental EBRT after TARGIT was necessary in 15.2% of patients who received TARGIT. Median follow-up for 3451 patients was nearly 2.5 years and 1222 had median follow-up of 5 years. The 5-year risk for local recurrence in the conserved breast was 3.3% for TARGIT versus 1.3% for EBRT (p = 0.042). Overall, breast cancer mortality was similar between groups (2.6% for TARGIT vs. 1.9% for EBRT; p = 0.56), but there were significantly fewer deaths related to non–breast cancer causes with TARGIT (1.4% vs. 3.5%; p = 0.0086) attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3.9% for TARGIT versus 5.3% for EBRT (p = 0.099). Wound-related complications were similar but grade 3 or 4 skin complications were significantly reduced with TARGIT (4 of 1720 vs. 13 of 1731; p = 0.029). The authors concluded that TARGIT

Intraoperative Irradiation

379

concurrent with lumpectomy within a risk-adapted approach should be considered as an option for carefully selected, eligible patients with breast cancer as an alternative to postoperative EBRT.95 Late-toxicity data was available in 305 patients with significantly fewer telangiectasias in the IORT arm.96 Silverstein et al. have performed a critical analysis of these two large randomized clinical trials.97,98 In summary, randomized trials to date show that IORT alone may result in slightly higher rates of ipsilateral breast cancer recurrence when compared with adjuvant EBRT techniques and that careful patient selection is warranted. Phase II trials. Extensive Phase II data from single or multiinstitutional IORT alone series are also available. Series design and outcomes can be found in the online supplement for this chapter.83,86,89,99–101

Intraoperative Radiotherapy Plus External Beam Radiotherapy In the Medical College of Ohio and Centre Regional de Lutte Contre le Cancer (France) combined series, 72 patients with early-stage breast cancer underwent lumpectomy with axillary lymph node dissection followed by 10 to 15 Gy IOERT using 6 MeV to 20 MeV electrons. Patients later received EBRT doses of 45 to 50 Gy at 1.8 to 2 Gy per fraction. No significant complications were observed and cosmetic results were described as excellent. Eight of 72 patients developed minor palpable fibrosis at the lumpectomy site. At a minimum 2-year follow-up in all patients, no patients had experienced local relapse.91 The University of Salzburg investigators used IOERT combined with EBRT in 351 consecutive patients from October 1998 to April 2002 and reported their results in the initial 170 patients treated through December 2000.92 LC results were compared with patients treated with EBRT alone. At the time of publication, 3-year LC with an IOERT compared with EBRT boost was 100% to ~ 97%. The University of Heidelberg reported a preliminary experience in 155 patients with breast cancer using a 20-Gy orthovoltage IORT boost followed by EBRT in women with T1-T2 breast cancers. The 5-year local relapse-free survival was 98.5% at a median follow-up of 34 months. Grade 3 fibrosis of the tumor bed was found in 5% of patients at 3 years.93 A European pooled analysis by Sedlmayer et al. evaluated 1200 patients with limited breast cancer resection plus IOERT (median dose, 9.7 Gy; range, 5-17 Gy) followed by whole-breast EBRT using standard fractionation. Patients undergoing immediate secondary mastectomy as a result of extensive margin involvement were excluded. At median follow-up of 59.6 months, local tumor control was 99.3%. The authors concluded that IOERT boost during breast-conservation therapy results in optimal dose delivery and outstanding LC rates.102,103 The most recent update of this experience with long-term follow-up (72.4 months median follow-up) reported a 99.2% local tumor control with an annual in-breast recurrence rate of 0.64%, 0.34%, 0.21%, and 0.16% in patients younger than 40 years, 40 to 49 years, 50 to 59 years, and older than 60 years, respectively.104 Early results of the TARGIT trial using IORT as boost therapy reported on 183 patients treated with the INTRABEAM system of 5 Gy or 7.5 Gy followed by EBRT. At a median follow-up of 16 months, actuarial 2-year LC was 99%, with serious complications (including fistula, wound dehiscence, and ulceration) occurring in 11% of patients.88 In summary, the available data suggest that IORT used as a boost technique with EBRT results in low rates of ipsilateral breast tumor recurrence. The validity of breast boost with electrons in triple-negative patients105 and post-neoadjuvant chemotherapy106 patients has been reported. In long-term follow-up, results appear equivalent to conventional radiotherapy approaches when compared with historical controls. Updated results of an unselected cohort of 770 breast cancer patients of all risk types was analyzed in terms of LC and survival outcome at 10 years.

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CHAPTER 22 The Montpellier Cancer Institute enrolled 42 patients—65 years or older, T0/1 N0, surgical margins greater than 2 mm—on a Phase II IORT trial.99 A dose of 21 Gy was delivered with a dedicated linear accelerator using electrons. Median age of enrolled patients was 72 years and median tumor size was 10 mm. No grade 3 acute toxicities were seen. At a median follow-up of 72 months, 4 of 42 patients had a local failure, treated with mastectomy. Cosmetic outcomes were good as reported by both patient and physician. A preliminary report from the Italian Collaborative Breast IOERT Group described a multicenter trial comparing IOERT alone following lumpectomy to conventional fraction EBRT in tumors less than 3 cm with negative margins. IORT patients received a single 21-Gy fraction using 6 MeV to 9 MeV electrons. Of 314 evaluable patients, no local recurrence was detected in either treatment group at a median follow-up of 31 months, although a significant difference in the incidence of grades 1 to 2 late toxicity was seen in favor of the IORT group (3% vs. 63%).85 A systematic review of seven published IORT-alone series in early breast cancer suggested that short-term LC, DFS, and OS were similar to reported EBRT series. Local recurrence rates ranged from 0% to 29% with IORT. However, many of these small, single-institution studies had short follow-up (median, 2 years).86

Intraoperative Irradiation

379.e1

Veronesi et al. reported on 237 patients with primary tumors less than or equal to 2 cm undergoing wide excision with either sentinel lymph node biopsy or axillary lymph node dissection.89 Patients received IOERT using 3 MeV to 9 MeV electrons with doses of 17 to 21 Gy (> 90% received 21 Gy as the prescribed dose). At a median follow-up of 19 months, the rate of posttreatment complications was low, with 1.7% developing breast fibrosis. A follow-up report of 574 patients revealed 3 patients with local recurrence and 3 additional patients with ipsilateral recurrence in other quadrants at a median follow-up of 20 months. A similar report by Veronesi et al. of 1822 patients treated with the ELIOT strategy, but outside of a randomized trial, showed that after a mean follow-up of 36 months, the incidence of local recurrence was 2.3% and the incidence of new primary ipsilateral carcinomas was 1.3%.100 Another report of long-term side effects and cosmetic results has been analyzed in 119 patients randomly selected from 1200 cases. After a median follow-up of 71 months, grade 2 fibrosis was observed in 31.9% of patients and grade 3 in 5.9% of patients. Physicians and patients scored cosmesis as excellent or good in 84% and 77% of cases, respectively.101 The addition of boost treatment following lumpectomy and conventional EBRT has been shown to reduce local recurrence rates by 50% in all age groups versus EBRT alone.90 Potential advantages of an IORT boost compared with EBRT boost are as follows: more precise delivery of irradiation to the tumor bed, skin sparing with avoidance of associated late cosmetic sequelae, and a smaller boost area with a more homogeneous dose distribution.

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380

SECTION II

Techniques and Modalities

After a median follow-up of 121 months (range, 4-200), 21 (2.7%) in-breast recurrences (IBRs) were observed, 107 patients (14%) died, and 106 (14%) developed metastases. Ten-year rates of LC, locoregional control, metastasis-free survival, OS, and breast cancer-specific survival were 97.2%, 96.5%, 86%, 85.7%, and 93.2%, respectively. In multivariate analysis, HER2+ and triple-negative breast cancer subtype (TN) turned out to be significant negative predictors for IBRs (respectively, HR, 15.02, 95% CI, 2.9-77.78; and HR, 12.87, 95% CI, 3.37-49; p < 0.05). Sorted by subtypes, 10-year LC rates were observed in 98.7% (range, 96.7%-99.5%; luminal A), 98% (range, 94%-99.3%; luminal B), 87.9% (range, 66.2%-96%; HER2+), and 89% (range, 76.9%-94.9%; TN), respectively.107

Mayo Clinic IOERT Analysis: Factors Influencing 5-Year Local Control and Survival in Resected Primary Retroperitoneal Sarcomas

TABLE 22.6

n

Future Possibilities A 2016 ASTRO consensus statement on accelerated partial breast irradiation incorporated single-dose intraoperative electrons (21 Gy) as a technical alternative, with a 100% agreement among experts regarding the recommendation.108 Multiple Phase II or III trials evaluating adjuvant IORT continue to actively accrue patients in the United States, Europe, United Kingdom, and Australia. These trials use varying IORT techniques, including 50-kV photons and low-energy electrons. Identification of patients appropriate for breast IORT remains an area of investigation. Long-term results from these and other trials will be necessary to demonstrate ultimate local recurrence, late effect, and survival data with these approaches.

Retroperitoneal and Pelvic Soft-Tissue Sarcomas National Cancer Institute Randomized Phase III Trial

The NCI conducted a randomized Phase III trial in patients undergoing surgical resection of primary retroperitoneal sarcoma. All patients underwent gross total resection, although most had microscopically involved margins. Patients were randomized to receive 20-Gy IOERT followed by 35 to 40 Gy of EBRT postoperatively versus postoperative EBRT alone to a dose of 50 to 55 Gy. Patients receiving IOERT were treated with concurrent misonidazole given 15 to 30 minutes pretreatment. EBRT treatments were delivered over 4 to 5 weeks at 1.5 to 1.8 Gy per fraction in both arms. However, patients receiving EBRT only received an additional 15 Gy using similar fractionation by reduced fields. The incidence of in-field locoregional recurrence was significantly lower among patients receiving IOERT compared with patients receiving EBRT only (3/15 vs. 16/20, p < 0.001). Patients receiving IOERT experienced fewer episodes of radiation enteritis than EBRT-alone patients (2/15 vs. 10/20, p < 0.05). However, radiation-related peripheral neuropathy was more frequent in patients receiving IOERT (9/15 vs. 1/20, p < 0.01). Of note, the IORT technique used may have resulted in overlapping fields contributing to the relatively high rate of neuropathy compared with other series.14

Mayo Clinic Experience Investigators at Mayo Clinic Rochester reported on 87 patients with primary or recurrent retroperitoneal or intrapelvic sarcomas receiving IOERT as a component of treatment.109 Seventy-seven patients received EBRT (53 preoperatively, 12 postoperatively, and 12 both) to a median dose of 48 Gy, usually through a shrinking-field technique. Fifteen patients (17%) had gross residual disease following resection, 56 (64%) microscopic residual disease, and 16 (18%) either negative margins or no residual disease. Median IOERT dose was 15 Gy (range, 9-30 Gy). Five-year OS was 47%. Patients with tumors greater than 10 cm experienced a significantly worse survival compared with smaller lesions (5-year OS, 28% vs. 60%, p = 0.01) and patients with gross residual disease following resection experienced worse 5-year survival versus gross totally resected patients (37% vs. 52%, p = 0.08). Five-year LC

OS (%)

Residual at IOERT None 11

62

Microscopic

25

54

Gross

7

29

Broder Grade 1-2

9

42

34

54

3-4

Tumor Sizea (cm) ≤ 10 23

66

> 10

33

19

p

LC (%)

p

100 92 0.15

60

10

92

19

p

n

LC (%)

5

100

100

25

Gross

3-4

LC (%)

RECURRENT TUMORS

31

36

< 0.01

8

67

24

28

0.32

20

58

30

50

0.80

14

34

ALL p

0.12

0.52

0.69

n

LC (%)

16

100

56

57

15

37

33

47

54

75

17

64

69

62

p

0.04

0.16

0.96

IOERT, Intraoperative electron beam radiotherapy; LC, local control.

eTABLE 22.5 Mayo Clinic Analysis: Factors Influencing Overall Survival at 5 Years in Resected Retroperitoneal Sarcomas With IOERT PRIMARY TUMORS I

OS (%)

RECURRENT TUMORS p

n

OS (%)

ALL p

n

OS (%)

Residual at IOERT None 11

62

5

80

16

68

Microscopic

25

54

31

44

56

48

Gross

7

29

8

45

15

37

Broder Grade 1-2

9

42

24

53

33

50

34

54

20

35

54

48

30

54

53

60

14

19

33

28

3-4

Tumor Sizea (cm) ≤10 23

66

>10

33

19

0.15

0.70

0.15

0.60

0.36

0.04

a

p

0.12

0.32

0.01

One value missing. IOERT, Intraoperative electron beam radiotherapy; OS, overall survival. Data from Petersen IA, Haddock MG, Donohue JH, et al. Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 2002;52(2):469–475; and Petersen I, Haddock M, Stafford S, et al. Use of intraoperative radiation therapy for retroperitoneal sarcomas. Update of the Mayo Clinic Rochester Experience. ISIORT 2008 Proceedings. Cancer. 2008;22:57.

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CHAPTER 22 In this group, patients with high-grade disease or involved margins received EBRT with or without IOERT, particularly when a localized area of close margin of residual tumor was identified. This study again demonstrated a trend for IORT to improve survival versus EBRT alone with significant increased time to both local and distant relapse. In patients who were completely resected, a trend toward improved survival with IOERT was seen compared with EBRT alone (5-year OS of 77% vs. 45%, p = 0.13).112

Pooled European Analysis A pooled European analysis described 122 curatively approached patients (81 recurrent) with retroperitoneal sarcoma undergoing maximum resection plus IOERT (median dose, 15 Gy). Most received adjuvant EBRT. Five-year OS, DFS, LC, and freedom from metastatic disease rates were 64%, 28%, 40%, and 50%, respectively. Five-year LC within the IOERT field was 72%. In patients receiving IOERT, EBRT, and R0 resection, 5- and 10-year OS were 80% and 5- and 10-year LC were 100%. Only 5% of patients experienced an in IOERT-field relapse after R0 resection, 23% after R1 resection, and 75% after R2 resection. Late complications greater than or equal to grade 2 were seen in 21% of patients. The authors concluded that, in selected patients, IOERT resulted in excellent LC and survival with acceptable morbidity.113

Additional/Prospective Studies A review from Germany of 156 retroperitoneal sarcoma patients (87 recurrent) was recently reported. Gross total resection was accomplished in 92%, with 65% displaying microscopically positive margins. Of these patients, 114 (73%) received additional external beam radiation, either pre- or postoperatively, to a median dose of 45 Gy. The median IORT dose was 15 Gy. Three- and 5-year LC rates were 57% and 50%, respectively. In primary tumors, 5-year local control was 71% and 79% following R0 resection. On multivariate analysis, recurrent disease, grade, margins, and EBRT were significant prognostic factors. Recurrent disease, grade, and margins were prognostic in terms of survival.114 A prospective single-arm interim analysis of a trial from the University of Heidelberg evaluating preoperative IMRT using simultaneous integrated boost to 50 to 56 Gy followed by surgery and IORT to 10 to 12 Gy was reported. Of the patients, 74% had microscopically positive margins. Most patients received IORT to a median dose of 12 Gy. Estimated 5-year LC was 72%, as was 5-year OS.115 The most recent update of the Heidelberg University experience reported 5-year LC and survival rates of 50% and 56%, respectively (156 patients, 62% recurrent, 65% with microscopically positive margins). Incomplete resection and recurrent status were unfavorable risk factors, while delivery of preoperative radiotherapy was a favorable outcomes factor.116 An Italian Phase I-II study evaluated the combination of concurrent ifosfamide and radiotherapy in the preoperative setting, with radiotherapy initiated at the second drug cycle, to a dose of 50.4 Gy. Of 83 patients enrolled, 60 completed treatment. Most patients received IORT. Of 79 surgery patients, 3- and 5-year relapse-free and OS rates were 56 (44%) and 74 (59%), respectively. Crude incidence of local recurrence and distant metastases at 5 years were 37% and 26%, respectively.117 Additionally, an analysis of 908 US patients treated from 1988 to 2013 reported a survival benefit of the combination of IOERT plus EBRT in the subgroup of patients with liposarcoma histology.118

Conclusions and Future Possibilities IORT combined with EBRT and resection offers an effective means of improving LC in patients with primary and recurrent retroperitoneal sarcomas, as demonstrated in a randomized trial from the NCI as well as multiple US and European single-institution studies.109–113,119–121 A randomized NCI trial showed an 80% tumor bed relapse rate with

Intraoperative Irradiation

381

adjuvant EBRT alone, likely as a result of an inability to deliver effective EBRT doses given normal tissue constraints. Because these results are similar to reports of resection alone, the use of adjuvant EBRT without IORT following marginal resection could be questioned. A more practical approach would be to administer preoperative EBRT following confirmation of diagnosis by thin-needle biopsy. This would be followed by resection at an institution with IORT capabilities. In addition to retroperitoneal disease, extremity soft-tissue sarcomas are amenable to several approaches entailing IORT, either as an anticipated boost at upfront resection or following preoperative EBRT (i.e., delayed boost), both with electrons or high-dose-rate brachytherapy. A 2017 review of clinical results analyzed major IORT series in extremity sarcoma in the period from 1999 to 2015, including recurrent patients and patients with R+ resections. The LC rates at 5 years ranged from 82% to 97%.122 Even with improved LC rates, locoregional and distant failures remain common modes of failure, emphasizing the need for improved therapies. Pilot studies are evaluating dose-escalated EBRT using IMRT techniques in combination with IORT as well as the role of concomitant radiochemotherapy with preoperative EBRT, IORT, and maintenance chemotherapy for resectable moderate- and high-grade retroperitoneal and pelvic sarcomas.123

Gynecological Cancers Patients with locally advanced or locally recurrent gynecological cancers often have involvement of the pelvic sidewall, pelvic lymph nodes, or paraaortic nodes. The use of radical resection and IORT with or without EBRT or chemotherapy may benefit patients when compared with EBRT alone. A Mayo Clinic analysis described 148 patients with primary (23 patients) or recurrent (125 patients) gynecological malignancies treated with IOERT-containing regimens.124–126 Preoperative or postoperative EBRT was delivered in 113 patients; 85 (57%) had received prior EBRT. The 5-year OS for all patients was 27%, and the 5-year local failure rate was 40% (Table 22.7).125,126 On subset analysis, patients with R0 or R1 resection (n = 115) had improved 5-year OS compared with patients with R2 resection (31% vs. 13%, p = 0.01); patients with uterine or ovarian primary origin had better survival than those with cervical or vaginal primaries (5-year OS, 41% vs. 18%, p = 0.002); patients with no prior EBRT had better 5-year OS than those with prior EBRT (35 vs. 15%, p = 0.01). The rate of distant metastases at 5 years was 49% (R0 resection, 41%; R1/R2, 63%; p = 0.04). Fewer metastases were seen in patients treated with MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) chemotherapy in a prior analysis.124

Cervical Cancer: Primary Locally Advanced Disease IOERT-containing regimens for locally advanced primary cervical cancers have been reported by several investigators. A Mayo Clinic analysis127 of 13 patients with locally advanced cervical cancer treated with preoperative EBRT followed by resection and IOERT (median, 12.5 Gy) and adjuvant chemotherapy in 77% reported a 29% 3-year survival and pelvic control in 69%. Spanish investigators treated 31 patients with primary locally advanced cervical cancer with 45-Gy EBRT in 1.8-Gy fractions followed by resection and 12-Gy IOERT. Survival at 10 years was 58% and LC was observed in 93%.128 A study from Xian Jiaotong University in China reported on 78 patients with stage IIb squamous cell carcinoma of the cervix who received IOERT during hysterectomy and selected lymphadenectomy. A comparison group of 89 patients was treated contemporaneously with standard therapy without surgery. IOERT-treated patients received 20-Gy EBRT at 2 Gy per fraction followed by 1 to 2 intracavitary brachytherapy HDR treatments with Ir-192, receiving 7 Gy per fraction to point A, followed by surgery and IOERT using 12-MeV electrons

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382

SECTION II

Techniques and Modalities

Mayo Clinic Analysis: Factors Influencing Local Control and Survival in Resected Gynecological Malignancies With IOERT

TABLE 22.7

Treatment Group All patients

SURVIVAL %

RELAPSE: 5 YR

No. Pts

Median (mo)

2 yr

5 yr

Local

148

19

41

27

40

51

28

115

21

44

31a

26

58

19

Distant

Central

Amount residual ≤ Microscopic

a

33

15

31

13

42

49

29

Uterine, ovary

58

30

53

41b

30

NA

17c

Cervix, vagina

86

17

34

18

47

NA

34

None

63

22

47

35a

37

46

26

Yes

85

15

33

15

45

58

32

Gross Site of primary

Prior EBRT

p = 0.01 p = 0.002 c p = 0.007 EBRT, External beam radiotherapy; IOERT, intraoperative electron radiotherapy; NA, not available. a

b

with doses of 18 to 20 Gy. Patients treated with standard therapy received 30-Gy EBRT whole pelvis and 20-Gy split pelvis, all in 2-Gy fractions, followed by 5 to 6 HDR insertions with Ir-192 delivering a dose of 35 to 40 Gy to point A. The 5-year OS, DFS, and LC in the IOERT patients were 89%, 87%, and 96%, respectively, versus 73%, 67%, and 73% in the standard therapy group (p < 0.05). Ten-year OS and LC were 85% and 94%, respectively, in the patients who underwent IOERT compared with 55% and 65%, respectively, in patients who underwent standard therapy. The patients who underwent IOERT had fewer rectal and bladder complications.129 Italian investigators reported the results of a Phase II trial containing IOERT as part of the multimodality regimen in patients with stage IIA bulky-IVA cervical cancer.130 Forty-two patients were treated with 50.4-Gy EBRT in 1.8-Gy fractions with concomitant cisplatin and 5-FU followed by radical hysterectomy and IOERT (median, 11 Gy; range, 10-15 Gy). Seven patients were not resected because of refusal (1), progression (3), unresectability (2), and hemorrhage (1). For the 35 patients with radical hysterectomy and IOERT, the 5-year OS and DFS were 49% and 46%, respectively. Crude pelvic control was observed in 63% and control within the IOERT fields was 89%.130

Cervical Cancer: Recurrent Disease Treatment of patients with recurrent cervical cancer is challenging, especially in those treated with high-dose radiotherapy for primary disease. There are several reports in the literature of curative attempt regimens, including surgery and IOERT with or without EBRT. Stanford investigators evaluated 17 patients with recurrent cervical cancer treated with orthovoltage IORT (median, 11.5 Gy). LC, distant metastasis-free survival, and disease-specific survival (DSS) rates at 5 years were 45%, 60%, and 46%, respectively.131 A University of Washington series included 22 patients with recurrent cervical cancer. IOERT doses ranged from 14 to 27.8 Gy and 12 patients had R2 resections, with R1 or close R0 in 10 patients. LC at 5 years was 48% and DSS was 48%. Peripheral neuropathy was observed in 32%.132 Spanish investigators reported on 36 patients with recurrent cervical cancer treated with IOERT (median, 15 Gy).128 Previously unirradiated patients were generally treated with preoperative EBRT to 45 Gy at 1.8 Gy per fraction with concurrent cisplatin and 5-FU. Previously irradiated patients underwent immediate resection or neoadjuvant

chemotherapy if unresectable. Ten-year LC rate (within the IOERT field) was 47%, control in the pelvic and paraaortic region was 42%, and 10-year survival was observed in 14%. Factors adversely influencing LC included involved parametrial margins, gross residual disease, and pelvic lymph node involvement. Patients with two or more risk factors had a 10-year LC rate of 0%, and there were no 10-year survivors with R2 resection. Six of 36 (17%) patients experienced nerve pain that resolved after a few months. All failures within the IOERT field occurred concomitant with relapse in the pelvis or distant metastases.128 Contrary to the relatively favorable results reported in most series, a French multi-institutional analysis found relatively poor survival and LC with IORT. Seventy patients were treated in seven institutions with IORT alone (40 patients) or IORT with EBRT (30 patients) in addition to surgery. The pelvic sidewall was involved in 80% of cases and resection was macroscopically complete in only 47% of patients. IORT doses ranged from 10 to 30 Gy with a median of 18 Gy in patients with R0-R1 resections and 19 Gy in patients with R2 resections. LC was observed in only 21% and 5-year survival was 8%.133 A Mayo Clinic series included 73 patients with recurrent cervical cancer treated with IOERT to a median dose of 17.5 Gy. EBRT (median, 45 Gy) was included as part of the treatment in 66% of patients and 48% received perioperative chemotherapy. The median OS was 17 months with 25% survival observed at 3 years. The 3-year cumulative incidences of central relapse, locoregional relapse, and distant relapse were 23%, 39%, and 44%, respectively. On multivariate analysis, central control and locoregional control were associated with pelvic exenteration and use of EBRT. R2 resection was associated with a higher risk of distant metastases and poorer cause-specific survival (CSS). High tumor grade and relapse within 6 months of primary diagnosis were associated with poor CSS and no patients treated within 6 months of primary diagnosis survived 3 years. Some degree of peripheral neuropathy was observed in 19% of patients.127

Endometrial Cancer: Recurrent Disease Mayo Clinic investigators reported on 25 patients treated with IOERT for recurrence of endometrioid endometrial cancer.134 Most patients (21/25, 84%) had involvement of the pelvic sidewall and the remaining 4 patients had paraaortic with and without upper abdominal involvement. EBRT was delivered to 21 patients (84%) to a median dose of 45 Gy

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CHAPTER 22

Intraoperative Irradiation

383

(range, 9-50.7 Gy). EBRT was given preoperatively in 81% of cases. The median IOERT dose was 15 Gy (range, 10-25 Gy). The surgical resection was R0 with close margins in 7 (28%) patients, R1 in 11 (44%) patients, and R2 in 7 (28%) patients. The 5-year OS was 47% and median survival was 57 months. Survival was associated with resection margins with 5-year OS of 71%, 40%, and 0% in R0, R1, and R2 patients, respectively. Central relapse within the IOERT field was observed in 4 patients (16%), local relapse with control in the IOERT field in 2 patients (8%), and distant relapse in 6 patients (24%). Peripheral neuropathy was observed in 8 patients (32%).134 An overview of the literature reporting 15 studies (564 patients) confirmed survival rates of over 40% in locally advanced cervix or endometrial cancer patients, while results in recurrent disease ranged from 9% to 25%.135

within the IOERT field was observed in 76%, with all central relapses occurring in patients with R1 resections. Distant relapse was observed in 9 patients (45%). Three patients experienced grades 1 to 2 peripheral neuropathy.139

Uterine Sarcoma

Locally advanced colorectal cancers are tumors that cannot be resected without microscopic or gross residual secondary to tumor adherence to adjacent structures. In selected patients, the optimal approach is to administer preoperative chemoradiation in efforts to “downstage” disease and facilitate surgical resection. At the time of resection, if clinical suspicion for involved margins is high, the use of IORT may be appropriate. In an MGH series, 64 patients with locally advanced primary rectal cancer underwent preoperative irradiation (with or without 5-FU) followed by resection and IOERT. Patients undergoing R0 resection had a 5-year LC and DSS of 91% and 63%, respectively. Patients with R1 resection experienced 5-year LC and DSS of 65% and 47%, respectively, and patients with R2 resection, 57% and 14%, respectively (Table 22.8).140 A Mayo Clinic Rochester report described 56 patients with primary locally advanced colorectal cancer undergoing EBRT (45-55 Gy, usually with concurrent 5-FU administration) followed by resection and IOERT (10-20 Gy). Five-year OS for all patients was 46%. Patients with R0 or R1 resection had an improved OS relative to patients with R2 resection (5-year OS of 59% vs. 21%, p = 0.0005). Failure within the IOERT field occurred in 4 of 16 patients (25%) with R2 resection versus 2 of 39 (5%) with R0 or R1 resection (p = 0.01)56 (see Table 22.8). An update from Mayo Clinic Rochester analyzed 146 patients with locally unresectable primary colorectal cancers who received IOERT in addition to preoperative or postoperative combined-modality therapy. Median survival was 44 months with 5-year OS of 52%. Three-year local and distant relapse rates were 10% and 43%, respectively. Patients receiving preoperative combined-modality therapy appeared to have a survival advantage versus those receiving postoperative therapy (median survival 76 months vs. 26 months, 5-year OS of 55% vs. 38%, p = 0.02).57 A pooled analysis from Mayo Clinic and Catharina Hospital investigators of IOERT containing regimens in T4 rectal cancer patients analyzed 417 patients treated with multimodality therapy, including IOERT, with a preferred treatment approach of preoperative chemoradiation, radical surgery, and IORT. Of the patients, 306 (73%) underwent R0 resection. Local recurrence and metastases occurred more frequently following R1-R2 resection. Preoperative chemoradiation was associated with higher probability of R0 resection. Increased waiting time after preoperative treatment was related to increased chance of developing local recurrence, especially after R+ resection, with 16% of all cases developing locoregional recurrence. Five-year disease-free and overall survival rates were 55% and 56%, respectively.141 Madrid investigators from the General University Hospital Gregorio Marañon described 558 patients with T3-T4 rectal cancer, 281 of whom received preoperative combined-modality therapy plus IOERT and 277 who received postoperative CRT without IOERT. Patients receiving preoperative therapy plus IOERT (despite higher-stage disease at presentation) had a significant improvement in pelvic control (92%

Mayo Clinic investigators reported on the use of IOERT as a component of therapy in 16 patients with primary (3) or recurrent uterine sarcoma, including 9 patients with leiomyosarcoma, 4 with stromal sarcoma, and 3 with carcinosarcoma. All were treated with perioperative EBRT (median, 50.4 Gy; range, 20-62.5 Gy) and 6 (38%) received perioperative chemotherapy. Surgical resection was classified as R0 in 8 (50%) patients, R1 in 2 (12.5%) patients, and R2 in 6 (37.5%) patients. The median IOERT dose was 12.5 Gy with a range of 10 to 20 Gy. The 5-year OS was 43% and CSS was 47%. There were no central relapses within the IOERT field and only 1 local relapse (6%). Nine patients (56%) relapsed in distant sites. Peripheral neuropathy was observed in 3 patients (19%).136

Ovarian Cancer Although the primary pattern of relapse of ovarian cancer is peritoneal, a subset of ovarian cancer patients experience isolated locoregional relapse. There are several reports on the use of IOERT in selected patients with ovarian cancer. A Chinese series included 25 patients with primary ovarian cancer and 20 with isolated local relapse. Intraperitoneal chemotherapy was delivered to 33 patients (73%) and intravenous chemotherapy to 7 (16%) patients. No EBRT was used. The IOERT dose was 18 to 20 Gy in 43 patients and 10 Gy in the remaining 2 patients. Five-year survival was observed in 64% in the primary group and 60% in the recurrent group. In the primary group, 8 patients (32%) relapsed locally and 3 (12%) distantly. In the recurrent group, there were 6 local relapses (30%) and 2 distant relapses (10%). The rate of central relapse within the IOERT field was 9% for the entire group. Five patients (11%) experienced peripheral neuropathy.137 Stanford investigators reported on 22 patients with recurrent ovarian cancer who received orthovoltage IORT as a component therapy.138 The median IORT dose was 12 Gy (range, 9-14 Gy) and treated sites included pelvis, paraaortic nodes, inguinal nodes, and the porta hepatis. Nine patients received whole abdominal EBRT, 5 received locoregional EBRT, and 6 received chemotherapy. The median survival was 26 months, 5-year OS was 22%, and DFS was 18%. Locoregional control was 68% at 22 months and 55% of patients experienced distant relapse. There were no long-term peripheral neuropathies.138 A Mayo Clinic analysis described 20 patients with recurrent ovarian cancer treated with IOERT as a component of therapy.139 Thirteen patients (70%) had epithelial ovarian carcinomas and the remaining histologies were granulosa cell tumor, malignant teratoma, adenosarcoma, stromal tumor, and squamous cell carcinoma. The site of recurrence was the pelvis in 14 patients, paraaortic nodes in 6, and inguinal nodes in 1. Sixteen patients received a median EBRT dose of 50 Gy (range, 20-54.3 Gy). Surgical resection was classified as R0 in 9 patients, R1 in 11, and R2 in 1. The median IOERT dose was 12.5 Gy (range, 10-22.5 Gy). Median survival was 30 months, with a 49% 5-year OS. Central control

Future Possibilities Because of the high incidence of distant metastases observed in patients with gynecological cancer with microscopic and gross residual disease following resection, evaluation of newer systemic and maintenance regimens is indicated. Investigation of newer chemotherapeutic and targeted biological agents may hold promise in improving distant metastases rates and ultimate survival in these malignancies.

Colorectal Cancer: Primary and Recurrent Disease Primary Locally Advanced Cancers

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Primary Rectal (MGH) or Colorectal (Mayo Clinic) IOERT Series: Disease Control and Survival by Degree of Resection and Amount of Residual Disease

TABLE 22.8

MGH RESULTS 5-YR ACTUARIAL (%)a,b

MAYO CLINIC RESULTS 5-YR ACTUARIAL (%)

Degree of Resection

N

LF

DSS

N

LF

DF

OS

No tumor

—

—

—

2

0

0

100

Complete resection

40

9

63

18

7

54b

69

Partial (subtotal) resection

24

37

35

—

—

—

—

Microscopic residual

17

35

47

19

14

50b

55

Gross residual

7

43

14

16

27

83b

21

No resection

—

—

—

—

—

—

0

Total series

64

56

16

59

46

a

Data from Gunderson LL, Nelson H, Martenson JA, et al. Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation ± 5-FU. Int J Radiat Oncol Biol Phys. 1997;37(3):601–614; and Willett CG, Shellito PC, Tepper JE, et al. Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma. J Clin Oncol. 1991;9(5):843–849. b Three-year actuarial DF of 43%, 38%, and 66%, respectively, for complete resection, microresidual, and gross residual. DF, Distant failure; DSS, disease-specific survival; IOERT, intraoperative electron radiotherapy; LF, local failure; MGH, Massachusetts General Hospital; OS, overall survival.

vs. 84%, p = 0.03), DFS (65% vs. 56%, p = 0.05), and OS (68% vs. 58%, p = 0.016).59 In a more recent and selected update of the postchemoradiation plus IORT presacral boost experience, 335 patients treated from 1995 to 2011 (median follow-up, 52.2 months) showed 5-year LC, in-field, and out-field control rates of 94.4%, 97.0%, and 93.4%, respectively. In multivariate analysis, nonsphincter-preserving surgery and grade 3 histology were associated with increased risk of presacral relapse.60 In a follow-up analysis with a median follow-up of 72.6 months, distal margin distance less than 1 cm, R1 resection, tumor regression grade 1-2, and tumor grade 3 were associated with increased risk of locoregional recurrence.142 A pooled European analysis of 651 patients treated with IOERT from four major centers showed that 5-year OS was 67% with 5-year LC of 88% in patients with locally advanced rectal cancer.61 Positive circumferential margins were a strong predictor for both OS and local relapse, and the addition of preoperative CRT appeared to improve 5-year OS (70% vs. 64%, p < 0.05). An update of the pooled European analysis in 605 patients demonstrated that CRT led to more downstaging and complete remissions compared with radiotherapy alone.62 Local recurrence, distant metastasis, and OS rates were 12%, 29%, and 67%, respectively. Risk factors for local recurrence included lack of downstaging with preoperative therapy, lymph node involvement, margin involvement, and lack of postoperative chemotherapy. The authors concluded that oncological results following multimodality therapy including IORT showed promising outcomes and the addition of adjuvant chemotherapy could potentially improve local recurrence rates. The feasibility of IOERT at the time of laparoscopic resection of locally advanced rectal cancer, after preoperative chemoradiation, has been reported by the Gregorio Marañon Hospital team. In a group of 125 patients, laparoscopic resection plus IOERT had significantly less blood loss and shorter hospital stay. Oncological and toxicity results were similar.63

Locally Recurrent Colorectal Cancer Patients developing local recurrence following curative resection of primary colon or rectal cancer are treated with palliative intent at many institutions. Local recurrence from rectosigmoid cancer often causes pelvic pain due to nerve involvement in the presacral space or pelvic sidewall. The likelihood of margin-negative resection is low. Patients undergoing surgery alone for pelvic recurrence from rectal cancer have a reported 5-year survival rate of 0%.143

When IOERT is combined with EBRT with or without chemotherapy and surgical salvage, 5-year OS in the range of 20% to 30% has been achieved.55,143–147 In an MGH analysis of 41 patients with locally recurrent rectosigmoid cancer undergoing IOERT, patients with gross residual disease experienced 5-year LC and DFS of 21% and 7%, respectively, versus 47% and 21% with clear or microscopically positive margins.144 Eindhoven investigators described a series of 147 patients with locally recurrent colorectal cancer receiving IOERT. Median OS was 28 months with 5-year OS, DFS, metastases-free survival, and LC rates of 32%, 34%, 50%, and 54%, respectively. R0 resection was associated with improved disease outcomes. Patients treated with IOERT alone had worse outcomes versus those who were reirradiated or treated with full-dose preoperative EBRT.145 The potential of extended resection in combination with IOERT and EBRT has been analyzed at the University Hospital Gregorio Marañon. In a 16-year experience, an adaptive surgical approach based on extent of recurrence extension was systematically combined with IOERT: 60 patients underwent extended surgery (43% multiorgan, 28% bone, 38% soft-tissue resection) and 22 had nonextended resection. With a median follow-up time of 36 months, locoregional control was 44% at 5 years and OS was 43%. On multivariate analysis, positive margins, EBRT at the time of rescue, lack of tumor fragmentation, and lack of lymph node metastasis were significant factors associated with locoregional relapse.148 A Mayo Clinic Rochester report described the outcome of 106 patients undergoing palliative resection of locally recurrent, nonmetastatic rectal cancer. Forty-two patients received IOERT as a component of treatment (most 15-20 Gy) and 41 EBRT (most ≥ 45 Gy). Patients with R2 resection had a significantly worse outcome versus R1 resection (5-year OS of 9% vs. 33%, p = 0.03). Patients who underwent IOERT compared with those who did not had a 5-year OS of 19% versus 7% (p = 0.0006).143 An updated Mayo Clinic analysis described 175 patients with locally recurrent colorectal cancer (123 no prior EBRT, 52 prior EBRT) undergoing IOERT. Five-year OS in previously unirradiated patients was 20% versus 12% in previously irradiated patients. Three-year LC rate in previously unirradiated patients was 75% versus 51% in those previously irradiated. Three-year distant metastases rates were 64% and 71%, respectively.149 An even more recent Mayo Clinic analysis described 607 patients with recurrent colorectal cancer who received IOERT as a component of treatment. Five-year OS was 30%. In patients undergoing R0 resection, 5-year OS was 46%. Prior in-field radiation was associated with an

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CHAPTER 22 increased risk of local relapse (3-year local relapse of 39% vs. 20%, p < 0.0001) but not with survival. On multivariate analysis, complete resection, no prior chemotherapy, and treatment after 1996 were associated with improved survival. Three-year local and distant relapse rates were 27% and 55%, respectively.58 A pooled analysis of IOERT-containing treatment from Mayo Clinic and Catharina Hospital evaluated 565 patients (44% R0, 45% previously irradiated), reporting a re-recurrence rate of 22% in R0 and 42% to 61% in R+ specimens, respectively. Reported OS at 5 years was 33% for the entire cohort, 48% in R0 patients and 17% to 25% in R+ patients. Short waiting times between preoperative treatment and IOERT were advised to reduce re-recurrence risk.150 Systematic reviews and meta-analysis are available to evaluate results of IORT in colorectal cancer. From 1965 to 2011, 14 prospective and 15 retrospective studies were identified meeting methodological quality and design (3003 patients involved: 1792 primary locally advanced category). When comparative studies were evaluated, a significant effect favoring improved LC (p = 0.003), DFS (p = 0.009), and OS (p = 0.001) was noted with no increase in total urological or anastomotic complications, although increased wound complications were observed after IORT (p = 0.049). Heterogeneity in methodology and reporting practice warrants caution in the interpretation of these results.151

Future Possibilities Based on the preceding and other data, it appears that improved LC and survival may be achieved when IORT is combined with preoperative chemoradiation for locally advanced or locally recurrent colorectal cancer. Many patients will develop distant metastases; relapse within the IORT and EBRT fields is common if gross total resection is not obtained. Based on the proven survival benefit of concurrent 5-FU–based regimens with EBRT in colorectal and other gastrointestinal malignancies, 5-FU–based chemotherapy should be administered concurrent with EBRT. Although adjuvant 5-FU with leucovorin has previously been shown to improve survival in patients with advanced-stage colorectal cancer, the addition of newer therapies (oxaliplatin, capecitabine, irinotecan, bevacizumab, cetuximab, and panitumumab) has demonstrated further survival benefit in patients with stage IV cancer. These agents have been evaluated as adjuvant therapy in patients with stages II and III cancer (see Colon and Rectal Cancer chapters). Given the high rate of subsequent distant metastases in patients with locally advanced and recurrent colorectal cancer, significant improvement in long-term survival will likely be achieved through further improvements in systemic agents.

Intraoperative Irradiation

385

malignancies. As stated previously, cancer sites in which IORT has been explored and found to be feasible include renal cancer,155,156 prostate cancer,157 extremity sarcomas,158 and pediatric cancers.159 Other potential avenues of future exploration with IORT include delivering it in combination with immunotherapy or other novel systemic agents (including radiosensitizing nanoparticles), as well as even development of IORT devices that implement protons or heavy ions.160

Intraoperative Radiotherapy: Technical Considerations Many limitations and perceived drawbacks of IORT in past decades were the result of inefficiencies associated with nondedicated facilities. Patients were often transported from the operating suite to the radiation oncology department, where they were treated with nondedicated LINACs. These inconveniences have been overcome with dedicated IOERT, HDR-IORT, or orthovoltage facilities. At present, dedicated IORT suites within or adjacent to the operating room exist at many institutions in the United States, Europe, and Far East. These facilities simplify treatment by avoiding transportation and sterility problems. A major limiting factor is the expense associated with outfitting a dedicated room (e.g., retrofitting an operating room with proper shielding, purchase of a LINAC dedicated for use in the operating room, construction of a separate IORT suite adjacent to the operating room, and so on). However, newer technologies have lowered these costs. Contemporary options include mobile IOERT units—for example, the Mobetron (Intraop Medical, Inc., Sunnyvale, CA)—as well as mobile HDR-IORT.161 The Mobetron is a mobile, self-shielded compact LINAC with a C-arm design that generates electron energies of 4 MeV to 12 MeV (Fig. 22.4). This can be transported in and out of the operating theater. HDR-IORT units are remote afterloading devices that use an Ir-192 source (Figs. 22.5 and 22.6). In contrast to the Mobetron, HDR-IORT requires room shielding, which may be achieved by retrofitting an existing room or construction of a smaller shielded room adjacent to the operating suite. In either situation, patients are monitored remotely by camera during radiation administration. After completion, the HDR-IORT unit can be transported to the radiation oncology department for outpatient HDR-appropriate malignancies, including gynecological and prostate malignancies. Mobile IOERT devices used in Europe include the LINAC machines as well as the NOVAC 7. The INTRABEAM system for breast cancer IORT consists of a 50-kV x-ray generator mounted on a flexible floor stand and a set of spherical applicators ranging from 1.5 cm to

CONCLUSIONS IORT is the delivery of radiation at the time of operation. This can be accomplished using different techniques, including IOERT, HDR-IORT, and orthovoltage. IORT is usually given in combination with EBRT, with or without chemotherapy and surgical resection. IORT allows exclusion of part or all dose-limiting sensitive structures, thereby increasing the effective dose to the tumor bed (and therefore improving LC) without significantly increasing normal tissue morbidity. Despite optimal therapy with non-IORT approaches, high rates of local relapse occur in patients with retroperitoneal sarcoma, pancreatic cancer, colorectal cancer, gynecological cancer, and other malignancies. IORT electron treatments have been reported in several other cancer models, such as head and neck152 renal,153 pediatric,154 and prostate cancer.135 The addition of IORT to conventional treatment methods has improved LC as well as survival in many disease sites in both the primary and recurrent disease settings. In view of newer, lower-cost treatment devices, the use of IORT in clinical practice will likely continue to grow, with increasing integration into the treatment of “nonconventional”

Fig. 22.4 The mobile electron-beam radiation device (Mobetron, seen here in the operating room) allows use in an existing operating room with little or no additional shielding required. (Courtesy IntraOp Medical, Inc., Sunnyvale, CA.)

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386

SECTION II

Techniques and Modalities

100% 100% 50%

50%

3 cm Fig. 22.7 Dose distribution characteristics of intraoperative electron radiotherapy (IOERT, left) and in high-dose-rate intraoperative radiotherapy (HDR-IORT, right). Note that IOERT is using 6 MeV electrons; HDR-IORT is using 1 cm surface applicator with dose prescribed to 0.5-cm depth.

Fig. 22.5 Source housing for Ir-192 source. This device allows computerassisted treatment delivery during intraoperative radiotherapy. (Courtesy Varian Medical Systems, Palo Alto, CA.)

clinical practice. The incorporation of treatment planning systems for IORT use will help decision-making processes and its registration will facilitate normalization of medical and surgical practice in IORT programs. Opportunities in radiation beam modulation, delivery, dosimetry and planning, infrastructure, and treatment factors are recognized and expected to be developed over the next decade.163 A detailed description of the relative advantages and disadvantages of IOERT and HDR-IORT has been discussed elsewhere and is beyond the scope of this chapter38 (eTable 22.6 and eTable 22.7). In summary, treatment or procedure times are generally shorter with IOERT compared with HDR-IORT. Additionally, IOERT allows variation of electron energies and therefore treatment of both superficial and deeper-seated targets, whereas HDR-IORT is appropriate only for targets less than or equal to 0.5 cm in thickness (Fig. 22.7). The flexible Harrison-Anderson-Mick (HAM) applicator used in HDR-IORT may allow more conformal treatment along curved body surfaces (e.g., large pelvic sidewall fields, lateral abdominal wall, and thoracic cage) that may prove difficult with rigid IOERT applicators (see Fig. 22.6). Separate, matching fields may be required to treat larger target areas with IOERT-based applicators. A comprehensive IORT program would ideally have IOERT, HDR-IORT, and perioperative brachytherapy available to treat all disease sites and situations. These modalities should be viewed as complementary and not competitive.

Future Possibilities

Fig. 22.6 Harrison-Anderson-Mick (HAM) applicator used to guide Ir-192 source during high-dose-rate intraoperative radiotherapy.

5 cm in diameter. A similar technique for partial breast IORT is possible with the Papillon system (Ariane Medical Systems Limited, Derby, UK), which uses a switchable 30/50-kV x-ray generator. Treatment planning systems specifically designed for IOERT are now commercially available (Radiance, GMV, Madrid, Spain). Initial clinical testing demonstrated feasibility and multispecialist agreement for simulation of different cancer sites and anatomic locations, including breast cancer, locally advanced rectal cancer, retroperitoneal sarcoma, and isolated recurrence of rectal and ovarian cancer.162 Research opportunities in IORT are a multidisciplinary endeavor that spans knowledge ranging from radiation beam adaptive development to advanced molecular biology for biopredictability of outcomes. Technical innovation requires further improvements in quality assurance and

Although there is a large body of data supporting the use of IORT in various malignancies, there is a paucity of Phase III randomized trials. This is at least in part because of the limited number of IORT facilities in any given country as well as the relative rarity of diseases commonly treated with IORT. Completion of Phase II/III trials will likely require cooperation among multiple institutions and countries. Future treatment approaches should include “standard” courses of EBRT, with or without concurrent chemotherapy and surgical resection, with the integration of novel radiation sensitizers, protectors, and targeted biological agents with IORT.164

Acknowledgments The chapter authors would like to thank Karen Rhodes for her assistance in the preparation of this work.

CRITICAL REFERENCES 2. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383(9917):603–613.

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CHAPTER 22

Intraoperative Irradiation

386.e1

eTABLE 22.6 Relative Advantages and Disadvantages of IOERT Versus HDR-IORT Brachytherapy After Gross Total or Near-Total Resection (Maximum Tumor Thickness ≤ 0.5 cm) IOERT Potential Advantage if Technically Feasible

Potential Disadvantages of IOERT

Potential Solution to Disadvantage

Better dose homogeneity Faster treatment time

Surface dose < 90% with 6 ± 9 MeV

Add bolus over tumor bed to improve surface dose; use HDR-IORT.

Less shielding required in operating room Can treat full thickness of organ or structure at risk with relative homogeneity (e.g., aorta or vena cava, bladder sidewall).

Unable to include area at risk in single field within either abdomen or pelvis.

Use abutting IOERT fields (difficult in pelvis): use HDR-IORT

Area at risk is technically inaccessible because of location.

Use HDR-IORT; surgically displace small bowel or stomach with vascularized flap (omentum, muscle) and give postoperative EBRT boost or perioperative brachytherapy.

EBRT, External beam radiotherapy; HDR-IORT, high-dose-rate intraoperative radiotherapy; IOERT, intraoperative electron beam radiotherapy.

eTABLE 22.7 Potential Differences Between IOERT and HDR-IORT IOERT

HDR-IORT

Actual treatment time

2-4 min

5-30 min

Total procedure lime

30-45 min

45-120 min

Treatment sites

Accessible locations

All areas where depth at risk is ≤ 0.5 cm from surface of applicator

Surface dose

Lower (75%-93%)

Higher (150%-200%)

Dose at depth (2 cm)

Higher (70%-100%)

Lower (30%)

Dosimetric homogeneity (surface to depth)

100% variation

HDR-IORT, high-dose-rate intraoperative radiotherapy; IOERT, intraoperative electron beam radiotherapy. From Nag S, Gunderson LL, Willett CG, et al. Intraoperative irradiation with electron-beam or high-dose-rate brachytherapy. In: Gunderson L, Willett C, Harrison L, Calvo F, eds. Intraoperative Irradiation—Techniques and Results. Totowa NJ: Humana Press; 1999:111–130.

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CHAPTER 22 14. Sindelar WF, Kinsella TJ, Chen P. Intraoperative radiotherapy and retroperitoneal sarcomas: final results of a prospective, randomized, clinical trial. Arch Surg. 1993;128:402–410. 21. Calvo FA, Sole CV, Lozano MA, et al. Intraoperative electron beam radiotherapy and extended surgical resection for gynecological pelvic recurrent malignancies with and without external beam radiation therapy: Long-term outcomes. Gynecol Oncol. 2013;130(3):537–544. 32. Leibel SA, Scott CB, Mohiuddin M, et al. The effect of local-regional control on distant metastatic dissemination in carcinoma of the head and neck: results of an analysis from the RTOG head and neck database. Int J Radiat Oncol Biol Phys. 1991;21(3):549–556. 33. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997;337(14):949–955. 36. Sauer R, Heinz B, Werner H, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–1740. 48. Sindelar WF, Johnstone PA, Hoekstra H, et al. Normal tissue tolerance to IORT. The NCI experimental studies. In: Gunderson LL, Willett CG, Harrison LB, et al, eds. Intraoperative Irradiation—Techniques and Results. Totowa, NJ: Humana Press; 1999:131–146. 56. Gunderson LL, Nelson H, Martenson JA, et al. Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation ± 5-FU. Int J Radiat Oncol Biol Phys. 1997;37(3):601–614. 58. Haddock MG, Miller RC, Nelson H, et al. Combined modality therapy including intraoperative electron irradiation for locally recurrent colorectal cancer. Int J Radiat Oncol Biol Phys. 2011;79(1):143–150. 62. Kusters M, Valentini V, Calvo FA, et al. Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases. Ann Oncol. 2010;21(6):1279–1284. 78. Cai S, Hong TS, Goldberg SI, et al. Updated long-term outcomes and prognostic factors for patients with unresectable locally advanced pancreatic cancer treated with intraoperative radiotherapy at the Massachusetts General Hospital, 1978 to 2010. Cancer. 2013;119(23):4196–4204. 82. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2000;355(9217):1757–1770. 89. Veronesi U, Orecchia R, Luini A, et al. Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery: experience with 590 cases. Ann Surg. 2005;242(1):101–106. PMCID: 1357710.

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90. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol. 2007;25(22):3259–3265. 94. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013;14(13):1269–1277. 96. Sperk E, Welzel G, Keller A, et al. Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A. Breast Cancer Res Treat. 2012;135(1):253–260. 100. Veronesi U, Orecchia R, Luini A, et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res Treat. 2010;124(1):141–151. 111. Gieschen HL, Spiro IJ, Suit HD, et al. Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2001;50(1):127–131. 130. Giorda G, Boz G, Gadducci A, et al. Multimodality approach in extra cervical locally advanced cervical cancer: chemoradiation, surgery and intra-operative radiation therapy. A phase II trial. Eur J Surg Oncol. 2011;37(5):442–447. 140. Willett CG, Shellito PC, Tepper JE, et al. Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma. J Clin Oncol. 1991;9(5):843–849. 148. Calvo FA, Sole CV, Alvarez de Sierra P, et al. Prognostic impact of external beam radiation therapy in patients treated with and without extended surgery and intraoperative electrons for locally recurrent rectal cancer: 16-year experience in a single institution. Int J Radiat Oncol Biol Phys. 2013;86(5):892–900. 149. Haddock MG, Gunderson LL, Nelson H, et al. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys. 2001;49(5):1267–1274. 163. Calvo FA, Sole CV, Gonzalez ME, et al. Research opportunities in intraoperative radiation therapy: the next decade 2013-2023. Clin Transl Oncol. 2013;15(9):683–690. 169. Tepper JE, Noyes D, Krall JM, et al. Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1991;21(5):1145–1149.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 22

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44. Kinsella TJ, DeLuca AM, Barnes M, et al. Threshold dose for peripheral neuropathy following intraoperative radiotherapy (IORT) in a large animal model. Int J Radiat Oncol Biol Phys. 1991;20(4):697–701. 45. Kinsella TJ, Sindelar WF, DeLuca AM, et al. Tolerance of the canine bladder to intraoperative radiation therapy: an experimental study. Int J Radiat Oncol Biol Phys. 1988;14(5):939–946. 46. Sindelar WF, Tepper J, Travis EL. Tolerance of bile duct to intraoperative irradiation. Surgery. 1982;92(3):533–540. 47. Sindelar WF, Tepper JE, Kinsella TJ, et al. Late effects of intraoperative radiation therapy on retroperitoneal tissues, intestine, and bile duct in a large animal model. Int J Radiat Oncol Biol Phys. 1994;29(4): 781–788. 48. Sindelar WF, Johnstone PA, Hoekstra H, et al. Normal tissue tolerance to IORT. The NCI experimental studies. In: Gunderson LL, Willett CG, Harrison LB, et al, eds. Intraoperative Irradiation—Techniques and Results. Totowa, NJ: Humana Press; 1999:131–146. 49. LeCouteur RA, Gillette EL, Powers BE, et al. Peripheral neuropathies following experimental intraoperative radiation therapy (IORT). Int J Radiat Oncol Biol Phys. 1989;17(3):583–590. 50. Gillette EL, Gillette SM, Vujaskovic Z, et al. Influence of volume on canine ureters and peripheral nerves irradiated intraoperatively. In: Schildberg FW, Willich N, Krämling H, eds. Intraoperative Radiation Therapy—Proceedings of the 4th International IORT Symposium, Munich, 1992. Essen, Germany: Verlag Die Blaue Eule; 1993:61–63. 51. Gillette EL, Gillette S, Powers BE, et al, eds. Studies at Colorado State University of Normal Tissue Tolerance of Beagles to IOERT, EBRT or a Combination. Totowa, NJ: Humana Press; 1999. 52. Shaw EG, Gunderson LL, Martin JK, et al. Peripheral nerve and ureteral tolerance to intraoperative radiation therapy: clinical and dose-response analysis. Radiother Oncol. 1990;18(3):247–255. 53. Miller RC, Haddock MG, Petersen IA, et al. Intraoperative electron-beam radiotherapy and ureteral obstruction. Int J Radiat Oncol Biol Phys. 2006;64(3):792–798. 54. Johnstone PA, Sindelar WF, Kinsella TJ. Experimental and clinical studies of intraoperative radiation therapy. Curr Probl Cancer. 1994;18(5):249–290. 55. Gunderson LL, Nelson H, Martenson JA, et al. Intraoperative electron and external beam irradiation with or without 5-fluorouracil and maximum surgical resection for previously unirradiated, locally recurrent colorectal cancer. Dis Colon Rectum. 1996;39(12):1379–1395. 56. Gunderson LL, Nelson H, Martenson JA, et al. Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation ± 5-FU. Int J Radiat Oncol Biol Phys. 1997;37(3):601–614. 57. Mathis KL, Miller R, Nelson H, et al. Unresectable colorectal cancer can be cured with multimodality therapy. Ann Surg. 2008;248:592–598. 58. Haddock MG, Miller RC, Nelson H, et al. Combined modality therapy including intraoperative electron irradiation for locally recurrent colorectal cancer. Int J Radiat Oncol Biol Phys. 2011;79(1):143–150. 59. Gomez M, Calvo F, Gonzalez C, et al, editors. Timing and intensity of neoadjuvant treatment in rectal cancer: results of pre (+IOERT) versus post (no IOERT) chemoradiation Rev Cancer ISIORT 2008, Madrid, 2008, Aran. 2008 June 10-13. 60. Calvo F, Sole CV, Gomez-Espi M, et al, editors. Post-Neoadjuvant intraoperative electron boost compensates adverse prognostic factors for pelvic recurrence in locally advanced rectal cancer: long-term results, 2013, ISIORT Europe. 61. Rutten H, Valentini V, Krempien R, et al, editors. Treatment of locally advanced rectal cancer by intraoperative electrobeam radiotherapy containing multimodality treatment, results of a European pooled analysis. Rev Cancer ISIORT 2008, Madrid, 2008, Aran. 2008 June 10-13. 62. Kusters M, Valentini V, Calvo FA, et al. Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases. Ann Oncol. 2010;21(6):1279–1284. 63. Calvo FA, Sole CV, Serrano J, et al. Postchemoradiation laparoscopic resection and intraoperative electron-beam radiation boost in locally advanced rectal cancer: Long-term outcomes. J Cancer Res Clin Oncol. 2013;139(11):1825–1833.

64. Vujaskovic Z. Structural and physiological properties of peripheral nerves after intraoperative irradiation. J Peripher Nerv Syst. 1997;2(4):343–349. 65. Azinovic I, Martinez Monge R, Javier Aristu J, et al. Intraoperative radiotherapy electron boost followed by moderate doses of external beam radiotherapy in resected soft-tissue sarcoma of the extremities. Radiother Oncol. 2003;67(3):331–337. 66. Gunderson L, Willett C, Harrison L, et al. Intraoperative Irradiation— Techniques and Results. 2nd ed. New York: Humana Press/Springer; 2011. 67. Iacobuzio-Donahue C, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;10(11):1806–1813. 68. Sindelar WF, Kinsella TJ. Studies of intraoperative radiotherapy in carcinoma of the pancreas. Ann Oncol. 1999;10(suppl 4):226. 69. Reni M, Panucci MG, Ferreri AJ, et al. Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2001;50(3):651–658. 70. Ogawa K, Karasawa K, Ito Y, et al. Intraoperative radiotherapy for resected pancreatic cancer: a multi-institutional retrospective analysis of 210 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):734–742. 71. Valentini V, Calvo F, Reni M, et al. Intra-operative radiotherapy (IORT) in pancreatic cancer: joint analysis of the ISIORT-Europe experience. Radiother Oncol. 2009;91(1):54–59. 72. Krempien R, Roeder F. Intraoperative radiation therapy (IORT) in pancreatic cancer. Radiat Oncol. 2017;12:8–14. 73. Valentini V, Balducci M, Tortoreto F, et al. Intraoperative radiotherapy: current thinking. Eur J Surg Oncol. 2002;28(2):180–185. 74. Roldan GE, Gunderson LL, Nagorney DM, et al. External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer. 1988;61(6):1110–1116. 75. Shibamoto Y, Manabe T, Ohshio G, et al. High-dose intraoperative radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 1996;34(1):57–63. 76. Shipley WU, Wood WC, Tepper JE, et al. Intraoperative electron beam irradiation for patients with unresectable pancreatic carcinoma. Ann Surg. 1984;200(3):289–296. PMCID: 1250473. 77. Willett CG, Del Castillo CF, Shih HA, et al. Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer. Ann Surg. 2005;241(2):295–299. PMCID: 1356915. 78. Cai S, Hong TS, Goldberg SI, et al. Updated long-term outcomes and prognostic factors for patients with unresectable locally advanced pancreatic cancer treated with intraoperative radiotherapy at the Massachusetts General Hospital, 1978 to 2010. Cancer. 2013;119(23):4196–4204. 79. Keane FK, Wo J, Ferrone C, et al. Intraoperative radiotherapy in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Am J Clin Oncol. 2018;41(6):607–612. 80. Mohiuddin M, Regine WF, Stevens J, et al. Combined intraoperative radiation and perioperative chemotherapy for unresectable cancers of the pancreas. J Clin Oncol. 1995;13(11):2764–2768. 81. Schuricht AL, Spitz F, Barbot D, et al. Intraoperative radiotherapy in the combined-modality management of pancreatic cancer. Am Surg. 1998;64(11):1043–1049. 82. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2000;355(9217):1757–1770. 83. Lemanski C, Azria D, Gourgon-Bourgade S, et al. Intraoperative radiotherapy in early-stage breast cancer: results of the Montpellier phase II trial. Int J Radiat Oncol Biol Phys. 2010;76(3):698–703. 84. Veronesi U, Gatti G, Luini A, et al. Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery. Arch Surg. 2003;138(11):1253–1256. 85. Arcangeli G, Arcangeli S, Giordano C, et al. Intraoperative (IORT) versus standard radiotherapy (EBRT) in breast cancer, an update of an ongoing Italian multicenter, randomized study. ISIORT Rev Cancer. 2008;22:13.

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CHAPTER 22 86. Cuncins-Hearn A, Saunders C, Walsh D, et al. A systematic review of intraoperative radiotherapy in early breast cancer. Breast Cancer Res Treat. 2004;85(3):271–280. 87. Vaidya JS, Baum M, Tobias JS, et al. Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost. Int J Radiat Oncol Biol Phys. 2006;66(5):1335–1338. 88. Majewski W, Wydmanski J, Kanieska-Dorsz Z, et al. Early results of a targeted intra-operative radiation therapy (TARGIT) as a boost in breast conserving treatment. ISIORT Rev Cancer. 2008;22:17. 89. Veronesi U, Orecchia R, Luini A, et al. Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery: experience with 590 cases. Ann Surg. 2005;242(1):101–106. PMCID: 1357710. 90. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol. 2007;25(22):3259–3265. 91. Battle JA, DuBois JB, Merrick HW, et al. IORT for breast cancer. In: Gunderson LL, Willett CG, Harrison LB, et al, eds. Intraoperative Irradiation—Techniques and Results. Totowa, NJ: Humana Press; 1999:521–526. 92. Reitsamer R, Peintinger F, Kopp M, et al. Local recurrence rates in breast cancer patients treated with intraoperative electron-boost radiotherapy versus postoperative external-beam electron-boost irradiation. A sequential intervention study. Strahlenther Onkol. 2004;180(1):38–44. 93. Wenz F, Welzel G, Blank E, et al. Intraoperative radiotherapy as a boost during breast-conserving surgery using low-kilovoltage X-rays: the first 5 years of experience with a novel approach. Int J Radiat Oncol Biol Phys. 2010;77(5):1309–1314. 94. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013;14(13):1269–1277. 95. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383(9917):603–613. 96. Sperk E, Welzel G, Keller A, et al. Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A. Breast Cancer Res Treat. 2012;135(1):253–260. 97. Silverstein MJ, Fastner G, Maluta S, et al. Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 1 – ELIOT. Ann Surg Oncol. 2014;21:3787–3792. 98. Silverstein MJ, Fastner G, Maluta S, et al. Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 2 – TARGIT. Ann Surg Oncol. 2014;21:3793–3799. 99. Lemanski C, Azria D, Gourgon-Bourgade S, et al. Intraoperative radiotherapy in early-stage breast cancer: late Results of the Montpellier phase II trial. Radiat Oncol. 2013;8:191. 100. Veronesi U, Orecchia R, Luini A, et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res Treat. 2010;124(1):141–151. 101. Leonardi MC, Ivaldi GB, Santoro L, et al. Long-term side effects and cosmetic outcome in a pool of breast cancer patients treated with intraoperative radiotherapy with electrons as sole treatment. Tumori. 2012;98(3):324–330. 102. Sedlmayer F, Fastner G, Merz F, et al. IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: results of an ISIORT pooled analysis. Strahlenther Onkol. 2007;183(2):32–34. 103. Sedlmayer F, Fastner G, Merz F, et al. ISIORT pooled analysis on linac-based IORT as boost strategy during breast conserving therapy. Rev Cancer. 2008;22:21–22. 104. Fastner G, Sedlmayer F, Merz F, et al. IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: long term results of an ISIORT pooled analysis. Radiother Oncol. 2013;108(2):279–286. 105. Fastner G, Hauser-Kronberger C, Moder A, et al. Survival and local control rates of triple-negative breast cancer patients treated with

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boost-IOERT during breast-conserving surgery. Strahlenther Onkol. 2016;192(1):1–7. 106. Fastner G, Reitsamer R, Ziegler I, et al. IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer–results of a case series after 5-year follow-up. Int J Cancer. 2015;136(5):1193–1201. 107. Kaiser J, Kronberger C, Moder A, et al. Intraoperative tumor bed boost with electrons in breast cancer of clinical stages I through III: updated 10-year results. Int J Radiat Oncol Biol Phys. 2018;102(1):92–101. 108. Correa C, Harris EE, Leonardi MC, et al. Accelerated Partial Breast Irradiation: executive summary for the update of an ASTRO Evidence-Based Consensus Statement. Pract Radiat Oncol. 2017;7(2): 73–79. 109. Petersen IA, Haddock MG, Donohue JH, et al. Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 2002;52(2):469–475. 110. Petersen I, Haddock M, Stafford S, et al. Use of intraoperative radiation therapy for retroperitoneal sarcomas. Update of the Mayo Clinic Rochester Experience. ISIORT 2008 Proceedings. Cancer. 2008;22:57. 111. Gieschen HL, Spiro IJ, Suit HD, et al. Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2001;50(1):127–131. 112. Pierie JP, Betensky RA, Choudry U, et al. Outcomes in a series of 103 retroperitoneal sarcomas. Eur J Surg Oncol. 2006;32(10):1235–1241. 113. Krempien R, Roeder F, Buchler MW, et al, editors. Intraoperative radiation therapy (IORT) for primary and recurrent retroperitoneal soft tissue sarcoma. First results of a pooled analysis, Madrid, 2008. Cancer ISIORT 2008. 114. Roeder F, Alldinger I, Uhl M, et al. Intraoperative electron radiation therapy in retroperitoneal sarcoma. Int J Radiat Oncol Biol Phys. 2018;100(2):516–527. 115. Roeder F, Ulrich A, Habel G, et al. Clinical Phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis. BMC Cancer. 2014;14:617. 116. Roeder F, Alldinger I, Uhl M, et al. Intraoperative electron radiation therapy in retroperitoneal sarcoma. Int J Radiat Oncol Biol Phys. 2018;100:516–527. 117. Gronchi A, Da Paoli A, Dani C, et al. Preoperative chemo-radiation therapy for localised retroperitoneal sarcoma: a phase I-II study from the Italian Sarcoma Group. Eur J Cancer. 2014;50(4):784–792. 118. Wang LB, McAneny D, Doherty G, et al. Effect of intraoperative radiotherapy in the treatment of retroperitoneal sarcoma. Int J Clin Oncol. 2017;22:563–568. 119. Gunderson LL, Nagorney DM, McIlrath DC, et al. External beam and intraoperative electron irradiation for locally advanced soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 1993;25(4):647–656. 120. Calvo FA, Azinovic I, Martinez R, et al. Intraoperative radiotherapy for the treatment of soft tissue sarcomas of central anatomic sites. IORT 94-5th International Symposium Abstracts. Hepatogastroenterology. 1994;41:4. 121. Dubois JB, Hay MH, Gely S, et al. Intraoperative radiation therapy (IORT) in soft tissue sarcomas. IORT 94-5th International Symposium Abstracts. Hepatogastroenterology. 1994;41:3. 122. Roeder F, Krempien R. Intraoperative radiation therapy (IORT) in soft-tissue sarcoma. Radiat Oncol. 2017;19:12–20. 123. Pisters PW, Ballo MT, Fenstermacher MJ, et al. Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol. 2003;21(16):3092–3097. 124. Haddock MG, Petersen IA, Webb MJ, et al. IORT for locally advanced gynecological malignancies. Front Radiat Ther Oncol. 1997;31:256–259. 125. Haddock MG, Petersen IA, Webb MJ, et al. Intraoperative radiation therapy for locally advanced gynecological (GYN) malignancies. Presented before the 3rd International ISIORT Meeting, Aachen, Germany. ISIORT Abstract 5.555; 2002.

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SECTION II

Techniques and Modalities

126. Haddock MG. Intraoperative radiation therapy for locally advanced gynecologic malignancies. ISIORT 2005 Proceedings; personal communication. 127. Barney BM, Petersen IA, Dowdy SC, et al. Intraoperative electron beam radiotherapy (IOERT) in the management of locally advanced or recurrent cervical cancer. Radiat Oncol. 2013;8(1):80. PMCID: 3641982. 128. Martinez-Monge R, Jurado M, Aristu JJ, et al. Intraoperative electron beam radiotherapy during radical surgery for locally advanced and recurrent cervical cancer. Gynecol Oncol. 2001;82(3):538–543. 129. Liu Z, Gao Y, Soong YL, et al. Intraoperative electron beam radiotherapy for primary treatment of stage IIB cervical cancer: a retrospective study. J Int Med Res. 2012;40(6):2346–2354. 130. Giorda G, Boz G, Gadducci A, et al. Multimodality approach in extra cervical locally advanced cervical cancer: chemoradiation, surgery and intra-operative radiation therapy. A phase II trial. Eur J Surg Oncol. 2011;37(5):442–447. 131. Tran PT, Su Z, Hara W, et al. Long-term survivors using intraoperative radiotherapy for recurrent gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2007;69(2):504–511. 132. Stelzer KJ, Koh WJ, Greer BE, et al. The use of intraoperative radiation therapy in radical salvage for recurrent cervical cancer: outcome and toxicity. Am J Obstet Gynecol. 1995;172(6):1881–1886. 133. Mahe MA, Gerard JP, Dubois JB, et al. Intraoperative radiation therapy in recurrent carcinoma of the uterine cervix: report of the French intraoperative group on 70 patients. Int J Radiat Oncol Biol Phys. 1996;34(1):21–26. 134. Dowdy SC, Mariani A, Cliby WA, et al. Radical pelvic resection and intraoperative radiation therapy for recurrent endometrial cancer: technique and analysis of outcomes. Gynecol Oncol. 2006;101(2):280–286. 135. Krengli M, Pisani C, Deantonio L, et al. Intraoperative radiotherapy in gynaecological and genito-urinary malignancies: focus on endometrial, cervical, renal, bladder and prostate cancers. Radiat Oncol. 2017; 12:18. 136. Barney BM, Petersen IA, Dowdy SC, et al. Long-term outcomes with intraoperative radiotherapy as a component of treatment for locally advanced or recurrent uterine sarcoma. Int J Radiat Oncol Biol Phys. 2012;83(1):191–197. 137. Gao Y, Liu Z, Chen X, et al. Intraoperative radiotherapy electron boost in advanced and recurrent epithelial ovarian carcinoma: a retrospective study. BMC Cancer. 2011;11:439. PMCID: 3198723. 138. Yap OW, Kapp DS, Teng NN, et al. Intraoperative radiation therapy in recurrent ovarian cancer. Int J Radiat Oncol Biol Phys. 2005;63(4):1114–1121. 139. Barney BM, Petersen IA, Dowdy SC, et al. Intraoperative electron beam radiotherapy (IOERT) in the management of recurrent ovarian malignancies. Int J Gynecol Cancer. 2011;21(7):1225–1231. 140. Willett CG, Shellito PC, Tepper JE, et al. Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma. J Clin Oncol. 1991;9(5):843–849. 141. Holman F, Haddock M, Gunderson L, et al. Results of intraoperative electron beam radiotherapy containing multimodality treatment for locally unresectable T4 rectal cancer: a pooled analysis of the Mayo Clinic Rochester and Catharina Hospital Eindhoven. J Gastrointest Oncol. 2016;7(6):903–916. 142. Sole C, Calvo F, Serrano J, et al. Post-chemoradiation intraoperative electron-beam radiation therapy boost in resected locally advanced rectal cancer: Long-term results focused on topographic pattern of locoregional relapse. Radiother Oncol. 2014;112(1):52–58. 143. Suzuki K, Gunderson LL, Devine RM, et al. Intraoperative irradiation after palliative surgery for locally recurrent rectal cancer. Cancer. 1995;75(4):939–952. 144. Willett CG, Shellito PC, Tepper JE, et al. Intraoperative electron beam radiation therapy for recurrent locally advanced rectal or rectosigmoid carcinoma. Cancer. 1991;67(6):1504–1508. 145. Dresen R, Goesns M, Martijm H, et al. Radical resection after IOERT containing multimodality treatment is an important determinant for

outcomes in patients treated for locally recurrent rectal cancer. ISIORT Rev Cancer. 2008;22:45–46. 146. Wallace HJ 3rd, Willett CG, Shellito PC, et al. Intraoperative radiation therapy for locally advanced recurrent rectal or rectosigmoid cancer. J Surg Oncol. 1995;60(2):122–127. 147. Abuchaibe O, Calvo FA, Azinovic I, et al. Intraoperative radiotherapy in locally advanced recurrent colorectal cancer. Int J Radiat Oncol Biol Phys. 1993;26(5):859–867. 148. Calvo FA, Sole CV, Alvarez de Sierra P, et al. Prognostic impact of external beam radiation therapy in patients treated with and without extended surgery and intraoperative electrons for locally recurrent rectal cancer: 16-year experience in a single institution. Int J Radiat Oncol Biol Phys. 2013;86(5):892–900. 149. Haddock MG, Gunderson LL, Nelson H, et al. Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys. 2001;49(5):1267–1274. 150. Holman FA, Bosman SJ, Haddock MG, et al. Results of a pooled analysis of IOERT containing multimodality treatment for locally recurrent rectal cancer: results of 565 patients of two major treatment centres. Eur J Surg Oncol. 2017;43:107–117. 151. Mirnezami R, Chang GJ, Das P, et al. Intraoperative radiotherapy in colorectal cancer: systematic review and meta-analysis of techniques, long-term outcomes, and complications. Surg Oncol. 2013;22(1):22–35. 152. Hilal L, Al Feghali KA, Ramia P, et al. Intraoperative radiation therapy: a promising treatment modality in head and neck cancer. Front Oncol. 2017;7:148. 153. Paly JJ, Hallemeier CL, Biggs PJ, et al. Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma. Int J Radiat Oncol Biol Phys. 2014;88(3):618–623. 154. Sole CV, Calvo FA, Polo A, et al. Intraoperative electron-beam radiation therapy for pediatric Ewing sarcomas and rhabdomyosarcomas: long-term outcomes. Int J Radiat Oncol Biol Phys. 2015;92(5):1069–1076. 155. Calvo FA, Sole CV, Martinez-Monge R, et al. Intraoperative EBRT and resection for renal cell carcinoma: Twenty-year outcomes. Strahlenther Onkol. 2013;189(2):129–136. 156. Paly J, Hallemeier C, Biggs P, et al. Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma. Int J Radiat Oncol Biol Phys. 2014;88(3):618–623. 157. Krengli M, Terrone C, Jereczek-Fossa BA, et al. May intra-operative radiotherapy have a role in the treatment of prostate cancer? Crit Rev Oncol Hematol. 2012;83(1):123–129. 158. Call J, Stafford S, Petersen IA, et al. Use of intraoperative radiotherapy for upper-extremity soft-tissue sarcomas: analysis of disease outcomes and toxicity. Am J Clin Oncol. 2014;37(1):81–85. 159. Rich BS, McEvoy MP, LaQuaglia MP, et al. Local control, survival, and operative morbidity and mortality after re-resection, and intraoperative radiation therapy for recurrent or persistent primary high-risk neuroblastoma. J Pediatr Surg. 2011;46(1):97–102. 160. Paunesku T, Woloschak G. Future directions of intraoperative radiation therapy: a brief review. Front Oncol. 2017;7:300. 161. Meurk ML, Goer DA, Spalek G, et al. The Mobetron: a new concept for IORT. Front Radiat Ther Oncol. 1997;31:65–70. 162. Pascau J, Santos Miranda JA, Calvo FA, et al. An innovative tool for intraoperative electron beam radiotherapy simulation and planning: description and initial evaluation by radiation oncologists. Int J Radiat Oncol Biol Phys. 2012;83(2):e287–e295. 163. Calvo FA, Sole CV, Gonzalez ME, et al. Research opportunities in intraoperative radiation therapy: the next decade 2013-2023. Clin Transl Oncol. 2013;15(9):683–690. 164. Merrick HW 3rd, Gunderson LL, Calvo FA. Future directions in intraoperative radiation therapy. Surg Oncol Clin N Am. 2003;12(4):1099–1105. 165. Zerbi A, Fossati V, Parolini D, et al. Intraoperative radiation therapy adjuvant to resection in the treatment of pancreatic cancer. Cancer. 1994;73(12):2930–2935.

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CHAPTER 22 166. Alfieri S, Morganti AG, Di Giorgio A, et al. Improved survival and local control after intraoperative radiation therapy and postoperative radiotherapy: a multivariate analysis of 46 patients undergoing surgery for pancreatic head cancer. Arch Surg. 2001;136(3):343–347. 167. Bachireddy P, Tseng D, Horoschak M, et al. Orthovoltage intraoperative radiation therapy for pancreatic adenocarcinoma. Radiat Oncol. 2010;5:105. PMCID: 2987939.

Intraoperative Irradiation

387.e5

168. Calvo FA, Sole CV, Atahualpa F, et al. Chemoradiation for resected pancreatic adenocarcinoma with or without intraoperative radiation therapy boost: Long-term outcomes. Pancreatology. 2013;13(6):576–582. 169. Tepper JE, Noyes D, Krall JM, et al. Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1991;21(5):1145–1149.

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23 Total Body Irradiation Christopher Andrew Barker, Jeffrey Y. C. Wong, and Joachim Yahalom

Total body irradiation (TBI) is a radiotherapy technique that has been applied to treat various benign and malignant diseases over the past century. The technique has evolved in parallel with an increase in the knowledge of the biologic response to ionizing radiation and improvements in radiation dosimetry and treatment delivery. TBI remains an important component of hematopoietic stem cell transplant (HSCT), with the goal of eradicating residual malignant cells or modulating the immune system of the transplant recipient. In the context of HSCT, TBI is advantageous because biologic effects can be exerted uniformly, without the sparing of “sanctuary” sites such as the nervous system or tests or interference from metabolic or resistance processes.

HISTORY OF TOTAL BODY IRRADIATION Only a decade after Roentgen described the “x ray,” German biophysical engineer Friedrich J. Dessauer1,2 first described a “new technique of radiotherapy” that involved homogenous irradiation of the entire body. In his initial report describing the technique in 1905, he proposed irradiating a supine patient using three simultaneously active, lowvoltage roentgen-ray sources (Fig. 23.1). In 1907, Aladár Elfer,3 a medical professor in Hungary, reported his experience using a TBI technique that spared the head in three patients with leukemia. Although there is a paucity of data regarding the early use of the technique, some have speculated that untoward hematologic toxicity probably limited its application.4 Early success using TBI to treat hematopoietic and lymphoid malignant tumors in Europe (there named the Teschendorf method) prompted the development of the technique in the United States.5–7 Arthur C. Heublein, in collaboration with Gioacchino Failla, is credited with the development of the first TBI unit in North America, located at Memorial Hospital in New York City. In the United States, the technique became known as Heublein therapy.8 A specially constructed treatment ward was designed to treat four patients at extended distance (5 to 7 m) simultaneously at an exposure rate of 0.7 roentgen (R)/hour, for about 20 hours/day, typically over 1 to 2 weeks, using a 185-kV x-ray tube at 3 mA, with a 2-mm copper filter. The goal was to deliver 25% of the erythema dose (750 R). In Heublein’s initial report, no hematopoietic toxicity was noted with this treatment schedule. Seven of 12 patients (58%) with advanced lymphomas and leukemias and 2 of 8 patients (25%) with metastatic breast, melanoma, and kidney cancers were noted to demonstrate some improvement after treatment.9,10 A later report of the experience with 270 patients with cancer from Memorial Hospital treated with TBI between 1931 and 1940 confirmed that the technique was more successful in patients with hematopoietic and lymphoid cancers compared with

those with carcinomas or sarcomas, for whom it was ineffective. The authors emphasized that the technique was safe if doses were prescribed cautiously. They did not recommend exposures greater than 300 R and noted hematopoietic and gastrointestinal toxicity with exposures as low as 50 to 100 R.8 In the early 1940s, World War II prompted an initiative to develop nuclear weapons, known as the Manhattan Project. Part of this endeavor sponsored research into the human biologic response to ionizing radiation, including TBI. The military’s interest in TBI was primarily to help understand human tolerance for radiation exposure during occupational duties and warfare and to develop radiation biodosimetric assays. Several research studies coordinated through the Manhattan Project were initiated in patients with advanced cancers,11–13 as well as patients with benign diseases.13 For example, studies of dose escalation, radiation biologic dosimetry, and cognitive and psychomotor function were carried out at the M. D. Anderson Hospital for Cancer Research.14 A detailed report of 30 patients treated at the maximum exposure level (200 R) in the initial study concluded that side effects primarily consisted of nausea, vomiting, and myelosuppression, and that intervention was necessary in 10% of patients treated with this dose of TBI.15 At Baylor University College of Medicine, studies using 25 R to 250 R of TBI with 250 kV to 2 MV photons were performed to find a biologic dosimeter, as well as to study acute effects of radiotherapy.16 The military conducted similar studies at the Naval Hospital in Bethesda, Maryland, and reported palliation of patients with radiosensitive diseases treated with fractionated TBI.17 The most recent research study of TBI sponsored by the U.S. Department of Defense was conducted at the University of Cincinnati. It focused on identifying biochemical markers in the urine that predicted response to TBI. Later, studies of the neuropsychiatric effects of TBI were initiated. Ultimately, only results regarding the palliation of advanced cancers were reported.18 Patients with advanced metastatic radioresistant malignant tumors, for whom chemotherapy was unavailable, were often treated with TBI in the absence of any clear anticipated benefit. Patients treated with TBI in this manner were included in research studies, often without consenting to participate. The ethics of this practice was called into question by a report written in 1995 by the U.S. Department of Energy’s Advisory Committee on Human Radiation Experiments,19 which may have contributed to the public’s general uneasiness regarding radiation.20 Not only used in malignant diseases, TBI was also considered the critical immunomodulator in the first successful solid organ transplant. In 1959, a kidney was successfully transplanted between dizygotic twins after TBI at exposures of up to 450 R (given to the recipient).21 Around the same time in France, successful kidney transplants after TBI were

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CHAPTER 23 being reported.22,23 Of the first seven patients who underwent kidney transplant following TBI or pharmacologic immunomodulation worldwide between 1959 and 1962, the two who did not experience kidney failure were treated with TBI alone (without chemical immunosuppression) before transplant, and each survived for more than 20 years after transplant.21–23 However, successful preclinical studies with pharmacologic therapy prompted the use of chemical immunosuppressants (corticosteroids, 6-mercaptopurine, and azathioprine) for solid organ transplantation after 1963.24 With an increased understanding of the human response to TBI and a rapidly growing body of preclinical in vivo studies of TBI, therapeutic protocols were developed to maximize benefit in patients with malignant diseases. In 1957, Nobel laureate E. Donnall Thomas25,26 first reported the use of bone marrow infusion in humans following whole body irradiation or chemotherapy; less than 1 year later he published his experience in using TBI with exposures up to 600 R followed by bone marrow transplantation. In the series of the first five patients with leukemia treated with TBI, who then received

Fig. 23.1 Diagram demonstrating the total body irradiation technique proposed by Dessauer in 1905. (Reprinted from Wetterer J, ed. Handbuch der Röntgentherapie nebst Anhang. In: Die Radium Therapie, Leipzig: Otto Nemnich; 1908.)

Proportion of HSCTs involving TBI (%)

90

AML

ALL

CML

CLL

Total Body Irradiation

intravenous infusion of normal donor marrow, Thomas et al.26 noted the difficulty of acute myelosuppression and resultant hemorrhage and infection during the period leading up to engraftment. The report also commented that low dose rates (delivery over 2 to 3 days) appeared preferable to higher dose rates, for metabolic and immunologic reasons. In addition, patients receiving 200 R to 300 R fared better than those receiving 400 R to 600 R. The problem of delivering an adequately homogenous dose was raised, and suggestions about using higher-energy photons were proposed. Thomas et al.27 later reported on syngeneic bone marrow transplantation in two children after 850 R to 1140 R was delivered in a single fraction over 22 to 25 hours, using cobalt-60 (60Co) sources. The authors concluded that 1000 R of TBI did not produce “troublesome” acute radiation sickness; it did produce remission of leukemia, but did not cure the disease. The first report of successful cure of a patient with leukemia with allogeneic transplantation after TBI was reported in 1969. The technique involved opposed 60Co sources, which operated at 5.8 R/ minute, to a total exposure of 1620 R, calculated to be 954 rad at midline. With appropriate supportive care, no major acute radiation sickness was noted, but the patient died of overwhelming cytomegalovirus infection, without evidence of leukemia.28 Over the next several years, techniques of combining chemotherapy and TBI were developed and refined, with promising results.29,30 Success in the treatment of advanced leukemias and severe aplastic anemia was achieved. Departure from the use of TBI alone was primarily fostered by the development of more effective cytotoxic chemotherapeutics and immunologic therapies, which when combined with TBI, yielded fewer leukemic recurrences.29 Although the use of TBI without HSCT has largely been abandoned, primarily for fear of inducing secondary malignant tumors and limiting later therapeutic options, some question the validity of this fear and still contend that low dose TBI (1.5 Gy to 2 Gy in 10 to 20 fractions over several weeks) is a viable option for initial therapy in advanced indolent lymphomas.31 Fig. 23.2 demonstrates how the use of TBI during HSCT has changed over a recent 15-year period.32

Other leukemia

MDS

Overall

80 70 60 50 40 30 20 10 0

389

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Year of HSCT Fig. 23.2 Temporal trends in the five diseases most frequently involving total body irradiation (TBI) as part of allogeneic HSCT, and overall. ALL, Acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; HSCT, hematopoetic stem cell transplant; MDS, myelodysplastic syndrome. (Data from Hong S, Barker CA, Klein JP, et al. Trends in utilization of total body irradiation (TBI) prior to hematopoietic cell transplantation (HCT), worldwide. Biol Blood Marrow Transplant. 2012;18(2 suppl 2):S336–S337.)

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390

SECTION II

Techniques and Modalities

HEMATOPOIETIC STEM CELL TRANSPLANT Hematopoietic stem cell transplant has evolved into a highly complex clinical discipline, firmly rooted in immune system and cancer biology, the details of which are beyond the scope of this chapter. When HSCT was initially performed bone marrow was extracted from the donor and infused intravenously into the recipient. Later, peripheral blood stem cells, instead of bone marrow, were collected from the donor as an alternative to bone marrow grafting. For this reason, bone marrow transplants are now more appropriately termed hematopoietic stem cell transplants because the critical component of the graft is the hematopoietic stem cell (HSC), independent of the source. The peripheral blood stem cells are often “mobilized” from the donor using hematopoietic growth-stimulating factors and are removed from the donor by apheresis. In addition, recent success using HSCs derived from human umbilical cord blood has been described. Depending on the source of HSCs, various postcollection processing measures (e.g., cell selection and depletion) may be undertaken to optimize the outcome. When transplant occurs between different individuals, the hematopoietic graft is said to be an allogeneic graft. This is in contradistinction to reinfusion of native HSCs back into the donor in an autologous transplant, more appropriately termed an autoplant, because nothing is being transferred between different individuals.33 A rare but alternative situation is when an organ from a genetically identical twin of a patient is transplanted (syngeneic transplant). Of these three methods of HSCT, autologous and syngeneic transplantations are generally associated with less risk because issues related to immunocompatibility are minimized. Allogeneic transplantations require the “matching” of donor and recipient and are typically carried out through identification of human leukocyte antigen (HLA) compatibility. The donor may be related to the recipient or may be identified through registries of volunteers, such as the National Marrow Donor Program. Before undergoing HSCT, most patients will require intensive antineoplastic or immunomodulatory therapy, often referred to as conditioning, in preparation for HSCT. Conditioning can involve cytotoxic chemotherapy, immunomodulators, antibody therapy, or radiation therapy. The nature of the conditioning regimen can be referred to as of high or reduced intensity or as myeloablative, submyeloablative, or nonmyeloablative, to carry out conventional or mini-(ature) transplants.33 Although agreed-on formal definitions of these regimens do not exist,34 the goal of high-intensity/myeloablative/conventional transplant is to eliminate completely the recipient’s native HSC compartment, which necessitates HSCT (autologous or allogeneic) for survival. High-intensity, myeloablative, and conventional transplants may or may not involve TBI to high doses (>5 Gy in a single fraction, >8 Gy in multiple fractions). Reduced-intensity, nonmyeloablative, minitransplant conditioning regimens are often used for older patients or for those with medical problems, for whom a high-intensity, myeloablative, and conventional transplant would cause excessive morbidity or mortality and may or may not involve TBI to lower doses. During and immediately after conditioning, the transplant recipient is at significant risk for infections and other hematologic complications. For this reason, the supportive care of HSCT recipients is complex and should only be undertaken in specialized facilities. Nonetheless, some groups have developed reducedintensity and myeloablative HSCT regimens, including TBI, that have been safely undertaken on an outpatient basis.35,36 After undergoing conditioning and HSCT, the major challenges are related to engraftment, the permanent reconstitution of the recipient’s hematopoietic system, and prevention of graft rejection and associated postengraftment complications. The former process can be facilitated through the use of hematopoietic growth-stimulating factors, and the latter can be mitigated with chemical and biologic immunomodulators.

Once the graft has successfully taken, the recipient is at risk of developing graft-versus-host disease (GVHD), in which engrafted HSCs recognize the host’s native, non-HSC tissues as foreign and attack them. Specific organs at risk are the skin, gastrointestinal tract, and liver. The risk of GVHD is only present in patients undergoing allogeneic HSCT. Moreover, it has been recognized that part of the beneficial effect of transplant is the graft-versus-tumor (GVT) effect, a fundamental component of the therapeutic effect of HSCT, which can occur in autologous or allogeneic transplants. According to data summarized by the Worldwide Network for Blood and Marrow Transplantation in 2006, the diseases most commonly treated with HSCT are lymphoproliferative disorders (54.5%, most often multiple myeloma [MM]; non-Hodgkin lymphoma [NHL], and Hodgkin lymphoma [HL]); leukemias (33.8%, most often acute myelogenous leukemia [AML]; acute lymphocytic leukemia [ALL]; myelodysplastic syndrome [MDS]; chronic myeloid leukemia [CML] and chronic lymphocytic leukemia [CLL]); solid tumors (5.8%); and nonmalignant disorders (5.1%).37 The 2014 National Comprehensive Cancer Network (NCCN) guidelines for therapy indicate that allogeneic or autologous HSCT may be a treatment option for testicular cancer, AML, MM, MDS, CML, HL, and NHL, depending on the clinical situation. HSCT with or without TBI-based conditioning has also been described in the treatment of solid tumors, including breast cancer, germ cell tumors, renal cell carcinoma, melanoma, neuroblastoma, and other pediatric cancers. Detailed discussion of these diseases and their management is beyond the scope of this chapter, and the reader is referred to other chapters in this text and other reviews.38–41 The role of TBI in nonmalignant diseases will be discussed in subsequent sections of this chapter.

RADIOBIOLOGY Experimental radiobiologists have described much of what is known regarding the fundamental biologic effects of TBI, and clinicians have applied these principles to optimize the therapeutic benefit for patients. The essential rationale for TBI in the context of HSCT is to eradicate malignant or dysfunctional cells or modulate immune system function. Therefore, the critical radiobiologic in vitro data related to efficacy of treatment deal with normal and malignant hematopoietic cells. Preclinical studies have helped define some of the fundamental radiobiologic properties of the normal lymphocytes. The D0 (radiation dose that reduces survival to e−1 [0.37] on the exponential portion of the survival curve) (see Chapter 1) of normal lymphocytes has been reported to be 0.5 Gy to 1.4 Gy,42–45 depending on the in vitro or in vivo model used to calculate this parameter. This D0 suggests that normal lymphocyte cells are sensitive to ionizing radiation. A small shoulder on the radiation cell survival curve has been noted,46,47 suggesting little repair between fractions of radiation. Clinical data have revealed similar findings in patients undergoing hyperfractionated TBI, with lymphocyte survival demonstrating an effective D0 of 3.8 Gy, according to one study.48 Other radiobiologic phenomena have been ill defined in other normal hematopoietic cells. Radiobiologically relevant levels of hypoxia are unlikely in the hematopoietic compartment. Repopulation is not likely to influence hematopoietic cell survival, given the short duration of most TBI regimens (1 to 5 days), although given the variable life span of leukocytes (days to years), it may be of some relevance. Redistribution would appear to be of significance, given the time scale for TBI; however, this has been difficult to assess.49 The radiobiology of malignant hematopoietic cells has been described. The D0 of leukemic cells generally ranges from 0.8 Gy to 1.5 Gy; however, compared with normal hematopoietic cells, a wider range of radiosensitivities has been described.50,51 Many have cited the technical nuances and variations in assay technique for this great

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CHAPTER 23 range.49,52 Similar to normal hematopoietic cells, their malignant counterparts are thought to demonstrate little sublethal damage repair,53–57 although split-dose-rate and low-dose-rate experiments have demonstrated the capacity of leukemic cells to repair radiationinduced damage.58–64 Generally, leukemic cells are thought to have a cell survival curve with a minimal shoulder or no shoulder, although this varies across cell types and cell lines.47,61–63,65 For example, Cosset et al.52,66 summarized preclinical and clinical findings, concluding that AML demonstrates little repair, whereas CML does demonstrate repair; ALL, myeloma, and lymphomas have not been well studied, but appear to demonstrate a wide range of repair capacity. Similar to that in normal hematopoietic cells, reoxygenation is unlikely to be radiobiologically relevant to malignant hematopoietic cells during TBI. Redistribution and repopulation, however, may be relevant but have not been systematically studied. Recent molecular studies suggest a significant effect of TBI on peripheral blood mononuclear cell immunerelated gene expression in patients.67 In vivo preclinical research laid the foundation for the first successful HSCT in humans. Studies in rats,68 dogs,69 and nonhuman primates70 demonstrated that reconstitution of the hematopoietic system was possible after TBI with supralethal doses of radiation. Later work in animals revealed that delivering TBI in several fractions required a higher total dose relative to the biologically isoeffective dose given in a single fraction.71,72 Another model demonstrated no significant difference in the effect of a low-dose-rate (0.04 Gy/minute), single-fraction of TBI compared with a hyperfractionated course of TBI given three times a day to the same total dose.73 Although the hematopoietic system is the target of TBI, normal tissues effectively limit the dose that can be safely delivered. The sparing of normal tissues with fractionated TBI was proposed by Peters et al.53,54 and subsequently was supported by preclinical data in mice74,75 and dogs76 that showed that less lung injury occurred with fractionated TBI regimens.

TABLE 23.1

Total Body Irradiation

391

IMMEDIATE TOXICITY AND MANAGEMENT IN TOTAL BODY IRRADIATION Although a good deal of what has been learned about the acute in vivo biologic effects of TBI has been derived from laboratory-based animal studies, whole-body irradiation also has been studied in people exposed during accidental or wartime nuclear events.77,78 These large-scale studies are valuable because they deal with apparently normal subjects; however, the retrospective nature limits the quality of the data. The reader is referred to several excellent reviews of acute and fatal radiation syndromes (gastrointestinal, hematopoietic, and cerebrovascular syndromes) that can be caused by TBI in an uncontrolled setting.79–81 Acute side effects of therapeutic TBI can be difficult to distinguish from other HSCT-related morbidities. However, Chaillet et al.82 conducted an informative prospective clinical study of the symptoms and signs that occur in patients after TBI, before the initiation of any other HSCT-related therapy. Thirty-one patients, 4.5 to 55 years of age, were treated using parallel-opposed anteroposterior 18-MV photons from a linear accelerator. Shielding was used to limit the lung dose to 8 Gy. A total dose of 10 Gy was given as a “single dose” as six discrete fractions of 1.6 Gy each given over 15 minutes, with a 30-minute break between fractions, for a mean dose rate of 0.04 Gy/minute and an instantaneous dose rate of 0.11 Gy/minute to 0.12 Gy/minute. Symptoms and signs were assessed regularly during the 4-hour TBI and for 20 hours after the completion of TBI. Antiemetics, but no chemotherapy or steroids, were given before the start of TBI. Table 23.1 displays the symptoms and signs experienced by patients during the 4 hours of TBI and within 24 hours of starting TBI. Fever was a common finding, and a maximum of 40.8° C (105.4° F) was noted in one patient. Tachycardia frequently paralleled febrile episodes; a maximum rate of 130 beats/minute was noted. Drowsiness was noted only in patients who received sedating antiemetics. Parotid gland pain was common, and bilateral parotid

Signs and Symptoms in Patients After Single-Dose or Fractionated TBI SINGLE-FRACTION TBI Percentage of Patients Experiencing During TBI

Percentage of Patients Experiencing After TBI

Fractionated TBI Percentage of Patients Experiencing During 3 Days of TBI

Nausea

90

45

43

Vomiting

80

23

23

Parotid gland pain

26

74

6

Xerostomia

61

58

30

Headache

42

33

15

Fatigue

N/R

N/R

36

Ocular dryness

None

16

N/R

Symptom/Sign

Esophagitis

N/R

N/R

4

Loss of appetite

N/R

N/R

16

Indisposition

N/R

N/R

25

Erythema

None

None

41

Pruritus

None

None

4

Diarrhea

None

None

4

No symptoms

N/R

N/R

17

Fever (>38° C)

42

97

N/R

Hypertension

42

None

N/R

N/R, Data not reported; TBI, total body irradiation. Data from Chaillet MP, Cosset JM, Socie G, et al. Prospective study of the clinical symptoms of therapeutic whole-body irradiation. Health Phys 1993;64(4):370–374, Buchali A, Feyer P, Groll J, et al. Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation. Radiother Oncol. 2000;54(2):157–162.

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Techniques and Modalities

swelling was noted in 29% of patients. Marked lacrimation was noted in 6% of patients, whereas 16% of patients experienced ocular dryness. Two patients experienced mild conjunctival edema. Hypertension was noted only during TBI. The results of a similar study conducted by Buchali et al.83 of patients who were treated with a fractionated course of TBI delivered mostly to a total dose of 12 Gy using 2 Gy per fraction, twice daily, 8 hours apart, with lung doses limited to 10 Gy, are also summarized in Table 23.1. A prospective clinical study showed that fractionation of TBI can reduce acute nausea, vomiting, mucositis, diarrhea, and parotitis, although the differences were not statistically significant. Late cutaneous eruptions were more common in patients undergoing fractionated TBI, although the numbers were not statistically significant. The same study, which randomized patients to either high- or low-dose rate TBI, revealed no differences in the acute toxicities mentioned when comparing dose rate.84 Another randomized controlled trial (RCT) reported that fractionating TBI revealed “no apparent difference in acute toxicity” compared with single-fraction TBI, with both regimens being “welltolerated.”85 Older studies cite nausea and vomiting as frequent side effects of TBI. These symptoms have been substantially lessened with the advent of more effective antiemetics, such as the 5-hydroxytryptamine (serotonin) receptor-3 (5-HT3) antagonists. Several small but high-quality controlled clinical studies support the prophylactic use of 5-HT3 antagonists to reduce nausea and vomiting during TBI86–90; they are summarized in eTable 23.1. The use of corticosteroids in conjunction with 5-HT3 antagonists is supported by a trial listed in eTable 23.1. However, given the toxicity associated with this approach, consensus regarding routine administration in conjunction with TBI is lacking.91–93 Of note, less nausea and vomiting have been noted in myeloablative conditioning regimens involving TBI compared with those that use chemotherapy alone, even with modern antiemetics.94 Oral mucositis is a side effect of TBI in up to 75% of patients undergoing myeloablative TBI, causing mouth pain and odynophagia and necessitating intensive supportive care such as total parenteral nutrition and opioid analgesics.95 In one study, intensive dental hygiene conferred a reduction in the rate of moderate and severe mucositis, although the authors thought the rate to be clinically insignificant.96 Topical oral agents, such as chlorhexidine digluconate and neutral calcium phosphate in conjunction with topical fluoride treatments, can decrease pain duration and severity of oral mucositis, as well as pain and need for opioid analgesics.97–99 Similarly, prophylactic oral sucralfate and clarithromycin have reduced moderate and severe oral mucositis rates.100,101 One study showed that when given prophylactically, amifostine limited the duration of mucositis, with an associated decrease in the rate of moderate and severe infections, with no effect on HSCT outcome.102 Low-level laser (650 nm) therapy has been reported to reduce the incidence of oral mucositis in an RCT.103 In one study, researchers noted that short-term intravenous recombinant granulocyte-macrophage colony–stimulating factor decreased rates of moderate to severe mucositis,104 but in another study, no effect was found when this agent was delivered topically.105 Recently, Spielberger et al.106 reported the results of a trial of the recombinant human keratinocyte growth factor palifermin, given before and after conditioning with 12 Gy of fractionated TBI. Palifermin reduced the rate and duration of moderate and severe mucositis by 35% and 3 days, respectively, and decreased mouth and throat pain, as reflected in reduced morphine usage and decreased need for total parenteral nutrition (by 24%). This study dealt only with patients undergoing autologous HSCT; however, in the setting of TBI for allogeneic HSCT, palifermin may also confer a protective effect on the mucosa, although studies suggesting this have been small and inadequately designed.107

Skin erythema may also be noted toward the end of a course of TBI; desquamation is rare. Hyperpigmentation may be noted in the long term. Alopecia typically occurs 7 to 14 days after TBI, and hair typically returns 3 to 6 months after treatment.108 Changes in the color or texture of regrown hair have been noted. Of note, myeloablative conditioning regimens using chemotherapy alone have produced a significantly higher incidence of permanent alopecia.109

LATER TOXICITY AND ITS MANAGEMENT IN TOTAL BODY IRRADIATION Hematopoietic Toxicity As previously mentioned (see Radiobiology section), the hematopoietic system is particularly sensitive to TBI; lymphopenia is often seen with doses of 0.5 Gy and can be seen with doses of 0.3 Gy. Lymphopenia is typically followed by neutropenia, thrombocytopenia, and finally anemia. Soon after a TBI dose of 4 Gy to 6 Gy has been given, lymphocytosis can be seen, but it typically is followed by neutropenia within 1 week. Three to 4 weeks after TBI, neutrophils fall to their minimum110 (Fig. 23.3). Regeneration of the HSC compartment depends on the total dose used because higher doses cause more rapid myelosuppression of greater duration. Administration of hematopoietic growth factors after TBI has the theoretical potential to alter hematopoietic system reconstitution, although reports in the setting of allogeneic HSCT have demonstrated an increased risk of GVHD and compromised survival111 and, therefore, routine use is controversial.112,113 Of note, hematopoietic growth factors have only been used in the period following TBI, given the concerns raised by a trial in lung cancer, where growth factors increased pulmonary toxicity and thrombocytopenia when given concurrently with chemoradiation therapy.114

Oral Toxicity As previously noted, the salivary glands frequently are affected by TBI. Although acute parotitis is typically self-limited and can be managed with anti-inflammatory medicines, long-term salivary gland dysfunction can result in xerostomia, which may lead to dental caries. In a study of children who underwent allogeneic HSCT, the risk of developing impaired salivary function was 22% in those who received TBI as part of conditioning versus 1% in those who did not.115 Salivary flow can improve up to 1 year after the completion of TBI.116 Fractionated TBI was shown to reduce salivary dysfunction by 54% in one study.117

Lymphocytes and neutrophils 14 10

Platelets Hemoglobin

16 12 6 8 4 2 0

300

Neutrophils

200

Lymphocytes

100

Platelets

SECTION II

Hemoglobin (g)

392

60 30 40 50 Days Fig. 23.3 Representative hematologic response to total body irradiation, given as a single fraction of 200 cGy on day 0. (Data from Andrews GA. Radiation accidents and their management. Radiat Res Suppl. 1967;7:390–397, fig. 1, with permission from Radiation Research Society.) 0

10

20

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CHAPTER 23

eTABLE 23.1

Undergoing TBI

392.e1

Randomized Controlled Trials of Prophylactic Antiemetics in Patients

No. Total TBI Dose/ Patients No. Fractions

Author

Total Body Irradiation

Experimental Antiemetic

Control of Antiemetic

Outcome

20

10.5 Gy/1

8 mg oral ondansetron at Placebo + standard start of TBI + standard (metoclopramide, (metoclopramide, dexamethasone, lorazepam) dexamethasone, lorazepam)

Significantly fewer emetic events with ondansetron (60% vs. 10%, p < 0.03) during TBI

Spitzer et al.87

20

13.2 Gy/11 (in 4 days)

8 mg oral ondansetron 1.5 h before TBI tid

Placebo

Significantly more patients had two or fewer episodes of emesis with ondansetron (60% vs. 10%, p < 0.03): significantly longer time to first emetic episode (p < 0.005) and significantly fewer episodes of emesis during the first 24 hours and over the entire study period (p < 0.05) with ondansetron

Prentice et al.88

30

7.5 Gy/1

3 mg IV granisetron 1 h before TBI

Metoclopramide, dexamethasone, and lorazepam 1 h before TBI

Significantly higher rates of complete control of emesis within first 24 h with granisetron (53% vs. 13%, p = 0.02) and significantly longer duration of emesis control (p < 0.005) with granisetron

Okamoto et al.89

58

74% of patients received 40 μg/kg IV granisetron bid TBI: 6-12 Gy/1-6 30 min before TBI

Various

Significantly higher rates of complete control of emesis within the first 24 h with granisetron (92% vs. 44%, p < 0.01) and throughout the duration of HSCT (68% vs. 0%, p < 0.001) with granisetron in patients receiving TBI

Matsuoka et al.90

50

64% of patients received 4 mg IV dexamethasone + TBI: 12 Gy/4–6 40 μg/kg granisetron bid 30 min before treatment

40 μg/kg IV granisetron twice Significantly higher (100% vs. 63%; daily 30 min before treatment p = 0.02) rates of complete emesis control within the first 24 h with dexamethasone in patients receiving TBI; insomnia, headache, flushing, and hyperglycemia were more common in patients with corticosteroid

Tiley et al.

86

bid, Twice daily; IV, intravenous; TBI, total body irradiation; tid, three times daily.

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CHAPTER 23

Pulmonary Toxicity The major dose-limiting toxicity of TBI is pneumonopathy (restrictive or obstructive lung disease), which can manifest early as pneumonitis or later as pulmonary fibrosis. In the setting of HSCT, radiation pneumonopathy can be difficult to distinguish from other causes of lung pathology; moreover, lung damage is likely multifactorial, with the risk of acute lung complications estimated to be 30% to 60%, depending on factors such as infection, conditioning regimen, GVHD, age, and diagnosis.123 Likewise, late pneumonopathy occurs in 10% to 26% of patients and is associated with underlying lung dysfunction, type of conditioning regimen, acute and chronic GVHD and prophylaxis, donor and recipient age and immunocompatibility, stage of disease, and genetic predisposition.124 TBI is a risk factor for idiopathic pneumonia syndrome,125 as well as for diffuse alveolar hemorrhage.126 Although rates of pneumonopathy in patients receiving TBI vary widely (10% to 84%),127 some series have reported pneumonitis in up to 20% of patients undergoing HSCT who never received TBI.128 In the modern era, with appropriate TBI techniques, the risk of pneumonopathy in patients treated with TBI may not be increased at all.129 Nevertheless, the significance of the problem is clear, given that mortality related to interstitial pneumonitis in patients treated with TBI can be 60% to 80%.128,130,131 Several TBI-specific factors (e.g., total dose, fractionation, dose rate, and use of lung shielding) have been shown to have a significant bearing on the development of pulmonary complications. The total dose used during TBI has frequently been cited as a major factor influencing lung complications.127,132,133 In two prospective RCTs using 12 Gy versus 15.75 Gy, higher rates of mortality were noted within the first 6 months in patients treated with 15.75 Gy, although pulmonary complications were not specifically cited as the cause of excess deaths.134–137 In a retrospective dosimetric study, a mean lung dose of more than 9.4 Gy was found to be an independent predictor for lethal pulmonary complications in patients receiving TBI to a total dose of 10 Gy in three daily fractions, at 0.055 Gy/minute using parallel opposed lateral fields.138 Two RCTs have demonstrated that fractionated TBI can reduce pneumonitis compared with single-fraction TBI, although only one study showed differences that were statistically significant.85,139,140 A retrospective study found no difference in pneumonitis rates when comparing a single fraction of 6 Gy and three daily fractions of 3.33 Gy, suggesting that total doses of less than 10 Gy may not require fractionation to prevent toxicity, although no randomized data support this.141 The necessity of hyperfractionation to prevent lung toxicity is unclear: A comparison of two prospective single-arm trials at the same institution revealed that conventional fractionation given with anteroposterior fields and lung blocks to a total dose of 12 Gy in daily 3-Gy fractions may not differ from hyperfractionated TBI given twice daily with 1.7 Gy per fraction to a total dose of 10.2 Gy over 3 days, using parallel opposed lateral fields and no blocks.142 An RCT suggested that the angiotensinconverting enzyme inhibitor, captopril, may mitigate pulmonary toxicity associated with TBI.143 Sampath et al.144 reviewed 26 studies involving 1096 patients to create a dose-response model for predicting the risk of pneumonitis from TBI

393

1 Cy 120 ! 1 fx Single fx (no Cy) Cy ! Bu Cyc 120 ! 2 fx Cyc 120 ! 4 fx

0.9 0.8 Incidence of IP

Myeloablative conditioning regimens with and without TBI have been associated with abnormalities in tooth development in children.117–119 In one series, myeloablative conditioning regimens using chemotherapy alone were associated with significantly higher rates of tooth developmental abnormalities than those involving TBI, although rates of salivary gland dysfunction were highest among the patients treated with single-fraction TBI.120 Because of the increased risk of oral pathology associated with TBI, careful pretransplant evaluation by a dental specialist is recommended to minimize the risk of serious morbidity.121 Pilocarpine has been noted to help relieve symptoms of xerostomia in patients treated with TBI.122

Total Body Irradiation

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0

3

6 9 12 15 Dose (Gy) Fig. 23.4 Incidence of pneumonitis based on dose-response model accounting for total body irradiation (TBI) fractionation, as well as chemotherapy effects. Bu, Busulfan; Cy and Cyc, cyclophosphamide; fx, fraction(s). (Data from Sampath S, Schultheiss TE, Wong J. Dose response and factors related to interstitial pneumonitis after bone marrow transplant. Int J Radiat Oncol Biol Phys 2005;63(3):876–884, fig. 2, © 2005, Elsevier, with permission from Elsevier.)

while taking other factors into consideration. Although unable to estimate the risk of pneumonitis for hyperfractionated regimens, they were able to determine the effect of fractionation, cyclophosphamide, and busulfan on the risk of developing pneumonitis, in a dose-response model, as seen in Fig. 23.4. Pneumonitis rates did not differ significantly in a trial that randomized patients to high- or low-dose-rate TBI.84 However, an abundance of retrospective clinical data suggest that lowering the dose rate ( CR2

Bone, spleen, node, 12 Gy liver, brain

20

2 Gy bid

Cy 100 mg/kg VP16 60 mg/kg

Phase I

Allogeneic

AML CR1 or CR2

Bone, spleen, node, 12 Gy liver, brain

18, 20

2 Gy bid

Cy 50 mg/m2/d × 2

City of Hope375,386 00544466

Pilot

Allogeneic

Advanced disease, age > 50 yrs or comorbidities ineligible for standard myeloablative regimens

Bone, nodes, spleen, ALL testes, brain

12

1.5 Gy bid

Flu 25 mg/m2/d × 4 Mel 140 mg/m2

City of Hope 00800150

Phase I

Allogeneic

Advanced disease, age > 50 yrs or comorbidities ineligible for myeloablative regimens

Bone, nodes, spleen, ALL testes, brain

12

1.5 Gy bid

Flu 25 mg/m2/d × 4 Mel 140 mg/m2

City of Hope 02446964

Phase I

Allogeneic haploidentical

AML, ALL, MDS CR1 high risk, CR2, CR3, refractory

Bone, spleen nodes 12 Gy liver, spleen 16 Gy testes ALL 12 Gy brain ALL

12, 14, 16, 18 20

1.5-2 Gy bid

Flu 25 mg/m2/d × 5 Cy 14.5 mg/kg/d × 2 ptCy 50 mg/kg/d × 2

City of Hope 03490569

Phase I

Allogeneic matched

AML, ALL, MDS, age > 55 yrs or comorbidities ineligible for standard myeloablative regimens

bone, spleen nodes 12 Gy spleen 16 Gy testes ALL

12, 14, 16, 18 20

1.5–2 Gy bid

Flu 30 mg/m2/d × 3 Mel 100 mg/m2

City of Hope 03490569

Phase I

Allogeneic haploidentical

AML, ALL, MDS, age > 55 yrs or comorbidities ineligible for standard myeloablative regimens

Bone, spleen nodes 12 Gy spleen 16 Gy testes ALL

12, 14, 16, 18 20

1.5-2 Gy bid

Flu 30 mg/m2/d × 3 Mel 100 mg/m2 ptCy 50 mg/d × 2

U. Illinois, Chicago370 00988013

Phase I

allogeneic

Refractory or relapse AML, ALL, MDS, MM, CML

bone

3, 6, 9, 12

1.5 Gy bid

Flu 40 mg/m2/d × 4 BU 4800 μM*min

U. Illinois, Chicago 03121014

Phase II

Allogeneic

Poor risk, refractory or relapse AML, MDS

Bone

9

1.5 Gy bid

Flu 40 mg/m2/d × 4 BU 4800 μM*min

U. Chicago 02333162

Phase I

Allogeneic

Recurrent AML, ALL, MDS undergoing second HCT

TMI

NS

bid over 2-5 days

Flu, Mel

Case Comprehensive Cancer Center NCT02129582

Phase I

Allogeneic

AML, ALL, NHL, HL, MM, MDS, CLL, CML ineligible for full myeloablative regimen

TMI

NS

bid over 4 days

Flu, Bu

Disease Type

Targets

Allogeneic

AML relapsed or refractory with active disease Not eligible for standard HCT

Phase I

Allogeneic

City of Hope 02094794

Phase II

City of Hope 03467386

City of Hope 00540995

Chemotherapy

Continued

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404.e2

SECTION II

Techniques and Modalities

eTABLE 23.7 Select TMI and TMLI Trials in Patients With Acute Leukemia or Advanced Hematologic Malignanciesa—cont’d Institution NCT Trial No. U. Minnesota393 00686556

Trial Type Phase I

HCT Type Allogeneic

Disease Type ALL, AML CR2, CR3, Relapse, IF

Targets Bone

TMI Dose (Gy) 15, 18, 21, 24

Fraction and Schedule 3 Gy QD

Ohio State 02122081

Pilot

Allogeneic

AML, ALL, MDS, age > 50 yrs or comorbities unable to undergo TBI based regimens;

Bone, brain, testes

12

2 Gy bid

Cy

Beijing 307 Hospital 03048223

Phase I

Allogeneic

AML, ALL IF, relapse, > CR2

Bone

12–20

4 Gy QD

Cy 60 mg/kg/d × 2

Beijing 307 Hospital 03408210

Interventional

Allogeneic

AML, ALL in CR1 or CR2

Bone

12

4 Gy QD

Cy 60 mg/kg/d × 2

University Hospitals of Geneva 03262220

Pilot

Allogeneic

Hematologic malignancy CR1, CR2, or CR3 Age 40 to 80 yrs

TMI

12 (13.5 to active BM)

4 Gy QD with 4.5 Gy QD boost to active BM

Chemotherapy Flu 25 mg/m2/d × 3 Cy 60 mg/m2/d × 2

a

Listed at www.cliniclatrials.gov. ALL, acute lymphoblastic leukemia; AML, acute myeloma; bid, twice per day; BM, bone marrow; Bu, busulfan; CR1, first complete remission; CR2, second complete remission; CR3, third complete remission; Cy, cyclophosphamide; Flu, fludarabine; Gy, Gray; HCT, hematopoietic cell transplantation; HL, Hodgkin’s lymphoma; IF, induction failure; MDS, myelodysplastic syndrome; Mel, melphalan; MM, multiple myeloma; NHL, non-Hodgkin’s lymphoma; ptCy, posttransplant cy; QD, once per day; TBI, total body irradiation; TMI, total marrow irradiation; TMLI, total marrow and lymphoid irradiation;; VP-16, etoposide.

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CHAPTER 23 had detectable blasts in marrow (median 52%, range 5% to 98% involvement) and 27 patients had circulating blasts in the week prior to HCT conditioning. Fig. 23.11 displays an example of a dose color wash. eTable 23.8 shows organ doses as a percentage of the prescribed target dose. Median organ doses ranged from approximately 16% to 60% of the prescribed marrow dose, with lung at 44%, esophagus 33%, and oral cavity 28%. Dose-limiting toxicity was observed in only one patient at the 15 Gy dose level (grade 3 mucositis Bearman scale392) and no further dose-limiting toxicities were observed up to 20 Gy. All patients engrafted without delays. TRM rates were low at 3.9% at day 100 and 8.1% at one year. With a median follow-up of 24.6 months in surviving patients, the overall one-year survival was 55.5% and disease progression-free survival 40.0%. Dose escalation was stopped at 20 Gy because lung D80 doses approached that of standard 12 Gy TBI, which predicted that further dose escalation would result in pneumonitis risks greater than standard TBI. The authors concluded that the TMLI/CY/ etoposide conditioning regimen was feasible with acceptable toxicities at TMLI doses up to 20 Gy and with encouraging results in this very poor risk population. A Phase II trial at the 20 Gy dose level is currently ongoing with the primary endpoint of two-year progression-free survival. Recently reported results are similar to those of the Phase I study.393 Other groups have evaluated TMI and TMLI containing conditioning regimens. Patel et al.371 were the first to deliver TMI using a VMAT approach (1.5 Gy twice days −8 to −5) with fludarabine (40 mg/m2 days −8 to −5) and busulfan (4800 μM*minute days −4 to −1). They reported on 14 patients (11 with advanced acute leukemia) and established an MTD of 9 Gy. Dose to those organs at risk ranged from 31% to 85% of the prescribed dose. All patients engrafted without delays and no impairment of immune reconstitution was observed. No specific dose-limiting toxicity was defined, but both patients at the highest dose level (12 Gy) died at days 85 to 86 after HCT (pneumonia, gastrointestinal hemorrhage). With a median follow-up of 1126 days, TRM was 29%, RFS 43%, and OS 50%. A Phase II trial evaluating 9 Gy TMI with fludarabine and busulfan is currently ongoing. Hui et al.394 reported the results using larger fraction sizes of 3 Gy. This Phase I trial combined TMI (3 Gy daily; days −5 to −1) with fludarabine (25 mg/m2; days −9 to −7) and cyclophosphamide (60 mg/ m2; days −8 and −7). Twelve patients with acute leukemia were treated at TMI dose levels of 12, 15, and 18 Gy. All patients engrafted. Although no specific dose-limiting toxicity was identified, 3 of 6 patients at the 18-Gy dose level experienced treatment-related mortality, establishing the 15-Gy dose level as the MTD. A contributing factor may have been oral cavity, esophagus, stomach, peritoneum, and liver doses that were equal or higher than standard TBI doses at the 18-Gy dose level. Other groups are also evaluating larger fraction sizes of up to 4 Gy daily in ongoing trials (see eTable 23.7). In summary, the clinical experience to date demonstrates that TMIbased conditioning regimens are feasible, with acceptable toxicity and with encouraging results in patients with high risk advanced disease, high tumor burden, and those who are not candidates for standard HCT approaches. Pilot and Phase I trials have been completed and Phase II trials are currently ongoing at a few centers. Clinical trials are also beginning to evaluate TMI-based regimens in patients with better prognosis, such as those with AML in first and second remission, which may eventually lead to TMI-based regimens being the preferred option over current established conditioning regimens in select patients. An increasing number of centers in Europe, North America, and Asia have initiated similar trials, but the early experience to date remains unpublished (see eTable 23.7). The clinical experience to date also demonstrates that TMI dose escalation is feasible. The total doses achieved have varied depending on the regimen and may be dependent on factors such as fraction size,

Total Body Irradiation

405

fractionation schedule, the magnitude of dose reduction to critical organs, and the specific chemotherapy agents used. The sequencing of chemotherapy with the delivery of TMI may also be an important factor. Dose escalation to the highest planned dose level of 20 Gy was feasible when TMI was completed prior to cyclophosphamide and etoposide.375 Dose escalation appears to be limited to lower dose levels when chemotherapy is delivered prior to or on the same days as TMI.371,394 At City of Hope, a Phase I trial has been initiated to determine whether dose escalation is feasible if TMLI is delivered prior to fludarabine and melphalan compared with a previous trial in which fludarabine and TMI were administered on the same days. IMRT-based TBI. Conventional methods to deliver TBI, which have been largely unchanged for the last 40 years, involve opposed fields at extended distances using blocks to reduce dose to critical organs, such as lung. This can lead to large variations of dose throughout the body and increased doses to lung.395 Some centers have focused on using IMRT to deliver TBI. Step and shoot IMRT,396 helical tomographic IMRT, and VMAT-based IMRT have been used to deliver standard TBI dose distributions.289,397–399 Potential advantages include improved dose uniformity throughout the body and improved sparing of critical organs, such as lung and kidney, compared with conventional TBI methods. This approach also may be useful in patients who require TBI, but where previously irradiated sites need to be spared. Other centers have combined TBI at full dose or partial doses with TMI to select targets areas as a form of localized boost. Corvo et al.400 demonstrated the feasibility of adding a 2-Gy TMI boost to bone marrow and spleen after standard TBI 12 Gy (2 Gy twice daily) using a linear accelerator and cyclophosphamide in 15 patients with AML and ALL. With a median follow-up of 310 days, they reported a cumulative TRM rate of 20%, relapse rate of 13%, and disease-free survival rate of 67%. Jiang et al.401 recently reported results of combining cyclophosphamide and a helical tomographic IMRT technique to deliver standard TBI to 10 Gy with simultaneous integrated boost to 12 Gy to bone marrow and sites of central nervous system and extramedullary leukemia to 12 Gy in 14 patients with high risk or relapsed/refractory ALL. Long-term toxicities with TMI. Total marrow irradiation-based regimens have the potential to reduce long-term toxicities compared with TBI. Recently, long-term toxicity data were reported in 142 patients with multiple myeloma (n = 59) or acute leukemia (n = 83) who received TMI as part of the conditioning regimen from 2005 to 2016 who were entered in a prospective long-term follow-up trial.402 Follow-up visits, thyroid panel, eye examinations, pulmonary function studies, serum creatinine, serum urea nitrogen, glomerular filtration rate, and urine analysis were performed per protocol at 100 days, 6 months, 1 year, and annually up to 8 years. TMI doses were 10 Gy (n = 3), 12 Gy (n = 64), 13.5 Gy (n = 3), 14 Gy (n = 2), 15 Gy (n = 17), 16 Gy (n = 30), 17 Gy (i = 7), 18 Gy (n = 10), and 19 Gy (n = 6). A fractionation schedule of 1.5 to 2.0 Gy twice daily 4 to 5 days was used. Median age at time of transplant was 52 years (range, 9 to 70 years). Median follow-up (range) for all patients was 2 years (0 to 8) and for alive patients (n = 50) 5.5 years (0 to 8). Of the 134 patients with normal thyroid function prior to TMI, hypothyroidism requiring thyroid supplementation developed in 8 patients (6.0%). Cataracts developed in 11 patients (7.7%). No radiation-induced nephropathy was observed. One patient developed radiation pneumonitis that reversed with steroids. TMI dose was 18 Gy and lung D80, D50, and V6 were 6.7 Gy, 7.5 Gy, and 95%, respectively, in this patient. There was no correlation of toxicity with organ dose or with conditioning regimen, although the number of observed events was low. The low incidence of hypothyroidism, cataract formation, nephropathy, and radiation pneumonitis observed after TMI at doses equivalent or higher than standard TBI compared favorably with that historically reported for TBI.

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CHAPTER 23

Total Body Irradiation

Median (D50) Organ Dose as a Percent of the Prescribed Target Dose (n = 51)374

eTABLE 23.8

Mean ± 1 SD

Organs

Range

Lens

15.0 ± 4.3

10.0–34.0

Oral Cavity

24.3 QD, once per day; 8.4

14.0–51.3

Rectum

33.1 QD, once per day; 8.2

17.9–54.1

Esophagus

30.8 QD, once per day; 5.8

16.3–44.2

Eyes

28.4 QD, once per day; 13.0

13.1–71.9

Stomach

39.7 QD, once per day; 7.4

27.1–58.3

Thyroid

44.6 QD, once per day; 12.7

15.3–88.9

Parotids

39.6 QD, once per day; 7.5

26.0–60.0

Lungs

41.5 QD, once per day; 6.3

32.0–55.0

Heart

42.2 QD, once per day; 10.3

28.8–69.2

Kidneys

37.9 QD, once per day; 9.2

21.8–67.5

Small Intestine

45.4 QD, once per day; 6.9

26.8–61.1

Bladder

54.5 QD, once per day; 12.5

25.3–89.2

SD, standard deviation.

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405.e1

406

SECTION II

Techniques and Modalities

Concerns have been raised regarding the effects the high-dose rates with TMI (≥ 200 cGy/minute) may have on toxicities compared with the low-dose-rates with conventional TBI (5 to 30 cGy/minute). The available clinical experience to date does not appear to demonstrate an increase in early or late toxicities compared with established regimens. Nonengraftment rates have not increased with the use of TMI. Preclinical studies have demonstrated that dose-rate effects are not as significant at dose-rates higher than approximately 25 cGy/minute and are further mitigated with fractionation.403,404 Reduction in organ doses may also offset any potential detrimental effects of higher dose rate. This may explain the lack of any dose-rate effect seen in the clinical trials to date. The TMI clinical experience is still early and the impact of dose rate still needs to be monitored, especially in clinical scenarios where fraction size is increased, total dose is escalated, and fewer organs are spared. Extramedullary recurrences with TMI regimens. Organ sparing with TMI has raised concerns of sparing of cancer cells and increased recurrence rates. Kim et al.405 reported on extramedullary recurrences in 101 patients undergoing allogeneic HCT with TMI as part of the conditioning regimen. With a median follow-up of 12.8 months, 13 patients developed extramedullary relapses at 19 sites. The site of relapse was not dose-dependent, with nine relapses occurring in the target region (≥ 12 Gy), five relapses in regions receiving 10.1 to 11.4 Gy, and five relapses in regions receiving 3.6 to 9.1 Gy.405 The risk of extramedullary relapse was comparable to that of standard TBI. In multivariate analysis extramedullary disease prior to HCT was the only predictor of extramedullary relapse. The authors concluded that use of TMI does not appear to increase the risk of relapse in nontarget regions compared to TBI.

FUTURE DIRECTIONS FOR TARGETED TBI In summary, strategies to deliver TMI, TMLI, and other forms of targeted TBI continue to be investigated actively. Initial results have been encouraging and demonstrate feasibility, acceptable toxicities, TRM rates that can compare favorably with standard conditioning regimens, and encouraging response and survival rates in advanced disease. Dose escalation is also feasible with certain regimens. The number of centers and trials continue to increase worldwide. This emerging area will soon be positioned to carry out multicenter trials to answer important clinical questions that remain. The optimum fractionation schedules, fraction sizes, chemotherapy agents, and chemotherapy/TMI sequencing need to be defined. The most appropriate target regions and target doses for a given patient population also need to be determined. Finally, the patient populations most appropriate for TMI approaches need to be determined. Should TMI strategies be reserved for poor risk patients with limited options or patients with better prognosis as a replacement for current conditioning regimens? Ultimately well designed clinical trials need to demonstrate that TMI-based conditioning regimens offer advantages over already established regimens. IMRT-based delivery of TMI, TMLI, and TBI represents a paradigm shift and is critically needed to redefine and expand the role of radiotherapy in HCT and hematologic malignancies. The International Lymphoma Radiation Oncology Group has recently published guidelines for both TBI and for TMI.406 The reader will find this manuscript a concise review of the topic.

Acknowledgments We thank Nikki Barker, Elle Barker, Charles Barker, Addison Barker, Kathleen Brennan, Lawrence Herman, Andreas Rimner, Robert Tokarz, Suzanne Wolden, Karen Chau, and the library staff at MSKCC for their assistance in the preparation of this chapter.

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A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 23

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SECTION II

Techniques and Modalities

51. Fitz Gerald TJ. Radiosensitivity of cloned permanent murine bone marrow stromal cell lines. Nonuniform effect of low dose rate. Exp Hematol. 1988;16(10):820–826. 52. Cosset JM. Radiobiological and clinical bases for total body irradiation in the leukemias and lymphomas. Semin Radiat Oncol. 1995;5(4):301–315. 53. Peters L. Discussion. The radiobiological bases of TBI. Int J Radiat Oncol Biol Phys. 1980;6(6):785–787. 54. Peters LJ. Radiobiological considerations in the use of total body irradiation for bone-marrow transplantation. Radiology. 1979;131(1):243–247. 55. Dutreix J. Time factors in total body irradiation. Pathol Biol. 1979;27(6):365–369. 56. Dutreix J. Biological problems of total body irradiation. J Eur Radiother. 1982;3(4):165–173. 57. Kimler BF, et al. Radiation response of human normal and leukemic hemopoietic cells assayed by in vitro colony formation. Int J Radiat Oncol Biol Phys. 1985;11(4):809–816. 58. Rhee JG, et al. Effect of fractionation and rate of radiation-dose on human-leukemic cells, HL-60. Radiat Res. 1985;101(3): 519–527. 59. Fitz Gerald TJ. Effect of x-irradiation dose rate on the clonagenic survival of human and experimental animal hematopoietic tumor cell lines. Evidence for heterogeneity. Int J Radiat Oncol Biol Phys. 1986;12(1):69–73. 60. Fitz Gerald TJ. Radiosensitivity of human bone marrow granulocytemacrophage progenitor cells and stromal colony-forming cells. Effect of dose rate. Radiat Res. 1986;107(2):205–215. 61. Steel GG, Wheldon TE. The radiation biology of paediatric tumors. In: Pinkerton PN, ed. Paediatric Oncology. London: Wiley; 1991. 62. Laver J. Effects of low dose rate irradiation on human marrow hematopoietic and microenvironmental cells. Sparing effect upon survival of stromal and leukemic cells. Bone Marrow Transplant. 1987;2(3):271–278. 63. Shank B. Hyperfractionation versus single-dose irradiation in human acute lymphocytic-leukemia cells. Application to TBI for marrow transplantation. Radiother Oncol. 1993;27(1):30–35. 64. Uckun FM, et al. Intrinsic radiation-resistance of primary clonogenic blasts from children with newly diagnosed B-cell precursor acute lymphoblastic-leukemia. J Clin Invest. 1993;91(3):1044–1051. 65. Fitz Gerald TJ. Radiosensitivity of permanent human bone marrow stromal cell lines. Effect of dose rate. Int J Radiat Oncol Biol Physi. 1988;15(5):1153–1159. 66. Cosset JM, et al. Single-dose versus fractionated total body irradiation before bone marrow transplantation. Radiobiological and clinical considerations. Int J Radiat Oncol Biol Phys. 1994;30(2):477–492. 67. Paul S, Barker CA, Turner HC, et al. Prediction of in vivo radiation dose status in radiotherapy patients using ex vivo and in vivo gene expression signatures. Radiat Res. 2011;175:257–265. 68. Odell TT, et al. The homotransplantation of functional erythropoietic elements in the rat following total body irradiation. Ann N Y Acad Sci. 1957;64(5):811–825. 69. Alpen EL, Baum SJ. Acute radiation protection of dogs by bone marrow autotransfusion. Radiat Res. 1957;7(3):298–299. 70. Crouch BG, Overman RR. Whole body radiation protection in primates. Fed Proc. 1957;16(1):27. 71. Storb R, et al. Comparison of fractionated to single-dose total body irradiation in conditioning canine littermates for DLA-identical marrow grafts. Blood. 1989;74(3):1139–1143. 72. Storb R, et al. Fractionated versus single-dose total body irradiation at low and high-dose rates to condition canine littermates for DLAidentical marrow grafts. Blood. 1994;83(11):3384–3389. 73. Girinski T, et al. Similar effects on murine hematopoietic compartment of low-dose-rate single-dose and high-dose-rate fractionated total body irradiation. Preliminary results after a unique dose of 750 Cgy. Br J Cancer. 1990;61(6):797–800. 74. Vegesna V, et al. Multifraction radiation response of mouse lung. Int J Radiat Biol. 1985;47(4):413–422.

75. Penney DP, et al. Morphological correlates of fractionated radiation of the mouse lung. Early and late effects. Int J Radiat Oncol Biol Phys. 1994;29(4):789–804. 76. McChesney SL, Gillette E, Powers BE. Response of the canine lung to fractionated irradiation. Pathologic changes and isoeffect curves. Int J Radiat Oncol Biol Phys. 1989;16(1):125–132. 77. Andrews GA. Criticality accidents in Vinca, Yugoslavia, and Oak Ridge, Tennessee. Comparison of radiation injuries and results of therapy. JAMA. 1962;179(3):191–193. 78. Cosset JM. ESTRO Breur Gold Medal Award Lecture 2001. Irradiation accidents, lessons for oncology? Radiother Oncol. 2002;63(1):1–10. 79. International Atomic Energy Agency. Safety reports series. In: World Health Organization, ed. Diagnosis and Treatment of Radiation Injuries. Vienna: International Atomic Energy Agency; 1998:49. 80. Waselenko JK, et al. Medical management of the acute radiation syndrome. Recommendations of the Strategic National Stockpile Radiation Working Group. Ann Intern Med. 2004;140(12):1037–1051. 81. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. 82. Chaillet MP, Cosset JM, Socie G, et al. Prospective study of the clinical symptoms of therapeutic whole body irradiation. Health Phys. 1993;64(4):370–374. 83. Buchali A, Feyer P, Groll J, et al. Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation. Radiother Oncol. 2000;54(2):157–162. 84. Ozsahin M, Pène F, Touboul E, et al. Total body irradiation before bone-marrow transplantation. Results of two randomized instantaneous dose rates in 157 patients. Cancer. 1992;69(11):2853–2865. 85. Thomas ED, Clift RA, Hersman J, et al. Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int J Radiat Oncol Biol Phys. 1982;8(5): 817–821. 86. Tiley C, Powles R, Catalano J, et al. Results of a double-blind placebo controlled study of ondansetron as an antiemetic during total body irradiation in patients undergoing bone marrow transplantation. Leuk Lymphoma. 1992;7(4):317–321. 87. Spitzer TR, Bryson JC, Cirenza E, et al. Randomized double-blind, placebo-controlled evaluation of oral ondansetron in the prevention of nausea and vomiting associated with fractionated total body irradiation. J Clin Oncol. 1994;12(11):2432–2438. 88. Prentice HG, Cunningham S, Gandhi L, et al. Granisetron in the prevention of irradiation-induced emesis. Bone Marrow Transplant. 1995;15(3):445–448. 89. Okamoto S, Takahashi S, Tanosaki R, et al. Granisetron in the prevention of vomiting induced by conditioning for stem cell transplantation. A prospective randomized study. Bone Marrow Transplant. 1996;17(5):679–683. 90. Matsuoka S, Okamoto S, Watanabe R, et al. Granisetron plus dexamethasone versus granisetron alone in the prevention of vomiting induced by conditioning for stem cell transplantation. A prospective randomized study. Int J Hematol. 2001;77(1):86–90. 91. Maranzano E, et al. Evidence-based recommendations for the use of antiemetics in radiotherapy. Radiother Oncol. 2005;76(3):227–233. 92. NCCN Clinical Practice Guidelines in Oncology: Antiemesis, V.3.2009. 2009. Available from: www.nccn.org/professionals/physician_gls/PDF/ antiemesis.pdf. Cited December 28, 2010. 93. Kris MG, et al. American Society of Clinical Oncology guideline for antiemetics in oncology. Update 2006. J Clin Oncol. 2006;24(18):2932–2947. 94. Orchard PJ, et al. A prospective randomized trial of the anti-emetic efficacy of ondansetron and granisetron during bone marrow transplantation. Biol Blood Marrow Transplant. 1999;5(6):386–393. 95. Woo SB, et al. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer. 1993;72(5):1612–1617. 96. Borowski B, et al. Prevention of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomized controlled trial comparing 2 protocols of dental-care. Eur J Cancer B Oral Oncol. 1994;30B(2):93–97.

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CHAPTER 23 97. Ferretti GA, et al. Chlorhexidine for prophylaxis against oral infections and associated complications in patients receiving bone-marrow transplants. J Am Dent Assoc. 1987;114(4):461–467. 98. Ferretti GA, et al. Control of oral mucositis and candidiasis in marrow transplantation: a prospective, double-blind trial of chlorhexidine digluconate oral rinse. Bone Marrow Transplant. 1988;3(5):483–493. 99. Papas AS, et al. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;31(8):705–712. 100. Castagna L, et al. Prevention of mucositis in bone marrow transplantation. A double blind randomised controlled trial of sucralfate. Ann Oncol. 2001;12(7):953–955. 101. Yuen KY, et al. Effects of clarithromycin on oral mucositis in bone marrow transplant recipients. Haematologica. 2001;86(5):554–555. 102. Hwang WYK, et al. A randomized trial of amifostine as a cytoprotectant for patients receiving myeloablative therapy for allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2004;34(1):1–56. 103. Schubert MM, Eduardo FP, Guthrie KA, et al. A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Support Care Cancer. 2007;15:1145–1154. 104. Ifrah N, et al. Intensive short term therapy with granulocytemacrophage-colony stimulating factor support, similar to therapy for acute myeloblastic leukemia, does not improve overall results for adults with acute lymphoblastic leukemia. Cancer. 1999;86(8):1496–1505. 105. van der Lelie H, et al. Effect of locally applied GM-CSF on oral mucositis after stem cell transplantation: a prospective placebocontrolled double-blind study. Ann Hematol. 2001;80(3):150–154. 106. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351(25):2590–2598. 107. Levine JE, Blazar BR, DeFor T, et al. Long-term follow-up of a phase I/II randomized, placebo-controlled trial of palifermin to prevent graftversus-host disease (GVHD) after related donor allogeneic hematopoietic cell transplantation (HCT). Biol Blood Marrow Transplant. 2008;14:1017–1021. 108. Thomas ED, et al. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979;54(2):468–476. 109. Ringden O, Remberger M, Ruutu T, et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation. Long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Blood. 1999;93(7):2196–2201. 110. Andrews GA. Radiation accidents and their management. Radiat Res Suppl. 1967;7:390–397. 111. Trivedi M, et al. Optimal use of G-CSF administration after hematopoietic SCT. Bone Marrow Transplant. 2009;43(12):895–908. 112. Smith TJ, et al. 2006 update of recommendations for the use of white blood cell growth factors. An evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187–3205. 113. Crawford J, et al. Hematopoietic growth factors. ESMO recommendations for the applications. Ann Oncol. 2009;20: 162–165. 114. Bunn PA, et al. Chemoradiotherapy with or without granulocytemacrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol. 1995;13(7):1632–1641. 115. Dahllof G, et al. Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol. 1997;33(5):327–331. 116. Bagesund M, et al. Longitudinal scintigraphic study of parotid and submandibular gland function after total body irradiation in children and adolescents. Int J Paediatr Dent. 2007;17(1):34–40. 117. Dahllof G. Oral and dental late effects after pediatric stem cell transplantation. Biol Blood Marrow Transplant. 2007;14(1):81–83. 118. Holtta P, et al. Agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation in young children. Cancer. 2005;103(1):181–190.

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119. Holtta P, et al. Disturbed root development of permanent teeth after pediatric stem cell transplantation: dental root development after SCT. Cancer. 2005;103(7):1484–1493. 120. Nasman M, Forsberg CM, Dahllof G. Long-term dental development in children after treatment for malignant disease. Eur J Orthod. 1997;19(2):151–159. 121. Jones LR, Toth BB, Keene HJ. Effects of total-body irradiation on salivary-gland function and caries-associated oral microflora in bone-marrow transplant patients. Oral Surg Oral Med Oral Pathol. 1992;73(6):670–676. 122. Singhal S, et al. Pilocarpine hydrochloride for symptomatic relief of xerostomia due to chronic graft-versus-host disease or total body irradiation after bone-marrow transplantation for hematologic malignancies. Leuk Lymphoma. 1997;24(5–6):539–543. 123. Peters SG, Afessa B. Acute lung injury after hematopoietic stem cell transplantation. Clin Chest Med. 2005;26(4):561–569. 124. Patriarca F, et al. Clinical presentation, outcome and risk factors of late-onset non-infectious pulmonary complications after allogeneic stem cell transplantation. Curr Stem Cell Res Ther. 2009;4:161–167. 125. Fukuda T, et al. Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation. Blood. 2003;102(8):2777–2785. 126. Robbins RA, et al. Diffuse alveolar hemorrhage in autologous bonemarrow transplant recipients. Am J Med. 1989;87(5):511–518. 127. Weiner RS, et al. Interstitial pneumonitis after bone marrow transplantation. Assessment of risk factors. Ann Intern Med. 1986;104(2):168–175. 128. Pino y Torres JL, et al. Risk factors in interstitial pneumonitis following allogenic bone marrow transplantation. Int J Radiat Oncol Biol Phys. 1982;8(8):1301–1307. 129. Savani BN, et al. Chronic GVHD and pretransplantation abnormalities in pulmonary function are the main determinants predicting worsening pulmonary function in long-term survivors after stem cell transplantation. Biol Blood Marrow Transplant. 2006;12(12):1261–1269. 130. Shank B, et al. Hyperfractionated total body irradiation for bone marrow transplantation. 1. Early results in leukemia patients. Int J Radiat Oncol Biol Phys. 1981;7(8):1109–1115. 131. Gogna NK, et al. Lung dose rate and interstitial pneumonitis in total body irradiation for bone marrow transplantation. Australas Radiol. 1992;36(4):317–320. 132. Keane TJ, Vandyk J, Rider WD. Idiopathic interstitial pneumonia following bone-marrow transplantation: the relationship with total body irradiation. Int J Radiat Oncol Biol Phys. 1981;7(10):1365–1370. 133. Bortin M, et al. Factors associated with interstitial pneumonitis after bone-marrow transplantation for acute leukaemia. Lancet. 1982;319(8269):437–439. 134. Clift RA, Bruckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with acute myeloid-leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76(9):1867–1871. 135. Clift RA, Bruckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with chronic myeloid-leukemia in the chronic phase: a randomized trial of two irradiation regimens. Blood. 1991;77(8):1660–1665. 136. Clift RA, Bruckner CD, Appelbaum FR, et al. Long-term follow-up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia. Blood. 1998;92(4):1455–1456. 137. Vandyk J, et al. Radiation pneumonitis following large single dose irradiation: a re-evaluation based on absolute dose to lung. Int J Radiat Oncol Biol Phys. 1981;7(4):461–467. 138. Della Volpe A, et al. Lethal pulmonary complications significantly correlate with individually assessed mean lung dose in patients with hematologic malignancies treated with total body irradiation. Int J Radiat Oncol Biol Phys. 2002;52(2):483–488. 139. Deeg HJ, Sullivan KM, Buckner CD, et al. Marrow transplantation for acute nonlymphoblastic leukemia in first remission. Toxicity and

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SECTION II

Techniques and Modalities

long-term follow-up of patients conditioned with single dose or fractionated total-body irradiation. Bone Marrow Transplant. 1986;1(2):151–157. 140. Girinsky T, Benhamou E, Bourhis JH, et al. Prospective randomized comparison of single-dose versus hyperfractionated total-body irradiation in patients with hematologic malignancies. J Clin Oncol. 2000;18(5):981–986. 141. Morgan TL, et al. A comparison of single-dose and fractionated total-body irradiation on the development of pneumonitis following bone marrow transplantation. Int J Radiat Oncol Biol Phys. 1996;36(1):61–66. 142. Gopal R, et al. Comparison of two total body irradiation fractionation regimens with respect to acute and late pulmonary toxicity. Cancer. 2001;92(7):1949–1958. 143. Cohen EP, Bedi M, Irving AA, et al. Mitigation of late renal and pulmonary injury after hematopoietic stem cell transplantation. Int J Radiat Oncol Biol Phys. 2012;83:292–296. 144. Sampath S, Schultheiss TE, Wong J. Dose response and factors related to interstitial pneumonitis after bone marrow transplant. Int J Radiat Oncol Biol Phys. 2005;63(3):876–884. 145. Beyzadeoglu M, et al. Effect of dose rate and lung dose in total body irradiation on interstitial pneumonitis after bone marrow transplantation. Tohoku J Exp Med. 2004;202(4):255–263. 146. Belkacemi Y, et al. Total-body irradiation before bone marrow transplantation for acute leukemia in first or second complete remission: results and prognostic factors in 326 consecutive patients. Strahlenther Onkol. 1998;174(2):92–104. 147. Ozsahin M, et al. Interstitial pneumonitis following autologous bone marrow transplantation conditioned with cyclophosphamide and total body irradiation. Int J Radiat Oncol Biol Phys. 1996;34(1):71–77. 148. Carruthers SA, Wallington M. Total body irradiation and pneumonitis risk. A review of outcomes. Br J Cancer. 2004;90(11):2080–2084. 149. Corvo R, et al. Total body irradiation correlates with chronic graft versus host disease and affects prognosis of patients with acute lymphoblastic leukemia receiving an HLA identical allogeneic bone marrow transplant. Int J Radiat Oncol Biol Phys. 1999;43(3):497–503. 150. Labar B, Bogdani V, Nemet D, et al. Total body irradiation with or without lung shielding for allogeneic bone-marrow transplantation. Bone Marrow Transplant. 1992;9(5):343–347. 151. Weshler Z, et al. Interstitial pneumonitis after total body irradiation: effect of partial lung shielding. Br J Haematol. 1990;74(1):61–64. 152. Girinsky T, Socie G, Ammarguellat H, et al. Consequences of two different doses to the lungs during a single dose of total body irradiation. Results of a randomized study on 85 patients. Int J Radiat Oncol Biol Phys. 1994;30(4):821–824. 153. Gore EM, et al. Pulmonary function changes in long-term survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys. 1996;36(1):67–75. 154. Tait RC, et al. Subclinical pulmonary function defects following autologous and allogeneic bone marrow transplantation. Relationship to total body irradiation and graft-versus-host disease. Int J Radiat Oncol Biol Phys. 1991;20(6):1219–1227. 155. Gandola L, et al. Prospective evaluation of pulmonary function in cancer patients treated with total body irradiation, high-dose melphalan, and autologous hematopoietic stem-cell transplantation. Int J Radiat Oncol Biol Phys. 1990;19(3):743–749. 156. Chien JW, et al. Comparison of lung function after myeloablative and 2 Gy of total body irradiation-based regimens for hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11(4): 288–296. 157. Soule BP, et al. Pulmonary function following total body irradiation (with or without lung shielding) and allogeneic peripheral blood stem cell transplant. Bone Marrow Transplant. 2007;40(6):573–578. 158. Beinert T, et al. Late pulmonary impairment following allogeneic bone marrow transplantation. Eur J Med Res. 1996;1(7):343–348. 159. Carver JR, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors. Cardiac and pulmonary late effects. J Clin Oncol. 2007;25(25):3991–4008.

160. Childrens Oncology Group, C: Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers, version 3.0, Radiation reference guide. 2008. Available from: www. survivorshipguidelines.org. Cited August 27, 2009. 161. Bhatia S, et al. Late mortality in survivors of autologous hematopoieticcell transplantation. Report from the Bone Marrow Transplant Survivor Study. Blood. 2005;105(11):4215–4222. 162. Bhatia S, et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors. Report from the Bone Marrow Transplant Survivor Study. Blood. 2007;110(10):3784–3792. 163. Tichelli A, et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation. A retrospective multicenter study of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2008;93(8):1203–1210. 164. Armenian SH, et al. Late congestive heart failure after hematopoietic cell transplantation. J Clin Oncol. 2008;26(34):5537–5543. 165. Auner HW, et al. Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophosphamide. Eur J Haematol. 2002;69(1):1–6. 166. Snowden JA, et al. Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant. 2000;26(3):309–313. 167. Uderzo C, et al. Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic hematopoietic stem cell transplantation. A prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties. Bone Marrow Transplant. 2007;39(11):667–675. 168. Tukenova M, et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol. 2010;28(8):1308–1315. 169. Mertens AC, et al. Cause-specific late mortality among 5-year survivors of childhood cancer. The Childhood Cancer Survivor Study. J Natl Cancer Inst. 2008;100(19):1368–1379. 170. Meacham LR, et al. Cardiovascular risk factors in adult survivors of pediatric cancer. A report from the Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev. 2010;19(1):170–181. 171. Baker KS, et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation. A report from the bone marrow transplantation survivor study. Blood. 2007;109(4): 1765–1772. 172. Armenian SH, Sun CL, Vase T, et al. Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of subsequent cardiovascular disease. Blood. 2012;120:4505–4512. 173. Shulman HM, et al. An analysis of hepatic venooclusive disease and centrilobular hepatic degeneration following bone marrow transplantation. Gastroenterology. 1980;79(6):1178–1191. 174. Wadleigh M, et al. Hepatic veno-occlusive disease. Pathogenesis, diagnosis and treatment. Curr Opin Hematol. 2003;10(6):451–462. 175. Ringdén O, Ruutu T, Remberger M, et al. A randomized trial comparing busulfan with total-body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia. A report from the Nordic Bone Marrow Transplantation Group. Blood. 1994;83(9):2723–2730. 176. Hartman AR, Williams S, Dillon JJ. Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation. A meta-analysis. Bone Marrow Transplant. 1998;22(5):439–443. 177. Shulman HM, Hinterberger W. Hepatic venoocclusive disease. Liver toxicity syndrome after bone-marrow transplantation. Bone Marrow Transplant. 1992;10(3):197–214. 178. McDonald GB, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation. A cohort study of 355 patients. Ann Intern Med. 1993;118(4):255–267.

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CHAPTER 23 179. Rozman C, et al. Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia. Bone Marrow Transplant. 1996;17(1):75–80. 180. Lawton CA, et al. Technical modifications in hyperfractionated total body irradiation for T-lymphocyte deplete bone marrow transplant. Int J Radiat Oncol Biol Phys. 1989;17(2):319–322. 181. Ohashi K, et al. The Japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation. Am J Hematol. 2000;64(1):32–38. 182. Park SH, et al. A randomized trial of heparin plus ursodiol vs heparin alone to prevent hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29(2):137–143. 183. Senzolo M, et al. Veno occlusive disease. Update on clinical management. World J Gastroenterol. 2007;13(29):3918–3924. 184. van Kempen-Harteveld ML, et al. Cataract after total body irradiation and bone marrow transplantation. Degree of visual impairment. Int J Radiat Oncol Biol Phys. 2002;52(5):1375–1380. 185. van Kempen-Harteveld ML, et al. Cataract-free interval and severity of cataract after total body irradiation and bone marrow transplantation. Influence of treatment parameters. Int J Radiat Oncol Biol Phys. 2000;48(3):807–815. 186. Dunn JP, et al. Bone marrow transplantation and cataract development. Arch Ophthalmol. 1993;111(10):1367–1373. 187. Deeg HJ, et al. Cataracts after total body irradiation and marrow transplantation. A sparing effect of dose fractionation. Int J Radiat Oncol Biol Phys. 1984;10(7):957–964. 188. Fife K, et al. Risk-factors for requiring cataract-surgery following total body irradiation. Radiother Oncol. 1994;33(2):93–98. 189. Zierhut D, et al. Cataract incidence after total body irradiation. Int J Radiat Oncol Biol Phys. 2000;46(1):131–135. 190. Belkacemi Y, et al. Cataractogenesis after total body irradiation. Int J Radiat Oncol Biol Phys. 1996;35(1):53–60. 191. Aristei C, et al. Cataracts in patients receiving stem cell transplantation after conditioning with total body irradiation. Bone Marrow Transplant. 2002;29(6):503–507. 192. Schneider RA, et al. Long-term outcome after static intensity-modulated total body radiotherapy using compensators stratified by pediatric and adult cohorts. Int J Radiat Oncol Biol Phys. 2008;70(1):194–202. 193. Belkacemi Y, et al. Cataracts after total body irradiation and bone marrow transplantation in patients with acute leukemia in complete remission, A study of the European Group for Blood and Marrow Transplantation. Int J Radiat Oncol Biol Phys. 1998;41(3):659–668. 194. Ferry C, et al. Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies. Bone Marrow Transplant. 2007;40(3):219–224. 195. Fahnehjelm KT, et al. Visual outcome and cataract development after allogeneic stem-cell transplantation in children. Acta Ophthalmol Scand. 2007;85(7):724–733. 196. Beyzadeoglu M, et al. Evaluation of fractionated total body irradiation and dose rate on cataractogenesis in bone marrow transplantation. Haematologica. 2002;32(1):25–30. 197. Ozsahin M, Belkacemi Y, Pène F, et al. Total body irradiation and cataract incidence. A randomized comparison of two instantaneous dose rates. Int J Radiat Oncol Biol Phys. 1994;28(2):343–347. 198. Kal HB, van Kempen-Harteveld ML. Induction of severe cataract and late renal dysfunction following total body irradiation: Dose-effect relationships. Anticancer Res. 2009;29(8):3305–3309. 199. van Kempen-Harteveld ML, et al. Eye shielding during total body irradiation for bone marrow transplantation in children transplanted for a hematological disorder. Risks and benefits. Bone Marrow Transplant. 2003;31(12):1151–1156. 200. Gurney JG, et al. Visual, auditory, sensory, and motor impairments in long-term survivors of hematopoietic stem cell transplantation performed in childhood. Results from the Bone Marrow Transplant Survivor study. Cancer. 2006;106(6):1402–1408. 201. Bell CM, et al. Surgeon volumes and selected patient outcomes in cataract surgery. A population-based analysis. Ophthalmology. 2007;114(3):405–410.

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202. Powe NR, et al. Synthesis of the literature on visual-acuity and complications following cataract-extraction with intraocular-lens implantation. Arch Ophthalmol. 1994;112(2):239–252. 203. Ellis MJ, et al. Chronic kidney disease after hematopoietic cell transplantation. A systematic review. Am J Transplant. 2008;8(11):2378–2390. 204. Hingorani S. Chronic kidney disease in long-term survivors of hematopoietic cell transplantation. Epidemiology, pathogenesis, and treatment. J Am Soc Nephrol. 2006;17(7):1995–2005. 205. Choi M, et al. Incidence and predictors of delayed chronic kidney disease in long-term survivors of hematopoietic cell transplantation. Cancer. 2008;113(7):1580–1587. 206. Weiss AS, et al. Chronic kidney disease following non-myeloablative hematopoietic cell transplantation. Am J Transplant. 2006;6(1): 89–94. 207. Hingorani SR, et al. Risk factors for chronic kidney disease (CKD) after hematopoietic cell transplantation (HCT). Biol Blood Marrow Transplant. 2005;11(2):72–73. 208. Kist-van Holthe JE, et al. Prospective study of renal insufficiency after bone marrow transplantation. Pediatr Nephrol. 2002;17(12):1032–1037. 209. Hingorani S, et al. Chronic kidney disease in long-term survivors of hematopoietic cell transplant. Bone Marrow Transplant. 2007;39(4):223–229. 210. Miralbell R, et al. Renal toxicity after allogeneic bone marrow transplantation. The combined effects of total-body irradiation and graft-versus-host disease. J Clin Oncol. 1996;14(2):579–585. 211. Miralbell R, et al. Renal insufficiency in patients with hematologic malignancies undergoing total body irradiation and bone marrow transplantation. A prospective assessment. Int J Radiat Oncol Biol Phys. 2004;58(3):809–816. 212. Lawton CA, et al. Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant. 1997;20(12):1069–1074. 213. Igaki H, et al. Renal dysfunction after total body irradiation. Significance of selective renal shielding blocks. Strahlenther Onkol. 2005;181(11):704–708. 214. Cheng JC, Schultheiss TE, Wong JYC. Impact of drug therapy, radiation dose, and dose rate on renal toxicity following bone marrow transplantation. Int J Radiat Oncol Biol Phys. 2008;71(5):1436–1443. 215. Lewis EJ, et al. The effect of angiotensin-converting enzyme-inhibition on diabetic nephropathy. N Engl J Med. 1993;329(20):1456–1462. 216. Moulder JE, Fish BL, Cohen EP. Noncontinuous use of angiotensin converting enzyme inhibitors in the treatment of experimental bone marrow transplant nephropathy. Bone Marrow Transplant. 1997;19(7):729–735. 217. Cohen EP, Fish BL, Moulder JE. Successful brief captopril treatment in experimental radiation nephropathy. J Lab Clin Med. 1997;129(5):536–547. 218. Cohen EP, et al. Captopril to mitigate chronic renal failure after hematopoietic stem cell transplantation. A randomized controlled trial. Int J Radiat Oncol Biol Phys. 2008;70(5):1546–1551. 219. Chemaitilly W, Sklar CA. Endocrine complications of hematopoietic stem cell transplantation. Endocrinol Metab Clin North Am. 2007;36(4):983–998. 220. Borgstrom B, Bolme P. Thyroid-function in children after allogeneic bone-marrow transplantation. Bone Marrow Transplant. 1994;13(1):59–64. 221. Boulad F, et al. Thyroid-dysfunction following bone-marrow transplantation using hyperfractionated radiation. Bone Marrow Transplant. 1995;15(1):71–76. 222. Sanders JE, et al. Thyroid function following hematopoietic cell transplantation in children. 30 years’ experience. Blood. 2009;113(2):306–308. 223. Al-Hazzouri A, et al. Similar risks for hypothyroidism after allogeneic hematopoietic cell transplantation using TBI-based myeloablative and reduced-intensity conditioning regimens. Bone Marrow Transplant. 2009;43(12):949–951.

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224. Sklar CA, et al. Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic-leukemia. A report from the Children’s Cancer Study Group. J Clin Oncol. 1990;8(12):1981–1987. 225. Green DM, et al. Fertility of male survivors of childhood cancer. A report from the Childhood Cancer Survivor Study. J Clin Oncol. 2010;28(2):332–339. 226. Mertens AC, et al. Patterns of gonadal dysfunction following bone marrow transplantation. Bone Marrow Transplant. 1998;22(4): 345–350. 227. Schmidt KT, et al. Risk of ovarian failure and fertility preserving methods in girls and adolescents with a malignant disease. BJOG. 2010;117(2):163–174. 228. Wong FL, Francisco L, Togawa K, et al. Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: impact of chronic graft-versus-host disease and total body irradiation. Blood. 2013;122:3973–3981. 229. Kauppila M, et al. Long-term effects of allogeneic bone marrow transplantation (BMT) on pituitary, gonad, thyroid and adrenal function in adults. Bone Marrow Transplant. 1998;22(4):331–337. 230. Thomas BC, et al. Growth following single fraction and fractionated total body irradiation for bone marrow transplantation. Eur J Pediatr. 1993;152(11):888–892. 231. Saenger P. Growth hormone in growth hormone deficiency. Start treatment early and give it for long enough. Br Med J. 2002;325(7355):58–59. 232. Rizzo JD, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant. 2006;37(3):249–261. 233. Fink JC, et al. Avascular necrosis following bone marrow transplantation. A case-control study. Bone. 1998;22(1):67–71. 234. Stern JM, et al. Bone density loss after allogeneic hematopoietic stem cell transplantation. A prospective study. Biol Blood Marrow Transplant. 2001;7(5):257–264. 235. Harder H, et al. Cognitive functioning and quality of life in long-term adult survivors of bone marrow transplantation. Cancer. 2002;95(1):183–192. 236. Peper M, et al. Neurobehavioral toxicity of total body irradiation. A follow-up in long-term survivors. Int J Radiat Oncol Biol Phys. 2000;46(2):303–311. 237. Wenz F, et al. Prospective evaluation of delayed central nervous system (CNS) toxicity of hyperfractionated total body irradiation (TBI). Int J Radiat Oncol Biol Phys. 2000;48(5):1497–1501. 238. Scherwath A, Schirmer L, Kruse M, et al. Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study. Psychooncology. 2013;22:1509–1516. 239. Syrjala KL, et al. Neuropsychologic changes from before transplantation to 1 year in patients receiving myeloablative allogeneic hematopoietic cell transplant. Blood. 2004;104(10):3386–3392. 240. Barba P, et al. Early and late neurological complications after reducedintensity conditioning allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15(11):1439–1446. 241. Smedler AC, Nilsson C, Bolme P. Total body irradiation. A neuropsychological risk factor in pediatric bone-marrow transplant recipients. Acta Paediatr. 1995;84(3):325–330. 242. Smedler AC, Bolme P. Neuropsychological deficits in very young bone-marrow transplant recipients. Acta Paediatr. 1995;84(4): 429–433. 243. Phipps S, et al. Cognitive and academic functioning in survivors of pediatric bone marrow transplantation. J Clin Oncol. 2000;18(5):1004–1011. 244. Simms S, et al. Neuropsychological outcome of children undergoing bone marrow transplantation. Bone Marrow Transplant. 1998;22(2):181–184.

245. Smedler AC, Winiarski J. Neuropsychological outcome in very young hematopoietic SCT recipients in relation to pretransplant conditioning. Bone Marrow Transplant. 2008;42(8):515–522. 246. Phipps S, et al. Cognitive and academic consequences of stem-cell transplantation in children. J Clin Oncol. 2008;26(12):2027–2033. 247. Schwartz DL, et al. Radiation myelitis following allogeneic stem cell transplantation and consolidation radiotherapy for non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2000;26(12):1355–1359. 248. Faraci M, et al. Severe neurologic complications after hematopoietic stem cell transplantation in children. Neurology. 2002;59(12): 1895–1904. 249. Baker KS, et al. Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation. Results from the Bone Marrow Transplant Survivor Study. Blood. 2004;104(6):1898–1906. 250. Rubin J, et al. Acute neurological complications after hematopoietic stem cell transplantation in children. Pediatr Transplant. 2005;9(1): 62–67. 251. Ades L, Guardiola P, Socie G. Second malignancies after allogeneic hematopoietic stem cell transplantation. New insight and current problems. Blood Rev. 2002;16(2):135–146. 252. Witherspoon RP, et al. Secondary cancers after bone-marrow transplantation for leukemia or aplastic-anemia. N Engl J Med. 1989;321(12):784–789. 253. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100(7):2292–2302. 254. Bhatia S, et al. Malignant neoplasms following bone marrow transplantation. Blood. 1996;87(9):3633–3639. 255. Taylor PRA, et al. Low incidence of myelodysplastic syndrome following transplantation using autologous non-cryopreserved bone marrow. Leukemia. 1997;11(10):1650–1653. 256. Krishnan A, et al. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma. An assessment of risk factors. Blood. 2000;95(5):1588–1593. 257. Sebban C, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma. The GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 2006;108(8):2540–2544. 258. Darrington DL, et al. Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol. 1994;12(12):2527–2534. 259. Milligan DW, et al. Secondary leukaemia and myelodysplasia after autografting for lymphoma. Results from the EBMT. Br J Haematol. 1999;106(4):1020–1026. 260. Park S, et al. Myelodysplasias and leukemias after autologous stem cell transplantation for lymphoid malignancies. Bone Marrow Transplant. 2000;26(3):321–326. 261. Sureda A, et al. Autologous stem-cell transplantation for Hodgkin’s disease. Results and prognostic factors in 494 patients from the Grupo Espanol de Linfomas/Transplante Autolog de Medula Osea Spanish Cooperative Group. J Clin Oncol. 2001;19(5):1395–1404. 262. Beauchamp-Nicoud A, et al. Therapy-related myelodysplasia and/or acute myeloid leukaemia after autologous haematopoietic progenitor cell transplantation in a prospective single centre cohort of 221 patients. Br J Haematol. 2003;122(1):109–117. 263. Hosing C, et al. Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. Ann Oncol. 2002;13(3):450–459. 264. Metayer C, et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma. A multicenter case-control study. Blood. 2003;101(5):2015–2023. 265. Brown JR, et al. Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total body irradiation and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23(10):2208–2214.

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CHAPTER 23 266. Landgren O, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113(20):4992–5001. 267. Curtis RE, et al. Risk of lymphoproliferative disorders after bone marrow transplantation. A multi-institutional study. Blood. 1999;94(7):2208–2216. 268. Micallef INM, et al. Lymphoproliferative disorders following allogeneic bone marrow transplantation. The Vancouver experience. Bone Marrow Transplant. 1998;22(10):981–987. 269. Gross TG, et al. B cell lymphoproliferative disorders following hematopoietic stem cell transplantation. Risk factors, treatment and outcome. Bone Marrow Transplant. 1999;23(3):251–258. 270. Curtis RE, et al. Solid cancers after bone marrow transplantation. N Engl J Med. 1997;336(13):897–904. 271. Kolb HJ, et al. Malignant neoplasms in long-term survivors of bone marrow transplantation. Ann Intern Med. 1999;131(10):738–744. 272. Socie G, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. 2000;18(2):348–357. 273. Bhatia S, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. 2001;19(2):464–471. 274. Baker KS, et al. New malignancies after blood or marrow stem-cell transplantation in children and adults. Incidence and risk factors. J Clin Oncol. 2003;21(7):1352–1358. 275. Friedman DL, et al. Second malignant neoplasms following hematopoietic stem cell transplantation. Int J Hematol. 2004;79(3):229–234. 276. Shimada K, et al. Solid tumors after hematopoietic stem cell transplantation in Japan. Incidence, risk factors and prognosis. Bone Marrow Transplant. 2005;36(2):115–121. 277. Leisenring W, et al. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol. 2006;24(7):1119–1126. 278. Gallagher G, Forrest DL. Second solid cancers after allogeneic hematopoietic stem cell transplantation. Cancer. 2007;109(1):84–92. 279. Cohen A, et al. Risk for secondary thyroid carcinoma after hematopoietic stem-cell transplantation. An EBMT Late Effects Working Party Study. J Clin Oncol. 2007;25(17):2449–2454. 280. Friedman DL, et al. Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation. A report from the FHCRC and the EBMT Late Effect Working Party. Blood. 2008;111(2):939–944. 281. Rizzo JD, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. 2009;113(5):1175–1183. 282. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2009. A review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin. 2009;59(1):27–41. 283. American Association of Physicists in Medicine (AAPM). Report 17, Task Group 29. The Physical Aspects of Total and Half Body Photon Irradiation. New York: American Institute of Physics; 1986:55. Available at: www. aapm.org/pubs/reports.RPT_17.pdf. 284. Wolden SL, Rabinovitch RA, Bittner NH, et al; American College of Radiology; American Society for Radiation Oncology. American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) practice guideline for the performance of total body irradiation (TBI). Am J Clin Oncol. 2013;36:97–101. 285. Khan FM. Total body irradiation. In: Kahn FM, ed. The Physics of Radiation Therapy. Philadelphia: Lippincott Williams & Wilkins; 2010:405–412. 286. Kim TH, Khan FM, Galvin JM. A report of the work party. Comparison of total-body irradiation techniques for bone-marrow transplantation. Int J Radiat Oncol Biol Phys. 1980;6(6):779–784. 287. Shank B. Techniques of magna-field irradiation. Int J Radiat Oncol Biol Phys. 1983;9(12):1925–1931. 288. Khan FM, et al. Basic data for dosage calculation and compensation. Int J Radiat Oncol Biol Phys. 1980;6(6):745–751. 289. Zhuang AH, Liu A, Schultheis TE, et al. Dosimetric study and verification of total body irradiation using helical tomotherapy and its comparison to extended SSD technique. Med Dosim. 2009;35(4):243–249.

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290. Wong JY, Forman S, Somlo G, et al. Dose escalation of total marrow irradiation with concurrent chemotherapy in patients with advanced acute leukemia undergoing allogeneic hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2013;85:148–156. 291. Lin SC, Hsieh PY, Shueng PW, et al. Total marrow irradiation as part of autologous stem cell transplantation for Asian patients with multiple myeloma. Biomed Res Int. 2013;2013:321762. 292. Pagel JM, et al. Allogeneic hematopoietic cell transplantation after conditioning with I-131-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009;114(27):5444–5453. 293. Koenecke C, et al. Radioimmunotherapy with [Re-188]-labelled anti-CD66 antibody in the conditioning for allogeneic stem cell transplantation for high-risk acute myeloid leukemia. Int J Hematol. 2008;87(4):414–421. 294. Copelan EA, Deeg HJ. Conditioning for allogeneic marrow transplantation in patients with lymphohematopoietic malignancies without the use of total-body irradiation. Blood. 1992;80(7):1648–1658. 295. Santos GW. Busulfan (Bu) and cyclophosphamide (Cy) for marrow transplantation. Bone Marrow Transplant. 1989;4:236–239. 296. Blaise D, Maraninchi D, Archimbaud E, et al. Allogeneic bone marrow transplantation for acute myeloid-leukemia in first remission. A randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen. A report from the Groupe d’Etudes de la Greffe de Moelle Osseuse. Blood. 1992;79(10):2578–2582. 297. Dusenbery KE, Daniels KA, McClure JS, et al. Randomized comparison of cyclophosphamide total body irradiation versus busulfan cyclophosphamide conditioning in autologous bone-marrow transplantation for acute myeloid-leukemia. Int J Radiat Oncol Biol Phys. 1995;31(1):119–128. 298. Blaise D, Maraninchi D, Archimbaud E, et al. Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission. Blood. 2001;97(11):3669–3671. 299. Socie G, et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia. Long-term follow-up of 4 randomized studies. Blood. 2001;98(13):3569–3574. 300. Litzow MR, et al. Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission. Br J Haematol. 2002;119(4):1115–1124. 301. Nagler A, Rocha V, Labopin M, et al. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen—a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2013;31:3549–3556. 302. Copelan EA, Hamilton BK, Avalos B, et al. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013;122:3863–3870. 303. Bredeson C, LeRademacher J, Kato K, et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood. 2013;122:3871–3878. 304. Vose JM, et al. Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23(3):461–467. 305. Clift RA, Buckner CD, Thomas ED, et al. Marrow transplantation for chronic myeloid-leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood. 1994;84(6):2036–2043. 306. Clift RA, Radich J, Appelbaum FR, et al. Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving

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allogeneic marrow transplants during chronic phase of chronic myeloid leukemia. Blood. 1999;94(11):3960–3962. 307. Devergie A, Blaise D, Attal M, et al. Allogeneic bone-marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan–total body irradiation as preparative regimen. A report from the French Society of Bone Marrow Graft (SFGM). Blood. 1995;85(8):2263–2268. 308. Kim I, et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective study of busulfan-cytoxan versus total body irradiation-cytoxan as preparative regimen in Koreans. Clin Transplant. 2001;15(3):167–172. 309. Kroger N, et al. Comparison of total body irradiation vs busulfan in combination with cyclophosphamide as conditioning for unrelated stem cell transplantation in CML patients. Bone Marrow Transplant. 2001;27(4):349–354. 310. Bunin N, Aplenc R, Kámani N, et al. Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia. A Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant. 2003;32(6):543–548. 311. Davies S. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol. 2000;18(2):340–347. 312. Granados E, et al. Hematopoietic cell transplantation in acute lymphoblastic leukemia. Better long-term event-free survival with conditioning regimens containing total body irradiation. Haematologica. 2000;85(10):1060–1067. 313. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma. Final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002;99(3):731–735. 314. Blume KG, Kopecky KJ, Henslee-Downey JP, et al. A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone-marrow transplantation in patients with leukemia who were not in first remission. A Southwest Oncology Group Study. Blood. 1993;81(8):2187–2193. 315. Shi-Xia X, et al. Total body irradiation plus cyclophosphamide versus busulphan with cyclophosphamide as conditioning regimen for patients with leukemia undergoing allogeneic stem cell transplantation. A meta-analysis. Leuk Lymphoma. 2010;51(1):50–60. 316. McAfee SL, et al. Dose-escalated total body irradiation and autologous stem cell transplantation for refractory hematologic malignancy. Int J Radiat Oncol Biol Phys. 2002;53(1):151–156. 317. Marks DI, Forman SJ, Blume KG, et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as patients conditioning regimens for undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant. 2006;12(4): 438–453. 318. Kal HB, et al. Biologically effective dose in total body irradiation and hematopoietic stem cell transplantation. Strahlenther Onkol. 2006;182(11):672–679. 319. Alyea E, et al. Effect of total body irradiation dose escalation on outcome following T-cell-depleted allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2002;8(3):139–144. 320. Bieri S, et al. Total body irradiation before allogeneic bone marrow transplantation: is more dose better? Int J Radiat Oncol Biol Phys. 2001;49(4):1071–1077. 321. Demirer T, Petersen FB, Appelbaum FR, et al. Allogeneic marrow transplantation following cyclophosphamide and escalating doses of hyperfractionated total body irradiation in patients with advanced lymphoid malignancies. A phase I/II trial. Int J Radiat Oncol Biol Phys. 1995;32(4):1103–1109. 322. Sobecks RM, et al. A dose escalation study of total body irradiation followed by high-dose etoposide and allogeneic blood stem cell

transplantation for the treatment of advanced hematologic malignancies. Bone Marrow Transplant. 2000;25(8):807–813. 323. Bornhäuser M, Kienast J, Trenschel R, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012;13:1035–1044. 324. Blaise D, Tabrizi R, Boher JM, et al. Randomized study of 2 reducedintensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation: prospective clinical and socioeconomic evaluation. Cancer. 2013;119:602–611. 325. Hegenbart U, et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2006;24(3):444–453. 326. Stelljes M, et al. Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood. 2005;106(9):3314–3321. 327. Hallemeier C, et al. Outcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure and total body irradiation, cyclophosphamide, unrelated donor bone marrow transplants. Biol Blood Marrow Transplant. 2004;10(5): 310–319. 328. Sorror ML, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23(16):3819–3829. 329. Kerbauy FR, et al. Hematopoietic cell transplantation from HLAidentical sibling donors after low-dose radiation-based conditioning for treatment of CML. Leukemia. 2005;19(6):990–997. 330. Khoury H, et al. Low incidence of transplantation-related acute complications in patients with chronic myeloid leukemia undergoing allogeneic stem cell transplantation with a low-dose (550 cGy) total body irradiation conditioning regimen. Biol Blood Marrow Transplant. 2001;7(6):352–358. 331. McSweeney PA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies. Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97(11):3390–3400. 332. Baron F, et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol. 2005;23(9):1993–2003. 333. Tomblyn M, et al. Similar and promising outcomes in lymphoma patients treated with myeloablative or nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14(5):538–545. 334. Maris MB, et al. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood. 2004;104(12):3535–3542. 335. Schmid C, et al. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23(24):5675–5687. 336. Laport GG, et al. Reduced-intensity conditioning follow by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant. 2008;14(2):246–255. 337. Hallemeier CL, et al. Long-term remissions in patients with myelodysplastic syndrome and secondary acute myelogenous leukemia undergoing allogeneic transplantation following a reduced intensity conditioning regimen of 550 cGy total body irradiation and cyclophosphamide. Biol Blood Marrow Transplant. 2006;12(7):749–757. 338. Maloney DG, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood. 2003;102(9):3447–3454. 339. Badros A, et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol. 2002;20(5):1295–1303. 340. Luznik L, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and

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CHAPTER 23 high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–650. 341. Gratwohl A, et al. Role of splenic irradiation in patients with chronic myeloid leukemia undergoing allogeneic bone marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2000;6(2A):211–213. 342. Shank B, et al. Total body irradiation for bone marrow transplantation. The Memorial Sloan Kettering Cancer Center experience. Radiother Oncol. 1990;18(suppl 1):68–81. 343. Quaranta BP, et al. The incidence of testicular recurrence in boys with acute leukemia treated with total body and testicular irradiation and stem cell transplantation. Cancer. 2004;101(4):845–850. 344. Alexander BM, et al. Utility of cranial boost in addition to total body irradiation in the treatment of high risk acute lymphoblastic leukemia. Int J Radiat Oncol Biol Phys. 2005;63(4):1191–1196. 345. Hoppe BS, et al. Involved-field radiotherapy before high-dose therapy and autologous stem-cell rescue in diffuse large-cell lymphoma. Long-term disease control and toxicity. J Clin Oncol. 2008;26(11):1858–1864. 346. van Bekkum DW. Conditioning regimens for the treatment of experimental arthritis with autologous bone marrow transplantation. Bone Marrow Transplant. 2000;25(4):357–364. 347. Saccardi R, et al. Autologous stem cell transplantation for progressive multiple sclerosis. Update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler. 2006;12(6):814–823. 348. Nash RA, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood. 2003;102(7):2364–2372. 349. Samijn JPA, et al. Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006;77(1):46–50. 350. Burt RK, et al. Hematopoietic stem cell transplantation for progressive multiple sclerosis. Failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood. 2003;102(7):2373–2378. 351. Fortun PJ, Hawkey CJ. The role of stem cell transplantation in inflammatory bowel disease. Autoimmunity. 2008;41(8):654–659. 352. Binks M, et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis. Procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001;60(6):577–584. 353. Farge D, et al. Autologous stem cell transplantation in the treatment of systemic sclerosis. Report from the EBMT/EULAR Registry. Ann Rheum Dis. 2004;63(8):974–981. 354. Nash RA, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis. Long-term follow-up of the US multicenter pilot study. Blood. 2007;110(4):1388–1396. 355. McSweeney PA, et al. High-dose immunosuppressive therapy for severe systemic sclerosis. Initial outcomes. Blood. 2002;100(5):1602–1610. 356. Sullivan KM, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378(1):35–47. 357. Iannone R, et al. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biol Blood Marrow Transplant. 2003;9(8):519–528. 358. Hsieh MM, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009;361(24):2309–2317. 359. Hale GA, et al. Allogeneic bone marrow transplantation for children with histiocytic disorders. Use of TBI and omission of etoposide in the conditioning regimen. Bone Marrow Transplant. 2003;31(11):981–986. 360. Coccia PF, et al. Successful bone-marrow transplantation for infantile malignant osteopetrosis. N Engl J Med. 1980;302(13):701–708. 361. Peters C, et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood. 1996;87(11):4894–4902. 362. Peters C, et al. Cerebral X-linked adrenoleukodystrophy. The international hematopoietic cell transplantation experience from 1982 to 1999. Blood. 2004;104(3):881–888.

Total Body Irradiation

407.e9

363. Grewal SS, et al. Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation. J Pediatr. 2004;144(5):569–573. 364. Staba SL, et al. Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. N Engl J Med. 2004;350(19):1960–1969. 365. Macmillan ML, et al. Haematopoietic cell transplantation in patients with Fanconi anaemia using alternate donors. Results of a total body irradiation dose escalation trial. Br J Haematol. 2000;109(1):121–129. 366. Beavis AW. Is tomotherapy the future of IMRT? Br J Radiol. 2004;77(916):285–295. 367. Wong JYC, Liu A, Schultheiss T, et al. Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation. Biol Blood Marrow Transplant. 2006;12:306–315. 368. Han C, Schultheiss T, Wong JY. Dosimetric study of volumetric modulated arc therapy fields for total marrow irradiation. Radiother Oncol. 2011;102(2):315–320. 369. Aydogan B, Yeginer M, Kavak GO, et al. Total marrow irradiation with rapidarc volumetric arc therapy. Int J Radiat Oncol Biol Phys. 2011;81(2):592–599. 370. Fogliata A, Cozzi L, Clivio A, et al. Preclinical assessment of volumetric modulated arc therapy for total marrow irradiation. Int J Radiat Oncol Biol Phys. 2011;80(2):628–636. 371. Patel P, Aydogan B, Koshy M, et al. Combination of linear acceleratorbased intensity-modulated total marrow irradiation and myeloablative Fludarabine/Busulfan: a Phase I study. Biol Blood Marrow Transplant. 2014;20:2034–2041. 372. Symons K, Morrison C, Parry J, et al. Volumetric modulated arc therapy for total body irradiation: a feasibility study using Pinnacle3 treatment planning system and Elekta AgilityTM linac. J Appl Clin Med Phys. 2018;19(2):103–110. 373. Schultheiss TE, Wong J, Liu A, et al. Image-guided total marrow and total lymphatic irradiation using helical tomotherapy. Int J Radiat Oncol Biol Phys. 2007;67(4):1259–1267. 374. Wong JYC, Hui S, Dandapani SV, Liu A. Biologic and image guided systemic radiotherapy. In: Wong JYC, Schultheiss TE, Radany EH, eds. Advances in Radiation Oncology. Cancer Treatment and Research. Heildelberg: Springer International Publishing; 2017:155–189. 375. Stein A, Palmer J, Tsai N-C, et al. Phase I trial of total marrow and lymphoid irradiation transplantation conditioning in patients with relapsed/refractory acute leukemia. Biol Blood Marrow Transplant. 2017;23:618–624. 376. Rosenthal J, Wong J, Stein A, et al. Phase 1/2 trial of total marrow and lymph node irradiation to augment reduced-intensity transplantation for advanced hematologic malignancies. Blood. 2011;117(1):309–315. 377. Hahn T, Wingard JR, Anderson KC, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant. 2003;9(1):4–37. 378. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999;93(1):55–65. 379. Somlo G, Spielberger R, Frankel P, et al. Total marrow irradiation: a new ablative regimen as part of tandem autologous stem cell transplantation for patients with multiple myeloma. Clin Cancer Res. 2011;17(1):174–182. 380. Somlo G, Liu A, Schultheiss TE, et al. Total marrow irradiation (TMI) with helical tomotherapy and peripheral blood progenitor cell rescue (PBPC) following high-dose melphalan (Mel) and PBPC as part of tandem autologous transplant (TAT) for patients with multiple myeloma. J Clin Oncol. 2015;33(suppl):abstr 8581. 381. Patel P, Oh AL, Koshy M, et al. A phase I trial of autologous stem cell transplantation conditioned with melphalan 200 mg/m2 and total marrow irradiation (TMI) in patients with relapsed/refractory multiple myeloma. Leuk Lymphoma. 2017. 382. Shueng PW, Lin SC, Chong NS, et al. Total marrow irradiation with helical tomotherapy for bone marrow transplantation of multiple myeloma: first experience in Asia. Technol Cancer Res Treat. 2009;8(1):29–38.

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407.e10

SECTION II

Techniques and Modalities

383. Samant R, Tay J, Nyiri B, et al. Dose-escalated total-marrow irradiation (TMI) for relapsed multiple myeloma. Int J Radiat Oncol Biol Phys. 2015;93(3S):S65–S66. 384. Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation? Blood. 2010;116(23):4762–4770. 385. Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus reducedintensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2017;35(11):1154–1161. 386. Petropoulos D, Worth LL, Mullen CA, et al. Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. Bone Marrow Transplant. 2006;37(5):463–467. 387. Jensen LJ, Stiller T, Wong JYC, et al. Total marrow lymphoid irradiation/ Fludarabine/Melphalan conditioning for allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018;24:301–307. 388. Chak LY, Sapozink MD, Cox RS. Extramedullary lesions in nonlymphocytic leukemia: results of radiation therapy. Int J Radiat Oncol Biol Phys. 1983;9(8):1173–1176. 389. Scarpati D, Frassoni F, Vitale V, et al. Total body irradiation in acute myeloid leukemia and chronic myelogenous leukemia: influence of dose and dose-rate on leukemia relapse. Int J Radiat Oncol Biol Phys. 1989;17(3):547–552. 390. Stein AS, O’Donnell MR, Synold T, et al. Phase-2 trial of an intensified conditioning regimen for allogeneic hematopoietic cell transplant for poor-risk leukemia. Bone Marrow Transplant. 2011;46:1256–1262. 391. Shigematsu A, Tanaka J, Suzuki R, et al. Outcome of medium-dose VP-16/CY/TBI superior to CY/TBI as a conditioning regimen for allogeneic stem cell transplantation in adult patients with acute lymphoblastic leukemia. Int J Hematol. 2011;94:463–471. 392. Bearman S, Appelbaum FR, Buckner CD, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol. 1988;6(10):1562–1568. 393. Stein AS, Tsai N-C, Palmer JM, et al: A Phase II study of total marrow and lymphoid irradiation (TMLI) in combination with Cyclophosphamide and Etoposide in patients with relapsed/refractory acute leukemia undergoing allogeneic hematopoietic cell transplantation. Presented at 2017 ASH Meeting. 2017. 394. Hui S, Brunstein C, Takahashi Y, et al. Dose escalation of total marrow irradiation in high-risk patients undergiong allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23:1110–1116.

395. Hui SK, Das RK, Thomadsen B, Henderson D. CT-based analysis of dose homogeneity in total body irradiation using lateral beam. J Appl Clin Med Phys. 2004;5(4):71–79. 396. Fog LS, Hansen V, Kjaer-Kristoffersen F, et al. A step and shoot intensity modulated technique for total body irradiation. Int J Radiat Oncol Biol Phys. 2017. 397. Penagaricano JA, Chao M, van Rhee F, et al. Clinical feasibility of TBI with helical tomotherapy. Bone Marrow Transplant. 2011;46:929–935. 398. Sarradin V, Simon L, Huynh A, et al. Total body irradiation using helical tomotherapy: treatment technique, dosimetric results and initial clinical experience. Cancer Radiother. 2018;22:17–24. 399. Springer A, Hammer J, Winkler E, et al. Total body irradiation with volumetric modulated arc therapy: dosimetric data and first clinical experience. Radiat Oncol. 2016;11(46):1–9. 400. Corvo R, Zeverino M, Vagge S, et al. Helical tomotherapy targeting total bone marrow after total body irradiation for patients with relapsed acute leukemia undergoing an allogeneic stem cell transplant. Radiat Oncol. 2011;98:382–386. 401. Jiang Z, Jia J, Yue C, et al. Haploidentical hematopoietic SCT using helical tomortherapy for total-body irradiation and targeted dose boost in patients with high-risk/refractory acute lymphoblastic leukemia. Bone Marrow Transplant. 2018;53:438–448. 402. Wong JYC, Liu A, Frankel P, et al, eds. Lung, Renal, Thyroid and Cataract Toxicities After Myeloablative Total Marrow Irradiation (TMI) in Patients Undergoing Hematopoietic Cell Transplantation (HCT). ASTRO 60th Annual Meeting. San Antonio, Texas: 2018. 403. Travis EL, Peters LJ, McNeil J, et al. Effect of dose-rate on total body irradiation: lethality and pathologic findings. Radiat Oncol. 1985;4:341–351. 404. Tarbell NJ, Amato DA, Down JD, et al. Fractionation and dose rate effects in mice: a model for bone marrow transplantation in man. Int J Radiat Oncol Biol Phys. 1987;13(7):1065–1069. 405. Kim JH, Stein A, Tsai N, et al. Extramedullary relapse following total marrow and lymphoid irradiation in patinets undergoing allogenejic hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2014;89(1):75–81. 406. Wong JY, Filippi AR, Dabaja BS, et al. Total body irradiation: guidelines from the International Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol Biol Phys. 2018;101(3):521–529.

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24 Charged Particle Radiotherapy Jacob E. Shabason, William P. Levin, and Thomas F. DeLaney

Over recent years, the interest and technologic advances in charged particle therapy have resulted in the opening of numerous charged particle radiation oncology centers across the globe. Interest in the use of charged particle radiotherapy derives from the superior dose distributions that can be achieved with these particles compared with those produced by standard photon therapy techniques, as well as the potential for higher biological effect in the tumor with heavier charged particles. Charged particles deposit energy in tissue through multiple interactions with electrons in the atoms of cells, although a small fraction of energy is also transferred to tissue through collisions with the nuclei of atoms. The energy loss per unit path length is initially relatively small and constant until near the end of the range where the residual energy is lost over a short distance, resulting in a steep rise in the absorbed dose (energy absorbed per unit mass). This portion of the particle track, where energy is rapidly lost over a short distance, is known as the Bragg peak (Fig. 24.1). The initial low-dose region in the depth-dose curve, before the Bragg peak, which is referred to as the plateau of the dose distribution, delivers about 30% of the Bragg peak maximum dose. The Bragg peak is too narrow for practical clinical applications. For the irradiation of most tumors, the beam energy is modulated to achieve a uniform dose over a significant volume, which has traditionally been accomplished by superimposing several Bragg peaks of descending energies (ranges) and weights to create a region of uniform dose over the depth of the target; these extended regions of uniform dose are called spread-out Bragg peaks (SOBP; see Fig. 24.1). Although the SOBP beam modulation does increase the entrance dose, the proton dose distribution is still characterized by a lower-dose region in normal tissue proximal to the tumor, a uniform high-dose region in the tumor, and nearly zero dose beyond the tumor. The protons are distributed laterally through the target volumes by a passive scattering foil, collimated with brass apertures, and contoured distally with customized range compensators to compensate for proton range differences from variable proton absorption by tissues of different radiologic density. Increasingly, however, charged particle therapy is being delivered by raster scanning a pencil beam of charged particles through the deepest slab of the target volume, then reducing the energy of the particle beam and repeating the process iteratively through the target volume. The pencil beam scanning technique delivers lower proximal dose than the traditional SOBP modulation with passive scattering; it can eliminate the need for machining customized apertures and range compensators and it provides greater flexibility in dose delivery, including dose painting and intensity modulation. Charged particles are generally characterized as having either high or low linear energy transfer (LET), which is the rate of energy loss by the particle in tissue. The LET influences the biologic impact of the energy deposited in tissue. X and gamma ray photons, protons, and

helium ions are considered to be forms of low LET radiation. Heavier charged particles (e.g., neon ions, carbon ions) are considered to be forms of high LET radiation. There is an initial increase in the relative biologic effectiveness (RBE) with an increase in LET.1 Carbon ions have an RBE of about 3, whereas the recommended RBE of protons is 1.1.2 Higher-LET radiation is less influenced by tissue oxygenation and less sensitive to variations in the cell cycle and DNA repair. For particle radiation, the gray (Gy) equivalent dose is calculated by multiplying the physical dose administered by the RBE for that particle; the recommended nomenclature for expressing the dose is Gy(RBE) = physical dose in Gy × RBE.3

PROTON BEAM RADIOTHERAPY The overall favorable dose distribution of proton radiotherapy can result in decreased patient morbidity and opens the door for investigational studies evaluating radiation dose escalation. Given the clinical benefits and technologic advances of proton radiotherapy, there has been a rapid increase in the development of proton therapy centers. Specifically, there are currently 79 charged particle centers (68 proton and 11 carbon ion) (Table 24.1) across the globe with another 46 under construction and 22 in planning.4 In addition, in recent years significant advances have been made in the basic, translational, clinical, and technologic research of proton and other charged particle therapy. This research is highlighted by the development of numerous comparative randomized clinical trials that will help clarify the clinical benefits of proton therapy for different cancers (Table 24.2). In this chapter we focus primarily on a selection of the clinical advances of proton therapy by disease site. We also provide a brief overview of other charged particle therapies.

CENTRAL NERVOUS SYSTEM AND SKULL BASE MALIGNANCIES Gliomas Increasing evidence indicates that a portion of patients with low-grade gliomas benefit from adjuvant radiotherapy.5 However, survivors may suffer chronic toxicity, including neurocognitive toxicity and endocrine imbalances, among others. By reducing dose to critical normal structures and uninvolved brain tissue, proton therapy can enormously impact the long-term outcomes for these patients. Accordingly, dosimetric comparisons of photon versus proton plans for patients with low-grade gliomas show a clear benefit to proton therapy when assessing a variety of neural subsites and structures, as well as integral dose to the brain as a whole.6 These dosimetric advantages appear to translate into a more tolerable treatment. A review of a multi-institutional prospective

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CHAPTER 24

Charged Particle Radiotherapy

409

Meningioma 100

Dose (%)

80 60 40 20

50

100

150

Depth (mm) SOBP 10 MV photon Pristine peak Fig. 24.1 Depth-dose distributions for a spread-out Bragg peak (SOBP, red), its constituent pristine Bragg peaks (green), and a 10-MV photon beam (blue). The SOBP dose distribution is created by adding the contributions of individually modulated pristine Bragg peaks. The penetration depth, or range (measured as the depth of the distal 90% of the plateau dose), of the SOBP dose distribution is determined by the range of the most distal pristine peak. The dashed lines (black) indicate the clinically acceptable variation in the plateau dose of ±2%. The dot-dashed lines (red) indicate the 90% dose and the spatial, range, and modulation width intervals. The SOBP dose distribution of even a single field can provide complete target volume coverage in depth and lateral dimensions, in sharp contrast to a single photon dose distribution; only a composite set of photon fields can deliver an appropriate clinical target dose distribution. Note the absence of dose beyond the distal fall-off edge of the SOBP. (Reprinted with permission from Levin WP, Kooy H, Loeffler JS, et al. Proton beam therapy. Br J Cancer. 2005;93:849–854.)

database of patients with low-grade gliomas treated with protons demonstrated a favorable acute toxicity profile with no patients experiencing grade 3 toxicities.7 Furthermore, Shih et al.8 published a 20-patient prospective trial of proton radiotherapy for low-grade gliomas. With 5.1 years of follow-up, no significant neurocognitive decline or overall quality of life decrement occurred. Endocrine abnormalities were found in 30% of patients; however, all but one of these patients had direct radiation to the hypothalamus-pituitary axis.8 Comparative sparing of brain function in IDH mutant grade 2 or 3 glioma patients is being assessed in an ongoing randomized phase II study (NRG Oncology Clinical Trial BN0005, Clinical Trials.gov Identifier NCT03180502) or IMRT versus protons. Patients with high-grade gliomas primarily relapse in the high-dose region.9 However, increasing evidence indicates that dose escalation may improve local control, and utilizing proton therapy may allow for safe dose escalation in this sensitive anatomic location.10 The question of dose escalation and the utility of protons in this setting is being evaluated in NRG Oncology Clinical Trial BN0001, where patients with glioblastoma will be randomized to the standard dose of 60 Gy using photons (intensity modulated radiation therapy (IMRT) or 3D conformal) or 75 Gy using either IMRT or protons (ClinicalTrials.gov Identifier NCT02179086).

Meningiomas are the most common intracranial primary brain tumor. Although, the majority are classified as World Health Organization (WHO) grade 1 and considered benign, WHO grade 2 and WHO grade 3 tumors act more aggressively with a higher rate of local relapse.11 Proton therapy may be beneficial in treating larger WHO 1 meningiomas that are not resectable or too large for stereotactic radiosurgery by sparing integral low dose to large portions of the brain,12 which could lead to less long-term neurocognitive toxicity and decrease the risk of a secondary malignancy,13 In addition, depending on the location of the meningioma, protons could spare certain critical organs at risk. Furthermore, high doses of radiation (≥ 60 Gy) appear necessary to treat high-grade meningiomas to maximize local control.14,15 Proton therapy permits safer dose escalation and sparing of critical organs at risk. The Paul Scherrer Institute recently published their series of 96 patients with meningiomas treated with definitive or adjuvant pencil beam scanning proton therapy. Their results indicate that proton therapy is safe and effective, particularly in the context that these patients were often referred specifically for protons because of the referring physician’s concern about the risks of treating with photons.16

HEAD AND NECK MALIGNANCIES Patients with head and neck malignancies may suffer from a plethora of acute and chronic toxicities related to their radiation treatments. Dosimetric comparisons of IMRT and proton plans in a variety of clinical settings (postoperative, definitive, unilateral neck radiation) reveal that protons have the ability to spare many critical normal structures, which may translate into less toxicity17–19 (Fig. 24.2). When analyzing matched patient cohorts of patients with oropharyngeal cancers treated with intensity modulated proton therapy (IMPT) versus IMRT, patients treated with protons had a lower risk of grade 3 weight loss and gastrostomy tube placement.20 Moreover, patient-reported outcomes suggest that IMPT can reduce the morbidity of the subacute phase of treatment.21 A common fear with proton therapy is that given the sharp dose gradient, patients will be at increased risk of a marginal failure. Importantly, no differences were seen in overall or progression-free survival in the two groups20 and no increase in marginal failures.22 The benefit of proton therapy as definitive treatment for oropharyngeal squamous cell carcinoma is being evaluated with a muti-institutional randomized Phase II/III trial comparing IMPT and IMRT with the primary outcome being late toxicity (ClinicalTrials.gov Identifier NCT01893307). In a variety of head and neck malignancies it is appropriate to limit the treatment volume to include only the unilateral draining lymph nodes in the neck, while avoiding the opposite side of the neck. In these instances, dosimetric comparisons show a significant benefit of proton therapy to spare both contralateral and midline structures17 that may contribute to significant patient morbidity. Accordingly, a retrospective comparison of patients treated with protons versus IMRT to the ipsilateral neck suggests that these dosimetric advantages translate into less patient morbidity with lower rates of dysguesia, mucositis, and nausea in the patients who received proton therapy.23 The benefit of protons in unilateral neck radiation is being further evaluated in a randomized trial (ClinicalTrials.gov Identifier NCT02923570). Proton therapy has also been evaluated in the setting of reirradiation for head and neck cancers. Reirradiation of the head and neck is potentially very toxic, and protons may significantly lower the morbidity of treatment by minimizing dose to surrounding tissues that have already been radiated. The largest series of pooled prospective proton registries demonstrates that, although still toxic and associated with a risk of significant treatment-related morbidity, including death, this modality

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410

SECTION II

TABLE 24.1 Country

Techniques and Modalities

Charged Particle Therapy Centers in Operation Institution

Particle Type

Opened

Austria

MedAustron, Wiener Neustadt

Proton

2017

Austria

MedAustron, Wiener Neustadt

Carbon

2017

Canada

TRIUMF, Vancouver

Proton

1995

Czech Republic

PTC Czech r.s.o., Prague

Proton

2012

China

WPTC, Wanjie, Zi-Bo

Proton

2004

China

IMP-CAS, Lanzhou

Carbon

2006

China

SPHIC, Shanghai

Proton

2014

China

SPHIC, Shanghai

Carbon

2014

England

Clatterbridge

Proton

1989

France

CAL/IMPT, Nice

Proton

1991, 2016

France

CPO, Orsay

Proton

1991, 2014

Germany

HZB, Berlin

Proton

1998

Germany

RPTC, Munich

Proton

2009

Germany

HIT, Heidelberg

Proton

2009, 2012

Germany

HIT, Heidelberg

Carbon

2009, 2012

Germany

WPE, Essen

Proton

2013

Germany

UPTD, Dresden

Proton

2014

Germany

MIT, Marburg

Proton

2015

Germany

MIT, Marburg

Carbon

2015

Italy

INFN-LNS, Catania

Proton

2002

Italy

CNAO, Pavia

Proton

2011

Italy

CNAO, Pavia

Carbon

2012

Italy

APSS, Trento

Proton

2014

Japan

HIMAC, Chiba

Carbon

1994, 2017

Japan

NCC, Kashiwa

Proton

1998

Japan

HIBMC, Hyogo

Proton

2001

Japan

HIBMC, Hyogo

Carbon

2002

Japan

PMRC 2, Tsukuba

Proton

2001

Japan

Shizuoka Cancer Center

Proton

2003

Japan

STPTC, Koriyama-City

Proton

2008

Japan

GHMC, Gunma

Carbon

2010

Japan

MPTRC, Ibusuki

Proton

2011

Japan

Fukui Prefectural Hospital PTC, Fukui City

Proton

2011

Japan

Nagoya PTC, Nagoya City, Aichi

Proton

2013

Japan

SAGA-HIMAT, Tosu

Carbon

2013

Japan

Hokkaido Univ. Hospital PBTC, Hokkaido

Proton

2014

Japan

Aizawa Hospital PTC, Nagano

Proton

2014

Japan

i-Rock Kanagawa Cancer Center, Yokohama

Carbon

2015

Japan

Tsuyama Chuo Hospital, Okayama

Proton

2016

Japan

Hakuhokai Group Osaka PT Clinic, Osaka

Proton

2017

Japan

Kobe Proton Centre, Kobe

Proton

2017

Poland

IFJ PAN, Krakow

Proton

2011, 2016

Russia

ITEP, Moscow

Proton

1969

Russia

JINR 2, Dubna

Proton

1999

Russia

MIBS, Saint-Petersburg

Proton

2018

South Africa

NRF - iThemba Labs

Proton

1993

South Korea

KNCC, IIsan

Proton

2007

South Korea

Samsung PTC, Seoul

Proton

2015

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TABLE 24.1

Charged Particle Therapy Centers in Operation—cont’d

Country

Institution

Particle Type

Opened

Sweden

The Skandion Clinic, Uppsala

Proton

2015

Switzerland

CPT, PSI, Villigen

Proton

1984, 1996, 2013

Taiwan

Chang Gung Memorial Hospital, Taipei

Proton

2015

The Netherlands

UMC PTC, Groningen

Proton

2018

USA

J. Slater PTC, Loma Linda

Proton

1990

USA

UCSF-CNL, San Francisco

Proton

1994

USA

MGH Francis H. Burr PTC, Boston

Proton

2001

USA

MD Anderson Cancer Center, Houston

Proton

2006

USA

UFHPTI, Jacksonville

Proton

2006

USA

ProCure PTC, Oklahoma City

Proton

2009

USA

Roberts PTC, U Penn, Philadelphia

Proton

2010

USA

Chicago Proton Center, Warrenville

Proton

2010

USA

HUPTI, Hampton

Proton

2010

USA

ProCure Proton Therapy Center, Somerset

Proton

2012

USA

SCCA ProCure Proton Therapy Center, Seattle

Proton

2013

USA

S. Lee Kling PTC, Barnes Jewish Hospital, St. Louis

Proton

2013

USA

ProVision Cancer Cares Proton Therapy Center, Knoxville

Proton

2014

USA

California Protons Cancer Therapy Center, San Diego

Proton

2014

USA

Willis Knighton Proton Therapy Cancer Center, Shreveport

Proton

2014

USA

Ackerman Cancer Center, Jacksonville

Proton

2015

USA

Mayo Clinic Proton Beam Therapy Center, Rochester

Proton

2015

USA

Laurie Proton Center of Robert Wood Johnson University Hospital, New Brunswick

Proton

2015

USA

Texas Center for Proton Therapy, Irving

Proton

2015

USA

St. Jude Red Frog Events Proton Therapy Center, Memphis

Proton

2015

USA

Mayo Clinic Proton Therapy Center, Phoenix

Proton

2016

USA

Maryland Proton Treatment Center, Baltimore

Proton

2016

USA

Orlando Health PTC, Orlando

Proton

2016

USA

UH Sideman CC, Cleveland

Proton

2016

USA

Cincinnati Children’s Proton Therapy Center, Cincinnati

Proton

2016

USA

Beaumont Health Proton Therapy Center, Detroit

Proton

2017

USA

Baptist Hospital’s Cancer Institute PTC, Miami

Proton

2017

Adapted with minor modifications from the Particle Therapy Co-Operative Group (PTCOG) website (www.ptcog.ch) Accessed April 2018.

TABLE 24.2

Randomized Clinical Trials Comparing Proton and Photon Radiation

Malignancy

Primary Endpoint

Phase

Clinical Trial Identifier

Head and Neck Cancer (unilateral neck radiation)

Grade ≥2 Mucositis

II

NCT02923570

Oropharyngeal Cancer

Late Grade 3–5 Toxicity

II/III

NCT01893307

Non–Small-Cell Lung Cancer (Locally Advanced)

Time to Treatment Failure

II

NCT00915005

Non–Small-Cell Lung Cancer (Locally Advanced)

Overall Survival

III

NCT01993810

Grade II/III Gliomas

Cognitive Changes

II

NCT03180502

Glioblastomaa

Overall Survival

II

NCT02179086

Glioblastoma

Time to Cognitive Failure

II

NCT01854554

Esophageal Cancer

Progression Free Survival

II/III

NCT01512589

Hepatocellular Carcinoma

Overall Survival

III

NCT03186898

Breast Cancer (partial breast)

Rate of Adverse Cosmesis

II

NCT02453737

Breast Cancer

Cardiac Events

III

NCT02603341

Prostate Cancer

2-year EPIC Bowel Score

III

NCT01617161

a

The primary endpoint of this trial is overall survival between dose escalated and standard dose radiation. Within the dose escalated arm, patients will receive protons or intensity-modulated radiation therapy (IMRT) and the overall survival between these groups is a secondary endpoint. Downloaded for [email protected] upr07 ([email protected]) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on April 23, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

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A

B Fig. 24.2 Comparison treatment plans of intensity-modulated radiation therapy (IMRT) versus intensity modulated proton therapy (IMPT) of patients with (A) nasopharyngeal carcinoma and (B) adenoid cystic carcinoma of the hard palate using IMRT. (Reprinted with permission from Blanchard P, Gunn GB, Lin A, et al. Proton therapy for head and neck cancers. Semin Radiat Oncol. 2018;28:53–63.)

appears favorable compared with historic reirradiation data using photons.24

THORACIC MALIGNANCIES Lung Cancer Locally advanced non–small-cell lung cancer (NSCLC) is often treated with definitive chemoradiation that can lead to significant acute and chronic toxicity. In particular, excessive dose to the lungs and heart can lead to significant morbidity and mortality. For example, it is well established that the lung V20 and mean dose are predictive for radiation pneumonitis, which can be fatal. In addition, recent data suggest the importance of cardiac dose to survival after chemoradiation.25 Given the favorable dosimetry of protons, this modality may improve the therapeutic ratio in locally advanced NSCLC. In support of the benefit of protons, a longitudinal study collecting patient-reported outcomes demonstrated less severe symptoms in patients who received proton therapy compared with IMRT or 3D conformal radiation.26 Furthermore, a recent open label Phase II trial of dose-escalated proton passive scattered radiation (74 Gy) with concurrent chemotherapy demonstrated favorable survival and toxicity outcomes.27 Similarly, proton therapy has demonstrated promising outcomes in prospective studies in small cell lung cancer28 and when utilized in the postoperative setting.29 However, a recent randomized Phase II trial comparing passive scattering proton therapy and IMRT for locally advanced NSCLC did not reveal any significant advantage to proton therapy. In particular, no difference was

found in local control or radiation pneumonitis. Proton therapy did improve the cardiac dose, but also resulted in an increase in the lung V20.30 However, this trial was conducted utilizing passive scattering proton therapy, and the dose distribution should be improved using the more advanced technique of IMPT. Such a trial comparing IMPT and IMRT with a simultaneous integrated boost for locally advanced NSCLC is in process (NCT01629498). This trial treats the entire volume to 60 Gy with a dose-escalating simultaneous boost to the gross tumor volume. The Phase I portion of this trial was recently reported, and in the IMPT group, the boost dose of 78 Gy resulted in excessive toxicity in the form of grade 3 or greater pneumonitis. As a result, the final randomized portion will escalate to 72 Gy.31 NRG Oncology is also conducting a randomized Phase III study of photons versus protons in the chemoradiation treatment of locally advanced non–small-cell lung cancer; the study endpoint is overall survival (NCT01993810). Local failure in patients with NSCLC remains a significant problem, but well-selected patients can be salvaged with reirradiation. Protons may mitigate the morbidity of such treatment by minimizing overlap with prior radiation fields. A multi-institutional prospective reirradiation trial for NSCLC demonstrated that even with double scatter protons, reirradiation can be very toxic with 6/57 grade 5 toxicities. Importantly, toxicity was correlated with higher overlap to the central airway, mean esophageal and cardiac doses, as well as concurrent chemotherapy.32 However, reirradiation with IMPT, which often results in improved dose distribution compared with double scatter proton therapy, had a much safer toxicity profile.33

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CHAPTER 24

Thymoma Thymomas are the most common malignancy of the anterior mediastinum.34 Radiation is an important part of the treatment of patients who present with nonresectable disease or with certain pathologic features after surgical resection. Given the location of thymomas, proton therapy can substantially reduce dose to the heart, lungs, esophagus, and breast, which can prevent both acute and long-term toxicity. Prospective data confirm that protons have a favorable toxicity profile with good tumor control outcomes.35 In addition, given the overall favorable tumor control outcomes of thymomas, mitigating the risk of a radiation-induced malignancy is an important consideration.36 Research using models of second malignancy risk predict that in this setting, proton therapy can prevent 5 excess second cancers per 100 patients compared with IMRT.37

Mesothelioma Malignant pleural mesothelioma is an aggressive malignancy of the pleural cavity. After treatment with pleurectomy and decortication, these tumors are especially difficult to radiate because of the circumferential nature of the treatment volume and the need to spare mediastinal structures, liver, and the contralateral lung. Although data are limited, IMPT following pleurectomy and decortication is feasible; it lowers the dose to the contralateral lung, heart, esophagus, kidney, and liver compared with IMRT.38 Similar advantages to IMPT are evident after patients are treated with an extrapleural pneumonectomy.39

BREAST CANCER Radiotherapy plays an integral role in the treatment of patients with localized breast cancer after breast conservation therapy and in certain instances after mastectomy. Because many patients exhibit excellent cancer control, it is increasingly important to mitigate the long-term toxicity of radiotherapy. In particular, long-term cardiac morbidity is an important consideration when treating left-sided breast cancers. Darby et al.40 identified the mean heart dose as a predictor of cardiac toxicity with an increased risk of 7.4% of a major cardiac event per Gy increase in the mean heart dose. Not only is the mean heart dose a critical parameter, it is becoming increasingly clear that dose to the left anterior descending artery, which often is included in tangent fields of left-sided cancers, can lead to stenosis and coronary artery disease.41 For many patients, when only the breasts are targeted, dose to the heart can be reduced with simple techniques such as treating with deep inspiration breath hold.42 However, cardiac sparing becomes increasingly challenging when treating regional draining lymph nodes, particularly the internal mammary chain. Dosimetric comparisons in the setting of regional node irradiation have demonstrated significant reduction in heart and lung doses when comparing protons with photon plans.43,44 The clinical implications of cardiac sparing with proton therapy is being investigated with the prospective multisite RADCOMP (Radiotherapy Comparative Effectiveness) clinical trial comparing proton and photon regional node irradiation for breast cancer (NCT02603341) with the primary outcome of major cardiac events. Proton therapy has also been investigated as an option for accelerated partial breast irradiation. In certain respects, protons seem like the ideal modality for partial breast radiation. Unlike brachytherapy, it is noninvasive and can spare more heart, lung, and uninvolved breast than photons.45–47 However, results from a Phase I/II trial demonstrated that those treated with passively scattered proton partial breast irradiation had worse acute and long-term skin toxicity compared with those receiving photon treatments. This resulted in worse physician-rated cosmesis, although patient-reported cosmesis was similar.48 On the basis of this initial experience, if protons were to be used in the setting of accelerated

Charged Particle Radiotherapy

413

partial breast irradiation, the authors of the study recommended the use of multiple fields and treatment of all fields per treatment session or the use of scanning or IMPT techniques to minimize skin toxicity.

GASTROINTESTINAL MALIGNANCIES Esophageal and Gastric Carcinoma In many instances the standard management of resectable locally advanced esophageal cancer is neoadjuvant chemoradiation followed by surgical resection.49 Several reports have described a dose to critical organs, namely the lung dose, as a strong predictor of perioperative complications that can sometimes be fatal.50,51 Proton therapy can significantly decrease dose to the lungs and heart (Fig. 24.3), which could translate into reduced perioperative morbidity.50,52 A multiinstitutional retrospective analysis of postoperative complications demonstrated that proton therapy or IMRT compared with 3D conformal radiation resulted in significantly fewer cardiac and pulmonary complications. Compared with IMRT, proton therapy had less wound complications and resulted in a shorter hospital stay postoperatively.53 Furthermore, when chemoradiation is the definitive treatment for esophageal cancer, proton therapy can be delivered safely with encouraging clinical results.53,54 Interestingly, in a large retrospective analysis, despite clear dosimetric advantages in dose to the lung and heart, protons did not reduce the toxicity of therapy, but did improve survival.53 This survival advantage needs to be confirmed in prospective trials, but could be related to lower cardiopulmonary doses, similar to locally advanced NSCLC.25 The role of radiation therapy in the management of gastric cancer is controversial, but in the United States, it is often used in the adjuvant setting. Although, minimal data exist for the utility of proton therapy in gastric cancer, dosimetric studies demonstrate reduced small bowel, heart, liver, kidney, and overall integral dose when comparing double scatter proton therapy with IMRT.55 An important consideration when irradiating the stomach is that variability in bowel gas patterns could have a significant impact on the dose distributions. However, verification scans during treatment show that the protons plan are very robust with no more than 2% variability.55

Hepatocellular Carcinoma Patients with hepatocellular carcinoma (HCC) who are not liver transplant candidates or are awaiting a liver transplant are often treated with local therapies including transarterial chemoembolization (TACE), radiofrequency ablation, or radiotherapy. Dosimetric and numerous clinical trials have demonstrated that protons can aid in safely achieving ablative doses that are necessary for optimal local control in this disease. Gandhi et al.56 determined, based on dosimetric analysis, that protons are particularly effective in maximally sparing uninvolved liver when tumors are central or in the dome of the liver. Numerous prospective trials have demonstrated the safety and efficacy of high-dose proton radiotherapy for HCC.57–61 In fact, Bush et al.61 recently reported the interim analysis of a randomized trial comparing proton irradiation (70.2 Gy in 15 fractions) with TACE for HCC. Overall, patients treated with proton therapy had fewer hospitalization days and a trend toward improved local control and progression-free survival.61 Therefore, protons appear to be better tolerated while possibly improving tumor control compared with TACE. The recently initiated NRG-Oncology-sponsored Phase III randomized trial will compare hypofractionated proton versus photon radiotherapy for HCC (NCT03186898). The primary objective of this trial is overall survival.

Pancreatic Carcinoma The role and timing of radiotherapy in the management of pancreatic cancer is controversial; nevertheless, local failure remains a significant

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Fig. 24.3 Dosimetric comparison of proton therapy versus Intensity-modulated radiation therapy (IMRT) for a distal esophageal cancer demonstrating significant normal tissue sparing with proton therapy, particularly to the lung, heart, and liver. (Reprinted with permission from Chuong MD, Hallemeier CL, Jabbour SK, et al. Improving outcomes for esophageal cancer using proton beam therapy. Int J Radiat Oncol Biol Phys. 2016;95:488–497.)

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CHAPTER 24 issue, as does toxicity from radiotherapy to nearby organs at risk. In the setting of nonresectable pancreatic cancer, dosimetric analysis suggests that proton therapy decreases low dose to the small bowel, stomach, and duodenum compared with IMRT, although this low-dose sparing is at the cost of increased exposure of the duodenum to high doses of radiation. This high dose to the duodenum is mitigated with pencil beam scanning (PBS), but is still worse compared with IMRT.62 Thus, ideal plans may require a combination of protons and IMRT. In fact, in a recent Phase I trial of radiation plus nab-paclitaxel for borderline resectable or nonresectable pancreatic carcinoma, the majority of patients were primarily treated with a combination plan of protons and IMRT.63 The safety profile was very encouraging with no grade 3 gastrointestinal toxicities, thus lending some clinical support for utilizing a combination of IMRT and protons for pancreatic cancer. Furthermore, dose-escalated proton therapy has also been investigated in the locally advanced setting with concurrent gemcitabine with encouraging local control and toxicity.64 Lastly, a short course of neoadjuvant proton therapy (25 Gy in 5 fractions) with concurrent capecitabine was shown to be safe with promising local control.65

Rectal Carcinoma The standard of care for patients with locally advanced rectal adenocarcinoma is neoadjuvant chemoradiation or short course radiation followed by total mesenteric excision. Although a paucity of clinical data support the benefit of protons, dosimetric analysis demonstrates, as expected, that protons better spare the small bowel from low doses of radiation.66,67 Reducing exposure of the small bowel to low doses of radiation has important implications as the volume of small bowel receiving at least 15 Gy (V15) is associated with worse gastrointestinal toxicity during chemoradiation for rectal cancer.68

Anal Carcinoma The standard management of anal carcinoma is definitive chemoradiation. Although the advent of IMRT has significantly reduced the morbidity of this treatment,69 patients may suffer from significant acute toxicity and long-term sequelae of their treatment. Dosimetric analysis demonstrates significant advantages for protons, which reduce dose to the small bowel, external genitalia, femoral head, pelvic bones, and bladder.70 This study did not investigate inguinal skin dose, which is a major source of morbidity from desquamation, although the investigators did recommend using posterior beams to spare the anterior skin and improve plan robustness. Although no clinical reports of proton therapy have been published for anal cancer, a feasibility trial recently completed accrual, where the primary outcome was to determine if the incidence of grade 3 dermatitis is less than the expected rate of 48% with 3D-conformal photon radiation (NCT01858025).

GYNECOLOGIC MALIGNANCIES Definitive or adjuvant radiation with or without chemotherapy plays an important role in the management of gynecological malignancies, including cervical, endometrial, vulvar, and vaginal cancer. However, radiotherapy can lead to significant acute and chronic gynecologic, gastrointestinal, and genitourinary toxicity. Furthermore, excessive radiation to pelvic bones leads to bone marrow suppression that can prevent optimal delivery of chemotherapy. A recent randomized trial of adjuvant radiation in endometrial and cervical cancer demonstrated that treatment with IMRT compared with 3D conformal radiation resulted in a reduction in acute and chronic bowel toxicity.71 Given the favorable dosimetry, protons could further decrease these toxicities. Lin et al.72 described the first clinical experience using pencil beam scanning to treat the pelvis in the posthysterectomy setting. In comparison with IMRT, protons better spared the bowel, bladder, and pelvic bone marrow

Charged Particle Radiotherapy

415

from low- and intermediate-dose radiation. However, IMRT was superior in sparing these organs at risk to high-dose radiation.72 The importance of sparing the bowel73,74 and bone marrow from low/intermediate-dose or high-dose radiation for bowel and hematologic toxicity75,76 is controversial. Therefore, further research is needed to understand if protons are advantageous in pelvic malignancies. Nonetheless, this study did report low rates of acute toxicity, albeit with a small sample size (n = 11). The benefit of adjuvant proton therapy for cervical and endometrial cancer is being further investigated in a prospective Phase II trial (NCT03184350).77 In certain clinical circumstances, the paraaortic lymph node chain is targeted when treating patients with endometrial or cervical carcinoma. Even with IMRT, a significant amount of small bowel is irradiated, leading to potential toxicity. Treating patients with a posterior beam angle using protons spares much of the bowel anterior to the target and, therefore, theoretically reduces toxicity. Accordingly, dosimetric studies utilizing IMRT to treat the pelvis and protons for the paraaortic chain demonstrated a significant reduction in dose to the small bowel, large bowel, liver, and left kidney.78 Many women with cervical cancer are diagnosed at a young age and, therefore, are at risk of a therapyinduced second malignancy. Although not assessed in cervical cancer directly, modeling studies comparing proton versus photon radiation for paraaortic radiation in seminoma demonstrated a theoretic reduction in radiation-induced malignancies when protons were utilized.79,80

GENITOURINARY MALIGNANCIES Prostate Cancer Prostate cancer is the most common cancer in men. The primary toxicities of prostate-directed radiation are erectile, urinary, and bowel dysfunction. Numerous dosimetric studies have demonstrated that, compared with IMRT, protons reduce the exposure of the bladder and rectum to low-dose radiation, but in general there is similar exposure to high doses of radiation.81–84 Several large retrospective studies have also indicated similar levels of genitourinary and bowel toxicity between IMRT and proton therapy.85,86 For example, using case-matched analysis, Fang et al.87 compared the genitourinary and bowel toxicity of patients treated with proton radiation versus IMRT at the University of Pennsylvania from 2010 to 2012. The authors found no difference in both early or late genitourinary or gastrointestinal toxicity in the two treatment groups, despite apparent dosimetric advantages of proton therapy.87 In addition, numerous investigators have interrogated various claims-based datasets to study the advantages and disadvantages of proton radiation for the treatment of prostate cancer.88–91 Overall, these studies do not demonstrate a benefit to proton therapy and suggest a possible increase in gastrointestinal toxicity from it. Most recently, Pan et al.88 utilized the MarketScan Commercial Claims and Encounters database of patients treated from 2008 to 2015. In this study, 693 patients who received proton therapy were matched to 3465 patients who were treated with IMRT. Overall, at 2 years postradiation, patients who received proton therapy had a lower risk of composite urinary symptoms (33% vs. 42%) and erectile dysfunction (21% vs. 28%), but these patients experienced a higher rate of bowel toxicity (20% vs. 15%). Importantly, the mean cost of proton therapy was almost double that of IMRT ($115,501 vs. $59,012).88 Given the current clinical evidence, there appears to be clinical equipoise between protons and IMRT. The possible benefit of proton radiation for prostate cancer will be defined better with the currently enrolling Prostate Advanced Technologies Investigating Quality of Life (PARTIQOL) trial (NCT01617161). This trial is a multiinstitutional, randomized trial of IMRT versus proton therapy, with the primary endpoint being mean Expanded Prostate Cancer Index Composite (EPIC) bowel score 2 years after therapy.

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Testicular Cancer When utilized for the treatment of testicular seminoma, radiation targets include the paraaortic lymph node chain, thus exposing a significant volume of bowel to radiation. Even though low doses are utilized, the significant volume of bowel irradiated can lead to significant acute and chronic gastrointestinal morbidity.92,93 Dosimetric studies demonstrate a very clear reduction in bowel dose when proton therapy is compared with IMRT or 3D conformal radiation,79,80,94 (Fig. 24.4), which should significantly reduce gastrointestinal toxicity. In addition, seminomas primarily occur in young males, so it is imperative to reduce the risk of a second malignancy in this highly curable cancer. Through modeling, several studies have predicted that protons would dramatically reduce the risk of a second cancer.79,80

Bladder Cancer Bladder preservation with definitive chemoradiation is an appropriate approach for certain patients with muscle-invasive bladder cancer. Although little has been published in the literature for utilizing protons in this setting, Takaoka et al.95 recently reported their experience of using protons as part of the bladder boost after treating the whole bladder with photons. This retrospective study demonstrated a favorable toxicity profile with no reported grade 3 or greater acute gastrointestinal or genitourinary toxicities and only 3% late genitourinary toxicities. Outcomes were also favorable with a low rate of local recurrence (6%). This low rate of local recurrence is possibly related to the escalated dose

used in these patients (77.7 Gy), which would be difficult to deliver with photons.

LYMPHOMA Hodgkin lymphoma predominantly affects adolescents and young adults. Cancer control outcomes are very good with a 10-year survival rate of approximately 90%. Although the primary treatment is often chemotherapy, radiation plays an integral role in the management of Hodgkin lymphoma, particularly those with stage I or II disease. Given the young age at presentation and high curability, these patients are at high risk of late radiation toxicity, most importantly the development of secondary malignancies, long-term cardiovascular side effects, pulmonary toxicities, and endocrinopathies.96 Non-Hodgkin lymphoma tends to occur in an older population, but patients are still at risk for many of the same longer-term radiation side effects as patients with Hodgkin lymphoma. In recent years, decreases in the radiation prescription dose and reduction in treatment volumes by targeting only the involved node or involved site should help mitigate both short- and long-term toxicity. However, in certain instances further gains can be made with proton therapy, as indicated by numerous dosimetric studies evaluating the advantages of protons in a variety of anatomic sites.97–101 One concern with the use of protons, is that in combination with already significant volume reductions, the steep dose gradient could lead to an increase in failures owing to marginal misses. To address this concern, Hoppe et al.102 reviewed the outcomes of 138 patients with Hodgkin lymphoma

Fig. 24.4 Plan comparison of proton therapy (left) versus 3D conformal photon therapy (right) for a patient with seminoma demonstrating significant normal tissue sparing with proton therapy. (Reprinted with permission from Efstathiou JA, Paly JJ, Lu HM, et al. Adjuvant radiation therapy for early stage seminoma: proton versus photon planning comparison and modeling of second cancer risk. Radiother Oncol. 2012;103:12–17.)

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CHAPTER 24 (primarily in the mediastinum) on registry studies who were treated with consolidative proton therapy. Importantly, the 3-year relapse-free survival rate was 92%, which is similar to studies using photon radiation. Although follow-up remains short, no patients have developed late grade 3 radiation toxicity.102 Proton radiation utilized for non-Hodgkin lymphoma has similarly resulted in comparable local control to prior photon studies.103

SARCOMA Soft Tissue Sarcoma Neoadjuvant or adjuvant radiotherapy is an integral part of the treatment paradigm for soft tissue sarcomas. For extremity sarcomas, the data are limited but, as expected, dosimetric studies demonstrate that protons can decrease low dose to the nearby bone and overall lower integral dose to the affected limb.104 Decreasing this low-dose bath could mitigate some of the long-term limb toxicity, including the risk of a second malignancy. However, particularly, in the neoadjuvant setting, a strong predictor of wound toxicity is the severity of radiation dermatitis.105 Historically, proton therapy was not able to spare the skin as well as IMRT, given the high entrance dose of radiation; however, this can now be mitigated using IMPT. Furthermore, tumor swelling is a well-known phenomenon that can often occur to soft tissue sarcomas during radiotherapy.106 Given that protons are very sensitive to anatomic shifts, it is imperative to monitor tumoral changes closely and replan, as needed. The role of perioperative radiation for retroperitoneal sarcoma is controversial and is being evaluated in a recently completed randomized trial (NCT01344018). However, if used, patients should be treated with radiation in the neoadjuvant setting to avoid large volumes of bowel and other critical organs. Protons are an ideal modality in this setting because tumors tend to be very large and thus protons can diminish radiation exposure to other critical surrounding structures.107 Furthermore, given the high rate of local recurrence, an area of interest in retroperitoneal sarcoma is selectively boosting the high-risk margin of these tumors. DeLaney et al.108 recently reported the results of a Phase I trial utilizing IMPT to treat the entire tumor to 50.4 Gy with a simultaneous integrated boost treating the high-risk margin to 63 Gy, all in 28 fractions. The regimen was safe and, although follow-up is still early, there were no local recurrences. This study is currently enrolling for the Phase II portion.108 There is a parallel Phase I/II study using IMRT that should provide comparative outcome data.

Bone Sarcoma Skull base chordomas and chondrosarcomas are optimally treated with maximal safe surgical resection and adjuvant high-dose radiotherapy. Protons are particularly helpful in this setting given the need for high-dose radiation (>70 Gy) and nearby critical structures, most importantly the brainstem. Long-term data from a variety of trials demonstrate that high-dose proton radiotherapy is safe and results in favorable local control, specifically in the 70% to 80% range for chordomas 109–112 and greater than 90% for chondrosarcomas.109,112,113 Thus, many consider proton therapy the standard of care for base of skull chondrosarcomas and chordomas. Similar to base of skull chordomas, spinal chordomas represent a challenging disease given the difficulties of surgery and the need for high doses of radiation. A retrospective series of 24 patients with nonresectable or medically inoperable spinal sarcomas treated with a combined proton/photon technique to a median dose of 77.4 Gy demonstrated very promising efficacy with 5-year local control of 79.8% and a chordoma-specific survival of 81.5%.114 An update of this experience, now including 40 patients, reported 5-year local control of 85.4%.115 Importantly, despite the very high doses, the therapy was well tolerated

Charged Particle Radiotherapy

417

with all patients remaining ambulatory. The most common toxicity was sacral insufficiency fracture (n = 8). Correspondingly, a prospective Phase II trial of spinal sarcomas (primarily chordomas and chondrosarcomas) treated with a combined photon/proton technique with or without resection demonstrated high rates of tumor control. Specifically, for primary tumors the 5- and 8-year local control rates were 94% and 85%, respectively. Importantly, no myelopathies were observed and the rate of late grade 3 to 4 radiation toxicity was 13%.116 Osteosarcomas are traditionally treated with combination chemotherapy and surgical resection. These tumors are thought to be radioresistant, and thus radiation therapy is often reserved for nonresectable tumors or those with residual disease after surgery. However, high-dose radiation, which can be more safely delivered with proton therapy, can provide very durable local control. In a series from Massachusetts General Hospital, 55 patients with nonresected or partially resected osteosarcomas treated to high-dose proton radiation (mean dose of 68.4 Gy) had a 3- and 5-year local control rate of 82% and 72%, respectively.117 Thus, patients with nonresectable or incompletely resected osteosarcoma would benefit from high-dose radiation which, depending on the location, may be most safely delivered with protons.

PEDIATRIC MALIGNANCIES In general, the positive benefit of proton therapy is most apparent when treating pediatric malignancies. By sparing many critical organs, particularly in developing tissue, which is more sensitive to radiation damage, protons can mitigate some of the late toxicities that pediatric cancer survivors experience. Furthermore, one of the most feared late complications of radiation therapy for children is the development of a secondary malignancy, and protons will uniformly lower this risk by decreasing the overall integral dose to the body.

Central Nervous System Malignancies The positive impact of proton therapy appears most striking when it is utilized to treat the entire cranial spinal axis for malignancies such as medulloblastoma, among others. Craniospinal irradiation delivered with photon techniques leads to significant unintended dose to the thorax, abdomen, and pelvis, resulting in significant acute gastrointestinal toxicity, but more importantly the risk of, long-term cardiopulmonary toxicity, gastrointestinal toxicity, infertility, and an increased risk of second malignancy. Protons can completely eliminate dose anterior to the cranial spinal axis and therefore mitigate or even eliminate many of the early and late toxicities (Fig. 24.5).118 Accordingly, retrospective comparisons of patients treated with proton or photon craniospinal irradiation demonstrated a clear advantage of protons in reducing acute nausea, esophagitis, weight loss, and hematologic toxicity.119 Moreover, a prospective Phase 2 trial of 59 children with medulloblastoma treated with proton craniospinal irradiation at the Massachusetts General Hospital had no reports of late cardiac, pulmonary, or gastrointestinal toxicity.120 Furthermore, for the boost portion of treatment, protons can significantly spare numerous critical neurologic structures, including the overall integral dose to the brain. Clinically, the use of protons has led to improved neurocognitive, hearing, and endocrine outcomes. Specifically, children with medulloblastoma treated in the aforementioned Phase II trial of proton craniospinal irradiation demonstrated an average decrease in IQ of 1.5 points per year.120 This IQ decrease compares favorably to historical studies using photon therapy, where IQ fell in the range of 1.9 to 5.8 points per year,121–124 despite that this proton study treated patients who had a younger median age and a higher portion of patients at high risk who receive a higher craniospinal dose. In addition, the rate of grade 3 or 4 hearing loss in this trial was lower than historical controls, presumably from lower dose to the cochlea.120

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120 %

120 %

80 %

80 %

30 %

30 %

A

B Fig. 24.5 (A) Isodose distribution in the axial projection at the level of the cochlea for x-rays, IMRT, and protons. Bilateral dark circular structures represent the cochlea. (B) Isodose distribution in the sagittal projection along the spinal column for x-rays, IMRT, and protons. (From St. Clair WH, et al. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys. 2004;58(3):727.)

Furthermore, a matched analysis of patients who received either proton or photon craniospinal irradiation demonstrated that proton therapy resulted in fewer endocrine abnormalities, specifically with a lower incidence of hypothyroidism, sex hormone deficiency, need for any endocrine replacement therapy, and a higher height standard deviation score.125 The benefits of proton therapy are also evident in other pediatric central nervous system malignancies, such as ependymoma, glioma, and germinoma.126

Noncentral Nervous System Malignancies Numerous studies have demonstrated the acute and long-term benefits of proton radiotherapy for children with neoplasms outside of the central nervous system. For example, Vogel et al.127 recently reported on the outcomes of 69 patients with pediatric head and neck malignancies. Although there were diverse histologies with different radiation doses included in the study, patients had very low rates of acute toxicity, with only 4% developing grade 3 oral mucositis.127 Longer follow-up is needed to determine the impact on late head- and neck-associated toxicity. Similarly, patients with pediatric rhabdomyosarcoma treated

with proton radiation in a prospective Phase 2 trial had superior radiation plans compared with IMRT,128 and follow-up from this trial resulted in low rates of acute and late toxicity, while maintaining similar cancer control outcomes compared with previous trials.129 Further, in general, patients treated with proton therapy for Ewing sarcoma demonstrated that it was well tolerated with a low rate of late toxicity and no compromise in cancer control outcomes.130,131 Others have demonstrated clear dosimetric advantages for proton therapy in other pediatric malignancies such as neuroblastoma132,133 and Wilms tumor.134 Importantly, because many of these tumors can occur in diverse anatomic locations, the benefits of proton therapy largely depend on the location. Nonetheless, protons will always decrease the integral dose and, consequently, the risk of a second cancer.

METASTATIC DISEASE When radiation therapy is indicated for patients with metastatic disease, it is most commonly for palliation, and the favorable dose distribution of proton therapy is not necessary. However, in certain instances the

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CHAPTER 24 favorable dosimetry of protons may be beneficial, particularly when stereotactic body radiotherapy (SBRT) is utilized to ablate oligometastatic disease or for stereotactic radiosurgery for brain metastases. In particular, Hong et al.135 recently reported the results of a single arm Phase II trial of proton-based SBRT for liver metastases. The therapy was well tolerated with no cases of radiation-induced liver disease or other grade 3 or greater toxicities, and similar local control compared with prior studies. Importantly, this study included a portion of larger tumors (≥ 6 cm), which are often omitted from other studies, making the results even more impressive.135 In addition, Atkins et al.136 recently reviewed the Massachusetts General Hospital experience in treating 815 brain metastases with proton-based stereotactic radiosurgery, demonstrating that the therapy is well tolerated and has good local control.136

COST EFFECTIVENESS OF PROTONS Owing to the very high cost of opening and operating proton facilities, it is important to investigate the cost effectiveness of proton radiotherapy in comparison with standard photon techniques. In fact, without the large difference in cost, one could argue that based on dosimetric advantages alone, almost every patient with cancer should be treated with proton therapy. An oversimplification of healthcare value can be defined as a certain healthcare outcome (e.g., survival or toxicity) divided by cost. Defining cost effectiveness in medicine is extraordinarily difficult, and always subject to what society as a whole values most. Furthermore, the cost of constructing proton therapy centers and delivering the therapy is becoming cheaper and more efficient, thus continuously lowering the denominator of the healthcare value equation. Certainly, the potential for proton therapy to reduce the incidence of long-term toxicity in pediatric cancer survivors, some of whom can require lifelong medical care, would be deemed as cost effective.137 However, in other patient populations and malignancies, the cost effectiveness is less obvious. It is not only the prevention of late radiation morbidity, as is often the case for treating children or young adults with protons, that may make protons more cost effective. For example, there is evidence that proton therapy utilized in the management of head and neck malignancies can reduce many of the acute and subacute toxicities,20 which can result in increased hospitalizations, medication use, and procedures such as gastrostomy tube placement. Many of the proton versus photon randomized trials are evaluating a toxicity outcome as the primary endpoint (Table 24.2). A direct comparison of toxicity, both acute and late, in different cancers will better define the value of proton therapy.

Immunotherapeutic Considerations of Protons Although radiation therapy has classically been thought of as a local therapy, increasing evidence indicates that radiation can enhance the antitumor immune response.138 As such, there is enormous preclinical and clinical interest in combining radiation with a variety of immunemodulating agents. Although radiotherapy can induce an immune response, it can also have immunosuppressive features. In particular, radiotherapy can impair the host immune system by killing circulating lymphocytes, which are extraordinarily sensitive to radiation. By minimizing the integral dose, and therefore sparing more circulating lymphocytes, protons may be advantageous in optimizing a robust radiation-induced anticancer immune response. In fact, in patients with locally advanced NSCLC, a larger treatment volume correlated with lower lymphocyte nadirs during chemoradiation and worse survival.139 At a basic level, treatment with proton irradiation demonstrates similar immunogenic responses compared with photon irradiation.140 Interestingly, preliminary laboratory evidence suggests that carbon ion radiotherapy can induce a more robust immune response as indicated by a larger infiltrate of T-cells compared with photons.141

Charged Particle Radiotherapy

419

CARBON ION RADIOTHERAPY Carbon ions have a slight physical advantage over protons in that they will have a narrower penumbra than protons, particularly for deep-seated tumors.142 On the other hand, carbon ions will also produce some spallation products deep to the Bragg peak. In addition, carbons have a higher RBE and lower oxygen enhancement ratio compared with protons, making this an intriguing modality for hypoxic and radioresistant tumors. However, whether the higher RBE and differential effect on hypoxic cells of carbon ions will translate into a clinical advantage remains to be determined, particularly because the clinical use of carbon has generally been with larger fraction sizes where there will be less RBE difference between carbon ions and protons. Carbon ions have a high ionization and double-strand break density and therefore have the greatest potential value in areas of gross tumor to minimize late normal tissue injury. Although more limited than proton therapy, increasing clinical evidence supports the safety and efficacy of carbon ion radiotherapy The clinical utility of carbon ion therapy has been studied extensively in a variety of sarcomas. First, Kamada et al.143 reported the results of a Phase I/II study evaluating the tolerance and effectiveness of carbon ion radiotherapy in patients with nonresectable bone and soft-tissue sarcomas. Of the patients, 57 with 64 sites of sarcomas not suited for resection received carbon ion therapy. Tumors involved the spine or paraspinal soft tissues in 19 patients, the pelvis in 32 patients, and the extremities in 6 patients. The total dose ranged from 52.8 to 73.6 carbon GyE and was administered in 16 fractions (3.3 GyE/fraction to 4.6 GyE/ fraction). Seventeen of the patients treated with the highest total dose of 73.6 GyE experienced Radiation Therapy Oncology Group (RTOG) grade 3 acute skin reactions. No other severe acute reactions (grade ≥ 3) were observed. The overall local control rates were 88% and 73% at 1 and 3 years of follow-up, respectively. The 1- and 3-year overall survival rates were 82% and 46%, respectively. In another retrospective study of nonresectable retroperitoneal sarcomas, carbon ion radiation was delivered in a dose of 52.8 to 73.6 GyE in 16 fractions with impressive tumor control. Specifically, local control rates at 2 and 5 years were 77% and 69%, respectively. Overall survival at 2 and 5 years was 75% and 50%, respectively. Despite treating large tumors to a high dose, no patients experienced any grade 3 or greater toxicity.144 Further clinical studies demonstrated the efficacy and safety of carbon ion radiotherapy for nonresectable head and neck sarcomas,145 nonresectable spinal sarcomas,146 and nonresectable pelvic sarcomas.147 Given the favorable dose distribution and higher biological effectiveness, carbon ion therapy appears to be a promising modality for skull base or spinal chordomas. Schulz-Ertner et al.148 demonstrated that treating chordomas of the skull base using raster scanning carbon ion radiation therapy was safe and effective. All 96 patients in this study had gross residual tumors. The median total dose was 60 Gy(RBE) (range, 60 Gy[RBE] to 70 Gy[RBE]), delivered in 20 fractions. The actuarial local control rates were 80.6% and 70% at 3 and 5 years, respectively. Target doses in excess of 60 Gy(RBE) and primary tumor status were associated with higher local control rates. Overall survival rates were 91.8% and 88.5% at 3 and 5 years, respectively. Grade 3 toxicity, which was seen in 4% of patients, consisted of fat necrosis and optic neuropathy. Similarly, carbon ion therapy is a safe and effective method of treating nonresectable sacral chordomas.149 Specifically, in a series of 188 patients treated to a dose of 64 to 73.6 GyE in 16 fraction, the therapy resulted in a 5-year local control, overall survival, and disease-free survival of 77.2%, 81.1%, and 50.3%, respectively. Furthermore, the therapy was overall well tolerated with six cases of grade 3 peripheral nerve toxicity and three cases of grade 3/4 skin toxicity. Almost all (97%) of the patients treated remained ambulatory.

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420

SECTION II

TABLE 24.3

Techniques and Modalities

Randomized Clinical Trials Comparing Proton and Carbon Ion Therapy

Malignancy

Primary Endpoint

Phase

Clinical Trial Identifier

Prostate Cancer

Proctitis and Cystitis (3 years)

II

NCT01641185

Glioblastoma

Overall Survival

II

NCT01165671

Sacrococcygeal Chordoma

Safety

II

NCT01811394

Skull Base Chordoma

Local Progression-Free Survival

III

NCT01182779

Skull Base Chondrosarcoma

Local Progression-Free Survival

III

NCT01182753

Similar to proton therapy, carbon ion radiation appears to be a favorable modality for treating liver tumors. Dosimetric comparison between carbon and photon SBRT demonstrate that carbon ion therapy can spare more normal liver.150 Kato et al.151 reported the results of a carbon ion dose escalation study for 24 patients with hepatocellular carcinoma. Fifteen fractions were delivered over 5 weeks; total doses ranged from 49.5 Gy to 79.5 GyE. The overall tumor response rate was 71%. The local control and overall survival rates were 92% and 92%, 81% and 50%, and 81% and 25% at 1, 3, and 5 years, respectively. Furthermore, a pooled analysis of two prospective Phase II trials of carbon ion therapy for hepatocellular carcinoma similarly demonstrated that the therapy was safe and effective.152 One of these studies had a Phase I portion that determined the recommended Phase II dose to be 52.8 GyE in 4 fractions. This dose was subsequently used in the Phase II portions of both trials. A total of 124 patients were treated in these two trials with 1-, 3-, and 5-year local control rates of 94.7%, 91.4%, and 90%, respectively. In addition, Combs et al.153 treated six patients with hepatocellular carcinoma with raster scanning technology to a dose of 40 GyE in 4 fractions. The local control was 100% with no grade 3 or greater toxicities. Therefore, carbon ion radiotherapy appears to be a promising and safe option for patients with hepatocellular carcinoma. Carbon therapy has also been utilized for pancreatic cancer with promising results. Shinoto et al.154 reported the results of a dose-escalated preoperative short-course carbon ion regimen for patients with resectable pancreatic cancer. Dose was escalated to 36.8 GyE in 8 fractions. Overall, the therapy was well tolerated with only one patient developing an acute grade 3 liver toxicity (abscess) and one patient developing a late grade 4 liver toxicity from portal vein stenosis. No other grade 3 or greater toxicities were observed. This therapy resulted in very promising efficacy with no reported local failures and with a 5-year survival rate of 42%. To date the only reported randomized trial involving carbon ion therapy is a randomized Phase II trial comparing proton versus carbon ion therapy in prostate cancer.155 In this trial, a total of 92 patients were treated to a dose of 66 Gy in 20 fractions. The acute gastrointestinal and genitourinary toxicity rates, as well as quality of life parameters, were similar between the two treatment groups. Of note, two patients in the proton arm did develop grade 3 rectal fistulas, but this was thought to be caused by improper spacer gel placement. Further follow-up is necessary to evaluate the long-term toxicity and cancer control outcomes. Although overall the therapy appears well tolerated, the side effect profile appears similar to those observed in modern IMRT trials and, therefore, the benefit of charged particles in this disease site remains to be determined. In addition to the aforementioned randomized trial of lower LET protons compared with higher LET carbon ions for prostate cancer, other randomized trials are underway (Table 24.3). Of note, there are no randomized trials comparing carbon ion to photon radiation.

NEON ION RADIOTHERAPY High-LET charged particle therapy with neon ions was studied in the treatment of glioblastoma because of the neon ion’s increased biologic potential for destruction of radioresistant tumors. At the University of California, San Francisco (UCSF), and Lawrence Berkeley Laboratories (LBL), 15 patients were entered into a randomized protocol comparing two dose levels of neon ion irradiation, either 20 Gy or 25 Gy in 4 weeks.156 However, there was no significant difference in overall survival time (13 to 14 months). Furthermore, an optimal dose level was not identified. Neon ions are not in current clinical use.

π-MESON RADIOTHERAPY Subatomic particles called π-mesons provide the nuclear binding force between nuclei. These particles are produced when protons (600+ MeV) interact with a target. Three types of mesons are produced: a neutral form, a positive form, and a negative form. It is the negative form, π− that is used for radiotherapy. When the π− slows down, it is “captured” by a nucleus, causing it to “explode” in a “star” event, producing neutrons and charged nuclear fragments having high-LET properties157 (Fig. 24.6). Negative π-mesons (pions) were used to treat 228 patients at the Los Alamos Meson Physics Facility between 1974 and 1981. Of these patients, 129 received pion therapy only. All patients had locally advanced disease, and a number of different sites were treated. Local control was achieved in 86% of patients with prostate cancer, in 26% with head and neck cancers, and in none with pancreatic cancer. A steep rise in the complication rate was seen beyond a dose level of 3750 cGy.158 Pions were also compared with photons in a randomized trial for the management of prostate cancer.159 Interestingly, treatment with pions resulted in increased acute genitourinary toxicity, but less late toxicity. No difference was found in local control between the two groups. Another randomized trial comparing pions with photons for the management of high-grade astrocytomas did not demonstrate a difference in tumor control or toxicity.160 π-Mesons are also no longer in clinical use.

HELIUM RADIOTHERAPY A retrospective study was done at UCSF and LBL to evaluate the use of helium ions in the treatment of uveal melanomas.161 Ten years after helium ion radiation, 208 of the 218 eyes irradiated had local tumor control (95.4%). At 10 years, 46 eyes (22%) had been enucleated, the majority resulting from anterior ocular segment complications. At 10 years, 51 patients (23%) had died of metastatic melanoma. The best corrected visual acuity after irradiation was greater than 20/40 in 21 of 93 eyes (23%) of patients who were alive and who had retained their eyes 10 or more years after treatment. Visual acuity was related to height of tumor and location near the nerve or fovea. Furthermore, helium ion therapy has been compared with Iodine-125 plaque brachytherapy

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CHAPTER 24 3 Depth to entrance dose ratio

Neutrons

E∏ = 96 MeV

“Stars” 2

1

Electrons 20

to be elucidated with the ongoing randomized trials comparing proton with photon techniques. Heavier charged particles have a sharper penumbra than protons when treating deep targets and may also confer a biologic advantage against tumors because of the higher RBE and differential effect on hypoxic cells. However, comparison studies with protons and photons are recommended to see if there is indeed a clinical advantage in using carbon ions over protons or photons, particularly given the greater complexity and cost of carbon or other heavier charged particles.

CRITICAL REFERENCES

0 10

421

Muons

Pions

0

Charged Particle Radiotherapy

30

40

Depth (cm-water) Fig. 24.6 Illustration of negative π− meson capture. When the π− slows down, it is “captured” by a nucleus, causing it to “explode” in a “star” event, producing neutrons and charged nuclear fragments with high-linear energy transfer properties.

for the management of uveal melanoma.162 Long-term follow-up demonstrated a significant local control benefit to helium therapy, 100% versus 84% at 5 years, and 98% versus 86% at 12 years. The enucleation rate was also significantly lower in patients treated with helium ion therapy, with a rate of 11% versus 22% at 5 years, and 17% versus 37% at 12 years. Schoenthaler et al.163 reported on the use of heavier charged particle irradiation for sacral chordomas. At LBL, 14 patients with sacral chordomas were treated with charged particles, either lower LET helium or higher LET neon. All patients were treated postoperatively; 10 had gross disease. With a median dose of 7565 cGy, the survival rate at 5 years was 85%, and the overall 5-year local control rate was 55%. A trend in improved local control at 5 years was seen in patients treated with neon ions compared with patients treated with helium ions (62% vs. 34%), in patients following complete resection versus patients with gross residual tumor (75% vs. 40%), and in patients who had treatment courses fewer than 73 days (61% vs. 21%). No patient developed neurologic sequelae or pain syndromes. One patient who had been irradiated previously required colostomy; one patient had delayed wound healing following a negative postradiation biopsy; and one patient developed a second malignant tumor. There were no genitourinary complications.

CONCLUSIONS As discussed, the main benefit of protons over conventional photon beam radiotherapy is a reduction in integral dose. With intensity modulation, dose conformality with protons and photons is comparable (assuming a small enough proton pencil beam diameter). It remains to be determined how much clinical benefit this reduction in integral dose achieves for patients. From planning studies, the greatest benefit is projected for larger targets (or larger targets relative to the size of the involved or closely approximated critical organ such as would be the case for eye tumors or skull-base tumors) and in younger patients, where studies project a reduction in second cancers164 and other late effects to render protons cost effective.137 With minimization of the normal tissue dose, protons may allow for further dose escalation as well as for better tolerance of combined chemotherapy and radiation therapy regimens. The clinical benefits of proton therapy will continue

8. Shih HA, Sherman JC, Nachtigall LB, et al. Proton therapy for low-grade gliomas: results from a prospective trial. Cancer. 2015;121:1712–1719. 16. Murray FR, Snider JW, Bolsi A, et al. Long-term clinical outcomes of pencil beam scanning proton therapy for benign and non-benign intracranial meningiomas. Int J Radiat Oncol Biol Phys. 2017;99: 1190–1198. 20. Blanchard P, Garden AS, Gunn GB, et al. Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer - A case matched analysis. Radiother Oncol. 2016;120:48–55. 30. Liao Z, Lee JJ, Komaki R, et al. Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer. J Clin Oncol. 2018;doi:10.1200/JCO.2017.74.0720. 35. Vogel J, Berman AT, Lin L, et al. Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma: early response and toxicity assessment. Radiother Oncol. 2016;118:504–509. 48. Galland-Girodet S, Pashtan I, MacDonald SM, et al. Long-term cosmetic outcomes and toxicities of proton beam therapy compared with photon-based 3-dimensional conformal accelerated partial-breast irradiation: a phase 1 trial. Int J Radiat Oncol Biol Phys. 2014;90:493– 500. 53. Lin SH, Merrell KW, Shen J, et al. Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer. Radiother Oncol. 2017;123: 376–381. 61. Bush DA, Smith JC, Slater JD, et al. Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for hepatocellular carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys. 2016;95:477–482. 65. Hong TS, Ryan DP, Borger DR, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89:830–838. 72. Lin LL, Kirk M, Scholey J, et al. Initial report of pencil beam scanning proton therapy for posthysterectomy patients with gynecologic cancer. Int J Radiat Oncol Biol Phys. 2016;95:181–189. 80. Efstathiou JA, Paly JJ, Lu HM, et al. Adjuvant radiation therapy for early stage seminoma: proton versus photon planning comparison and modeling of second cancer risk. Radiother Oncol. 2012;103:12–17. 88. Pan HY, Jiang J, Hoffman KE, et al. Comparative toxicities and cost of intensity-modulated radiotherapy, proton radiation, and stereotactic body radiotherapy among younger men with prostate cancer. J Clin Oncol. 2018;doi:10.1200/JCO.2017.75.5371. 95. Takaoka EI, Miyazaki J, Ishikawa H, et al. Long-term single-institute experience with trimodal bladder-preserving therapy with proton beam therapy for muscle-invasive bladder cancer. Jpn J Clin Oncol. 2017;47: 67–73. 102. Hoppe BS, Hill-Kayser CE, Tseng YD, et al. Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma. Ann Oncol. 2017;28:2179–2184. 103. Sachsman S, Flampouri S, Li Z, et al. Proton therapy in the management of non-Hodgkin lymphoma. Leuk Lymphoma. 2015;56:2608–2612.

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Techniques and Modalities

108. DeLaney TF, Chen YL, Baldini EH, et al. Phase 1 trial of preoperative image guided intensity modulated proton radiation therapy with simultaneously integrated boost to the high risk margin for retroperitoneal sarcomas. Adv Radiat Oncol. 2017;2:85–93. 115. Kabolizadeh P, Chen YL, Liebsch N, et al. Updated outcome and analysis of tumor response in mobile spine and sacral chordoma treated with definitive high-dose photon/proton radiation therapy. Int J Radiat Oncol Biol Phys. 2017;97:254–262. 116. DeLaney TF, Liebsch NJ, Pedlow FX, et al. Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol. 2014;110:115–122. 117. Ciernik IF, Niemierko A, Harmon DC, et al. Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer. 2011;117:4522–4530. 120. Yock TI, Yeap BY, Ebb DH, et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol. 2016;17:287–298.

129. Ladra MM, Szymonifka JD, Mahajan A, et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol. 2014;32:3762–3770. 143. Kamada T, Tsujii H, Tsuji H, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin Oncol. 2002;20: 4466–4471. 152. Kasuya G, Kato H, Yasuda S, et al. Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: combined analyses of 2 prospective trials. Cancer. 2017;123:3955–3965. 154. Shinoto M, Yamada S, Yasuda S, et al. Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer. Cancer. 2013;119:45–51. 162. Mishra KK, Quivey JM, Daftari IK, et al. Long-term results of the UCSF-LBNL randomized trial: charged particle with helium ion versus iodine-125 plaque therapy for choroidal and ciliary body melanoma. Int J Radiat Oncol Biol Phys. 2015;92:376–383.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 24

REFERENCES 1. Demizu Y, Kagawa K, Ejima Y, et al. Cell biological basis for combination radiotherapy using heavy-ion beams and high-energy X-rays. Radiother Oncol. 2004;71:207–211. 2. Koike S, Ando K, Oohira C, et al. Relative biological effectiveness of 290 MeV/u carbon ions for the growth delay of a radioresistant murine fibrosarcoma. J Radiat Res. 2002;43:247–255. 3. DeLuca PMJ, Wambersie AWG. Prescribing, recording, and reporting proton-beam therapy. J ICRU. 2007;7:1–210. 4. http://www.ptcog.ch/. Accessed April 1, 2018. 5. Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016;374: 1344–1355. 6. Harrabi SB, Bougatf N, Mohr A, et al. Dosimetric advantages of proton therapy over conventional radiotherapy with photons in young patients and adults with low-grade glioma. Strahlenther Onkol. 2016;192:759–769. 7. Wilkinson B, Morgan H, Gondi V, et al. Low levels of acute toxicity associated with proton therapy for low-grade glioma: a proton collaborative group study. Int J Radiat Oncol Biol Phys. 2016;96:E135. 8. Shih HA, Sherman JC, Nachtigall LB, et al. Proton therapy for low-grade gliomas: results from a prospective trial. Cancer. 2015;121:1712–1719. 9. Minniti G, Amelio D, Amichetti M, et al. Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiother Oncol. 2010;97:377–381. 10. Mizumoto M, Yamamoto T, Takano S, et al. Long-term survival after treatment of glioblastoma multiforme with hyperfractionated concomitant boost proton beam therapy. Pract Radiat Oncol. 2015;5: e9–e16. 11. Combs SE, Adeberg S, Dittmar JO, et al. Skull base meningiomas: Long-term results and patient self-reported outcome in 507 patients treated with fractionated stereotactic radiotherapy (FSRT) or intensity modulated radiotherapy (IMRT). Radiother Oncol. 2013;106:186–191. 12. Baumert BG, Norton IA, Lomax AJ, et al. Dose conformation of intensity-modulated stereotactic photon beams, proton beams, and intensity-modulated proton beams for intracranial lesions. Int J Radiat Oncol Biol Phys. 2004;60:1314–1324. 13. Arvold ND, Niemierko A, Broussard GP, et al. Projected second tumor risk and dose to neurocognitive structures after proton versus photon radiotherapy for benign meningioma. Int J Radiat Oncol Biol Phys. 2012; 83:e495–e500. 14. Hug EB, Devries A, Thornton AF, et al. Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy. J Neurooncol. 2000;48:151–160. 15. McDonald MW, Plankenhorn DA, McMullen KP, et al. Proton therapy for atypical meningiomas. J Neurooncol. 2015;123:123–128. 16. Murray FR, Snider JW, Bolsi A, et al. Long-term clinical outcomes of pencil beam scanning proton therapy for benign and non-benign intracranial meningiomas. Int J Radiat Oncol Biol Phys. 2017;99:1190–1198. 17. Kandula S, Zhu X, Garden AS, et al. Spot-scanning beam proton therapy vs intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison. Med Dosim. 2013;38: 390–394. 18. Holliday EB, Kocak-Uzel E, Feng L, et al. Dosimetric advantages of intensity-modulated proton therapy for oropharyngeal cancer compared with intensity-modulated radiation: a case-matched control analysis. Med Dosim. 2016;41:189–194. 19. Apinorasethkul O, Kirk M, Teo K, et al. Pencil beam scanning proton therapy vs rotational arc radiation therapy: a treatment planning comparison for postoperative oropharyngeal cancer. Med Dosim. 2017;42:7–11. 20. Blanchard P, Garden AS, Gunn GB, et al. Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer - A case matched analysis. Radiother Oncol. 2016;120:48–55. 21. Sio TT, Lin HK, Shi Q, et al. Intensity modulated proton therapy versus intensity modulated photon radiation therapy for oropharyngeal cancer:

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first comparative results of patient-reported outcomes. Int J Radiat Oncol Biol Phys. 2016;95:1107–1114. 22. Gunn GB, Blanchard P, Garden AS, et al. Clinical outcomes and patterns of disease recurrence after intensity modulated proton therapy for oropharyngeal squamous carcinoma. Int J Radiat Oncol Biol Phys. 2016; 95:360–367. 23. Romesser PB, Cahlon O, Scher E, et al. Proton beam radiation therapy results in significantly reduced toxicity compared with intensitymodulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiother Oncol. 2016;118:286–292. 24. Romesser PB, Cahlon O, Scher ED, et al. Proton beam reirradiation for recurrent head and neck cancer: multi-institutional report on feasibility and early outcomes. Int J Radiat Oncol Biol Phys. 2016;95:386–395. 25. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-bytwo factorial phase 3 study. Lancet Oncol. 2015;16:187–199. 26. Wang XS, Shi Q, Williams LA, et al. Prospective study of patientreported symptom burden in patients with non-small-cell lung cancer undergoing proton or photon chemoradiation therapy. J Pain Symptom Manage. 2016;51:832–838. 27. Chang JY, Verma V, Li M, et al. Proton beam radiotherapy and concurrent chemotherapy for unresectable stage III non-small cell lung cancer: final results of a phase 2 study. JAMA Oncol. 2017;3:e172032. 28. Rwigema JM, Verma V, Lin L, et al. Prospective study of proton-beam radiation therapy for limited-stage small cell lung cancer. Cancer. 2017; 123:4244–4251. 29. Remick JS, Schonewolf C, Gabriel P, et al. First clinical report of proton beam therapy for postoperative radiotherapy for non-small-cell lung cancer. Clin Lung Cancer. 2017;18:364–371. 30. Liao Z, Lee JJ, Komaki R, et al. Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer. J Clin Oncol. 2018;doi:10.1200/JCO.2017.74.0720. 31. Jeter MD, Gomez D, Nguyen QN, et al. Simultaneous integrated boost for radiation dose escalation to the gross tumor volume with intensity modulated (photon) radiation therapy or intensity modulated proton therapy and concurrent chemotherapy for stage II to III non-small cell lung cancer: a phase 1 study. Int J Radiat Oncol Biol Phys. 2018;100: 730–737. 32. Chao HH, Berman AT, Simone CB 2nd, et al. Multi-institutional prospective study of reirradiation with proton beam radiotherapy for locoregionally recurrent non-small cell lung cancer. J Thorac Oncol. 2017;12:281–292. 33. Ho JC, Nguyen QN, Li H, et al. Reirradiation of thoracic cancers with intensity modulated proton therapy. Pract Radiat Oncol. 2018; 8:58–65. 34. Riedel RF, Burfeind WR Jr. Thymoma: benign appearance, malignant potential. Oncologist. 2006;11:887–894. 35. Vogel J, Berman AT, Lin L, et al. Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma: early response and toxicity assessment. Radiother Oncol. 2016;118:504–509. 36. Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg. 2004;77: 1860–1869. 37. Vogel J, Lin L, Litzky LA, et al. Predicted rate of secondary malignancies following adjuvant proton versus photon radiation therapy for thymoma. Int J Radiat Oncol Biol Phys. 2017;99:427–433. 38. Pan HY, Jiang S, Sutton J, et al. Early experience with intensity modulated proton therapy for lung-intact mesothelioma: a case series. Pract Radiat Oncol. 2015;5:e345–e353. 39. Lee H, Zeng J, Bowen SR, et al. Proton therapy for malignant pleural mesothelioma: a three case series describing the clinical and dosimetric advantages of proton-based therapy. Cureus. 2017;9:e1705. 40. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368: 987–998.

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41. Nilsson G, Holmberg L, Garmo H, et al. Distribution of coronary artery stenosis after radiation for breast cancer. J Clin Oncol. 2012;30:380–386. 42. Remouchamps VM, Vicini FA, Sharpe MB, et al. Significant reductions in heart and lung doses using deep inspiration breath hold with active breathing control and intensity-modulated radiation therapy for patients treated with locoregional breast irradiation. Int J Radiat Oncol Biol Phys. 2003;55:392–406. 43. Bradley JA, Dagan R, Ho MW, et al. Initial Report of a Prospective Dosimetric and Clinical Feasibility Trial Demonstrates the Potential of Protons to Increase the Therapeutic Ratio in Breast Cancer Compared With Photons. Int J Radiat Oncol Biol Phys. 2016;95:411–421. 44. MacDonald SM, Jimenez R, Paetzold P, et al. Proton radiotherapy for chest wall and regional lymphatic radiation; dose comparisons and treatment delivery. Radiat Oncol. 2013;8:71. 45. Taghian AG, Kozak KR, Katz A, et al. Accelerated partial breast irradiation using proton beams: initial dosimetric experience. Int J Radiat Oncol Biol Phys. 2006;65:1404–1410. 46. Bush DA, Slater JD, Garberoglio C, et al. A technique of partial breast irradiation utilizing proton beam radiotherapy: comparison with conformal x-ray therapy. Cancer J. 2007;13:114–118. 47. Wang X, Amos RA, Zhang X, et al. External-beam accelerated partial breast irradiation using multiple proton beam configurations. Int J Radiat Oncol Biol Phys. 2011;80:1464–1472. 48. Galland-Girodet S, Pashtan I, MacDonald SM, et al. Long-term cosmetic outcomes and toxicities of proton beam therapy compared with photon-based 3-dimensional conformal accelerated partial-breast irradiation: a phase 1 trial. Int J Radiat Oncol Biol Phys. 2014;90:493–500. 49. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–2084. 50. Wang J, Wei C, Tucker SL, et al. Predictors of postoperative complications after trimodality therapy for esophageal cancer. Int J Radiat Oncol Biol Phys. 2013;86:885–891. 51. Lee HK, Vaporciyan AA, Cox JD, et al. Postoperative pulmonary complications after preoperative chemoradiation for esophageal carcinoma: correlation with pulmonary dose-volume histogram parameters. Int J Radiat Oncol Biol Phys. 2003;57:1317–1322. 52. Chuong MD, Hallemeier CL, Jabbour SK, et al. Improving outcomes for esophageal cancer using proton beam therapy. Int J Radiat Oncol Biol Phys. 2016;95:488–497. 53. Lin SH, Merrell KW, Shen J, et al. Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer. Radiother Oncol. 2017;123: 376–381. 54. Ishikawa H, Hashimoto T, Moriwaki T, et al. Proton beam therapy combined with concurrent chemotherapy for esophageal cancer. Anticancer Res. 2015;35:1757–1762. 55. Dionisi F, Avery S, Lukens JN, et al. Proton therapy in adjuvant treatment of gastric cancer: planning comparison with advanced x-ray therapy and feasibility report. Acta Oncol. 2014;53:1312–1320. 56. Gandhi SJ, Liang X, Ding X, et al. Clinical decision tool for optimal delivery of liver stereotactic body radiation therapy: photons versus protons. Pract Radiat Oncol. 2015;5:209–218. 57. Kawashima M, Furuse J, Nishio T, et al. Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol. 2005;23:1839–1846. 58. Fukumitsu N, Sugahara S, Nakayama H, et al. A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2009;74:831–836. 59. Bush DA, Kayali Z, Grove R, et al. The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial. Cancer. 2011;117:3053–3059. 60. Hong TS, DeLaney TF, Mamon HJ, et al. A prospective feasibility study of respiratory-gated proton beam therapy for liver tumors. Pract Radiat Oncol. 2014;4:316–322. 61. Bush DA, Smith JC, Slater JD, et al. Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for

hepatocellular carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys. 2016;95:477–482. 62. Thompson RF, Mayekar SU, Zhai H, et al. A dosimetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas. Med Phys. 2014;41:081711. 63. Shabason JE, Chen J, Apisarnthanarax S, et al. A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer. Cancer Chemother Pharmacol. 2018;81:609–614. 64. Terashima K, Demizu Y, Hashimoto N, et al. A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis. Radiother Oncol. 2012;103:25–31. 65. Hong TS, Ryan DP, Borger DR, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89:830–838. 66. Colaco RJ, Nichols RC, Huh S, et al. Protons offer reduced bone marrow, small bowel, and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer. J Gastrointest Oncol. 2014;5:3–8. 67. Wolff HA, Wagner DM, Conradi LC, et al. Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: a planning study with clinical implications. Radiother Oncol. 2012;102:30–37. 68. Chen RC, Mamon HJ, Ancukiewicz M, et al. Dose–volume effects on patient-reported acute gastrointestinal symptoms during chemoradiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys. 2012;83:e513–e517. 69. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys. 2013;86:27–33. 70. Anand A, Bues M, Rule WG, et al. Scanning proton beam therapy reduces normal tissue exposure in pelvic radiotherapy for anal cancer. Radiother Oncol. 2015;117:505–508. 71. Klopp AH, Yeung AR, Deshmukh S, et al: A Phase III Randomized Trial Comparing Patient-Reported Toxicity and Quality of Life (QOL) During Pelvic Intensity Modulated Radiation Therapy as Compared to Conventional Radiation Therapy, American Society for Radiation Oncology. Radiat Oncol. 2016;96(2 suppl):S3. 72. Lin LL, Kirk M, Scholey J, et al. Initial report of pencil beam scanning proton therapy for posthysterectomy patients with gynecologic cancer. Int J Radiat Oncol Biol Phys. 2016;95:181–189. 73. Simpson DR, Song WY, Moiseenko V, et al. Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity modulated radiation therapy and concurrent cisplatin. Int J Radiat Oncol Biol Phys. 2012;83:e81–e86. 74. Chopra S, Dora T, Chinnachamy AN, et al. Predictors of grade 3 or higher late bowel toxicity in patients undergoing pelvic radiation for cervical cancer: results from a prospective study. Int J Radiat Oncol Biol Phys. 2014;88:630–635. 75. Klopp AH, Moughan J, Portelance L, et al. Hematologic toxicity in RTOG 0418: a phase 2 study of postoperative IMRT for gynecologic cancer. Int J Radiat Oncol Biol Phys. 2013;86:83–90. 76. Albuquerque K, Giangreco D, Morrison C, et al. Radiation-related predictors of hematologic toxicity after concurrent chemoradiation for cervical cancer and implications for bone marrow-sparing pelvic IMRT. Int J Radiat Oncol Biol Phys. 2011;79:1043–1047. 77. Arians N, Lindel K, Krisam J, et al. Prospective phase-II-study evaluating postoperative radiotherapy of cervical and endometrial cancer patients using protons - the APROVE-trial. Radiat Oncol. 2017;12:188. 78. Milby AB, Both S, Ingram M, et al. Dosimetric comparison of combined intensity-modulated radiotherapy (IMRT) and proton therapy versus IMRT alone for pelvic and para-aortic radiotherapy in gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2012;82: e477–e484.

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CHAPTER 24 79. Simone CB 2nd, Kramer K, O’Meara WP, et al. Predicted rates of secondary malignancies from proton versus photon radiation therapy for stage I seminoma. Int J Radiat Oncol Biol Phys. 2012;82:242–249. 80. Efstathiou JA, Paly JJ, Lu HM, et al. Adjuvant radiation therapy for early stage seminoma: proton versus photon planning comparison and modeling of second cancer risk. Radiother Oncol. 2012;103:12–17. 81. Cella L, Lomax A, Miralbell R. Potential role of intensity modulated proton beams in prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys. 2001;49:217–223. 82. Trofimov A, Nguyen PL, Coen JJ, et al. Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison. Int J Radiat Oncol Biol Phys. 2007;69:444–453. 83. Chera BS, Vargas C, Morris CG, et al. Dosimetric study of pelvic proton radiotherapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2009;75:994–1002. 84. Vargas C, Fryer A, Mahajan C, et al. Dose-volume comparison of proton therapy and intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:744–751. 85. Gray PJ, Paly JJ, Yeap BY, et al. Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer. 2013;119:1729–1735. 86. Hoppe BS, Michalski JM, Mendenhall NP, et al. Comparative effectiveness study of patient-reported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer. 2014;120: 1076–1082. 87. Fang P, Mick R, Deville C, et al. A case-matched study of toxicity outcomes after proton therapy and intensity-modulated radiation therapy for prostate cancer. Cancer. 2015;121:1118–1127. 88. Pan HY, Jiang J, Hoffman KE, et al. Comparative toxicities and cost of intensity-modulated radiotherapy, proton radiation, and stereotactic body radiotherapy among younger men with prostate cancer. J Clin Oncol. 2018;doi:10.1200/JCO.2017.75.5371. 89. Kim S, Shen S, Moore DF, et al. Late gastrointestinal toxicities following radiation therapy for prostate cancer. Eur Urol. 2011;60:908–916. 90. Sheets NC, Goldin GH, Meyer AM, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA. 2012;307: 1611–1620. 91. Yu JB, Soulos PR, Herrin J, et al. Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl Cancer Inst. 2013;105:25–32. 92. Yeoh E, Horowitz M, Russo A, et al. The effects of abdominal irradiation for seminoma of the testis on gastrointestinal function. J Gastroenterol Hepatol. 1995;10:125–130. 93. Malas S, Sur RK, Levin V, et al. Toxicity in patients with testicular seminoma treated with radiotherapy. Different dose levels and treatment fields. Acta Oncol. 1996;35:201–206. 94. Hoppe BS, Mamalui-Hunter M, Mendenhall NP, et al. Improving the therapeutic ratio by using proton therapy in patients with stage I or II seminoma. Am J Clin Oncol. 2013;36:31–37. 95. Takaoka EI, Miyazaki J, Ishikawa H, et al. Long-term single-institute experience with trimodal bladder-preserving therapy with proton beam therapy for muscle-invasive bladder cancer. Jpn J Clin Oncol. 2017;47: 67–73. 96. Tseng YD, Cutter DJ, Plastaras JP, et al. Evidence-based review on the use of proton therapy in lymphoma from the Particle Therapy Cooperative Group (PTCOG) lymphoma subcommittee. Int J Radiat Oncol Biol Phys. 2017;99:825–842. 97. Hoppe BS, Flampouri S, Su Z, et al. Effective dose reduction to cardiac structures using protons compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2012;84: 449–455. 98. Hoppe BS, Flampouri S, Zaiden R, et al. Involved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study. Int J Radiat Oncol Biol Phys. 2014;89:1053–1059. 99. Chera BS, Rodriguez C, Morris CG, et al. Dosimetric comparison of three different involved nodal irradiation techniques for stage II Hodgkin’s lymphoma patients: conventional radiotherapy,

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intensity-modulated radiotherapy, and three-dimensional proton radiotherapy. Int J Radiat Oncol Biol Phys. 2009;75:1173–1180. 100. Maraldo MV, Brodin NP, Aznar MC, et al. Doses to head and neck normal tissues for early stage Hodgkin lymphoma after involved node radiotherapy. Radiother Oncol. 2014;110:441–447. 101. Sachsman S, Hoppe BS, Mendenhall NP, et al. Proton therapy to the subdiaphragmatic region in the management of patients with Hodgkin lymphoma. Leuk Lymphoma. 2015;56:2019–2024. 102. Hoppe BS, Hill-Kayser CE, Tseng YD, et al. Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma. Ann Oncol. 2017;28:2179–2184. 103. Sachsman S, Flampouri S, Li Z, et al. Proton therapy in the management of non-Hodgkin lymphoma. Leuk Lymphoma. 2015;56:2608–2612. 104. Fogliata A, Scorsetti M, Navarria P, et al. Dosimetric comparison between VMAT with different dose calculation algorithms and protons for soft-tissue sarcoma radiotherapy. Acta Oncol. 2013;52:545–552. 105. LeBrun DG, Guttmann DM, Shabason JE, et al. Predictors of Wound Complications following Radiation and Surgical Resection of Soft Tissue Sarcomas. Sarcoma. 2017;2017:5465130. 106. Remick J, Regine W, Malyapa R, et al. Excellent pathologic response and atypical clinical course of high-grade extremity sarcoma to neoadjuvant pencil beam scanning proton therapy. Cureus. 2017;9:e1687. 107. Swanson EL, Indelicato DJ, Louis D, et al. Comparison of threedimensional (3D) conformal proton radiotherapy (RT), 3D conformal photon RT, and intensity-modulated RT for retroperitoneal and intraabdominal sarcomas. Int J Radiat Oncol Biol Phys. 2012;83:1549–1557. 108. DeLaney TF, Chen YL, Baldini EH, et al. Phase 1 trial of preoperative image guided intensity modulated proton radiation therapy with simultaneously integrated boost to the high risk margin for retroperitoneal sarcomas. Adv Radiat Oncol. 2017;2:85–93. 109. Ares C, Hug EB, Lomax AJ, et al. Effectiveness and safety of spot scanning proton radiation therapy for chordomas and chondrosarcomas of the skull base: first long-term report. Int J Radiat Oncol Biol Phys. 2009;75:1111–1118. 110. Deraniyagala RL, Yeung D, Mendenhall WM, et al. Proton therapy for skull base chordomas: an outcome study from the university of Florida proton therapy institute. J Neurol Surg B Skull Base. 2014;75:53–57. 111. McDonald MW, Linton OR, Moore MG, et al. Influence of residual tumor volume and radiation dose coverage in outcomes for clival chordoma. Int J Radiat Oncol Biol Phys. 2016;95:304–311. 112. Weber DC, Badiyan S, Malyapa R, et al. Long-term outcomes and prognostic factors of skull-base chondrosarcoma patients treated with pencil-beam scanning proton therapy at the Paul Scherrer Institute. Neuro Oncol. 2016;18:236–243. 113. Feuvret L, Bracci S, Calugaru V, et al. Efficacy and safety of adjuvant proton therapy combined with surgery for chondrosarcoma of the skull base: a retrospective, population-based study. Int J Radiat Oncol Biol Phys. 2016;95:312–321. 114. Chen YL, Liebsch N, Kobayashi W, et al. Definitive high-dose photon/ proton radiotherapy for unresected mobile spine and sacral chordomas. Spine. 2013;38:E930–E936. 115. Kabolizadeh P, Chen YL, Liebsch N, et al. Updated outcome and analysis of tumor response in mobile spine and sacral chordoma treated with definitive high-dose photon/proton radiation therapy. Int J Radiat Oncol Biol Phys. 2017;97:254–262. 116. DeLaney TF, Liebsch NJ, Pedlow FX, et al. Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol. 2014;110:115–122. 117. Ciernik IF, Niemierko A, Harmon DC, et al. Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer. 2011; 117:4522–4530. 118. Rowe LS, Krauze AV, Ning H, et al. Optimizing the benefit of CNS radiation therapy in the pediatric population—part 2: novel methods of radiation delivery. Oncology (Williston Park). 2017;31:224–226, 228. 119. Barney CL, Brown AP, Grosshans DR, et al. Technique, outcomes, and acute toxicities in adults treated with proton beam craniospinal irradiation. Neuro Oncol. 2014;16:303–309.

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120. Yock TI, Yeap BY, Ebb DH, et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol. 2016;17:287–298. 121. Ris MD, Walsh K, Wallace D, et al. Intellectual and academic outcome following two chemotherapy regimens and radiotherapy for average-risk medulloblastoma: COG A9961. Pediatr Blood Cancer. 2013;60: 1350–1357. 122. Palmer SL, Goloubeva O, Reddick WE, et al. Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis. J Clin Oncol. 2001;19:2302–2308. 123. Ris MD, Packer R, Goldwein J, et al. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol. 2001;19:3470–3476. 124. Moxon-Emre I, Bouffet E, Taylor MD, et al. Impact of craniospinal dose, boost volume, and neurologic complications on intellectual outcome in patients with medulloblastoma. J Clin Oncol. 2014;32:1760–1768. 125. Eaton BR, Esiashvili N, Kim S, et al. Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma. Neuro Oncol. 2016;18:881–887. 126. Ladra MM, MacDonald SM, Terezakis SA. Proton therapy for central nervous system tumors in children. Pediatr Blood Cancer. 2018;e27046. 127. Vogel J, Both S, Kirk M, et al. Proton therapy for pediatric head and neck malignancies. Pediatr Blood Cancer. 2018;65. 128. Ladra MM, Edgington SK, Mahajan A, et al. A dosimetric comparison of proton and intensity modulated radiation therapy in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study. Radiother Oncol. 2014;113:77–83. 129. Ladra MM, Szymonifka JD, Mahajan A, et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol. 2014;32:3762–3770. 130. Weber DC, Murray FR, Correia D, et al. Pencil beam scanned protons for the treatment of patients with Ewing sarcoma. Pediatr Blood Cancer. 2017;64. 131. Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy for pediatric Ewing’s sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys. 2012;82:1142–1148. 132. Fuji H, Schneider U, Ishida Y, et al. Assessment of organ dose reduction and secondary cancer risk associated with the use of proton beam therapy and intensity modulated radiation therapy in treatment of neuroblastomas. Radiat Oncol. 2013;8:255. 133. Hill-Kayser C, Tochner Z, Both S, et al. Proton versus photon radiation therapy for patients with high-risk neuroblastoma: the need for a customized approach. Pediatr Blood Cancer. 2013;60:1606–1611. 134. Vogel J, Lin H, Both S, et al. Pencil beam scanning proton therapy for treatment of the retroperitoneum after nephrectomy for Wilms tumor: a dosimetric comparison study. Pediatr Blood Cancer. 2017;64:39–45. 135. Hong TS, Wo JY, Borger DR, et al. Phase II study of proton-based stereotactic body radiation therapy for liver metastases: importance of tumor genotype. J Natl Cancer Inst. 2017;109. 136. Atkins KMPI, Bussiere MR. Proton stereotactic radiosurgery for brain metastases: a single institution analysis of 370 patients. Int J Radiat Oncol Biol Phys. 2018. 137. Lundkvist J, Ekman M, Ericsson SR, et al. Cost-effectiveness of proton radiation in the treatment of childhood medulloblastoma. Cancer. 2005;103:793–801. 138. Shabason JE, Minn AJ. Radiation and immune checkpoint blockade: from bench to clinic. Semin Radiat Oncol. 2017;27:289–298. 139. Tang C, Liao Z, Gomez D, et al. Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol Biol Phys. 2014;89:1084–1091. 140. Gameiro SR, Malamas AS, Bernstein MB, et al. Tumor cells surviving exposure to proton or photon radiation share a common immunogenic modulation signature, rendering them more sensitive to T cell-mediated killing. Int J Radiat Oncol Biol Phys. 2016;95:120–130. 141. Brownstein JM, Wisdom AJ, Castle KD, et al. Characterizing the Potency and Impact of Carbon Ion Therapy in a Primary Mouse Model of Soft Tissue Sarcoma. Mol Cancer Ther. 2018;17:858–868.

142. Schulz-Ertner D, Nikoghosyan A, Thilmann C, et al. Results of carbon ion radiotherapy in 152 patients. Int J Radiat Oncol Biol Phys. 2004;58:631–640. 143. Kamada T, Tsujii H, Tsuji H, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin Oncol. 2002;20: 4466–4471. 144. Serizawa I, Kagei K, Kamada T, et al. Carbon ion radiotherapy for unresectable retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys. 2009;75:1105–1110. 145. Jingu K, Tsujii H, Mizoe JE, et al. Carbon ion radiation therapy improves the prognosis of unresectable adult bone and soft-tissue sarcoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012;82:2125–2131. 146. Matsumoto K, Imai R, Kamada T, et al. Impact of carbon ion radiotherapy for primary spinal sarcoma. Cancer. 2013;119:3496–3503. 147. Demizu Y, Jin D, Sulaiman NS, et al. Particle therapy using protons or carbon ions for unresectable or incompletely resected bone and soft tissue sarcomas of the pelvis. Int J Radiat Oncol Biol Phys. 2017;98: 367–374. 148. Schulz-Ertner D, Karger CP, Feuerhake A, et al. Effectiveness of carbon ion radiotherapy in the treatment of skull-base chordomas. Int J Radiat Oncol Biol Phys. 2007;68:449–457. 149. Imai R, Kamada T, Araki N, et al. Carbon ion radiation therapy for unresectable sacral chordoma: an analysis of 188 cases. Int J Radiat Oncol Biol Phys. 2016;95:322–327. 150. Abe T, Saitoh J, Kobayashi D, et al. Dosimetric comparison of carbon ion radiotherapy and stereotactic body radiotherapy with photon beams for the treatment of hepatocellular carcinoma. Radiat Oncol. 2015;10:187. 151. Kato H, Tsujii H, Miyamoto T, et al. Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis. Int J Radiat Oncol Biol Phys. 2004;59:1468–1476. 152. Kasuya G, Kato H, Yasuda S, et al. Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: combined analyses of 2 prospective trials. Cancer. 2017;123:3955–3965. 153. Combs SE, Habermehl D, Kieser M, et al. Phase I study evaluating the treatment of patients with locally advanced pancreatic cancer with carbon ion radiotherapy: the PHOENIX-01 trial. BMC Cancer. 2013; 13:419. 154. Shinoto M, Yamada S, Yasuda S, et al. Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer. Cancer. 2013;119:45–51. 155. Habl G, Uhl M, Katayama S, et al. Acute toxicity and quality of life in patients with prostate cancer treated with protons or carbon ions in a prospective randomized phase II Study–The IPI trial. Int J Radiat Oncol Biol Phys. 2016;95:435–443. 156. Castro JR, Phillips TL, Prados M, et al. Neon heavy charged particle radiotherapy of glioblastoma of the brain. Int J Radiat Oncol Biol Phys. 1997;38:257–261. 157. Thornton AFTLG. Particle Therapy; 2000. 158. von Essen CF, Bagshaw MA, Bush SE, et al. Long-term results of pion therapy at Los Alamos. Int J Radiat Oncol Biol Phys. 1987;13:1389–1398. 159. Pickles T, Goodman GB, Fryer CJ, et al. Pion conformal radiation of prostate cancer: results of a randomized study. Int J Radiat Oncol Biol Phys. 1999;43:47–55. 160. Pickles T, Goodman GB, Rheaume DE, et al. Pion radiation for high grade astrocytoma: results of a randomized study. Int J Radiat Oncol Biol Phys. 1997;37:491–497. 161. Char DH, Kroll SM, Castro J. Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol. 1998;125:81–89. 162. Mishra KK, Quivey JM, Daftari IK, et al. Long-term results of the UCSF-LBNL randomized trial: charged particle with helium ion versus iodine-125 plaque therapy for choroidal and ciliary body melanoma. Int J Radiat Oncol Biol Phys. 2015;92:376–383. 163. Schoenthaler R, Castro JR, Petti PL, et al. Charged particle irradiation of sacral chordomas. Int J Radiat Oncol Biol Phys. 1993;26:291–298. 164. Miralbell R, Lomax A, Cella L, et al. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int J Radiat Oncol Biol Phys. 2002;54: 824–829.

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25 Targeted Radionuclide Therapy Joseph G. Jurcic, Jeffrey Y. C. Wong, Susan J. Knox, Daniel R. Wahl, Todd L. Rosenblat, Lucia Baratto, Andrei Iagaru, Ruby F. Meredith, and Chul S. Ha

Selective delivery of radionuclides to cancer cells using an antibody or other conjugate has been under investigation for more than 30 years. In 2002, the first US Food and Drug Administration (FDA) approval was issued for a radiolabeled antibody. Initially, this form of radionuclide therapy mainly involved the use of antibodies or antibody-derived constructs as carriers of radionuclides; therefore, it is called radioimmunotherapy (RIT). However, because the concept also includes binding to nonantigen receptors, targeted radionuclide therapy (TaRT) is a more comprehensive term, and Paul Wallner coined the acronym STaRT for systemic targeting. The development of TaRT has required the cooperation of basic scientists in the areas of radiation biology, chemistry, physics, and immunology with multiple clinical specialists. With the exception of some gene therapy approaches, TaRT differs from externalbeam radiation therapy (EBRT) in that selective targeting can be at the cellular rather than target volume level. Among its potential applications, TaRT provides a means of irradiating multiple tumor sites throughout the body with relative sparing of normal tissues. A number of challenges hampering the use of TaRT have been overcome, whereas others are areas of active investigation. Many of these are covered in more detail in other reviews.1-15 A more extensive version of this chapter can be found online. The supplemental text contains tables, figures, and references that enhance the print version of this chapter.

TUMOR TARGETING Antibodies The efficacy of TaRT is dependent on a number of factors, including properties of the targeted antigen or receptor, tumor, and targeting agent. Antigen/receptor variables include affinity, avidity, density, availability, shedding, and heterogeneity of expression.16 Tumor factors include vascularity, blood flow, and permeability. Antibody features to consider are specificity of the binding site, which affects selective tumor uptake; immunoreactivity, which can affect localization; stability in vivo; and both avidity and affinity.16-18 Affinity can be described by an intrinsic association constant K that characterizes binding of a univalent ligand (formation of a stable antibody-antigen complex) and can be calculated from the ratio of the rate constants for association and dissociation. Because intact antibodies and most antigens are multivalent, the tendency to bind depends on the affinity, number of binding sites, and other nonspecific factors involved in aggregation. The term avidity encompasses all of these factors and, therefore, is used to describe the overall tendency of antibody to bind to antigen. Additional discussion can be found online. A wide variety of antibodies have been made against tumor-specific and tumor-associated antigens that, although present on some normal

cells, are usually expressed at lower levels than on the targeted tumor cells. Most RIT trials have used monoclonal antibodies (Mabs), and many have used intact murine immunoglobulin G (IgG) antibodies. Early on, the immunogenicity of the nonhuman antibodies was recognized as a serious limitation of TaRT.29 With the exception of patients with lymphoma, who are less prone to develop an immune response to murine antibodies (human antimouse antibody [HAMA] response), > 80% of patients usually develop an immune response against a therapeutically administered murine or other species antibody after a single injection of antibody.29 Such an immune response can occur even after doses as small as 1 mg used for imaging studies or following administration of antibody fragments or smaller constructs (but with less frequency than found following administration of intact IgG). Administration of antibody in a patient with a HAMA response can result in a severe immune reaction and rapid blood clearance, limiting tumor uptake of radiolabeled antibody.30 Several approaches have been employed in an effort to ameliorate the problem of antibody immunogenicity, such as (1) the development of less immunogenic (chimeric and humanized) antibodies, (2) the use of immunosuppression by cyclosporine or deoxyspergualin to prevent an immune response, (3) the removal of HAMA directed to the therapeutic antibody by administration of an excess of unlabeled antibody before the administration of the radioimmunoconjugate, or (4) posttreatment removal of immune complexes by passing the patient’s blood through an extracorporeal immunoadsorption column.31-34 Genetic engineering has been successful in providing numerous targeting agents with reduced immunogenicity and has allowed for optimization of other aspects of the therapy.35-37 Genetic constructs have been produced that vary in specificity and can be altered by conjugating them to other agents (e.g., cytokines, toxins, or radiosensitizers) to form fusion proteins.38,39 Technological advances have provided a wide variety of antibodies and constructs varying in specificity, size and number of antigen combining sites, rapidity of distribution, immunogenicity, and immunological function.40 Use of small antibody constructs such as single-chain antigen-binding proteins may be most useful for diagnostic studies or for multistep targeting strategies.41 The decreased immunogenicity of fragments/constructs and human and humanized antibodies now allows for administration of repeat courses or fractionated TaRT dosing.42 As immunogenicity of antibodies has been ameliorated, some investigators have had concerns about the potential immunogenicity of other components of therapy. For example, as more macrocyclic chelators have been developed to improve stability of conjugates, some data suggest that these molecules may be immunogenic, as has been the streptavidin used in some pretargeting schemes.43-45 Thus, immunogenicity

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CHAPTER 25

ABBREVIATIONS ADCC = antibody-dependent cellular cytotoxicity AML = acute myeloid leukemia APL = acute promyelocytic leukemia ASCT = autologous stem cell transplant BED = biological equivalent dose BMT = bone marrow transplantation BU = busulfan CLL = chronic lymphocytic leukemia CR = complete response with no evidence of disease for ≤ 1 month CTCL = cutaneous T-cell lymphoma CY = cytoxan or cyclophosphamide DLCL = diffuse large-cell lymphoma EGFR = epidermal growth factor receptor FU = fluorouracil HACA = human antichimeric antibodies HAMA = human antimouse antibodies HCT = hematopoietic cell transplantation HSG = histamine-succinyl-glycine ID = injected dose IP = intraperitoneal IV = intravenous KPS = Karnofsky performance status LDR = low dose rate LET = linear energy transfer Mab = monoclonal antibodies MDS = myelodysplastic syndrome MHC = major histocompatibility complex MIRD = Medical Internal Radiation Dose Committee of the Society of Nuclear Medicine MR = minor response of 25% to 49% decrease from baseline in overall tumor size for ≤ 1 month MW = molecular weight NA = not available NED = no evidence of disease NHL = non-Hodgkin lymphoma OS = overall survival PCR = polymerase chain reaction PEG = polyethylene glycol PFS = progression-free survival PR = ≤ 50% decrease from baseline in overall tumor size for ≤ 1 month PRRT = peptide receptor radionuclide therapy PSMA = prostate-specific membrane antigen RBE = relative biological effectiveness RIT = radioimmunotherapy ROIs = regions of interest RT = reverse transcriptase scFv = single-chain monovalent constructs SCT = stem cell transplant SPECT = single-photon emission tomography TaRT = targeted radionuclide therapy TBI = total body irradiation TLDs = thermoluminescent dosimeters TMZ = temozolomide T½ = half time VH = variable heavy regions VL = variable light regions

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Increased antibody affinity or avidity does not always correlate with increased in vivo efficacy—the optimal level of affinity remains controversial.17,19 One might expect that higher-affinity antibodies would result in increased tumor uptake, retention, and improved efficacy.20-22 High-affinity antibodies, however, may preferentially bind to perivascular regions in the periphery of tumors, whereas antibodies of lower affinity are able to penetrate deeper into tumors.23,24 Hence, the optimal affinity of an antibody is likely to depend on a number of factors, including level of target antigen expression, vascular permeability, and bulkiness of disease.25 In many cases, targeting of radiolabeled antibodies to tumor can also be improved through preinfusion of unlabeled antibody, which decreases splenic and urinary uptake of radiotracer.26 The optimal amount of unlabeled antibody remains undetermined for most agents, but relatively high doses have been as good or better than lower doses in most imaging studies.26,27 Efforts by the Seattle transplant team to optimize the amount of unlabeled antibody for individual patients by tracer studies with varying amounts often showed the highest concentration studied to be as good or better for direct RIT with iodine-131 (131I)-antibody conjugates.28

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424

SECTION II

Techniques and Modalities

of the various components of TaRT remains a challenge that requires further innovation.

Receptor-Mediated Tumor Targeting The receptor-mediated targeting of tumors starts with a single key event: the binding of a signaling molecule (ligand) to a target molecule on the cell surface (receptor or tumor antigen). This binding can activate intracellular signaling cascades that lead to different final results, depending on the selected type of receptor. Receptors are membrane-spanning proteins that include components both outside and inside the cell surface. While the extracellular domain represents the binding site for the signal, the intracellular domain’s role is to activate intracellular signaling pathways after the signal binds.46 Ligands can be antibodies or peptides, such as hormones or single elements. They can behave as a receptor’s agonists (binding to the receptor and producing an effect within the cell) or as a receptor’s antagonists (blocking the receptor to its natural agonist). Peptides occupy the space between small molecules and large biologics, exploiting the advantages of both classes of compounds: they have fast clearance, like small molecules, and a high degree of selectivity for their receptor, like large biologics.47 Compared to antibodies, peptides have a lower molecular weight (generally around 1500 Da), they are not immunogenic, and, usually, they have excellent tumor penetration, with low bone marrow accumulation. Furthermore, when peptides are a receptor’s agonists, the complex ligand-receptor is internalized, leading to a longer residence time of the radionuclide in the target cells.48

Peptide Receptor Radionuclide Therapy Radiolabeled peptides have been used to deliver radiation to cancer cells for the past 25 years. The origin of peptide receptor radionuclide therapy (PRRT) dates back to 1992 when, for the first time, a patient with a glucagonoma was successfully treated with high doses of 111Inpenteotride, using the specific physical characteristics of the Auger and conversion electrons of 111In.49 Currently, PRRT is mainly used to treat patients with neuroendocrine tumors (NETs) targeting somatostatin receptors (SSTRs) and with prostate cancer–targeting prostate-specific membrane antigen (PSMA). Usually, the molecular target used for PRRT is also labeled with a diagnostic radionuclide to image patients before, during, and after treatment. The aim of creating such theragnostic agents is to couple the diagnostic imaging with targeted therapy, using positron emission tomography/computed tomography (PET/CT) or positron emission tomography/magnetic resonance imaging (PET/MRI) to quantitate target expression and select patients most likely to benefit from treatment. The most used radionuclides for therapy are the beta-emitters yttrium-90 (90Y) and lutetium-177 (177Lu). Recently, however, alphaemitters such as actinium-225 (225At) and bismuth-213 (213Bi) have also been studied. The differences between beta- and alpha-emitters is that the former have a longer range of tissue penetration and a shorter linear energy transfer (LET). The longer range of electrons of beta-emitters increase the average dose delivered to the tumor but also to the surrounding healthy tissues. By contrast, alpha-emitters release a lethal dose to tumor cells (high LET) with no damage to surrounding healthy tissues (short range of penetration).50 Thus, alpha-emitters seem to be more suitable for treating microscopic or small-volume disease.

Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors NETs are the second most common gastrointestinal cancer, with a prevalence of approximately 120,000 cases in the United States, 296,000 in Europe, and 2.4 million worldwide.51 NETs are characterized by high expression of SSTRs. Five subtypes of SSTRs have been described (sst1,

sst2, sst3, sst4, sst5), with sst2 receptor being the most frequently expressed subtype in NETs.52 Although NETs can originate from many regions of the body, 60% to 70% derive from the gastro-entero-pancreatic system (GEP-NET).53 Due to their relatively indolent nature, the diagnosis is usually made when the disease is already metastatic, with the liver being the most frequently involved organ. The first therapeutic choice is surgical resection of the primary tumor. Medical therapy includes bioactive agents (somatostatin analogs or interferon) and chemotherapy, with various degrees of success but not with curative intent. PRRT in NETs has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic GEP-NETs. PRRT started in the early 1990s in Rotterdam, where Krenning and colleagues used 111In-pentetreotide to scan patients with NETs.54 The next step was to have a therapeutic agent. While 111In-pentetreotride was first used for PRRT in NETs in 1992,49 it quickly became clear that it was not the most suitable option for PRRT because the short tissue range of Auger electrons resulted in modest tumor shrinkage. During the same period, DOTA-chelated peptides started becoming available,55,56 making it easier to label with beta-emitters such as 90Y, better suited for therapeutic use. One of the first experiences using 90 Y-DOTA-d-Ph1-Tyr3-octreotide (DOTATOC) was in Basel in 1999.57 Twenty-nine NET patients were treated with four or more single doses of 90Y-DOTATOC with increasing activity at intervals of approximately 6 weeks (cumulative dose: 6120 ± 1347 MBq/m2). The treatment was monitored by CT and 111In-DOTATOC scintigraphy. Twenty patients out of 29 had stable disease on 111In-DOTATOC, two showed partial remission (decrease of ≥ 50% in tumor volume on CT scans), four showed a reduction in tumor size < 50% and three developed progressive disease. Renal toxicity was registered in 5 out of 29 patients; none had received amino-acids (Hartmann-Hepa 8% solution) during any of the treatment cycles. In 2011, Imhof et al. published the results of a clinical Phase II single-center, open-label trial, which enrolled 1109 patients with neuroendocrine cancers who were treated with repeated cycles of [90Y-DOTA]-TOC, with a single intravenous injection dose of 3.7 GBq/ m2 body surface.58 Of the 1109 patients, 378 (34.1%) experienced a morphological response, 172 (15.5%) a biochemical response, and 329 (29.7%) a clinical response. Multivariable regression analysis revealed that high tumor uptake of the radiopeptide in the initial imaging study was significantly associated with longer survival after 90Y-DOTATOC treatment, whereas the initial kidney uptake was predictive for severe renal toxicity. For several years, 90Y was widely used as the radionuclide of choice for PRRT in NETs.3,59-61 Overall, 90Y PRRT resulted in objective response rates ranging from 4% to 33%; however, some studies reported renal toxicity even when amino acids were administered during cycles with the intent of reducing the tubular uptake of the radionuclide and minimizing renal damage.62,63 177Lu became available in 2000, attached through the chelator DOTA to Tyr3-octreotate. Owing to the lower tissue penetration range (resulting in lower dosimetry to kidneys and other normal tissues) and to the gamma emitted in addition to beta in the decay scheme (the photon allows for imaging used in dosimetry estimates), 177Lu became the radiometal of choice over 90Y for PRRT. The first clinical prospective study with 177Lu-DOTATATE started in 2000 in Rotterdam. A total of 504 patients, 310 of whom had GEPNETs, were treated with a cumulative dose range of 750 to 800 mCi (27.8-29.6 GBq), usually in four PRRT cycles, with treatment intervals of 6 to 10 weeks. Complete and partial remissions were reported in 2% and 28% of 310 GEP-NET patients, respectively. Minimal response (decrease in size > 25% and < 50%) occurred in 16% and stable disease was seen in 35% of cases. The overall objective tumor response rate

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CHAPTER 25 was 46%, with a median overall survival (OS) of 46 months and a median time to progression (TTP) of 40 months. Serious adverse events likely attributable to the treatment were myelodysplastic syndrome and temporary liver toxicity in 3 and 2 patients, respectively.64 In 2003, the same group published other results using 177LuDOTATATE therapy in 35 patients with GEP-NETs. Patients were treated with doses of 100, 150, or 200 mCi 177Lu-octreotate, for a final cumulative dose of 600 to 800 mCi, with cycle intervals of 6 to 9 weeks. The effects of the therapy on tumor size were evaluable in 34 patients. Three months after administration, complete remission was found in 1 patient (3%), partial remission in 12 (35%), stable disease in 14 (41%), and progressive disease in 7 (21%). Tumor response positively correlated with a high uptake on the 111In-pentetreotide evaluation, confined hepatic tumor mass, and a high Karnofsky Performance Score.65 The number of NET patients treated with 177Lu-DOTATATE dramatically increased in Europe and Australia66-68 and, from 2013, it started to be used in the United States.69 In January 2017, the results of the Phase III NETTER-1 trial were published.70 This international multicenter, randomized, controlled trial evaluated the efficacy and safety of 177Lu-DOTATATE in comparison with high-dose octreotide in patients with advanced, progressive, somatostatin-receptor–positive midgut NETs. Treatment with 177 Lu-DOTATATE resulted in markedly longer progression-free survival (PFS) and a significantly higher response rate than with high-dose octreotide long-acting repeatable. Based on this study, 177Lu-DOTATATE was approved by regulatory agencies both in the European Union (September 2017) and in the United States (January 2018) as “treatment for unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive GEP-NETs in adults.”70a,70b Alpha-emitters for PRRT have been used as salvage therapy in metastatic patients refractory to beta-emitter PRRT. A study from 2014 included a total of eight patients with NETs refractory to therapy with 90 Y-/177Lu-DOTATOC who were treated with 213Bi-DOTATOC.71 Seven received intraarterial administration of 213Bi-DOTATOC for liver metastases; one was treated systemically for diffuse bone infiltration from neuroendocrine prostate cancer. The specific tumor binding of 213 Bi-DOTATOC was assessed by pretherapy 68Ga-DOTATOC PET/CT and single-photon emission computed tomography (SPECT) images performed within 60 minutes after injection, using the gamma coemission of 213Bi. Overall, therapy with 213Bi-DOTATOC resulted in a high number of long-lasting tumor responses, with moderate hematological and renal toxicity. Therapy of progressive NETs using 225Ac-DOTATOC has been clinically tested in a follow-up investigation with 34 patients.72 The primary endpoint was to find the maximum tolerable dose (MTD) of a single cycle of 225Ac-DOTATOC. An empiric dose escalation was performed and the MTD of a single cycle was considered to be 40 MBq, with multiple fractions tolerated since 25 MBq every 4 months or 18.5 MBq every 2 months. A cumulative activity of 75 MBq was found to be tolerable in regard to delayed toxicity. The observed radiological treatment response was without clear preference of a particular fractionation concept.

Peptide Receptor Radionuclide Therapy in Prostate Cancer PRRT has been used in prostate cancer patients targeting PSMA. PSMA is a transmembrane protein overexpressed in prostate cancer73 and, thus, widely used as a biomarker and targeting receptor for prostate cancer therapy. Prostate cancer is the most frequent noncutaneous cancer and the second most frequent cause of cancer deaths for adult men.74 Therapies with curative intent are radical prostatectomy, EBRT, and brachytherapy, but approximately 20% to 40% of men experience a biochemical failure with a rise of prostate-specific antigen (PSA) within 10 years from the primary prostate cancer treatment.75 In this scenario,

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treatment options include androgen-deprivation therapy along with chemotherapy in the case of disease progression.76 PRRT with 177Lu-labeled PSMA is a novel approach for treating metastatic castration-resistant prostate cancer (mCRPC), a condition defined as “disease progression despite castrated levels of testosterone, which may present as either a continuous rise in serum PSA levels, the progression of pre-existing disease, and/or the appearance of new metastases.”77 Several retrospective studies of 177Lu-PSMA have reported favorable biochemical and imaging responses as well as significant pain relief.78-84 A study from 2015 evaluated 177Lu-PSMA therapy in 10 hormone and/or chemorefractory patients with distant metastases and progressive disease.78 Eight weeks after the therapy, a relevant PSA decline was detected in seven patients; for six, the decline was greater than 30% and for five greater than 50%. Three patients showed progressive disease based on PSA increase. A German retrospective, multicenter study evaluated 145 patients with mCRPC.79 They were treated with 177Lu-PSMA-617 in 12 centers with 1 to 4 therapy cycles and an activity range of 2 to 8 GBq per cycle. During the median observation period of 16 weeks, they registered an overall biochemical response rate of 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. In May 2018, results of an open-label, single-arm, nonrandomized pilot study of 177Lu-PSMA-617 were published.85 Thirty men with mCRPC and progressive disease after standard treatments were treated with 177 Lu-PSMA-617. Primary endpoints included safety and efficacy as defined by PSA response, quality of life, and imaging response. The mean administered radioactivity was 7.5 GBq per cycle for up to four cycles of treatment at 6 weekly intervals. In a median follow-up of 25 months, the results showed a remarkable 57% PSA response rate (> 50% reduction) and 71% interim response rate in soft-tissue lesions (as measured by RECIST [response evaluation criteria in solid tumors]). Overall, 29 (97%) of 30 patients experienced a PSA decline and patients with PSA decline of 50% or higher had a significantly longer PSA PFS and OS compared with those with a decline less than 50% (PFS 9.9 months vs. 4.1 months; overall survival 17.0 months vs. 9.9 months, respectively). A low rate of adverse events was registered, with dry mouth being the most common treatment-related toxic effect. Significantly improved quality of life scores and reduction in pain scores were recorded in 37% and 43% of patients, respectively. 177 Lu-PSMA targeted therapy appears to be promising and effective treatment for prostate cancer. Prospective, randomized trials are planned to determine the impact of 177Lu-PSMA on survival, toxicities, and dosimetry, and to rigorously assess the clinical benefits compared with other treatments for prostate cancer, including chemotherapy, EBRT, and androgen blockade. Reports of the use of alpha-emitters labeled PSMA have been published.86,87 Therapy with 225Ac-PSMA-617 was evaluated in 40 patients with advanced mCRPC.88 They received 3 cycles of 100 kBq/kg of 25 Ac-PSMA-617 at 2-month intervals. In patients surviving at least 8 weeks (n = 38), a PSA decline > 50% was observed in 24 of 38 (63%) and any PSA response in 33 of 38 (87%) of patients. Median duration of tumor-control was 9 months and 5 patients presented with enduring responses of > 2 years. However, xerostomia was the main reason to discontinue the treatment, indicating that better management of the therapy and dosimetry is needed to enhance the therapeutic range. Gastrin-releasing peptide receptors are also evaluated as cellular targets both for diagnosis and therapy of prostate cancer. The neuropeptide bombesin (BBN) is an analog to the mammalian gastrin-releasing peptide, which is widely distributed in both the peripheral nervous system and peripheral tissues, particularly in the gastrointestinal tract.89 Different synthetic BBN analogs have been described, mainly radiolabeled with 68 Ga for diagnostic purposes. Overall, a high sensitivity and specificity in

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Comparison of Selected Beta-Emitting Radionuclides Used in Targeted Radionuclide Therapy

TABLE 25.1

Isotope 90

Y

131

I

T1/2 (days)

γ Energy (keV)

Percent γ Intensity

2.7 8.0

364

81

β RANGE IN TISSUE (mm) Maximum

Mean

Advantages

Disadvantages

11.9

2.5

Long β range

Chelator, bone seeker

2.4

0.3

No chelator needed

Dehalogenation, toxicity from γ

186

Re

3.7

137

9

5.0

0.9

Less γ than

I

Chelator, scarce

67

Cu

2.5

184

48

2.2

0.4

Less γ than 131I

Chelator, scarce

177

6.7

208/113

11 and 7

2.2

0.3

Less γ than 131I

Chelator, scarce

125

60.4

35

7

—

Low-normal tissue toxicity

Does not image well

188

0.8

155

15

2.4

Long β range

Chelator, scarce

Lu I Re

0.02 11.0

detection of primary and recurrent prostate cancer has been reported.90-95 PRRT using BBN analogs is still in the early stages of evaluation; however, interesting results have been reported,96-100 making them promising candidates for patients.

SELECTION OF RADIONUCLIDES The utility of a given radionuclide for TaRT is influenced by a number of radionuclide-specific factors, such as half-life, emission profile, path length, efficiency of energy transfer, and ease of conjugation to its targeting ligand, and disease-related factors such as bulkiness of disease and heterogeneity of antigen expression. In a one-step RIT, it is important to match the physical half-life of the radionuclide with the initial peak of tumor-to-nontumor antibody concentration to ensure that decay occurs when the antibody is bound to tumor rather than in circulation.101 Pretargeting strategies, discussed in more detail later in the chapter, allow for use of radionuclides with shorter half-lives because unlabeled methods of tumor targeting precede administration of the radionuclide.102 Additional discussion can be found online. The emission profile of radionuclides also influences their suitability for therapy and imaging. A variety of radionuclides have been used in TaRT, including alpha-emitters; low-, medium-, and high-energy beta-emitters; and those that work through electron capture or internal conversion (Auger electrons). Gamma-emitters, on the other hand, are more appropriate for imaging.12 Some radionuclides, such as 131I, have beta and gamma emissions that allow for both therapy and imaging. The therapeutic effect from such radionuclides is primarily the result of the beta radiation, whereas the gamma component allows for imaging and associated dosimetry but may contribute to normal tissue toxicity.595 Features of some of these radionuclides are compared in Table 25.1. Tumor characteristics such as size (e.g., micrometastases vs. bulky masses) and the level and heterogeneity of antigen expression help dictate the efficacy of a given radionuclide for TaRT. Beta-emitters (e.g., 131 I and 90Y) have been the most popular radionuclides for clinical TaRT trials to date. These radionuclides have the advantage of not needing to target every individual tumor cell because the mean radiation range is approximately 0.4 mm and 2.5 mm, respectively. This long path length allows for “cross-fire” (e.g., killing of nonantigen-expressing tumor cells); however, it can also be associated with increased normal tissue toxicity. Hence, beta-emitters may be more effective for sizable tumors and those with heterogeneous antigen expression but less useful in the setting of micrometastatic disease. Auger electron emitters, such as iodine-125 (125I), may be suitable for treatment of micrometastases that abundantly

131

express internalizing antigen on every cell because targeting of the nucleus is necessary for effective cell killing with this very short-range emitter (mean path length, 10 nM). Compared with beta-emitters, alpha-emitters typically have shorter path lengths (40 μM-80 μM), higher LET, and higher kinetic energies.112 Together, these features allow alpha-emitters to efficiently kill tumor cells by directly inducing double-stranded DNA breaks over a radius of several cells, even when antigen expression is heterogeneous. Hence, alpha-emitters may be most useful for the treatment of micrometastatic disease, such as leukemia in bone marrow, minimal intraperitoneal disease, and intratumoral delivery.113 The direct induction of doublestranded DNA breaks renders alpha-emitters independent of oxygen levels, which suggests that they may be preferred for hypoxic tumors.113a These favorable characteristics of alpha-emitters have led to considerable progress in their use in clinical trials as well as improving their availability.106,114-117 The National Laboratories of the United States have established cooperation to increase the supply of actinium-225 (225Ac), and Orano Med (formerly AREVA Med, Plano, TX) has developed the ability to ship 212Pb generators all over the world.118,119 The alpha-emitters bismuth-213 (213Bi) and 225Ac have been conjugated to anti-CD33 antibodies and have shown promising results in early clinical trials in acute myeloid leukemia (AML), with 225Ac now being studied in a large Phase II, multi-institutional trial.120-122 Alpha-emitters also have increasingly been used in the treatment of metastatic prostate cancer. Radium-223 (223Ra) is an unconjugated alpha-emitting calcium-mimetic that accumulates in areas of high bone turnover by physiological rather than ligand-guided targeting.123 The alpha-particles emitted by 223Ra are high energy and have a relatively short path length of 10 μM, which allows efficient tumor cell killing with minimal marrow suppression.124 In a Phase III clinical trial, treatment with 223Ra improves survival compared with placebo in patients with metastatic prostate cancer. Similar results have not been achievable with bone-targeted beta-emitters such as strontium-89, which are limited by marrow suppression presumably because of their longer path lengths.123-125 These results, along with considerable experience in Europe, led to FDA approval for 223Ra in 2013, making it the first alpha-emitter to receive such approval. Efforts are now ongoing to determine the optimal timing of 223Ra for patients with prostate cancer and to evaluate potential combination therapies with next-generation antiandrogens and cytotoxic chemotherapy.125a

RADIOBIOLOGY Biological effects of TaRT may be associated with both the radionuclides and their carriers, either alone or in combination.126-128 This is particularly

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CHAPTER 25

Targeted Radionuclide Therapy

The development of labeling and chelation chemistry for the production of stable radioconjugates has greatly facilitated TaRT. Iodine-131 (131I) can be directly attached to antibody without a chelator. However, if a targeted antigen/receptor undergoes modulation (internalization), the tumor cells can dehalogenate the conjugate and release free iodine. 131 I can also be attached by a secondary molecule conjugated through an iodinatable linker rather than directly linked to antibodies. These radioimmunoconjugates appear to be more resistant to dehalogenation.103 A variety of increasingly stable chelators have been developed for 90Y and other metal radionuclides, but some have been found to be immunogenic (probably partly as a result of aggregation).43,104 The chemistry, stability, and in vivo processing of radioimmunoconjugates also have implications for toxicity. The filtration of small radioconjugates or their metabolites through the kidneys may result in considerable radiation to the kidneys. Renal toxicity has been reported to be the dose-limiting toxicity for some small molecular weight (MW) peptide conjugates and alpha-emitter conjugates.105,106 Hepatic uptake, metabolism of radioimmunoconjugates, and retention of 90Y complexes in the liver are potentially dose limiting in myeloablative TaRT.107 Designing chelators with special characteristics can also affect radionuclide “matching” with the targeting agent. For example, selective degradation of a cathepsinsensitive chelate reduced liver uptake of radiometal.108 The use of such chelators may allow for dose escalation of radiometal conjugates such as copper-67 (67Cu) that otherwise would be limited by hepatic toxicity. Other conditionally cleavable chelators are also under study.109 The synthesis of the 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10tetra-(2-carbamonyl methyl)-cyclododecane (TCMC) chelator has allowed progress in the use of lead-212 (212Pb).110 Macrocyclic chelators, such as DOTA, which have been developed for stable chelation to 90Y, and other beta-emitting radiometals have shown acid lability with 212Pb, and likely other alpha-emitters.111 To overcome this, the bifunctional chelating agent TCMC was synthesized, characterized, and subsequently used in several animal studies.110

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426.e1

CHAPTER 25 true for certain antibody carriers that may have antitumor efficacy alone (e.g., anti-CD20 antibodies). Another important determinant of efficacy may be whether or not the antibody in internalized.129 Antibodyinduced responses can include apoptosis, complement-dependent cytotoxicity, and antibody-dependent cell-mediated cytotoxicity.130 Radiation effects can result in cell death during mitosis or by apoptosis, necrosis, or a metabolic cell death. The relative importance of these types of cell death depends on factors such as the inherent genetic makeup of the cells. For lymphomas, apoptosis is an important mechanism of cell death, whereas apoptosis usually plays less of a role in killing solid tumor cells. Lymphomas are especially sensitive to apoptosis induced not only by radiation, but by a variety of cytotoxic agents, including antibody therapy alone.131-134 Several signal transduction pathways have been found to be associated with radiation-induced apoptosis. These have been reviewed by Hernandez and Knox.126 Antibody-induced intracellular signaling may also function to enhance the effects of TaRT, and dose rate effects as well as the relative biological effectiveness of the associated radiation (e.g., high LET of alpha-particle emitter labeled monoclonal antibodies for treatment of microscopic residual/small-volume disease and eradication of cancer stem cells) may be important to the efficacy of TaRT as well.135,136 Several studies have shown that cells exposed to either continuous or exponentially decreasing low dose rate (LDR) radiation arrest in the radiosensitive G2/M phase of the cell cycle and undergo apoptosis.137-140 This G2/M block from LDR radiation as delivered via TaRT may also sensitize tumor cells to killing by other therapies such as EBRT.141 Data from some experiments showing this effect suggest that therapy may be optimized by using TaRT before EBRT.141,142 EBRT has also been given before TaRT to increase tumor uptake of radionuclide conjugates. In addition, regulating cell-cycle distribution or altering the underlying apoptotic potential by drugs or biological response modifiers in tumor cells can affect the susceptibility of such cells to radiation-induced apoptosis.143 Recent studies include the exploration of the use of gene transfer technology to induce expression of high-affinity membrane receptors to enhance the specificity of radioligand localization or the use of genetically engineered antibody molecules (e.g., diabodies: noncovalent single-chain Fv dimers) as carriers for TaRT that may be able to enhance the efficacy of this therapy.144-147 Although there is usually a positive correlation between the level of radiation-induced cell killing and dose rate, an inverse dose rate effect has been reported with LDR irradiation in the range of about 0.3 Gy/h, with some cell types being more sensitive to this inverse dose rate effect than others.148 Knox et al. showed lymphoma cells to be sensitive to 131 I-labeled antibody LDR radiation in a direct comparison to high dose rate external beam irradiation.149 At least one mechanism for this observation appears to be greater arrest in the G2/M phase of the cell cycle. Another mechanism of lymphoma radiation sensitivity may be less efficient DNA repair among lymphomas compared with some other cell types.126,127 More discussion on this topic is available online.

Targeted Radionuclide Therapy

or intracavitary administration may be advantageous. Intraperitoneal RIT has generally been more efficacious than intravenous RIT for the treatment of small-volume disease confined to the peritoneal cavity, but there are conflicting reports concerning the relative merits of arterial and venous routes of administration of radiolabeled antibodies for other sites.150-154

Radioimmunotherapy of Solid Tumors RIT for solid tumors is a form of systemic targeted radiotherapy that continues to be evaluated in a variety of tumors. Table 25.2 provides an overview of Mabs that have been evaluated in clinical trials. RIT has been evaluated in most major disease sites, including gastrointestinal, breast, brain, ovarian, head and neck, medullary thyroid, melanoma, renal, lung, and prostate cancers. Results from selected solid tumor trials evaluating systemically administered nonmyeloablative doses of RIT as single modality are

TABLE 25.2 Examples of Monoclonal Antibodies Evaluated for Radioimmunotherapy of Nonhematological Malignancies Malignancy

Antigen

Antibody

Colorectal cancer

CEA

cT84.66, hMN-14, A5B7, F6

TAG-72

B72.3, CC49

A33

anti-A33

EpCAM

NR-LU-10, NR-LU-13, 17-1A

DNA histone H1

chTNT-1/B

MUC1

huBrE-3, m170

L6

chL6

TAG-72

CC49

CEA

cT84.66

MUC1

HMFG1

Folate receptor

cMov18

TAG-72

B72.3, CC49

PSMA

huJ591, CYT-356

TAG-72

CC49

DNA histone H1

chTNT-1/B

TAG72

CC49

Head and neck cancer

CD44v6

U36, BIWA4

Gliomas

EGFR

425

Tenascin

816C, BC4

p97

96.5

Chondroitin sulfate proteoglycan

9.2.27

Breast cancer

Ovarian cancer

Prostate cancer Lung cancer

Melanoma

CLINICAL RESULTS A wide variety of human malignancies have been treated with RIT in the setting of clinical trials. Antibodies carrying radionuclides have targeted tumor-associated antigens, growth factor receptors, and other cell surface markers, usually expressed at a high level on malignant cells and to a lesser extent on subsets of normal cells. Nonantibody targeting has primarily been against neuroendocrine receptors. Several routes of administration have been employed, including intravenous, intraarterial, intrathecal, intraperitoneal, intratumoral, and, rarely, intrapleural administration. The most prevalent route of administration has been intravenous for systemic therapy. However, for localized disease, regional

427

Melanin

6D2

Renal cancer

Carbonic anhydrase IX

cG250

Pancreatic cancer

PAM4 reactive mucin

hPAM4

CEA

KAb201

Medullary thyroid

CEA

cT84.66, hMN-14, NP-4

Neuroblastoma

Ganglioside GD2

3F8

NCAM

UJ13A, ERIC-1

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CHAPTER 25

Targeted Radionuclide Therapy

Ongoing studies will help elucidate the radiobiology of TaRT, which will facilitate optimization of TaRT therapy in the future and provide the prerequisite understanding of underlying biological mechanisms to determine how best to use TaRT in combination with other treatment modalities.

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427.e1

428

SECTION II

Techniques and Modalities

Intact MAb 160 kDa

F(ab′)2 110 kDa

Fab 50 kDa

Odds ratio Variable domains scFv Diabody Minibody Constant domains 25 kDa 55 kDa 80 kDa Fig. 25.1 Comparison of the variable and constant domains for six types of engineered antibodies.

summarized in eTable 25.1. Early efforts used Mabs labeled with 131I because of availability and ease of labeling, with subsequent trials using radiometals such as 90Y, rhenium-186 (186Re), and 177Lu, and alphaemitters. Dose-limiting toxicities have primarily been thrombocytopenia and leukopenia. Tumor doses from RIT are dependent not only on amount of radioactivity localizing to the tumor but also on the retention time of that activity at the tumor site. Doses of approximately 10 to 20 Gy, with select tumors occasionally achieving doses of 20 to 70 Gy or greater, have been reported155-166 (eTable 25.2). Most of the clinical experience has involved Phase I trials, evaluating RIT as monotherapy in patients with advanced, bulky, chemotherapy-refractory disease progressing into therapy. As expected in this patient population, partial and complete responses (CRs) have been infrequent regardless of disease type,157,159,167-175 with most antitumor effects reported as stable disease and serological, mixed, or minor responses.a This is in contrast to clinical results observed with RIT in more radiosensitive lymphomas, with objective responses ranging from 30% to 85%.183,194-201 RIT doses currently achievable are at levels that can potentially result in clinically important antitumor effects in solid tumors, particularly in patients with subclinical or microscopic disease. To further increase response rates, a number of strategies have been evaluated, which include (1) improving the antibody delivery system to either increase antibody targeting to tumor or decrease uptake to critical organs; (2) decreasing dose-limiting toxicity (usually marrow toxicity), which would allow for escalation of administered activity; (3) altering the tumor environment to enhance radiolabeled macromolecule targeting; and (4) increasing the tumoricidal effect of the targeted radiation dose. Approaches that have been investigated in the past include (1) autologous stem cell support and dose escalation,107,171,202-206 (2) fractionation of administered activity,207,208 (3) adding agents that increase tumor antigen expression209-212 or increase tumor vascular permeability to increase dose to tumor,213,214 (4) adding additional dose through EBRT,215-223 or (5) adding hyperthermia.224 Approaches that continue to be studied include regional administration, combined modality approaches, and therapy in the minimal tumor

a

References 155, 156, 158, 161, 164, 176-193.

burden or adjuvant setting. Engineering the immunoconstruct and pretargeting antibody-based delivery strategies seek to amplify the differences between tumor and normal organ uptake and continue to be explored. There has also been increasing interest in the use of high-LET alpha-emitters in patients with solid tumors. A discussion on engineered immunoconstructs can be found online.

Minimal Tumor Burden Setting (See eTable 25.1) Tumor size plays a dominant role in influencing antibody uptake and clinically important outcomes are predicted if systemic RIT is applied in the subclinical or microscopic disease setting. Jain et al.23,249 have identified key physiological factors that limit uptake of macromolecules. These factors include spatial heterogeneity of tumor vascularity, increased interstitial pressure in poorly vascularized areas, and limited diffusion distances of macromolecules, which work to significantly limit the ability of the antibody to reach all sites within the tumor. These factors are amplified as the tumor grows, resulting in an exponential decrease in tumor antibody uptake, which has been demonstrated in vivo250-253 and in clinical trials.254,255 Given this inverse exponential relationship, a very modest reduction in tumor size will result in a substantial increase in antibody uptake. RIT, therefore, should have its greatest impact in the adjuvant setting and in the treatment of minimal or microscopic disease. A number of trials have evaluated this strategy primarily in patients with colorectal cancer. After initial Phase I and Phase II trials in patients with macroscopic disease, a Phase II adjuvant RIT trial of 131I-hMN14 anti-CEA administered after resection of colorectal cancer liver metastases was carried out. Twenty-three patients who underwent R0 resection of liver metastases from colorectal cancer received a single administration of 40 to 60 mCi/m2 of 131I-hMN14 anti-CEA.256 Results were compared to a contemporaneous control group of 19 patients from the same institution treated postresection with chemotherapy regimens based on 5-fluorouracil (5-FU). A statistically significant improvement in median overall survival in the RIT group (58 months vs. 31 months) was reported. Median disease-free survival was greater for the RIT group (18 months vs. 12 months). A Phase II adjuvant RIT study of up to two cycles of 131I-hMN14 in patients with colorectal cancer after R0 resection of liver metastases was reported recently.257 Median time to progression was 165 months and median overall survival was 55 months

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2008

1992

1996

1997

1997

1999

1999

2002

Mittal224

Juweid156

Juweid170

376

Behr169

Juweid173

Hajjar232

1999

2002

2002

Behr605

605

2007

2008

2017

2000

Liersch256

Liersch606

Sahlmann 257

Wong188

Behr

Behr

172

Juweid

Ychou

Ychou193

1996

Yu184

1998

2009

Meyer213

171

1994

1992

Year

Lane168

Breitz

159

Study (First Author)

eTABLE 25.1

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Y-DTPA-cT84.66

90

I-hMN-14

131

I-hMN-14

131

I-hMN-14

131

I-hMN-14

131

I-hMN-14

131

I-hMN-14

I-hMN-14

131

131

I-MN-14 F(ab′)2

131

Re-MN-14

I-MN-14

186

131

I-NP-4

I-NP4 F(ab′)2

131

131

I-NP4

131

I-F6 F(ab′)2

131

I-F6 F(ab′)2

I-COL-1

131

131

I-A5B7

131

I-A5B7 intact/F(ab′)2

131

Re-NR-CO-2 F(ab′)2

186

Radiolabeled Antibody

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

Antigen

I

II

II

II

II

II

I

I

I/II

I

I

I/II

I

I/II

II

I/II

I

I/II

Pilot

I

Study Type

22

63

32

23

9

21

12

17

15

11

14

57

13

6

13

10

18

12

19

26

Patient No.

CEA+

Colorectal

Colorectal

Colorectal

Colorectal

Colorectal

Colorectal

Colorectal, GI

Thyroid

Colon, pancreas

Ovary

CEA+

CEA+

Colorectal

Colorectal

Colon

GI

GI

CEA+

Colorectal, lung, breast

Tumor Type

Median OS 55 mo Median OS 75.6 mo for 39 patients with negative CEA and no suspicious lesions remaining postsurgery

DFS 18 mo Adjuvant RIT DFS 6 mo Non-adjuvant RIT

DFS 18 mo OS 59 mo

7/9 NED 24-36+ mo

3/19 (16)

2/11 (16)

1/12 (8)

1/14 (7)

1/57 (2)

1/6 (13)

DFS 12 mo OS 50 mo

1/9 (11)

2/19 (11)

1/31 (3)

Objective Responses (%)

12/22 (54) 7/22 > 50% ↓ CEA (33)

8/19 (42)

5/11 (45)

11/12 (92)

2/14 (14)

4/57 (7)

4/13 (31)

5/6 (88) ↓ CEA

3/9 (33)

4/18 (22)

1/10 (10)

11/31 (35)

Minor/Mixed Response or Stable Disease (%)

DTPA infusion post-RIT Continued

All patients post-R0 resection of liver mets

Resected liver mets 24 pts received 2 cycles RIT 16 no gross residual (adjuvant) 16 gross residual (nonadjuvant)

Adjuvant RIT R0 resection liver mets

Adjuvant RIT after R0 resection of liver mets

Small-volume liver mets ≥ 3.0 cm

Small-volume lesions ≥ 2.5 cm

Given in 2-3 divided doses every 3-4 days

Small-volume disease

Liver mets, hyperthermia combined with RIT

Adjuvant RIT after R0 resection of liver mets

Autologous marrow infused in 5 pts

RIT combined with combretastatin (CA4P)

Hepatic arterial infusion in 5 pts

Comments

Select Systemic Monoclonal Antibody RIT Clinical Trials in Nonhematologic Malignancies

CHAPTER 25 Targeted Radionuclide Therapy

428.e1

1992

1994

Meredith176

155

1995

1995

1996

1997

1998

Mulligan182

Meredith209

Macey210

211

1993

1995

1997

Weiden177

Meredith181

DeNardo161

1996

609

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2011

610

Gulec

2005

Chong163

Welt

1994

Welt179

O’Donnell

2001

1992

Breitz159

189

1999

Meredith212

Slovin

Divgi

1995

608

1994

Divgi208

Wheeler

180

Murray178

1994

2009

Sultana607

I-CC49+ I-COL-1

Y-hPAM4

90

I-huA33

131

I-A33

I-A33

125

131

Y-m170

Y-BrE-3

90

90

I-chimeric 17-1A

125

Re-NR-LU-13

186

Re-NR-LU-10

186

I-CC49

131

I-CC49

I-CC49

131

131

131

131

Lu-CC49

177

I-CC49

I-CC49

131

131

I-CC49

I-CC49

131

131

I-CC49

I-cB72.3

131

131

I-KAb201

131

Radiolabeled Antibody 90 Y-DOTA-cT84.66

PAM4-reactive mucin

A33

A33

A33

MUC1

MUC1

EpCAM

EpCAM

EpCAM

TAG-72

TAG-72

TAG-72

TAG-72 CEA

TAG-72

TAG-72

TAG-72

TAG-72

TAG-72

TAG-72

TAG-72

CEA

Antigen CEA

I

I

I/II

I/II

I

I

I

I

I

II

II

II

II

I

I

I

II

II

II

I

I/II

Study Type I

20

15

21

23

17

6

28

9

15

14

14

15

14

9

6

24

15

15

15

12

19

Patient No. 13

Pancreas

Colorectal

Colorectal

Colorectal

Prostate

Breast

Colorectal

GI, lung, breast

Colorectal, lung, breast

Prostate

Prostate

Breast

Colorectal

Colorectal, breast, lung

Colorectal

Colorectal

Colorectal

Colorectal

Prostate

Colorectal

Pancreatic

Tumor Type CEA+

3/20 (15)

1/15 (7)

1/18 (6)

Objective Responses (%)

4/20 (20)

4/15 (27)

14/20 (70)

3/20 (15)

8/13 ↓ pain (62) 7/17 SD SA (41)

3/6 (50)

10/28 (36)

2/9 (22)

8/14 (57) 5/6 ↓ pain (83) 3/14 >50% ↓ PSA (21)

4/14 (29)

5/15 (33)

4/14 (29)

2/9 (22)

6/24 (25)

5/15 (33)

3/14 (21)

10/15 (67) 5/15 > 50% ↓ PSA (33) 6/10 ↓ bone pain (60)

4/12 (33)

Minor/Mixed Response or Stable Disease (%) 5/13 (38)

α-interferon

γ-interferon

α-interferon

α-interferon

15 mCi/m2 biweekly × 4

IL-1 to reduce hematopoietic toxicity

12-18 mCi/m2 weekly × 2-3

Human-sheep chimeric antibody 50-75 mCi IV (9 pts) or IA (10 pts)

Comments DOTA conjugated antibody DTPA infusion post-RIT

Select Systemic Monoclonal Antibody RIT Clinical Trials in Nonhematologic Malignancies—cont’d

SECTION II

Meredith

Year 2006

Study (First Author) Wong233

eTABLE 25.1

428.e2 Techniques and Modalities

2000

2003

1998

Colnot187

Borjesson190

613

1999

2004

2005

2013

2015

2006

2005

2000

1997, 1994

Steffens174

Divgi164

Brouwers614

Stillebroer551

Muselaers615

Street165

Chen175

van ZantenPryzbysz158

DeNardo157,616

Divgi

2013

2005

Tagawa285

Bander

192

2004

Kahn

Milowsky191

1996

Deb183

1999

2004

Chen612

186

Year 1994

Study (First Author) Sharkey611

I-chL6

131

I-cMOv18

131

I-chTNT-1/B

131

I-chTNT-1/B

131

Lu-cG250

177

Lu-cG250

177

I-cG250

131

I-cG250

131

I-cG250

131

I-G250

Re-hu BIWA 4

131

186

Re-chimeric U36

186

Lu-huJ591

177

Lu-huJ591

Y-huJ591

177

90

Y-CYT-356

Y-CYT-356

90

90

I-Hepema-1

131

Radiolabeled Antibody 131 I-Mu-9

L6

Folate receptor

DNA histone H1

DNA histone H1

Carbonic anhydrase IX

Carbonic anhydrase IX

Carbonic anhydrase IX

Carbonic anhydrase IX

Carbonic anhydrase IX

Carbonic anhydrase IX

CD44v6

CD44v6

PSMA

PSMA

PSMA

PSMA

PSMA

Antigen Colon-specific antigen-p Glycoprotein

I

Pilot

II

I

II

I

I

I

I

I/II

I

I

II

I

I

II

I

I

Study Type I

10

3

107

21

14

23

15

27

8

33

17

13

47

35

29

8

12

32

Patient No. 25

Breast

Ovary

Lung

Colorectal

Renal

Renal

Renal

Renal

Renal

Renal

Head and neck

Head and neck

Prostate

Prostate

Prostate

Prostate (rising post-op PSA)

Prostate

Tumor Type Colorectal, pancreas Hepatocellular

4/10 (40)

4/107 (3.7) CR 33/107 (30.8) PR Median survival 11.7 mo

1/14 (7)

1/23 (4)

1/8 (13)

1/12 (8) PR

2/29 (7) PR

1 yr survival 31% Median survival 4 mo

Objective Responses (%)

2/10 (20)

3/3 (100)

59/107 (55.1) SD

5/21 (24)

8/14 (57%) SD

17/23 (74%) SD

5/27 SD

8/15 SD

1/8 (13)

17/33 (52)

4/17 (24)

Targeted Radionuclide Therapy

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Continued

200 mg cold Mab prior to RIT, resulting in ↑ serum IL-2, IL-2R, C3, C4, and ADCC, and twofold to threefold ↑ tumor Mab uptake

IV or intralesional

20 patients given second cycle

Given in 3-7 divided doses every 2-3 days

Single-infusion 65-70 mCi/m2

5/47 ≥ 50% ↓ PSA 17/47 ≥ 30% ↓ PSA 1/13 (8)

16 patients 2-3 cycles

Comments

4/35 (11) ≥ 50% ↓ PSA 16/35 (46) stable PSA

6/29 (21) SD

4/8 SD PSA (50)

2/12 ↓ pain (17)

4/20 (20) normal AFP 13/20 (65) > 50% ↓ AFP

Minor/Mixed Response or Stable Disease (%)

CHAPTER 25

428.e3

1984

2011

2013

Carrasquillo617

115

Klein618

Re-6D2

188

Bi-9.2.27

I-anti-p97

213

131

Radiolabeled Antibody 131 I-UJ13A

melanin

Melanoma chondroitan sulfate proteoglycan

p97

Antigen NCAM

I

I

Pilot

Study Type Pilot

20

38

10

Patient No. 5

melanoma

Melanoma

Melanoma

Tumor Type Neuroblastoma 10% PR

1/3 (33)

Objective Responses (%) 1/5 (20)

6/20 (30) SD

40% SD

1/3 (33)

Minor/Mixed Response or Stable Disease (%) 1/5 (20) Comments

Select Systemic Monoclonal Antibody RIT Clinical Trials in Nonhematologic Malignancies—cont’d

SECTION II

ADCC, Antibody-dependent cellular cytotoxicity; AFP, alpha-fetoprotein; CR, complete response; DFS, disease-free survival; DOTA, 1,4,7,10-tetraazacylcodecane-N,N′,N″,N -tetraacetic acid; DTPA, diethylenetriaminepentaacetic acid; GI, gastrointestinal; IL-1, interleukin-1; IL-2, interleukin-2; IL-2R, interleukin-2 receptor; mets, metastases; NED, no evidence of disease; OS, overall survival; PR, partial response; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; RIT, radioimmunotherapy.

Allen

Year 1987

Study (First Author) Lashford167

eTABLE 25.1

428.e4 Techniques and Modalities

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CHAPTER 25

Targeted Radionuclide Therapy

428.e5

eTABLE 25.2 Tumor Doses and Objective Response Rates From Selected Solid Tumor and Lymphoma Radioimmunotherapy Trials

Study (First Author), Year

RadionuclideAntibody

Tumor Type

No. Tumors Analyzed

Tumor Dose (cGy/Cycle)

Objective Response Rate (%)

Meredith,155 1994

131

Prostate

4

208-1083

0

156

131

Colorectal, lung, pancreas, thyroid

4

511-6476

0

131

Breast

7

120-3700 (~ 1300 mean)

131

Ovary

3

600-3800

0

Breitz,159 1992

186

Lung, colorectal, breast, ovary, renal

5

500-2100

4

Postema,160 2003

186

Re-hu BIWA 4

Head and neck

16

380-7610 (1240 median)

0

90

Y-BrE-3

Breast

16

442-1887

0

Wong,162 2003

90

Colorectal

31

46-6400 (1320 mean)

0

Chong,163 2005

131

Colorectal

NS

1170-3180 (2119 mean)

0

Divgi,164 2004

131

Renal

20

320-2330

0

Juweid,

I-CC49

1996

I-NP4 F(ab’)2

DeNardo,157 1997

I-chL6

158

van Zanten-Pryzbysz,

161

DeNardo,

165

1997

2000

I-cMOv18 Re-NR-CO-2 F(ab’)2

Y-cT84.66 I-huA33 I-cG250

40

131

I-chTNT-1/B

Colorectal

8

365-4560

Wiseman,166 2000

90

Y-2B8

Non-Hodgkin lymphoma

18

580-6700 (1700 median)

67

Vose,381 2000

131

Non-Hodgkin lymphoma

NS

795 mean

57

1996

131

Non-Hodgkin lymphoma

NS

141-2584 (925 mean)

79

1997

131

Non-Hodgkin lymphoma

45

16-1485 (241 median)

54

131

Non-Hodgkin lymphoma

NS

166-861

33

2006

Street,

397

Kaminski,

619

Lamborn,

Vose,620 2000

I-anti-B1 I-anti-B1 I-Lym-1 I-LL2

NS, Not stated.

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0

428.e6

SECTION II

Techniques and Modalities

eTABLE 25.3 Antibody Immunogenicity After Single Administration (Selected Solid Tumor Radioimmunotherapy Trials) Study (First Author, Year)

Antibody

Type

No. of Patients

Breitz,159 1992

186

Murine

15

100

131

Murine

15

100

131

Murine

23

100

177

Murine

9

100

Yu,184 1996

131

I-COL-1

Murine

18

83 prevented additional RIT in 2

DeNardo,161 1997

90

Y-BrE-3

Murine

6

83 prevented additional RIT in 3

Behr,169 1997

131

Murine

32

94

131

Murine

14

100

131

Murine

33

100

155

Meredith,

Re-NR-LU-10

1994

I-CC49

Welt,179 1994 182

Mulligan,

173

Juweid,

I-mAb A33

1995

Lu-CC49

I-NP-4

1999

I-MN-14

Divgi,613 1998 193

I-mG250

Antiantibody Response (%)

131

Murine

13

77

Meredith,207 1992

131

Chimeric

12

58

Weiden,177 1993

186

Chimeric

8

75

1995

125

Chimeric

15

13

1997

131

Chimeric

10

80 prevented additional RIT in 4

131

Chimeric

12

8

131

Chimeric

3

0

Colnot,187 2000

186

Re-U36

Chimeric

12

42

Wong,188 2000

90

Y-DTPA-cT84.66

Chimeric

21

52 prevented additional RIT in 8

Wong,233 2006

90

Chimeric

13

62 prevented additional RIT in 5

Street,165 2006

131

Chimeric

19

37

2009

131

Chimeric

19

100

Kramer,229 1998

111

Humanized

7

14

Hajjar,232 2002

131

I-hMN-14

Humanized

15

47

Bander,192 2005

90

Y-huJ591

Humanized

35

0

610

90

Humanized

21

10

Wong, 2013 (unpublished)

90

Humanized

16

13

Borjesson,190 2003

186

Humanized

20

10

Chong,163 2005

131

Humanized

15

27

2008

Ychou,

181

Meredith,

157

DeNardo,

I-F6 F(ab’)2 I-cB72.3 Re-NR-LU-13 I-17-1A I-chL6

Steffens,174 1999 van Zanten-Przybysz,

607

Sultana,

Gulec,

I-cG250

158

2000

I-cMOv18

Y-DOTA-cT84.66 I-chTNT-1/B

2011

I-KAb201 In-huBrE3

Y-hPAM4 Y-M5A T84.66 Re-BIWA 4 I-hu-A33

RIT, Radioimmunotherapy.

Engineered Immunoconstructs Recombinant DNA technology has been used to genetically engineer antibody constructs with properties to improve tumor to normal organ biodistribution, enhance in vivo stability, reduce immunogenicity, aid in conjugation and radiolabeling, and increase clearance kinetics. Reducing antibody immunogenicity through modification of the antibody molecule using recombinant DNA techniques to replace murine with human antibody domains (e.g., chimeric antibodies, in which the murine variable domains are retained, and humanized antibodies, in which only the murine complementarity determining region [CDR] antigen recognition sites are retained) to permit multiple administrations has been successful in the clinicb (eTable 25.3).

b

References 42, 157, 163, 165, 187, 190, 225-233.

Antibody fragments and other smaller molecular weight antibody constructs may ultimately prove superior for therapy because of their faster clearance, greater tumor penetration,23 more uniform distribution in tumor,234 higher initial dose rate in tumor,235 decreased immunogenicity,236 higher tumor-to-background ratios,237 and potential for higher administered activities and tumor doses for the same level of toxicity. Constructs have ranged from approximately 25 to 160 kDa in size. Small monovalent scFv, 28 kDa, clears rapidly from the circulation, increasing the tumor-to-blood ratio, making them attractive as potential imaging agents.238,239 However, the absolute peak uptake and retention time in tumors are often reduced, limiting their use as therapy agents.238-240 In addition, low-molecular-weight constructs can filter through the renal glomeruli, resulting in increased kidney uptake and radiation dose compared with higher-molecular-weight constructs. A more suitable construct for therapy might be bivalent, of intermediate molecular

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CHAPTER 25 weight, and exhibit uptake and retention in tumor comparable to intact antibodies, but with faster clearance times than an intact Mab, resulting in an improved therapeutic ratio. Fig. 25.1 shows an engineered series of recombinant fragments derived from the intact anti–carcinoembryonic antigen (anti-CEA) T84.66 MAb.241 The cT84.66 minibody has been evaluated in biodistribution trials labeled with 123I and 111In as a potential therapy agent. These trials demonstrated that renal uptake was higher than predicted from murine preclinical models and that, even for intermediate-sized constructs, other strategies would need to be developed to reduce renal uptake to allow for these agents to be used for therapy.

Targeted Radionuclide Therapy

428.e7

Other groups have investigated similar strategies.240,242-246 Forero et al. reported on a 153 kDa 131I-labeled humanized CH2 domain deleted construct (HuCC49ΔCH2) derived from CC49 anti-TAG72.247 Early results from a Phase I dose escalation therapy trial in metastatic colorectal cancer indicated reduced hematological toxicity compared with intact murine 131I-CC49. At the initial dose level of 75 mCi/m2, only 25% of patients (1 of 4) developed more than grade 3 hematopoietic toxicity, compared with > 60% of patients with 131I-murine CC49 in a previous trial.248

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CHAPTER 25 and 75.6 months in the 39 patients with normal CEA; no suspicious lesions were seen on imaging postsurgery. An adjuvant RIT trial in colorectal cancer was carried out by Ychou et al.,193 who administered a preoperative dose of 131I-F6 F(ab′)2 anti-CEA (8-10 mCi) prior to planned surgery to 22 patients with one to four liver metastases. After complete resection (R0), 13 patients, including 10 who had tumor-to-liver uptake ratios of > 5, received 180 to 200 mCi/ m2 of 131I-F6 F(ab′)2 anti-CEA RIT. With a median follow-up of 127 months, median disease-free survival was 12 months and median OS was 50 months. One patient remained disease free at 93 months. Recently, the feasibility and toxicities of a combined modality approach in the minimal tumor burden setting was evaluated in a Phase I study. Anti-CEA 90Y-cT84.66 RIT combined with hepatic arterial fluorodeoxyuridine (FUdR) and systemic gemcitabine was administered to patients with colorectal cancer after resection or radiofrequency ablation of liver metastases258 (eTable 25.4). Although postresection tumor burden was not reduced to an adjuvant therapy level, patients were resected to minimal disease not to exceed 3.0 cm. No dose-limiting toxicities were observed in 16 patients with FUdR of 0.1 to 0.2 μg/kg/ day × 14 days, gemcitabine 105 mg/kg, and RIT 16.6 mCi/m2. Median time to progression was 9.6 months, with two patients still progression free at 45 and 113 months. Encouraging results in the minimal tumor burden setting are also promising with regional administration of RIT, detailed in the next section.

Radioimmunotherapy and Chemotherapy (See eTable 25.4) Multiple preclinical studies have documented additive or supra-additive antitumor effects when RIT is combined with radiation-enhancing chemotherapy or other systemic agents, including gemcitabine,259-261 taxanes,262,263 cisplatin,264 5-FU,265-267 doxorubicin,268 halogenated pyrimidines,269 topoisomerase inhibitors,267,270,271 tirapazamine,272,273 epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors,274 and anti-EGFR Mabs.275 A growing number of clinical trials have demonstrated the feasibility and potential improved efficacy of concomitant chemotherapy and RIT in a number of different solid tumor types, including ovarian, breast, prostate, medullary thyroid, and colorectal cancers. In colorectal cancer, radiolabeled anti-CEA Mabs have been evaluated in Phase I trials in combination with single-agent chemotherapy. AntiCEA 90Y-cT84.66 has been evaluated in combination with continuousinfusion 5-FU205 and standard radiochemotherapy (60 Gy and cisplatin/ etoposide or carboplatin/paclitaxel in non–small cell lung cancer) (unpublished data). Recently. 131I-huA33 was evaluated in a Phase I study with concurrent capecitabine.276 In pancreatic cancer, 90Y-hPAM4 has been evaluated with low-dose gemcitabine (200 mg/m2 weekly).277 In a recent Phase 1b multicenter trial, patients with stage IV pancreatic cancer were randomly assigned to receive either 90Y-hPAM4 RIT alone (6.5 mCi/m2 weekly × 3) alone or combined with gemcitabine (200 mg/m2 weekly × 3).278 The median survival with the combination was 7.9 months versus 3.4 months for RIT alone (p = 0.004). In medullary thyroid cancer, escalating doses (20-50 mCi/m2) of 90Y-hMN-14 anti-CEA were combined with singlecycle doxorubicin at 60 mg/m2.279 Taxanes have shown promise in combination with systemic and intraperitoneal (IP) RIT. 90Y-m170 at 5 to 20 mCi/m2 with paclitaxel 75 mg/m2 has been evaluated in prostate and breast cancers.280,281 90 Y-CC49, paclitaxel 60 to 80 mg/m2, and interferon, to increase tumor antigen expression, was administered to 34 patients with stage IIB and stage IV non–small cell lung cancer. In patients with ovarian cancer with recurrent or refractory microscopic disease or macroscopic disease < 5 cm, combination therapy was evaluated, consisting of a single cycle

Targeted Radionuclide Therapy

429

of IP 177Lu-CC49 RIT, IP paclitaxel, and subcutaneous alpha-interferon.282 A pilot study of IP 90Y-cT4.66 anti-CEA RIT and IP gemcitabine in patients with CEA-expressing cancers with disease primarily confined to the peritoneal cavity demonstrated that the combination was well tolerated with no dose-limiting toxicities observed (unpublished data). Regional RIT is also actively being evaluated in combination with chemotherapy in patients with high-grade gliomas.

Radioimmunotherapy Using Antibodies With Immunomodulatory or Biologic Activity (eTable 25.1) Although most Mabs evaluated have had no significant biological activity, there have been some exceptions. HuJ591, which recognizes an external domain of PSMA, was evaluated in several trials in patients with hormone-refractory metastatic prostate cancer. PSMA is a transmembrane glycoprotein that is overexpressed in almost all prostate cancers and plays a role in folate uptake, cell migration, and cell proliferation. It is also expressed on the endothelial cells of tumor neovasculature. The initial Phase I trial treated 14 patients with 4 weekly doses of HuJ591 with dose levels of 25, 50, 100, or 200 mg/m2.283 PSA stabilization was observed in 3 patients. This was followed by a pilot trial of 14 patients, with each patient receiving four escalating doses of unlabeled Mab of 10, 25, 50, and 100 mg.284 Increasing ADCC activity was seen with increasing antibody dose. One patient demonstrated > 50% reduction in PSA. HuJ591 has been radiolabeled with 90Y and 177Lu and evaluated in Phase I RIT trials with encouraging results.191,192 In a Phase II trial, 47 patients with hormone-refractory prostate cancer received single administration 65 to 70 mCi/m2 of 177Lu-HuJ591.285 A total of 10.6% of patients experienced ≥ 50% decline in PSA and 36.2% experienced ≥ 30% decline in PSA. Median overall survival was 22.2 months for those with any PSA decline compared to 11.4 months for those with no decline. Phase I trials evaluating fractionated schedules of 177Lu-HuJ591 alone or combined with docetaxel have been completed recently.286 Also promising are nonantibody small-molecule radioligands that bind PSMA. Several have been evaluated in the clinic radiolabeled with 131 I or 177Lu79,287 with most studies reporting a reduction in PSA of > 50% in approximately 40% to 60% of patients.288 In a recent German multicenter retrospective analysis of 145 mCRPC patients, 45% experienced over a 50% decrease in PSA after 1 to 4 cycles of 177Lu-PSMA-617 radioligand therapy.79 A recent meta-analysis reported a decline of PSA of over 50% in 44% of 669 patients who received 177Lu-PSMA radioligand therapy versus 22% of 1338 patients who received other third-line therapy (p = 0.0002).289 Antibodies now used as part of standard regimens in nonhematological malignancies are also being evaluated as potential radioimmunotherapeutics. This concept is attractive because these antibodies have known antitumor effects that can add to the cytotoxic effects of RIT. Trastuzumab (Herceptin) is one the first Mabs to be approved for use in the treatment of nonhematological malignancies and recognizes EGFR 2 (HER2/neu), which is overexpressed by 20% to 30% of breast cancers. Trastuzumab radiolabeled with the beta-emitters 90Y, 177Lu, and 188Re, the Auger electron emitter 111In, and alpha-particle emitters 212Pb, 211At, and 225Ac has been evaluated in in vitro and in vivo preclinical therapy studies113,290-296 and a recent pilot clinical biodistribution study297 with encouraging results. Recently, Meredith and colleagues demonstrated safety of IP administration of 212Pb-trastuzumab in 18 patients with peritoneal-based disease from ovarian and colorectal cancer who received 0.2 to 0.74 mCi/m2 of therapy.298 In this first human study of IP alphaemitter RIT, no late cardiac, renal, liver, or hematopoietic toxicities were observed up to 1 year posttherapy. Ten of 18 patients demonstrated stable disease at 6 weeks and decline of TAG-72 tumor antigen levels were observed with increasing administered activity.

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I

I

I

I

I

I/II

I

Pilot

I

Pilot

I

Wong,162 2003

Sharkey,279 2005

Shibata,621 2009

Wong, unpublished

Cahan,258 2017

Wong, unpublished

Buchegger,216 2000

Herbertson,276 2014

Carabasi,223 1999

Meredith,282 2001

Lu-CC49

177

I-CC49

131

I-huA33

131

I-F(ab’)2 mab 35 mab B7 mab B93

131

Y-cT84.66

90

Y-cT84.66

90

Y-cT84.66

90

Y-cT84.66

90

Y-hMN-14

90

Y-cT84.66

90

Y-cT84.66

90

Antibody

TAG-72

TAG-72

A33

CEA

CEA

CEA

CEA

CEA

CEA

CEA

CEA

Antigen

IP

IV

IV

IV

IV

IV

IP

IV

IV

IV

IV

Route

Ovary (recurrent/ persistent tumor ≥ 5 cm after second-look laparoscopy)

Prostate, breast

Colorectal, metastatic

Colorectal with limited liver mets

CEA+ stage III non–small cell lung

Colorectal

CEA+

CEA+

Medullary thyroid

Colorectal

CEA+ Breast

Tumor Type

44

12

19

6

11

19

5

32

14

21

8

Pt. No.

1

1

1

1

1 cycle

15-1 cycle 1-2 cycles

1

25-1 cycle 4-2 cycles 3-3 cycles

1

13-1 cycle 8-2 cycles

1

No. Cycles

4/17 PR (measurable disease)

4/12 PR

1/19 PR

3 pts progression free at 5, 14 and 70+ mo

2 pts no progression (45 and 113+ mo) Median time to progression 9.6 mo

1/32 PR

1/14 PR

Objective Responses

Median TTP 13 mo 4/27 nonmeasurable disease progression free 18+, 21+, 21+, 37+ mo

1/9 MR

10/19 SD Tumor dose 5.1-26.9 Gy

1/6 MR 3/6 SD 5/6 ↓ CEA

2/5 SD

10/32 SD

2/14 MR 4/14 SD

1 MR 11 SD 3-8 mo

4/8 MR/SD 3-14 mo

Other Antitumor Effects

Select Radioimmunotherapy Trials Using Combined Modality Approaches

Study Type

1999

Wong,

205

Study (First Author, Year)

eTABLE 25.4

IP paclitaxel 25-100 mg/m2 α-interferon RIT 32-45 mCi/m2

RT (TBI 13.2 Gy) RIT 100-150 mCi/m2

Continued

Capecitabine oral twice daily × 14 days × 4 cycles

Whole liver RT (20 Gy) RIT 186 mCi (mean) (127 mCi-227 mCi)

EBRT (60 Gy) Chemotherapy (cisplatinum/etoposide or carboplatin/paclitaxel)

RIT 16.6 mCi/m2 DTPA post-RIT Intraarterial FUdR 0.1-0.2 μg/kg/d × 14 days Gemcitabine 105 mg/m2 days 9, 11 Liver mets resection

IP gemcitabine 40 mg/m2 days 1, 4, 8 IP RIT 19 mCi/m2 DTPA post-RIT

Gemcitabine 30-165 mg/m2 days 1,3 RIT 16.6 mCi/m2 DTPA post-RIT

Doxorubicin 60 mg/m2 day 3 Autologous stem cell supported RIT 20-50 mCi/m2

5-FU 700-1000 mg/m2/day × 5 cont. infusion RIT 16/6 mCi/m2 DTPA post-RIT

Cisplatin 25 mg/m2 days 1-4 Gemcitabine 100 mg/m2 days 2, 8 RIT 15-31.4 mCi/m2 day 2 DTPA post RIT Autologous stem cell reinfusion

Comments

CHAPTER 25 Targeted Radionuclide Therapy

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429.e1

Study Type I

I

I

I/II

Ib

I

I

pilot

II

I/II

Forero,488 2005

Meredith,333 2012

Ocean,277 2012

Picozzi,278 2015

DeNardo,280 2005

Richman,281 2005

Anderson,622 2003

Wygoda,623 2006

Bartolomei,343 2004

Pretargeting three-step BC-4-biotin Avidin 90 Y-biotin

I-425

125

I-chTNT1/B

131

Y-m170

90

Y-m170

90

90Y-hPAM4

Y-hPAM4

90

Y-CC49 177 LuCC49

Tenascin

EGFR

DNA histone 1

MUC1

MUC1

PAM4 positive mucin

PAM4 positive mucin

TAG-72

TAG-72

Antigen TAG-72

IC

IV

IV

IV

IV

IV

IV

IP

IV

Route IP

GBM recurrent/ progressive

Primary grade 3/4 gliomas. RT vs. RT + RIT

Carcinoid, leiomyosarcoma, colorectal

Prostate, breast

Prostate

Pancreas

Pancreas

Ovary (recurrent/ persistent tumor ≥ 5 cm)

Lung (NSLC) stage IIB and IV

Tumor Type Ovary (recurrent/ persistent tumor ≥ 5 cm)

73 38 RIT alone 35 RIT + TMZ

18

6

12

23

58

38

92

34

Pt. No. 20

Median 3 (2-7)

3 weekly

1

1

1

Weekly

Weekly

1

1

No. Cycles 1

1

2/27 PR with RIT + gemcitabine

6/38 PR

Significant ↑ in time to progression for tumors 2 cm 1/10 PR if < 2 cm 0/1 if positive cytology 10/11 NED at 6-15 mo if negative cytology

Hird,630 1993

90

MUC1

I/II

Ovary (after surgery, chemotherapy, and second-look laparoscopy)

52

Median survival 11 mo if > 2 cm at second look (n = 14) Median survival IIB pts with negative second look (n = 15) not reached and significantly better compared with matched historical controls

Nicholson,330 1998

90

MUC1

II

Ovary (after surgery, chemotherapy, and negative second-look laparoscopy)

25

5-yr actuarial survival 80% vs. 55% matched historical controls (p = 0.0035)

Epenetos,516 2000

90

MUC1

II

Ovary (after surgery, chemotherapy, and negative second-look laparoscopy)

21

73% survival 10 yr Median survival not reached

Verheijen,331 2006

90

MUC1

III

Ovary (after surgery, chemotherapy, and negative second-look laparoscopy) then randomized to standard therapy vs. standard therapy + RIT

447

Meredith,631 1998

177

Lu-CC49

TAG-72

I

Ovary (residual disease at second-look laparoscopy)

27

1/12 PR if > 1 cm 3/15 NED for 3-5 yr if < 1 cm or positive cytology

Rosenblum,632 1999

90

Y-B72.3

TAG-72

I

Ovary, fallopian tube, papillary serous

58

2/57 CR 9-12 mo (both < 3 cm)

Muto,633 1992

131

CA-125

I

Ovary (refractory)

29

Mahe,634 1999

131

CA-125

II

Ovary (< 0.5 cm residual after second-look laparoscopy)

Jacobs,635 1993

186

Ep-CAM

I

Ovary (recurrent or persistent)

17

4/7 PR if ≥ 1 cm 0/10 if > 1 cm (p < 0.05)

4/13 ↓ CA-125

Crippa,636 1995

131

Folate receptor

I

Ovary (< 0.5 cm residual after second-look laparoscopy)

16

5/16 CR

6/16 stable

Y-HMFG1

Y-HMFG1

Y-HMFG1

Y-HMFG1

I-OC125 F(ab′)2 I-OC125 F(ab′)2

Re-NR-LU-10 I-Mov18

Objective Responses

Other Antitumor Effects

Antibody

No difference in OS or time to relapse between 2 arms

RIT resulted in a significant ↓ in IP recurrence but an offsetting ↑ in extraperitoneal recurrences in the subgroup with residual disease after primary surgery (Oei, Verheijen et al. 2007422).

2/57 minor 30/57 stable median 6 mo 1/28 NED at 41 mo

6

3/6 stable

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430.e4

SECTION II

eTABLE 25.6 Study (First Author), Year Riva,637 1991

Techniques and Modalities

Select Intraperitoneal Radioimmunotherapy Trials—cont’d

Antibody 131 I-FO23C5, BW494/32, B72.3,AUA1

Antigen CEA TAG-72

Phase II

Tumor Type Colorectal

Wong (unpublished)

90

CEA

I

GI, pseudomyxoma

Buckman,638 1992

131

Mucin

I/II

Meredith 298 2016

212

HER-2

I

Y-cT84.66 I-mab 2G3

Pb-TCMCtrastuzumab

Patient No. 16

Other Antitumor Effects 3/15 stable 6/10 ↓ CEA

Objective Responses 2/15 CR (6-12 mo) 2/15 PR (3-16 mo)

13

5/13 stable 2/13 resolution of ascites

Malignant ascites— ovary, breast

9

3/4 temporary ↓ ascites if > 50 mCi administered

Intraperitoneal carcinomatosis (ovary, colorectal)

18

10/18 SD at 6 wk

No late renal, liver, cardiac or hemotopoietic toxicities observed up to 1 year Correlation with administered activity and decrease in TAG-72 levels

CR, Complete response; IP, intraperitoneal; NED, no evidence of disease; OS, overall survival; PR, partial response.

eTABLE 25.7

Select Central Nervous System Radioimmunotherapy Trials

Study, Year (First Author)

Phase

Antibody

Antigen

Route

Tumor Type

Brady,354 1990

I

125

EGFR

IA

Glioma, grade 2-4 recurrent

15

Li,356 2010

II

125

EGFR

IV

Glioma, grade 4 newly diagnosed

192

Kim,357 2013

II

125

EGFR

IV

Glioma, grade 43 newly diagnosed

80

Kalofonos,353 1989

I

131

EGFR, Placental alkaline phosphatase

IV or IA

Glioma, grade 3/4 Recurrent

10

Casaco,346 2008

I

188

EGFR

IC

Glioma, grade 3/4 recurrent

11

S

2/11 CR 1/11 PR

6.1 mo for whole group

Bigner,335 1998

I

131

Tenascin

IC

Recurrent glioma or metastases amenable to surgery

34

S

14/33 stable

60 wk for whole group 56 wk for grade 4

Cokgor,334 2000

I

131

Tenascin

IC

Glioma, grade 3/4 newly diagnosed

42

S, RT, C

79 wk for whole group 69 wk for grade 4

Reardon,221 2002

II

131

Tenascin

IC

Glioma, grade 3/4 newly diagnosed

32

S, RT, C

86.7 wk for whole group 79.4 wk for grade 4

Reardon,639 2006

II

131

Tenascin

IC

Glioma, grade 3/4 recurrent

43

S

69 wk for whole group 64 wk for grade 4

Zalutsky,116 2008

I

211

Tenascin

IC

Glioma, grade 3/4 recurrent

18

S

54 wk for grade 4 52 wk for grade 3

I-425 I-425

I-425

I-EGFR1 or H17E2

Re-h-R3 I-81C6

I-81C6

I-81C6

I-81C6

At-ch81C6

Patient No.

Other Therapies

Antitumor Effects

Median Overall Survival

1/12 CR 11/12 stable

8 mo median for whole group

S, RT, C (59 pts) TMZ (60 pts)

15.7 mo

S, RT

55.6 mo 1/10 NED for 3+ yr;

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CHAPTER 25

eTABLE 25.7

Targeted Radionuclide Therapy

430.e5

Select Central Nervous System Radioimmunotherapy Trials—cont’d

Study, Year (First Author) Brown,350 1996

Phase I

Riva,338 1995

Patient No. 31

Median Overall Survival

Other Therapies

Antitumor Effects 1/31 PR 13/31 stable

S, RT

3/50 CR 6/50 PR 11/50 stable 11/50 NED mean mo

20 mo for whole group 18 mo recurrent 23 mo newly diagnosed

S, RT, C (56 pts)

1/74 CR 9/74 PR 10/74 stable 23/74 NED

19 mo for grade 4

Antibody I-81C6

Antigen Tenascin

Route IT or IC

Tumor Type High-grade glioma, ependymoma, medulloblastoma

I

131

Tenascin

IC and intralesional

Glioma, grade 3/4 recurrent and newly diagnosed

50

Riva,640 1999

I/II

131

Tenascin

IC and intralesional

Glioma, grade 3/4 recurrent and newly diagnosed

111

Goetz,341 2003

Pilot

131

Tenascin

IC

Glioma, grade 3/4 newly diagnosed

37

S, RT

17 mo for grade 4 For grade 3, median not reached, estimate 85% 5-yr survival

S, RT

For grade 3, median OS 77.2 mo For grade 4 median OS 18.9 mo

131

I-BC-24 and BC-4

I-BC-24 and BC-4

I or Y-BC-4

90

Reulen,342 2015

pilot

131

I or 90Y -BC-24 and BC-4

Tenascin

IC

Glioma WHO grade 3/4

63

Papanastassiou,347 1993

pilot

131

I-ERIC-1

NCAM

IC

Glioma, WHO grade 3/4 recurrent

7

Hopkins,348 1995

pilot

90

Y-ERIC-1

NCAM

IC

Glioma, grade 3/4 recurrent

15

6 mo median for whole group 3 alive at 4, 6, and 26 mo

Shapiro,345 2006

I

131

DNA Histone H1

Intralesional

Glioma grade 3, 4 recurrent

12

27.3 wk for grade 4 138 wk for grade 3

Shapiro,345 2006

II

131

DNA Histone H1

Intralesional

Glioma grade 3, 4 recurrent, newly diagnosed

39

23 wk for grade 4, recurrent

Kemshead,351 1996

pilot

131

Multiple

IT

Meningeal disease carcinomas, melanoma and PNET

27

3/7 CR carcinoma pts 7/18 PR in PNET

Pizer,641 1991

pilot

131

Multiple

IT or intraventricular

Relapsed medulloblastoma

14

2/11 CR 2/11 PR 1/11 stable

Kramer,352 2018

II

131

GD2

Intraventricular

High-risk and relapsed medulloblastoma

43

1/22 near CR 9/22 SD

I-chTNT1/B I-chTNT1/B I-HMFG-1, Mel-14, M340,

I-UJ181.4, M340, UJ13A, Mel-14 I-3F8

3/7 stable

24.9 mo

C, Chemotherapy; CR, complete response; IA, intraarterial; IC, intracavitary; IT, intrathecal; IV, intravenous; NED, no evidence of disease; PNET, primary neuroectodermal tumor; PR, partial response; RT, external beam radiotherapy; S, surgery; TMZ, temozolomide; WHO, World Health Organization.

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430.e6

SECTION II

Techniques and Modalities

Studies have investigated intracavitary administration after surgical resection, intralesional, intraarterial, or intrathecal administration. Early efforts in patients with recurrent disease were encouraging, leading to trials evaluating this approach as adjuvant therapy in combination with standard surgical resection, EBRT, and chemotherapy in patients with newly diagnosed high-grade gliomas. Reported toxicities have been acceptable and were primarily hematological and neurological, including temporary headache, seizure, and worsening of neurological symptoms, with a few studies reporting irreversible neurological symptoms in a small subset of patients at maximum tolerated doses.221,334 Intracavitary and intralesional delivery of radioiodinated antibodies against tenascin, an extracellular matrix protein expressed by gliomas but not by normal brain tissue, has been evaluated as single-cycle therapy by investigators at Duke University and as multicycle therapy in Europe. Bigner et al. have evaluated single administration of intracavitary 131I-81C6334,335 in recurrent and newly diagnosed high-grade gliomas (see eTable 25.7). This led to a Phase II adjuvant RIT trial.221 Thirty-three patients with previously untreated high-grade gliomas received a single administration of 120 mCi 131I-81C6 directly into the surgical resection cavity, followed by conventional radiation therapy and 1 year of alkylator-based chemotherapy. The average radiation dose from RIT to the 2-cm rim around the resection cavity was 48 Gy. A median survival of 86.7 weeks for all patients and 79.4 weeks for glioblastoma patients was observed. A pilot study with 131I-murine 81C6 was completed (see eTable 25.4)336 in which RIT was combined with standard therapy in 21 patients with newly diagnosed high-grade gliomas. After surgical resection, RIT was administered into the surgical cavity to deliver 44 Gy to the cavity rim, followed by 55 to 60 Gy EBRT and chemotherapy. Toxicities were acceptable, demonstrating the feasibility of this combined-modality first-line therapy approach. With a median follow-up of 151 weeks, the median OS was 90.6 weeks for patients with glioblastomas. A Phase I study evaluated a 131I-labeled chimeric version of 81C6 in a similar combined-modality approach, also demonstrating encouraging results (see eTable 25.4).337 Finally, chimeric 81C6 radiolabeled with the alphaemitter 211At is being evaluated in a Phase I setting.116 Intracavitary and intralesional radiolabeled antitenascin RIT in patients with resected high-grade glioma has also been evaluated in Europe (see eTable 25.7).338-341 Reulen et al. reported the long-term results of 63 patients receiving intra-cavitary 131I- and 90Y-labeled anti-tenascin, reporting a median OS of 77.2 months from patients with grade 3 and 18.9 months for grade 4 gliomas, respectively.342 Recent efforts have also focused on pretargeting approaches combined with chemotherapy (see eTable 25.4).343,344 In a Phase I/II trial of 73 patients with recurrent glioblastomas, 38 received RIT alone versus 35 who received RIT and temozolomide. A median of three cycles of therapy was administered. With RIT and temozolomide, the OS was 25 months and PFS was 10 months, which compared favorably to the RIT-alone group with OS of 17.5 months and PFS of 5 months.

Other antibodies have been evaluated in a similar approach,345,346 with mean doses to the cavity rim of 5120 cGy347 and 5500 cGy.348 In addition, regional intrathecal administration has been evaluated in meningeal carcinomatosis and medulloblastoma, with objective responses observed.349-351 A recent Phase II study of intraventricular 131I-3F8 in high-risk and recurrent medulloblastoma reported a median OS of 24.9 months and an average total CSF absorbed dose of 1453 cGy.352 CNS malignancies have also been treated through intraarterial, intravenous, and intracavitary approaches using antibodies directed against EGFR.346,353,354 Brady et al.154,220,346,353-355 have administered 125I-Mab 425, an internalizing murine IgG2a directed against EGFR, in patients with high-grade gliomas (see eTable 25.7). A Phase II study was conducted in 192 patients with newly diagnosed glioblastoma multiforme who received adjuvant RIT using 125I-Mab 425 6 weeks after conventional radiotherapy and debulking surgery.356 Approximately 31% received nitrosoureas and another 31% received temozolomide. The median survival was 15.7 months. For the subgroups receiving 125I-Mab 425 alone versus 125I-Mab 425 and temozolomide, the median survival was 14.5 versus 20.2 months, respectively. Median survival for 80 patients with anaplastic astrocytoma was 55.6 months and 5-year survival was 47% (eTable 25.7).357

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CHAPTER 25 and transarterial chemoembolization (TACE) resulted in superior 1- and 2-year OS compared with TACE alone in patients with hepatocellular carcinoma.361

High Linear Energy Transfer Alpha-Particle Emitters There has been increasing interest in evaluating RIT using alpha-particle emitters in patients with nonhematological malignancies. Zalutsky et al. evaluated the feasibility and safety of intracavitary administration of the antitenascin chimeric antibody 211At-ch81C6 in 18 patients with recurrent grade 2/4 gliomas after surgical resection (see eTable 25.7).116 No dose-limiting toxicities were observed. Median survival for patients with glioblastoma multiforme was 54 weeks. Andersson et al. administered 211At-MX35 F(ab′)2 to 9 patients with recurrent ovarian cancer in complete clinical remission after second-line chemotherapy and after negative second-look laparoscopy.362 The antigen recognized by MX35 is a sodium-dependent phosphate transport protein overexpressed by ovarian cancers (NaPi2b). No dose-limiting toxicities were observed. Absorbed dose to the peritoneum was 15.6 and red marrow 0.14 mGy/ MBq/L. The authors concluded that therapeutic doses to microscopic IP disease were achievable without significant toxicity. Meredith et al. recently demonstrated safety of IP administration of 212Pb-trastuzumab in 18 patients with peritoneal-based disease from ovarian and colorectal cancer who received 0.2 to 0.74 mCi/m2 of therapy298 (see eTable 25.6). Finally, Allen et al. have evaluated systemic alpha-particle RIT using 213 Bi-cDTPA-9.2.27 in patients with stage IV metastatic melanoma or in-transit metastases (see eTable 25.1).115 Thirty-eight patients were treated with 1.25 to 25 mCi in this Phase I study. Partial responses were observed in 10% and stable disease of at least 8 weeks’ duration seen in 40%. Intralesional administration of 213Bi-cDTPA-9.2.27 has been reported by the same group in 16 patients.363

Summary of Solid Tumors As one of the first forms of targeted therapy, the introduction of radiolabeled antibodies into the clinic was understandably accompanied with high expectations. What has been learned through preclinical and clinical studies is a better understanding of the limitations and challenges associated with RIT, many of which apply to both nonhematological and hematological malignancies. As with other emerging therapies, RIT will likely find its role not as monotherapy but rather as a therapy used rationally in combination with other modalities. Although a number of strategies to increase tumor uptake and antitumor effects of these agents have proven encouraging, it is likely that no single strategy will be sufficient and that multiple strategies will be needed to realize clinically important results in the solid tumor setting. As clinical trials suggest, RIT will likely be best defined in the minimal tumor burden or adjuvant setting.

Radioimmunotherapy of Lymphoma and Leukemia RIT has been most successful for the treatment of lymphoma and leukemia. Representative clinical trials using RIT for B-cell non-Hodgkin lymphoma (NHL) and T-cell lymphoma and leukemia have been summarized in eTables 25.826-28,198,200,364-389 and 25.9390-393 in terms of general study design (nonmyeloablative vs. myeloablative), radionuclide and antibody used, number of treatments, number of treated evaluable patients, and responses. Myeloablative studies have included bone marrow or peripheral stem cell collection and reinfusion. These trials differ in terms of eligibility criteria, antibody and radionuclides used, dose, number of treatments, doses of unlabeled antibody preinfused or coinfused, and the biodistribution or dosimetry estimations required for administration of a therapeutic dose of radiolabeled antibody. The results summarized in eTable 25.8 are particularly promising and show a relatively high response rate with a number of durable PRs and CRs,

Targeted Radionuclide Therapy

431

with a subset of these responses ongoing at ≤ 5 years, and many patients experiencing remissions of longer duration than had been achieved with previous chemotherapy. The highest overall response and CR rates and the longest remission durations have been reported in patients treated with high doses of radiolabeled antibody in single doses in conjunction with autologous bone marrow transplantation (BMT) or stem cell transplantation (SCT).28,370,375,394,395 Although higher doses of RIT have tended to be more efficacious, there has not been a direct correlation between dose and response in most reported studies. These results are particularly encouraging because all of the patients treated in these trials have had recurrent disease following at least one form of conventional therapy. Many of the patients had failed multiple courses of therapy, and some were unable to tolerate additional chemotherapy for a variety of reasons. Two anti-CD20 Mabs conjugated to either 131I (131I-tositumomab or Bexxar) or 90Y (90Y-ibritumomab tiuxetan or Zevalin) have been approved by the FDA for patients with relapsed or refractory low-grade or transformed B-cell NHL381,383,385 and have demonstrated efficacy in patients even after the use of rituximab (Rituxan).384,386 90Y-ibritumomab was also approved for upfront treatment of previously untreated patients with low-grade B-cell NHL in 2009. The Bexxar (tositumomab and l31 I-tositumomab) regimen consists of the sequential administration of a dose of unlabeled murine Mab, tositumomab, to optimize biodistribution and increase tumor localization of the 131I-tositumomab that is administered thereafter.196,396 An initial biodistribution study uses a dosimetric dose to allow for the calculation of a patient-specific therapeutic dose to deliver an absorbed whole-body dose of 75 cGy in patients with a platelet count of ≤ 150,000/μL. FDA approval was based on a study in 40 patients with relapsed/refractory disease after rituximab therapy and was further supported by the demonstration of durable responses in four other studies enrolling 190 patients with relapsed/ refractory disease following chemotherapy. Objective tumor responses occurred in approximately 60% of patients, with CRs in approximately 30%. Median response durations have been in excess of 12 months, with occasional durable CRs lasting for years.381,383,397,398 Despite these encouraging results, manufacturing of 131I-toxitumomab was discontinued in 2014 because of its limited clinical use. The 90Y-ibritumomab tiuxetan (or Zevalin) regimen uses the chimeric anti-CD20 antibody rituximab for predosing. The pivotal study that supported FDA approval of Zevalin randomized 143 patients to receive either rituximab alone (four weekly doses of 375 mg/m2, as it is used as a therapeutic agent) or RIT with a lower dose (250 mg/ m2) of rituximab for purposes of optimizing the biodistribution of Indium-111 (111In)-labeled ibritumomab tiuxetan for an imaging/ dosimetry study. Seven days later, patients received 250 mg/m2 rituximab followed by 0.4 mCi/kg 90Y-labeled ibritumomab tiuxetan. Based on the International Workshop NHL Response Criteria, the overall response rate was 80% for 90Y-ibrutumomab tiuxetan versus 56% in the rituximab arm (p = 0.002). CRs were achieved in 30% of patients with 90Y-ibrutumomab tiuxetan versus 16% for rituximab (p = 0.04).385 Of those patients who have since progressed, the time to next therapy was 11.5 months after 90Y-ibrutumomab tiuxetan and 7.8 months after rituximab. Two randomized studies of either 90Y-anti-CD20 Mab385 or 131I-antiCD20 Mab387 versus unlabeled anti-CD20 Mab have demonstrated the importance of the radiation associated with RIT as a determinant of both the efficacy and toxicity of the RIT treatment. The radiobiology of RIT targeting the CD20 antigen is critical to tumor and normal-tissue effects associated with this therapy and has been reviewed.126 Retreatment with radiolabeled anti-CD20 Mab has also been reported to be well tolerated and efficacious in a subset of patients.26,372,399 More discussion on this topic is available online.

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CHAPTER 25

eTABLE 25.8

Targeted Radionuclide Therapy

431.e1

Radioimmunotherapy Trials for Relapsed B-Cell Lymphoma

Antibody (Cumulative mg) Nonmyeloablative LYM-1 (8-676)

Radionuclide (Cumulative mCi) 131

I (26-1044) I (40-100/m2/treatment)

131

Treatments

No. of Evaluable Patients

Responses

References (First Author)

1-16 1-4

57 21

11 CR, 20 PR 7 CR, 4 PR

Lewis,369 DeNardo,373 DeNardo642

LYM-1 (30-67)

131

I (50-267)

1-2

13

4 PR

Kuzel,367 Meredith368

LYM-1 (17-290)

67

Cu (40-438) Y (0.185-0.370 GBq/m2)

1-4 1

12 8

1 CR, 4 PR, 2 MR 5 PR or SD

O’Donnell,377 O’Donnell,378 O’Donnell380

90

LL2- (epratuzumab) (1.1 mg IgG-157 mg F(ab1)2)

131

1-7

17

2 CR, 2 PR, 2 MR

Juweid200

LL2 (N/A)

186

1

15

1 CR, 4 PR

Postema388

Humanized LL-2 (41-139)

131

1

13

1 CR, 1 PR

Juweid376

1

13

8 objective responses

Chatal389

2-8

21

5 CR, 2 PR

Vose372

I (15-343) Re (0.5-2.0 GBq/m2) I (15-59)

90

2

Y (15-22.5 mCi/m )

131

LL2 (0-160)

2

I (30-120 mCi/m )

MB-1 (40)

131

1

10

1 CR, 2 PR, 1 MR

Kaminski365

OKB7 (25)

131

I (90-200)

3-4

18

1 PR, 12 MR

Czuczman366

Anti-idiotype (1000-4050)

90

Y (10-54)

1-4

9

2 CR, 1 PR, 1 MR

Parker,364 White371

Tositumomab (2-110)

90

1

4

1 CR, 1 PR

Knox26

Tositumomab (10-518)

131

1

59

20 CR, 22 PR

Kaminski379

Tositumomab (484-487)

131

I (45-177)

1

47

15 CR, 12 PR

Vose381

Tositumomab (450-506)

131

I (0 ≥ 198)

1

60

10 CR, 29 PR

Kaminski383

Tositumomab (485)

131

1

42

14 CR, 9 PR

Davis643

Tositumomab (485)

131

I (N/A)

1

38

8 CR, 14 PR

Horning384

Chimeric C2B8 (rituximab; cumulative mg N/A)

90

Y (51-109)

1

7

3 CR, 1 PR, 2 MR

Weiden382

Ibritumomab tiuxetan 2B8 (55-294)

90

1-2

14

5 CR, 6 PR

Knox26,a

Ibritumomab tiuxetan 2B8 (rituximab; 100-250 mg/m2 × 2)

90

1

50

13 CR, 21 PR

Witzig27

Ibritumomab tiuxetan 2B8 (rituximab; 250 mg/m2 × 2)

90

1

73

25 CR, 33 PR

Witzig385

Ibritumomab tiuxetan 2B8 (rituximab; 250 mg/m2 × 2)

90

1

54

8 CR, 32 PR

Witzig386

Rituximab

131

1

24

3 CR, 2 PR

Kang400

Rituximab

131

I (≤ 200, median 501)

1-6

31

13 CR, 8 PR

Kang401

Rituximab

177

Lu-DOTA (740-1850 mBq/m2)

1

29

6 CR, 9 PR

Forrer402

I (25-161)

Y (14-22) I (33-161)

I (N/A)

Y (20-53) Y (12-32) Y (≥ 32) Y (N/A) I (200)

a

A Phase I dose escalation trial; two patients required stem cell reinfusion of four patients treated at the highest dose (50 mCi). CR, Complete response; MR, minor response; N/A, not available; PR, partial response. Adapted from Knox SJ. Radioimmunotherapy of the non-Hodgkin’s lymphomas. Semin Radiat Oncol. 1995;5(4):331–341.

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431.e2

SECTION II

eTABLE 25.9

Techniques and Modalities

Radioimmunotherapy Trials for T-Cell Lymphoma and Leukemia

Radionuclide (Cumulative mCi)

Antibody (Cumulative mg)

Nonmyeloablative 131 I (25-50)

T101 (10)

1

131

Treatments

No. of Evaluable Patients

Responses

References

4

0a

Zimmer33

I (100-150)

T101 (10-16)

1b

6

2 PR, 4 MR

Rosen391

90

Y (N/A)

T101 (N/A)

1

6

3 CR

Raubitschek392

90

Y (5-15)

Anti-Tac (2-10)

1-9

2 CR, 9 PR

Waldmann393,c

16

a

No objective clinical responses were observed; however, a transient decrease in peripheral blood lymphocytes was observed in 1 patient. Three patients were subsequently retreated, but responses shown are for the first treatment with a single dose of 131I-T101. c Adult T-cell leukemia. CLL, Chronic lymphocytic leukemia; CR, complete response; CTCL, cutaneous T-cell lymphoma; MR, minor response; N/A, not available; PR, partial response. Adapted from Knox SJ. Radioimmunotherapy of the non-Hodgkin’s lymphomas. Semin Radiat Oncol. 1995;5(4):331–341. b

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CHAPTER 25

Targeted Radionuclide Therapy

131

I-rituximab has also been studied in patients with relapsed/ refractory B-cell NHL, with a response rate of 46% and median PFS of 4.5 months in patients with low-grade B-cell lymphoma compared with only a 9% response rate and 1.3-month PFS in patients with diffuse large B-cell lymphoma.400 Repeat treatment with 131I-rituximab was well tolerated and resulted in a two-fold increase in response rate and median duration of response.401 Recently, 177Lu-DOTA-rituximab was also studied for safety and feasibility for the treatment of follicular and mantle cell lymphoma with encouraging results.402

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431.e3

432

SECTION II

Techniques and Modalities

The optimal time to use RIT in the course of NHL has not been defined.11,403 A trial using 131I-tositumomab as primary therapy for low-grade disease in 76 previously untreated follicular lymphoma patients has shown impressive results, with a response rate of 95% and evidence of conversion to molecular negativity by polymerase chain reaction (PCR) testing for Bcl-2 rearrangements in 80% of patients with a CR. Actuarial 5-year survival was 59%, with a median PFS of 6.1 years.404 Similarly, fractionated 90Y-ibritumomab as initial therapy in 74 patients with follicular lymphoma resulted in an overall response rate of 95.8% and CR/CRu (complete remission unconfirmed) of 69.4%, with estimated 3-year PFS of 58% and OS of 95%.405 Patients who have failed BMT have experienced excellent tumor responses to RIT as well.372,389 In addition, RIT is also being studied in other histologies, such as diffuse large-cell lymphoma (DLCL), mantle cell lymphoma,406 early-stage extranodal indolent ocular adnexal lymphoma,407 extranodal marginal-zone lymphoma,408 and multiple myeloma409 with encouraging results.410-412 For example, in a study of 104 patients with relapsed B-cell DLCL following treatment with either chemotherapy alone or chemotherapy and rituximab, the overall response rate was 44%, with median OS of approximately 22 months for patients previously treated with chemotherapy and 4.6 months for patients who had failed chemotherapy plus rituximab.410 RIT has also been useful as a preparatory regimen for transplantation.28,370,375,394,395 In a clinical trial comparing high-dose RIT with conventional high-dose chemotherapy with hematopoietic SCT, the RIT group had higher OS and PFS than the group of patients who received the conventional preparatory regimen for transplantation.413 Other trials of 131I-tositumomab combined with etoposide, cyclophosphamide, and autologous stem cell transplant (ASCT) compared with total body irradiation (TBI) combined with etoposide, cyclophosphamide, and ASCT also demonstrated improved OS and PFS in the group receiving RIT.414 In a Phase II trial of this regimen in patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL), RIT-based ASCT resulted in significantly better survival outcomes for patients with high-risk disease (relapse within 12 months of R-chemo of refractory disease to last salvage regimen) when compared to standard TBI-based conditioning.415 The same regimen has yielded encouraging results in patients with mantle cell lymphoma, with 3-year PFS of 61%.416 An update of 162 patients with mantle cell lymphoma who underwent ASCT further demonstrated that this RIT-based conditioning regimen was associated with reduced risk of treatment failure and mortality after adjusting for imbalances in important risk factors.417 131I-tositumomab has also been studied in combination with bis-chloroethylnitrosourea (BCNU), etoposide, cytosine arabinoside (Ara-C), and melphalan (BEAM) followed by ASCT. Toxicity was similar to BEAM alone. The CR rate was 57% and overall response rate was 65%, with 3-year event-free survival 39% and OS 55%.418 However, when conditioning with standard doses of 131I-tositumomab added to BEAM before ASCT was compared to rituximab and BEAM in 224 patients with relapsed DLBCL, no difference in PFS or OS was seen.419 The lack of benefit may be the result of decreased administered activity of 131I compared with other myeloablative transplantation approaches. In another study, 131 I-rituximab combined with BEAM conditioning and ASCT for relapsed/ refractory aggressive NHL resulted in a very high CR rate (15/16), with 12 out of 16 patients alive and disease free at a median of 44 months posttransplantation.420 A similar approach using 90Y-ibritumomab with BEAM has also yielded promising results.421 In a matched-cohort analysis of 90Y-ibritumomab with BEAM versus 12-Gy fractionated TBI with etoposide and cyclophosphamide as a conditioning regimen for ASCT in DLCL, the 4-year cumulative incidence of relapse/progression was similar, but OS at 4 years was 81% for the RIT group compared with 52.7% for the TBI group

perhaps as a result, in part, of the lower incidence of cardiac toxicity in the TBI group.422 Another study of 90Y-ibritumomab, fludarabine, and 2-Gy TBI as a conditioning regimen for allogeneic transplantation for patients with persistent high-risk B-cell lymphoma resulted in an estimated 30-month survival, PFS, and nonrelapse mortality of 54.1%, 31.1%, and 15.9%, respectively, with an acceptable toxicity profile.423 90Y-ibritumomab therapy with stem cell support is also being investigated with encouraging early results in studies of RIT as part of a reduced-intensity conditioning regimen for allogeneic stem cell transplant.424,425 Investigators at M. D. Anderson Cancer Center found a 3-year PFS of 87% for chemosensitive patients with relapsed follicular lymphoma after conditioning with 90Y-ibritumomab tiuxetan, fludarabine, and cyclophosphamide and an 80% 3-year PFS for patients with chemorefractory disease.426 A variety of extended Phase II trials using RIT combined with high-dose chemotherapy are ongoing to better define the safety and efficacy of this therapeutic approach, which may be further improved by radiobiological optimization of RIT for stem cell transplantation.427 Other approaches to increasing the efficacy of RIT in B-cell NHL include the use of a pretargeting regimen using an anti-CD20-fusion peptide, which is discussed later in this chapter.317 This approach is based on the dissociation of the delivery of antibody from the delivery of radionuclide, with a clearing agent used in between to eliminate unbound circulating antibody that, if radiolabeled, would be a source of nonspecific radiation and, therefore, toxicity. Proof of principle for this platform technology has been demonstrated in a clinical trial with significantly increased tumor-to–whole-body, tumor-to-blood, and tumor-to-normal organ ratios than achievable with directly labeled Mab.317 Another area of active investigation is the study of RIT as part of a combined-modality approach with either nonmyeloablative chemotherapy or conventional radiation therapy.428,429 For example, the combination of low-dose–involved field radiation therapy to active sites of disease prior to RIT in patients with relapsed/refractory B-cell lymphoma was well tolerated, did not add toxicity to that of RIT alone, and resulted in excellent PFS, with a longer median freedom from progression than in patients treated with RIT alone.430 In addition, a small study of 18-Gy whole-brain radiation combined with RIT following CNS chemotherapy resulted in a 100% CR rate, with no relapses after 12 to 20 months and no associated neurocognitive function decline.431 Numerous trials have explored the combination of RIT with a variety of chemotherapy drugs. The combination of RIT, cyclophosphamide/ doxorubicin hydrochloride/vincristine sulfate/prednisone (CHOP), and involved field radiotherapy in aggressive DLCL (SWOG 0313) was reported to result in outcomes that compared favorably to historical experience.432 Additionally, combination fludarabine or CHOP chemotherapy with RIT as upfront therapy in Phase II trials has resulted in high overall response and excellent PFS.433 In a Phase II trial (SWOG 9911) of CHOP chemotherapy combined with 131I-tositumomab as consolidation in 90 patients newly diagnosed with follicular NHL, the CR rate was 39% with CHOP alone and 69% for patients receiving both CHOP and RIT, respectively. Five-year PFS and OS was 67% and 87%, respectively, for patients receiving the combination therapy.291 These results provided the rationale for a Phase III trial (SWOG 0016) comparing CHOP plus rituximab with CHOP followed by 131I-tositumomab. In this trial, with a median follow-up of 4.9 years, the 2-year estimated PFS was 76% for the CHOP-R arm and 80% for the CHOP-RIT arm (p = 0.11), with a 2-year OS of 97% for CHOP-R and 93% for CHOP-RIT (p = 0.08).434 Chemotherapy combined with RIT has also been studied in 20 previously untreated elderly patients with DLBCL, using CHOP and 90 Y-ibritumomab tiuxetan.435 In this Phase II trial, the overall response rate was 100%, with 95% CRs. Importantly, four of five patients with an initial PR to CHOP alone converted to CRs following consolidative

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CHAPTER 25 RIT. With median follow-up of 15 months, 2-year PFS is 75% with a 2-year OS of 95%. In the SWOG S0433 trial, 84 patients with newly diagnosed advanced-stage or bulky stage II DLBCL received R-CHOP with 131-I-tositumomab consolidation with an estimated 2-year PFS of 69% and 2-year OS of 77% at a median follow-up of 3.9 years.436 A randomized Phase III study of induction chemotherapy followed by observation or 90Y-ibritumomab in 409 patients with advanced-stage follicular NHL, with a median of 7.3 years follow-up, demonstrated that 90 Y-ibritumomab consolidation after PR or CR/CRu following induction resulted in a 3-year benefit in median PFS, with a durable 19% PFS advantage at 8 years, and improved median time to next treatment by 5.1 years.437 Other studies have investigated the role of 90Y-ibritumomab therapy as consolidative therapy following CHOP and CHOP/rituximab therapy, respectively, in early-stage disease. In a Phase II trial of R-CHOP followed by 90Y-ibritumomab in patients with previously untreated stages I and II diffuse large cell NHL (ECOG E3402), 78% of patients who received both R-CHOP and RIT were progression free with ongoing CRs, and 94% were alive at 5 years.438 Other data suggests that consolidative RIT with 90Y-ibritumomab tiuxetan may prolong survival of patients with chemosensitive mantle cell lymphoma who achieve a clinical response after chemotherapy.439 Indeed, data from multiple trials have demonstrated that consolidative RIT increases rates of complete remission and duration of response.440 Encouraging results have also been reported in patients with untreated mantle cell lymphoma using 90Y-ibritumomab following four cycles of rituximab/CHOP with a 75% response rate (43% CR) and 93% OS at 18 months.406 It is noteworthy that patients with NHL who undergo RIT can well tolerate subsequent chemotherapy regimens or ASCT with toxicity from subsequent therapy being similar to that observed in patients not previously treated with RIT.441 More recently, RIT is being studied in combination with biological response modifiers, such as bortezomib, to try to further increase the therapeutic index of RIT.442 RIT has also been studied in combination with immunostimulatory CpG 7909 oligodeoxynucleotide in relapsed B-cell lymphoma with promising results.443 Results from clinical studies of RIT for the treatment of patients with recurrent Hodgkin lymphoma have been encouraging. These studies have used 131I-444 or 90Y-labeled194,445-447 antiferritin antibody. Overall, 134 patients with recurrent Hodgkin disease have been treated in five different studies with radiolabeled antiferritin antibody.448 Results obtained with 90Y-antiferritin antibody were better than those obtained with 131I-antiferritin antibody. 90Y-antiferritin antibody therapy resulted in a response rate of 60%, with a CR rate of 30%. The extent of response was associated with survival, with 50% of patients with CR, PR, and progressive disease alive at 2 years, 1 year, and 4 months, respectively.448 Responses in these studies were more common in patients with disease histories longer than 3 years, tumor volumes less than 30 cm3, and in patients receiving at least 0.4 mCi/kg of 90Y-labeled antiferritin antibody.448 131I-tositumomab has also been studied in recurrent lymphocytic-predominant Hodgkin lymphoma.449 More recently, 90Y-antiCD25 Mab therapy in patients with refractory and relapsed Hodgkin lymphoma yielded encouraging results, with 9 PRs and 14 CRs in 46 patients.450 A variety of radiolabeled MAbs have shown significant antitumor activity in leukemia with the potential to enhance the antileukemic effects of hematopoietic cell transplant (HCT) conditioning regimens (e.g., beta-emitting 131I-anti-CD33, 90Y-anti-CD33, 131I-anti-CD45, 188 Re-anti-CD66c, 90Y-anti-CD66, and alpha-emitting 211At; eTables 25.9 and 25.10).451 Additional discussion is available online. In a Phase I/II study of AML or MDS patients aged 55 to 65 years, RIT with anti-CD66 Mabs was added to a dose-reduced conditioning

Targeted Radionuclide Therapy

433

regimen followed by a T-cell–depleted stem cell graft.464 Eight patients received 188Re-labeled and 12 received 90Y-labeled anti-CD66. The mean dose of radiation delivered to the marrow was 21.9 Gy, with a significantly higher dose when 90Y was used. The cumulative incidence of relapse was 55%, and the 2-year survival was 52%. Dosimetry for the 90Y construct was significantly better than for 188Re, with marrow-to-kidney dose ratios of 5.4 and 2.3, respectively.464 Evidence of nephropathy was seen in 6 of 93 patients (6.4%) after receiving 188Re but in none of the 21 patients receiving 90 465 Y. Investigators have developed physiologically based pharmacokinetic models allowing prediction of therapeutic time-integrated coefficients for patients receiving 90Y-anti-CD66 RIT. Considerable variability of red marrow time-integrated activity coefficients supports the need for patientbased dosimetry with this modality.466 More discussion on this topic is available online. In an effort to overcome the limitations of beta-emitting radionuclides for the treatment of leukemia, alpha-emitting radioimmunoconjugates have been studied with promising results. Because of the short range (50-90 μm) and high LET (approximately 8 MeV) of alpha-particles, use of these isotopes has the potential to increase the efficacy of RIT without the nonspecific effects of beta-emitting radionuclides. Therefore, targeted alpha-particle therapy can theoretically kill cancer cells with one or two alpha-emissions with minimal bystander effects.468 More discussion on this topic is available online. A full discussion of alpha-emitting constructs using 213Bi-, 225Ac-, and 211At-labeled MAbs for treatment of leukemia is available online.

TOXICITIES ASSOCIATED WITH TART AND METHODS TO AMELIORATE THESE EFFECTS There are a number of well-established factors that influence radionuclide toxicity. Among these are genetic makeup, immune factors, physiological conditions, age, gender, radionuclide characteristics, dose rate, heterogeneous dose distribution, other prior and concomitant therapies, recovery from prior therapy, and radioprotector/sensitizer use. Many of these have been discussed in more detail in prior reviews.475,479,480 Bone marrow suppression has been the primary dose-limiting toxicity of most conventional systemic and IP TaRT. That is changing, however, with the increasing use of small-molecule radionuclide delivery. Among multiple factors that may influence the extent and duration of myelosuppression, marrow reserve, recovery from prior therapy, and radioconjugate stability appear to be predominant determinants of this effect.481,482 Hematological support with transfusions and growth factors has been helpful, and bone marrow or peripheral stem cell reinfusion has allowed dose escalation of radioconjugates to at least three-fold over the dose that resulted in dose-limiting hematopoietic toxicity. 413 Interleukin-1 and GM-CSF have been reported to have radioprotective effects on the hematopoietic system.483,484 The adjuvant use of these cytokines with TaRT has resulted in modest protection. Additionally, the radioprotector amifostine has been helpful in preclinical radionuclide studies for the therapy of thyroid disease with 131I,485,486 and for reduction of renal toxicity from small-molecule conjugates.487 Similar effects with other radioconjugates are expected, but this potential effect has not yet been well studied. Adjuvant use of chelating agents in combination with unstable metal radioconjugates can help to minimize toxicity, but some have had only a minor protective effect on myelosuppression when used with stable chelators.488-490 In addition to chelators that remove unbound radioactivity from the blood, “chasing” the radiolabeled antibody with a second unlabeled antibody directed against the radiolabeled antibody has been reported to modestly decrease toxicity.491 Pretargeting approaches, which dissociate and delay the

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CHAPTER 25

eTABLE 25.10 First Author, Year

Targeted Radionuclide Therapy

433.e1

Selected Clinical Trials Using Radioimmunotherapy for AML and MDS

Agent

Phase of Study

Antigen

Isotope Dose

No. of Patients

Results

Comments

Schwartz,452 1993

131

I

CD33

50-210 mCi/m2

24

CR in 3 of 8 patients receiving BMT

5 patients received autologous BMT; 3 received allogeneic BMT

Burke,455 2003

131

I

CD33

120-230 mCi/m2

31

24/25 evaluable patients had marrow remissions; long-term DFS in 3 patients

Used with BU/CY before allogeneic BMT

I-M195

I-M195, I-Lintuzumab

131

Matthews,456 1999

131

I

CD45

76-612 mCi

44

7 of 25 patients with AML or MDS had long-term DFS

Given with CY/TBI before BMT

Pagel,457 2006

131

I/II

CD45

102-298 mCi

46

3-yr DFS, 61%

Given with BU/CY prior to allogeneic BMT to patients in first remission

Pagel,458 2009

131

I

CD45

246-1084 mCi

58

100% CR, 1-yr DFS, 41%

Given to older patients with advanced AML/MDS with Flu/ low-dose TBI as part of reduced-intensity transplant

Mawad,459 2014

131

I

CD45

332-1561 mCi

15

1-yr OS, 83%; 5-yr OS 41%

Doses to marrow and liver escalated safely to 43 and 21 Gy in younger patients

Bunjes,461 2001

188

I/II

CD66

10.3 GBq (mean)

57

47% DFS at median of 26 mo

Given as part of preparative regimen prior to BMT

Ringhoffer M,464 2005

188

I/II

CD66

12.2 GBq (mean) for 188 Re; 3.8 GBq (mean) for 90Y

20

1- and 2-yr OS, 70% and 52%, respectively

More favorable marrow-tokidney dose ratios for 90Y

Jurcic,120 2002

213

I

CD33

0.28-1 mCi/kg

18

14 patients had reductions in marrow blasts; no CRs

First demonstration of safety of systemically administered α-particle therapy

Rosenblat,121 2010

213

Bi-Lintuzumab

I/II

CD33

0.5-1.25 mCi/kg

31

2 CRs, 2 CRp, 2 PRs

Given after partial cytoreduction with cytarabine

Jurcic,122 2011

225

Ac-Lintuzumab

I

CD33

0.5-4 μCi/kg

18

10 patients with reductions in marrow blasts; 3 with ≥ 5%

Given to patients with relapsed/ refractory AML

Jurcic,472 2016

225

I

CD33

1 μCi/kg-4 μCi/kg (in 2 fractions)

18

1 CR, 2 CRp, 2 CRi, overall response, 28%

Given in combination with low-dose cytarabine to older untreated AML patients

Finn,473 2017

225

II

CD33

4 μCi/kg (in 2 fractions)

9

2 CRp, 3 CRi, overall response, 56%

Given as single-agent to older untreated AML patients; accrual continues at 1.5 μCi/ kg in 2 fractions due to prolonged myelosuppression

I-BC8

I-BC8

I-BC8

I-BC8

Re-BW 250/183 Re- or 90Y-BW 250/183 Bi-Lintuzumab

Ac-Lintuzumab

Ac-Lintuzumab

AML, Acute myeloid leukemia; BMT, bone marrow transplantation; BU, busulfan; CR, complete response; CRi, complete response with incomplete count recovery; CRp, complete response with incomplete platelet recovery; CY, cyclophosphamide; DFS, disease-free survival; Flu, fludarabine; MDS, myelodysplastic syndrome; OS, overall survival; PR, partial response; TBI, total body irradiation.

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433.e2

SECTION II

Techniques and Modalities

Studies using RIT to target CD33, a cell surface antigen expressed on early myeloid progenitor cells and myeloid leukemia cells, were among the first to demonstrate the possibility of incorporating this approach into conditioning regimens before HCT. In a dose escalation trial of the 131I-labeled murine anti-CD33 Mab M195 in patients with relapsed or refractory myeloid leukemias, 8 of 24 patients treated with 50 to 210 mCi/m2 in divided doses had sufficient marrow cytoreduction to proceed to HCT and 3 patients achieved marrow remission.452 Nevertheless, 37% of assessable patients developed HAMA. Because of the immunogenicity of murine M195, humanized M195, also known as lintuzumab, was developed with an avidity 4 to 8.6 times higher than its murine counterpart.453 Lintuzumab was studied in a Phase IB trial in patients with relapsed or refractory myeloid leukemia at dose levels of 0.5 to 10 mg/m2.454 Patients received 6 doses over 18 days. Optimal biodistribution occurred at 3 mg/m2, and HAMA responses were not observed.454 Subsequently, both 131I-M195 and 131I-lintuzumab at doses of 120 to 230 mCi/m2 were combined with busulfan (Bu) and cyclophosphamide (Cy) in an effort to intensify therapy prior to HCT.455 Thirty-one patients with overt relapsed or refractory AML, accelerated or myeloblastic chronic myeloid leukemia (CML), or advanced myelodysplastic syndrome (MDS) were treated. Absorbed doses up to 1470 cGy were delivered to the marrow without toxicities beyond those expected with Bu/Cy conditioning alone. Among all patients, 24 (77%) achieved remission, and 3 of the 16 patients with AML have remained in remission for more than 5 years.455 Encouraging results have been achieved using RIT targeting the pan-leukocyte antigen CD45 with 131I-labeled BC8 antibody. In a Phase I study, 44 patients with acute leukemia and MDS received a trace-labeled dose of 131I-BC8 (anti-CD45) to determine biodistribution.456 The antibody delivered an estimated 6.5 ± 0.5 cGy/mCi to the marrow and 13.5 ± 1.3 cGy/mCi to the spleen with significantly less absorbed doses to liver, lung, kidney, and total body. Thirty-seven patients had favorable biodistribution with higher estimated absorbed doses to the marrow and spleen than to normal organs. Thirty-four patients received a therapeutic dose of 131I-anti-CD45 labeled with 76 to 612 mCi 131I in addition to Cy and TBI. The maximum tolerated dose delivered 10.5 Gy to the liver with an average absorbed dose of 24 Gy to the bone marrow. Seven of 25 treated patients with AML/MDS survived disease free for 26 to 100 months posttransplantation, and 3 of 9 patients with acute lymphoblastic leukemia (ALL) were disease free 34 to 82 months posttransplantation.456 This was followed by a trial of 131I-anti-CD45 combined with Bu and Cy in patients with AML in first remission.457 Fifty-two of 59 patients (88%) had favorable biodistribution, and 46 patients went on to receive 102 to 298 mCi of 131I-BC8 with an estimated mean

dose of 11.3 Gy and nearly 30 Gy to the marrow and spleen, respectively. The estimated 3-year nonrelapse mortality was 21%, and the 3-year disease-free survival was 61%. These results were superior to those expected with Bu/Cy alone.457 The use of 131I-anti-CD45 as part of a reduced-intensity conditioning regimen along with fludarabine and TBI (2 Gy) was examined in 58 patients older than 50 years with advanced AML and high-risk MDS.458 Of the patients, 86% had more than 5% blasts at the time of transplantation, and all patients attained remission. Although 7 patients died of nonrelapse causes by day 100, the probability of recurrence at 1 year was 40%, and the 1-year survival rate was 41%.458 These encouraging results have led to a randomized Phase III multicenter trial in which older patients with relapsed or refractory AML are randomized to standard therapy with salvage chemotherapy followed by a conventional reduced-intensity conditioning regimen or 131I-BC8/Flu/TBI prior to HCT in the setting of overt AML (NCT02665065). In patients under age 50 years with advanced AML or MDS, higher doses of 131I-antiCD45 Mabs were safely combined with Flu/TBI, delivering an average of 27 Gy to the bone marrow, 84 Gy to the spleen, and 21 Gy to the liver.459 Among 15 patients treated, the 1-year survival was 73% and six patients were alive with a median follow-up duration of 5 years.459 In subsequent preclinical studies, conditioning with 90Y-anti-CD45 and Cy, without TBI or fludarabine, followed by haploidentical BMT led to stable engraftment and prolonged survival in a murine leukemia model. This finding suggests that anti-CD45 RIT has the potential to replace TBI and simplify HCT preparative regimens before alternative donor transplantations.460 188 Re- and 90Y-labeled anti-CD66 Mabs have also been studied as part of conditioning before HCT. Since CD66 is expressed on myeloid cells but not leukemic blasts, the antitumor effects of these constructs depend on “cross-fire” from β particles. Fifty-seven patients with high-risk AML or MDS received 188Re-anti-CD66 antibody BW250/183 followed by one of three preparative regimens. Most patients received a T-cell– depleted allogeneic graft. The mean bone marrow dose was 15.5 Gy. With median follow-up of 26 months, disease-free survival was 64% for patients with < 15% bone marrow blasts and 8% for patients with > 15% bone marrow blasts.461 In a subsequent study, 188Re-anti-CD66 was administered in combination with either myeloablative doses of Bu/Cy or a reduced-intensity regimen in 21 patients with high-risk AML. With median follow-up of 42 months, the disease-free survival was 43%.462 Others have shown that 188Rh-anti-CD66 could be safely combined with a reduced-intensity conditioning regimen of fludarabine and Bu with in vivo T-cell depletion using alemtuzumab in older patients with AML or MDS.463

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CHAPTER 25

Targeted Radionuclide Therapy

RIT with 90Y outside the setting of HCT has shown promise for the treatment of ALL. Seventeen patients with relapsed or refractory B-cell ALL expressing CD22 received two doses of 90Y-labeled epratuzumab (anti-CD22) tetraxetan at doses of 2.5 to 10 mCi/m2 approximately 1 week apart.467 The most common adverse effects were pancytopenia and infection, but only one patient treated at the highest dose level experienced dose-limiting toxicity (bone marrow aplasia lasting 8 weeks). Two patients achieved CRs and one had a CR with incomplete platelet recovery. Among these, one patient achieved a complete molecular response. Response durations lasted 6 to 10 months. Given these promising results, a Phase II study is planned at the recommended dose of 10 mCi/m2 for two doses given 1 week apart.

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433.e3

433.e4

SECTION II

Techniques and Modalities

Alpha-particle-emitting radioimmunoconjugates have also shown promise for the treatment of leukemia. In an early study, 213Bi, an alphaemitting radiometal with a half-life of 45.6 minutes, was conjugated to the anti-CD33 Mab lintuzumab. A Phase I dose-escalation study using 213Bi-lintuzumab in patients with refractory and relapsed myeloid leukemias demonstrated rapid targeting of disease sites within minutes and evidence of antileukemic effects even at low dose levels.120 There was no significant extramedullary toxicity, and the median time to hematological recovery was 22 days. Target-to–whole-body dose ratios were greatly enhanced compared with those seen with immunoconjugates using beta-emitters in this patient population. With this therapy, 78% of patients had a decrease in the percentage of bone marrow blasts. When 213Bi-lintuzumab was used sequentially following cytarabine in patients with AML, significant reductions in marrow blasts were seen at all dose levels. Among patients treated at the MTD of 1 mCi/kg or higher, responses were seen in 24%, with a median duration of 6 months.121 The short half-life of 213Bi, however, remains a major obstacle to its widespread use. To address this issue, methods to directly conjugate the longer-lived parent of 213Bi, actinium-225 (225Ac; t½ = 10 days) to a variety of antibodies using the macrocyclic ligand 1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) were developed. A two-step labeling method designed to minimize radiolysis and maximize kinetic stability of the products was used successfully in clinical trials of 225Ac-lintuzumab.469 More recently, a method for efficient one-step labeling of actinium to antibody-DOTA constructs was described.470 In addition to its longer half-life, intracellular decay of 225Ac to short-lived therapeutic daughter alpha-emitters (221Fr, 217At, 213Bi) significantly increases its effectiveness compared with 213Bi.471 A Phase I trial investigating the use of 225Aclintuzumab in patients with relapsed and refractory AML was conducted

in 18 patients.122 Dose-limiting toxicity was prolonged myelosuppression. There was no evidence of radiation-induced nephrotoxicity, despite the known uptake of free 213Bi by the kidneys. Bone marrow blast reductions were seen in 10 of 15 evaluable patients (67%), including 3 patients who achieved marrow blast reductions to 5% or less.122 Based on these findings, 225Ac-lintuzumab was investigated in a multicenter Phase I/II trial in combination with low-dose cytarabine for older patients with untreated AML.472 Patients received low-dose cytarabine subcutaneously every 4 to 6 weeks. During the first cycle, two fractions of 225Ac-lintuzumab at 0.5 to 2 μCi/kg/fraction were administered 1 week apart after completion of chemotherapy. Doselimiting toxicity, as in previous studies, was prolonged myelosuppression, but the MTD was not reached. Five of the 18 patients (28%) had objective responses with a median response duration of 9.1 months. Only patients receiving 1 μCi/kg/fraction or higher responded, and all responses occurred after the first cycle.472 The peripheral blood blast count proved to be a strong predictor of outcome, as responses were seen only in patients with peripheral blast counts of < 200/μL. This is most likely explained by preferential antibody binding to peripheral sites in patients with higher circulating blast counts, leading to decreased marrow targeting.472 Because of this observation, a Phase II trial of 225Ac-lintuzumab monotherapy using hydroxyurea to lower peripheral blast counts if needed is now underway to define the response rate, PFS, and OS in older patients with untreated AML (NCT02575963). To date, following two 2 μCi/kg fractions of 225Ac-lintuzumab, objective responses were seen in 5 of the initial 9 patients (56%). Myelosuppression, however, was considered to be longer than acceptable in this population. Therefore, accrual to this study is continuing at 1.5 μCi/kg/fraction with the goal to shorten recovery times while maintaining efficacy.473

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CHAPTER 25

Targeted Radionuclide Therapy

Targeted alpha-particle therapy is an attractive strategy for conditioning before HCT. Investigators at the Fred Hutchinson Cancer Research Center studied 213Bi-labeled Mabs against CD45474 and the T-cell receptor (TCRαβ)475 before dog leukocyte antigen (DLA)-identical HCT in a canine model. Administration of both constructs along with additional immunosuppressive agents resulted in engraftment of transplanted marrow and stable mixed chimerism. Transient myelosuppression and liver enzyme abnormalities were observed. In similar studies, dogs receiving 213Bi-anti-CD45 Mab achieved a high level of donor chimerism after receiving haploidentical grafts.476 The use of 213Bi for this application in humans, however, may be limited by the high activities required to attain engraftment. Subsequently, these investigators have shown in preclinical models that 211At-anti-CD45 can produce sufficient immunosuppression to allow stable long-term engraftment in a canine HCT model.477 In syngeneic HCT studies, 211At-labeled anti-CD45 improved the median survival of mice in a disseminated AML model.478 Based on these data, 211At-labeled anti-CD45 antibody is currently being investigated as conditioning before HCT using human leukocyte antigen (HLA)-matched related or unrelated donors in patients with high-risk acute leukemia and MDS (NCT03128034).

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433.e5

434

SECTION II

Techniques and Modalities

delivery of the radionuclide from that of the targeting agent, can decrease toxicity. Although the second dose-limiting organ toxicity for myeloablative TaRT may vary with radionuclide, cardiopulmonary and liver toxicity has been reported for 131I and anticipated for 90Y immunoconjugates, respectively.107,370,492 The importance of stable chelators also impacts other potential toxicities, as demonstrated with alpha-emitters. Renal accumulation leading to nephrotoxicity has been noted from a 212Bi conjugate with an unstable chelator and may be dose limiting for some applications. This was reported by Macklis et al. after IP administration of 212 Bi-anti-Thy 1.2 IgM conjugate to mice with EL-4 tumor cells.111 In the Macklis study, 8% of the injected radioactivity was in the cardiac blood pool by 2 hours and accumulation to kidneys was similar to that of free 206Bi, indicating instability of the 212Bi conjugate with the DTPA chelator. Subsequently, nephrotoxicity has been reduced with stable chelate-conjugates, including clinical experience in patients with AML receiving up to 1 mCi/kg 213Bi.106 Additionally, nephrotoxicity resulting from free 213Bi could be mitigated by the use of adjuvant agents, including dithiol chelators and reninangiotensin-aldosterone system inhibitors, as demonstrated in preclinical models.493,494 Acute symptoms from systemic RIT are usually related to administration of antibody products, not the radioactivity. The symptoms have usually been mild and have included rash, fever, chills, myalgia, diaphoresis, pruritus, nausea, vomiting, diarrhea, nasal congestion, and hypotension.495 These side effects are transient and usually respond to antihistamines, acetaminophen, and nonsteroidal anti-inflammatory agents. Rarely, more severe symptoms—including rigors, bronchospasm, or laryngeal edema—have been noted. These often respond quickly to steroids, antihistamines, oxygen, and meperidine. With CNS administration, various transient symptoms have been described, which are usually mild but can include cerebral edema, nuchal rigidity, aseptic meningitis, increased intracranial pressure, and seizure. Steroids have usually ameliorated these symptoms. A serum sickness–type phenomenon has been commonly observed with IP administration of murine antibody conjugates (affecting about one-third of patients) but is rare among patients receiving intravenous RIT, even with the same radioimmunoconjugate. Serum sickness–like symptoms occur about 2 weeks after treatment and may persist more than a week. Variations in the manifestation of symptoms may depend, in part, on the particular radioimmunoconjugate used because skin rash has been noted by the Hammersmith group, whereas fever with joint or muscle aches, but no rash, has been common among patients treated at the University of Alabama at Birmingham with a different radiolabeled monoclonal antibody.496,497 Other acute effects can include a temporary increase in bone pain for radionuclide targeting of bone metastases and gastrointestinal disturbance, which usually manifests as nausea. Nausea has been more commonly associated with PRRT than conventional RIT. However, nausea from PRRT may be more related to the amino acid infusion given to reduce renal toxicity than to the radionuclide therapy itself. The targeting of receptors along the gastrointestinal tract may also contribute to nausea in PRRT. Nausea and vomiting can occur after oral 131I as used in thyroid ablation or treatment of metastatic disease sites. 131I therapy can also lead to sialadenitis, taste changes, transient swelling and pain at sites of metastasis, ocular dryness, nasolacrimal duct obstruction, and bone marrow suppression.498 Radiation sickness has been reported with doses in excess of 300 mCi.499 There are various reports concerning how fertility is impacted by the 131I thyroid therapy. Short-term gonadal function may be impaired and the incidence of miscarriages may increase, but there appears to be no increase in malformed offspring.500,501 Also, the risk for development of certain

malignancies shifts after 131I thyroid therapy, with increases for some organs with excess exposure, such as stomach and salivary glands but decreases for cancer of the lung and cervix.498,502 In TaRT using small molecules such as peptides or radionuclide conjugates used in pretargeting approaches, the kidney and bladder usually receive much higher doses than other normal organs. For these therapies, renal rather than bone marrow toxicity can be dose limiting.9,45,63,503 Fractionated radionuclide delivery may reduce toxicity and increase efficacy.9,13,504 Limited clinical studies and radiobiological considerations of fractionated TaRT have been reviewed elsewhere.505 Fractionation of dosing has been helpful for decreasing toxicity associated with peptide-radionuclide therapy and has been investigated in other TaRT applications.505 Acute symptoms from PRRT are often related to adjuvant agents (amino acids with amifostine) used to decrease renal toxicity rather than “foreign substance reaction” that may occur with larger immunoglobulin products. The nausea and vomiting commonly associated with use of the adjuvant agents may be ameliorated with antiemetics and other measures. The importance of dose rate in urinary tract (renal and bladder) toxicity is suggested by early experience with PRRT and in patients with myeloma receiving holmium-166 (166Ho). Although the calculated renal dose from high-dose 166Ho-DOTMP was only 710 cGy when 40 Gy was delivered to marrow, 30% of patients experienced grades 2 to 4 renal toxicity, with severe thrombotic microangiopathy. The risk of hemorrhagic cystitis was decreased by continuous bladder irrigation during the 166Ho infusion.506 Unexpected rates of renal toxicity were also noted in early use of PRRT. Although the mean renal doses were well below tolerance limits for fractionated EBRT, the rapid accumulation of radioactivity in the renal cortex resulted in higher doses in that area, which were delivered at a relatively high dose rate. Further study has shown that renal toxicity of PRRT is associated with risk factors such as prior renal insufficiency and diabetes, whereas adjuvant infusion of amino acids and amifostine can help to prevent toxicity.63,507 Incorporation of “protective” measures in PRRT regimens has allowed escalation of the fractionated radioactivity administered by as much as 50%.487 The impact of the administration of lysine was shown in an animal study directly comparing autoradiographs of the same radionuclide conjugate with and without amino acid infusion (see eFig. 25.1).508 A 40% reduction in 111In-octreotide accumulation in rat kidney was obtained in animals treated with either IV or oral lysine compared with controls. A similar illustration of the impact of lysine administration is demonstrated in SPECT images of a patient by Valkema et al.487,508 Other efforts to understand and ameliorate the problem of renal toxicity by more accurate prediction of dose parameters includes publication of six age-dependent Medical Internal Radiation Dose (MIRD) Committee models that allow subregion radionuclide dose calculation,509 a continuing education session at the 2003 Society of Nuclear Medicine Meeting from which contributions have been published, and MIRD suborgan modeling.510,511 MIRD #20 examines renal toxicity from radionuclide therapy by modeling effects of (1) dose rate (BED), (2) heterogeneity of activity distribution over time, and (3) correlation of absorbed radiation dose and BED with observed clinical toxicity. The impact of application of patient-specific dosimetry on renal toxicity is illustrated by Barone et al.512 Nonsystemic administration of radionuclides has been associated with other types of toxicity, dependent on the site of administration and other factors. Late bowel toxicity after IP RIT has been infrequent, which is an advantage compared with nonspecific radionuclide therapy (e.g., 32P chromic phosphate solution). However, the most severe toxicities of 32P therapy include fibrosis and necrosis of bowel or body wall, the result of misplacement of the therapeutic agent into bowel

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CHAPTER 25

Control

Lysine treated

A

C

B

D

Targeted Radionuclide Therapy

Hematoxylin-eosin staining

F

E eFig. 25.1 Ex vivo autoradiograms of renal tissue slices of control rats (A and B) and lysine-treated rats (C-E) 24 hours after injection of [111InDTPA]-octreotide, 3 MBq/0.5 μg. Greatest reduction of renal radioactivity was seen in rats treated with intravenous lysine coinjected with tracer (C) or lysine (400 mg/kg) orally 60 minutes before tracer (D). Increasing the interval between oral lysine (400 mg/kg) and tracer to 120 minutes (E) did not lead to greater renal reduction. (F) Hematoxylin- and eosinstained section adjacent to D shows high uptake of radioactivity in cortex and outer medulla but almost no uptake in inner medulla. (Reproduced with permission from Verwijnen S, et al: J Nucl Med. 2005;46:2057.)

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CHAPTER 25 lumen, loculation sac, or body wall rather than the IP space.512a Even with proper administration, there has been an increased risk of bowel complications compared with chemotherapy, especially among patients who also received EBRT to the pelvis. Although nearly three-quarters of postsurgery patients with ovarian cancer receiving 15 μCi 32P IP in an early GOG trial reported no side effects, some of the remaining patients had mild to moderate gastrointestinal symptoms. One developed bacterial peritonitis and four developed bowel obstruction.513 A later GOG study compared cyclophosphamide/cisplatin to IP 32P after surgical debulking. More patients treated with 32P as compared with chemotherapy had bowel problems. Some had suboptimal distribution of the radionuclide within the peritoneal cavity with areas of loculation and likely would not currently have been considered candidates for IP therapy.514 With targeted therapy using antibody carriers for radionuclides and pretreatment scans to rule out loculation, severe bowel toxicity has been infrequent.282,515,516 In > 90 patients treated at the University of Alabama at Birmingham with IP 90Y- or 177Lu-CC49 antibody therapy for relapsed ovarian cancer, no incidences of bowel toxicity severe enough to require surgery were observed, although a portion of patients who underwent surgery for recurrent disease were found to have areas of palpable fibrosis.517 Specimen analysis after IP alpha-emitter administration has not shown tissue changes and early clinical experience with alpha-emitter conjugates have not reported peritoneal toxicity.362,518,519 32 P has also been injected into malignant lesions and other cavities, such as the pleural space for treatment of malignant effusions, and intraarticular spaces for hemarthroses.499 Relatively high concentrations of 32P injected directly into malignant lesions have been well tolerated locally and have occasionally resulted in dose-limiting toxicity in other organs, such as stomach and lungs, from shunting. To overcome this potential hazard, pretreatment scans have been obtained to assess trace radionuclide distribution prior to administration of a therapeutic dose.520 32 P injected directly into subcutaneous nodules and pretargeted interstitial administration of 90Y-radionuclide into more diffuse areas of chest wall recurrence of breast cancer have been well tolerated.521 In contrast, accidental delivery of radionuclide to subcutaneous tissues from intravenous infiltration has resulted in local necrosis.522 32P applied as a skin patch for treatment of basal cell carcinoma has been well tolerated and effective.523 Higher concentrations of beta- and alpha-emitters have been injected into glioma cavities than could be tolerated systemically with infrequent reports of severe toxicity.116,522 Edema and seizures are the most common adverse events reported. Intrathecal radionuclide therapy has resulted in aseptic meningitis and occasional seizure activity.524 There are a number of other organs at risk for toxicity that have not been extensively addressed. For instance, cataracts would be anticipated as a risk after high-dose total body radiation based on external beam data but have not been reported in long-term follow-up studies.525 Lung fibrosis is of concern for 131I therapy of lung metastases and is under study in animals after plutonium inhalation.526,527 Animal model radium inhalation studies have shown an increased risk of lung cancer that is enhanced by smoking.528 Thus far, late organ dysfunction following RIT with 131I-labeled antibodies has been uncommon except for abnormal thyroid function.375 Despite measures to block thyroid uptake, elevated thyroidstimulating hormone levels occurred in 59% of patients treated with myeloablative doses of 131I-anti-CD20 antibodies at a median of 6 months after treatment.375 Some patients who received nonmyeloablative doses of 131I have also had elevated thyroid-stimulating hormone levels later. Salivary gland inflammation and damage can be an acute or late toxicity. Parotiditis, which may result in xerostomia, has been more common with treatment of thyroid cancer than high-dose

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radioconjugate therapy. However, this remains a potential toxicity of 131I-antibody therapy.529 Risk of a second malignancy is of concern even if it has not been noted for any particular radionuclide therapy. A small percentage of patients treated with high-dose RIT for lymphoma have developed second malignancies. Myelodysplasia is the potential TaRT-related toxicity of most concern in the treatment of hematological malignancies. Some lymphoma patients who were diagnosed with myelodysplasia after TaRT had evidence of dysplasia prior to radionuclide therapy.383,530,531 These patients were also considered at increased risk for myelodysplasia because of prior alkylating agents with or without conventional EBRT. The risk of second malignancy for RIT lymphoma patients has been modest at 0.5% per year compared to that of patients with NETs receiving 131 I-metaiodobenzylguanidine (MIBG).437,532 Leukemia risk for adults treated with 32P for polycythemia appears dose related, whereas leukemia has been noted after lower doses (0.6-1.5 mCi) of intraarticular 32P administration in children.533 Second malignancies will be especially of concern as more radionuclide therapy is developed for children (e.g., MIBG, 90Y-ibritumomab) because an age effect in malignancy induction has been noted for thyroid cancer and other malignancies after 131I exposure and MDS has been observed after MIBG.534

DOSIMETRY Dosimetry is the process of relating the administered amount of radioactivity to the absorbed radiation dose in tumors, organs, or remaining body tissues. Dosimetry is important for dose correlation with clinical results and, in some instances, for treatment planning to avoid excess toxicity. Details for the combination of EBRT and TaRT show the importance of precise calculations in critical cases for which there is need for tumoricidal radiation delivery while limiting dose to normal organs that are in close proximity.535 In general, the doses calculated for TaRT are less accurate than for EBRT for a variety of reasons. These include limited radiation dose input data (e.g., few sample points for therapy using continuous exponentially decreasing irradiation), inhomogeneous dose distributions, and the assumptions/calculation methodology used to estimate TaRT absorbed doses.536 Dose calculation is also more complicated for internally distributed radionuclides than for EBRT. Alpha-particle dosimetry adds the complication of decay scheme cascade and daughter products that may have a different distribution than the parent radionuclide.537-539 Additionally, the higher relative biological effectiveness (RBE) delivered by alpha- compared to betaradionuclide therapy needs to be considered.540 Data required for TaRT dose estimate calculations include the mass of tumors and normal organs, the cumulative radioactivity taken up by organs and tumors, and the pharmacokinetics of the administered radioactivity.541 Data are usually acquired by serial gamma camera imaging. Bone marrow dose estimates are based on imaging studies of active marrow, such as the spine, or blood pharmacokinetics.542-544 Bremsstrahlung images from radionuclides that do not have gamma emissions are generally of suboptimal quality, making accurate quantitation difficult. However, progress with sophisticated methods has provided images useful for dose estimates.545 As an alternative appropriate for many circumstances, estimates are often made for poor gamma-emitters from tracer studies using a robust gamma-emitter that has a similar chemistry to that of the therapeutic radionuclide. Because animal studies have shown that the biodistribution is similar, although not usually identical, for 111In and 90Y, tracer/dosimetry studies with 111In-labeled antibody have frequently been performed in conjunction with 90Y-labeled antibody therapy to estimate the subsequent biodistribution/dosimetry of the 90Y-immunoconjugate.107,546,547 Quantitative immuno-PET with 89 Zr-labeled antibody has shown good correlation with 111In-labeled

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Techniques and Modalities

antibody biodistribution and may be useful as a positron-emitting surrogate for 90Y-labeled antibody therapy.548 PET scanning with 124 I-labeled conjugates can be useful for radionuclide dosimetry.549,550 PET images from 89Zr-cG250 antibody have been superior to those of 111 In-cG250 antibody in an animal model and compare favorably with 124 551,552 I. Other examples include use of 99mTc-antibody for imaging/ dosimetry studies in conjunction with 186Re-antibody therapy and 68Ga for the FDA-approved 177Lu-DOTATATE.553 Another variable in estimating the expected dose from therapeutic TaRT using a preliminary biodistribution/dosimetry is that even when a small amount of a therapeutic agent is used, the correlation between doses predicted and later delivered has ranged up to ~ 30% between estimated absorbed doses for the two procedures in the same patient.178,370,554,555 With continued progress in refinement of methodology, improved correlation is anticipated. For instance, quantitative SPECT reports accuracy within 5% to 15% for diagnostic or therapeutic levels of radionuclide. Additional discussion is available online. The MIRD Committee is one entity that provides guidance for methods to calculate radiation absorbed dose estimates for the whole body and organs.560 This methodology has been adapted for TaRT, with continuing effort by this committee and others to further improve the models and methods available.509,541,544,556,560-571 A Java applet was created in collaboration with the MIRD Committee to provide worldwide access (http://mirdcell.njms.rutgers.edu/) to new software that facilitates multicellular dosimetry and biological-response modeling. In addition to MIRD publications and information posted through the Society of Nuclear Medicine & Molecular Imaging website (www. SNMMI.org), other informational publications, websites, and computer programs have been developed to assist with dosimetry calculations.571-574 Among websites available, www.doseinfo-radar.com was developed to provide information in a number of areas, including standardized dose estimates, decay data, and absorbed fractions. With fusion of anatomic and physiological images, dose estimates can be calculated in three dimensions at the voxel level, taking into account heterogeneity of radioactivity distribution within an organ.575-580 With expanded clinical activity and availability of alpha-emitters, a 2015 monograph contains a chapter on alpha dosimetry.581 Additional discussion is available online. The relationship between outcome and radiation dose–related factors has been variable, with some studies showing a strong correlation, whereas others show no correlation.587-589 Some of the factors making it more difficult to establish a dose-response relationship for TaRT, as compared with EBRT, may include relative uncertainty associated with TaRT dose calculations, the heterogeneity of dose deposition that occurs with TaRT, dose rate effects, and agent/patient variation in excretion/clearance. Whereas most normal organ tolerance levels for EBRT have been established using high dose rate radiation and vary as a function of fraction size, the dose rate is often low and variable with TaRT, limiting the validity of extrapolating from high dose rate tolerance levels to those expected with TaRT. Fractionation of TaRT, as with external beam, can increase the total radionuclide dose tolerated.503,505 Several studies have demonstrated how biological factors affect tolerance but are not accounted for in standard dose/toxicity reporting. Many of these have been summarized in a review.474 Improved dose/toxicity correlations for marrow suppression has included adjustment of calculated absorbed marrow dose for levels of a biomarker involved in hematopoiesis as well as cellularity and patient-specific marrow mass.482,590,591 Although data suggest the presence of a relationship between TaRT radiation dose and tumor response, early analyses with relatively small numbers of patients receiving a limited dose range fail to show strong correlation between these two factors.557,592 As dosimetry accuracy has improved and nondosimetry factors (that affect biological response) have been considered,

better correlation has been observed between estimated dose delivered and tumor control.593,594 Despite the progress toward improving accuracy of dosimetry and need for individualized dose administration,549,557,595-599 most studies are still being done without required organ or tumor dosimetry in the nontransplant setting. Activity is usually given per kilogram or per square meter. For one of the FDA-approved agents (131I-tositumomab), whole-body effective half time is used to individualize administered activity, but no organ or tumor dosimetry is required.595 As better correlation is achieved between dosimetry results and clinical outcome, additional tumor dosimetry may be required, as has usually been needed for high-dose therapy followed by stem cell rescue.600-602 Individualized kidney dosimetry has been important in predicting toxicity of PRRT.603 Like marrow dose versus toxicity studies, adjustment for diseases, conditions, and factors that influence kidney function, such as hypertension, have resulted in better correlation of calculated kidney dose and renal toxicity in peptide TaRT therapy.596 More discussion on this topic is available online.

FUTURE CONSIDERATIONS TaRT is a promising therapeutic modality that has been successful as monotherapy in both solid and hematological malignancies. It is expected that, for many diseases, TaRT will be most useful as a component of multimodality therapy121,162,403,428 and future studies should continue to define how to optimally combine TaRT with other therapeutic modalities, including immunotherapy. More investigation is needed to determine agents/schedules that result in synergistic antitumor activity without significantly greater toxicity. Active areas of investigation include studies of TaRT using alpha-particles, small nonantibody targeting agents, immunotherapy, and other approaches for increasing tumor uptake of radionuclide and enhancing efficacy.604

Acknowledgments This work was supported by the National Institutes of Health through grants NIH P50 CA83591, NIH 1 R01 CA82617, and NIH P50 CA89019.

CRITICAL REFERENCES 16. Rudnick SI, Adams GP. Affinity and avidity in antibody-based tumor targeting. Cancer Biother Radiopharm. 2009;24(2):155–161. 50. Marcu L, Bezak E, Allen BJ. Global comparison of targeted alpha vs targeted beta therapy for cancer: in vitro, in vivo and clinical trials. Crit Rev Oncol Hematol. 2018;123:7–20. 51. Fahey F, Zukotynski K, Jadvar H, et al. Proceedings of the second NCI-SNMMI workshop on targeted radionuclide therapy. J Nucl Med. 2015;56(7):1119–1129. 70. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of (177) Lu-DOTATATE for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–135. 76. Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71(4):630–642. 85. Hofman MS, Violet J, Hicks RJ, et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825–833. 114. Baidoo KE, Yong K, Brechbiel MW. Molecular pathways: targeted alpha-particle radiation therapy. Clin Cancer Res. 2013;19(3):530–537. 120. Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood. 2002;100(4):1233–1239. 121. Rosenblat TL, McDevitt MR, Mulford DA, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16(21):5303–5311.

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CHAPTER 25

Targeted Radionuclide Therapy

For many dose estimates, conjugate views of the whole body and regions of interest (ROIs) (e.g., tumors and normal organs, such as the liver) are obtained.542 The activity for each ROI is measured from the counts in that region at multiple time points. The counts in each ROI are corrected for background. Attenuation correction factors are calculated for each patient and a sample of the administered radionuclide is used for calibration so that counts per minute can be converted to units of radioactivity (mCi or MBq). Scatter correction may also be applied. SPECT for ROIs can provide superior definition and quantitation.556 Despite expansion of this technology, SPECT has not yet become the standard for most quantitation, as it is more time-consuming than planar conjugate view methodology.557,558 Absorbed radiation doses can be calculated from radioactivity quantitation and the specific absorbed fraction for the target. The specific absorbed fraction takes into account the type and energy of radiation emissions, the fraction of energy from the source absorbed by the target, and mass of the target.559 The mass of each ROI is usually determined by estimating volumes from CT, MRI, or other methods such as 99mTc-sulphur colloid liver scans, and converting volume to mass by assuming a unit density of 1 g/mm3 for most soft tissues. Accounting for excretory routes is needed in quantitating changes in radioactivity distribution over time. For radionuclides such as 131I for which the major route of excretion is renal, urinary activity measurements can provide an estimate of total body clearance if it is not feasible to obtain whole-body counts.

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436.e2

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Techniques and Modalities

Biopsy results are infrequently used for as a sole measure for dosimetry. Although biopsy provides a direct measurement and can be used for autoradiography, it is invasive and not practical for most tumor or organ dosimetry. Biopsy data are of interest to correlate with other methods of dosimetry, but it is often of limited value alone because of the small sample size, which may not be representative, and is usually done only once. Thus, biopsy dosimetry usually does not allow a timeactivity curve to be generated. However, the development of alpha cameras now allows activity over time to be measured.575,577,582-584 Implanted thermoluminescent dosimeters (TLD) and other devices have also been used for quantitation in experimental preclinical studies and in limited clinical trials.585 When used in patients with ovarian cancer treated with intraperitoneal TaRT, TLD-obtained dose measurements were in the range of those estimated with other methods.553 As with biopsy, TLDs provide a direct measurement of absorbed dose but also usually require an invasive procedure for placement that has the disadvantage of potentially introducing a sampling error. Like most other dosimetry methods, TLDs do not account for dose rate, which may be an important determinant of dose-response relationships. Another implantable dosimeter has been developed and applied to EBRT that can give real-time wireless feedback to a computer. This technology should be applicable to radionuclides but, similar to TLDs, will provide data from only a small area.586

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CHAPTER 25

Targeted Radionuclide Therapy

As experience grows and dosimetry techniques improve, insight may be provided for tolerance of new agents that become available. An example is the group of marrow studies pertinent to alpha-emitter 223Ra.577

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CHAPTER 25 123. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3): 213–223. 126. Hernandez MC, Knox SJ. Radiobiology of radioimmunotherapy: targeting CD20 B-cell antigen in non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys. 2004;59(5):1274–1287. 128. Pouget JP, Navarro-Teulon I, Bardies M, et al. Clinical radioimmunotherapy– the role of radiobiology. Nat Rev Clin Oncol. 2011;8(12):720–734. 279. Sharkey RM, Hajjar G, Yeldell D, et al. A phase I trial combining high-dose 90Y-labeled humanized anti-CEA monoclonal antibody with doxorubicin and peripheral blood stem cell rescue in advanced medullary thyroid cancer. J Nucl Med. 2005;46(4):620–633. 333. Meredith R, You Z, Alvarez R, et al. Predictors of long-term outcome from intraperitoneal radioimmunotherapy for ovarian cancer. Cancer Biother Radiopharm. 2012;27(1):36–40. 410. Morschhauser F, Illidge T, Huglo D, et al. Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood. 2007;110(1):54–58. 411. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26(32):5156–5164. 412. Mitchell R, et al. Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantel-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. 2012;30(25):8. 423. Gopal AK, Guthrie KA, Rajendran J, et al. 90Y-Ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma. Blood. 2011;118(4):1132–1139.

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424. Bethge WA, Lange T, Meisner C, et al. Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced non-Hodgkin lymphoma: results of a phase 2 study. Blood. 2010;116(10):1795–1802. 425. Bethge WA, von Harsdorf S, Bornhauser M, et al. Dose-escalated radioimmunotherapy as part of reduced intensity conditioning for allogeneic transplantation in patients with advanced high-grade non-Hodgkin lymphoma. Bone Marrow Transplant. 2012;47(11):1397–1402. 426. Khouri IF, Saliba RM, Erwin WD, et al. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012;119(26):6373–6378. 437. Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol. 2013;31(16):1977–1983. 477. Chen Y, Kornblit B, Hamlin DK, et al. Durable donor engraftment after radioimmunotherapy using alpha-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation. Blood. 2012;119(5):1130–1138. 576. Baechler S, Hobbs RF, Boubaker A, et al. Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy. Med Phys. 2012;39(10):6118–6128. 581. Allen BJ, Hobbs RF, Roeske JC, et al. Alpha-particle dosimetry. In: Sgouros G, ed. MIRD Monograph-Radiobiology and Dosimetry for Radiopharmaceutical Therapy. Reston, VA: Society of Nuclear Medicine and Molecular Imaging; 2015.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 25

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49. Krenning EP, Kooij PP, Bakker WH, et al. Radiotherapy with a radiolabeled somatostatin analogue, [111In-DTPA-D-Phe1]-octreotide. A case history. Ann N Y Acad Sci. 1994;733:496–506. 50. Marcu L, Bezak E, Allen BJ. Global comparison of targeted alpha vs targeted beta therapy for cancer: in vitro, in vivo and clinical trials. Crit Rev Oncol Hematol. 2018;123:7–20. 51. Fahey F, Zukotynski K, Jadvar H, Capala J, organizing committee, contributors, and participants of the second NCI–SNMMI Workshop on Targeted Radionuclide Therapy. Proceedings of the Second NCI-SNMMI Workshop on Targeted Radionuclide Therapy. J Nucl Med. 2015;56(7): 1119–1129. 52. Hofland LJ, Lamberts SW. Somatostatin receptor subtype expression in human tumors. Ann Oncol. 2001;12(suppl 2):S31–S36. 53. Lee ST, Kulkarni HR, Singh A, Baum RP. Theranostics of neuroendocrine tumors. Visc Med. 2017;33(5):358–366. 54. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20(8):716–731. 55. Albert R, Smith-Jones P, Stolz B, et al. Direct synthesis of [DOTADPhe1]-octreotide and [DOTA-DPhe1,Tyr3]-octreotide (SMT487): two conjugates for systemic delivery of radiotherapeutical nuclides to somatostatin receptor positive tumors in man. Bioorg Med Chem Lett. 1998;8(10):1207–1210. 56. Otte A, Jermann E, Behe M, et al. DOTATOC: a powerful new tool for receptor-mediated radionuclide therapy. Eur J Nucl Med. 1997;24(7):792–795. 57. Otte A, Herrmann R, Heppeler A, et al. Yttrium-90 DOTATOC: first clinical results. Eur J Nucl Med. 1999;26(11):1439–1447. 58. Imhof A, Brunner P, Marincek N, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol. 2011;29(17):2416–2423. 59. Waldherr C, Pless M, Maecke HR, et al. The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol. 2001;12(7):941–945. 60. Paganelli G, Zoboli S, Cremonesi M, et al. Receptor-mediated radiotherapy with 90Y-DOTA-D-Phe1-Tyr3-octreotide. Eur J Nucl Med. 2001;28(4):426–434. 61. Bushnell DL Jr, O’Dorisio TM, O’Dorisio MS, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010;28(10):1652–1659. 62. Cybulla M, Weiner SM, Otte A. End-stage renal disease after treatment with 90Y-DOTATOC. Eur J Nucl Med. 2001;28(10): 1552–1554. 63. Bodei L, Cremonesi M, Ferrari M, et al. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging. 2008;35(10):1847–1856. 64. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124–2130. 65. Kwekkeboom DJ, Bakker WH, Kam BL, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA(0),Tyr3]octreotate. Eur J Nucl Med Mol Imaging. 2003;30(3):417–422. 66. Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23(12):2754–2762. 67. Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy with (1)(7)(7)Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38(12):2125–2135. 68. Ezziddin S, Attassi M, Yong-Hing CJ, et al. Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med. 2014;55(2):183–190.

69. Delpassand ES, Samarghandi A, Zamanian S, et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience. Pancreas. 2014;43(4):518–525. 70. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of (177) Lu-DOTATATE for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–135. 70a. For European approval: https://www.ema.europa.eu/en/medicines/ human/EPAR/lutathera. Accessed on May 15, 2019. 70b. For USA approval: https://www.fda.gov/news-events/pressannouncements/fda-approves-new-treatment-certain-digestive-tract -cancers. Accessed on May 15, 2019. 71. Kratochwil C, Giesel FL, Bruchertseifer F, et al. 2)(1)(3)Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014;41(11):2106–2119. 72. Kratochwil C, Bruchertseifer F, Giesel F, et al. Ac-225-DOTATOC - dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2015;42(suppl 1):S36. 73. Ross JS, Sheehan CE, Fisher HA, et al. Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer Res. 2003;9(17):6357–6362. 74. Center MM, Jemal A, Lortet-Tieulent J, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012;61(6):1079–1092. 75. Ward JF, Moul JW. Rising prostate-specific antigen after primary prostate cancer therapy. Nat Clin Pract Urol. 2005;2(4):174–182. 76. Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71(4):630–642. 77. Saad F, Chi KN, Finelli A, et al. The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer (CRPC). Can Urol Assoc J. 2015;9(3–4):90–96. 78. Ahmadzadehfar H, Rahbar K, Kurpig S, et al. Early side effects and first results of radioligand therapy with (177)Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study. EJNMMI Res. 2015;5(1):114. 79. Rahbar K, Ahmadzadehfar H, Kratochwil C, et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med. 2017;58(1):85–90. 80. Kratochwil C, Giesel FL, Stefanova M, et al. PSMA-targeted radionuclide therapy of metastatic castration-resistant prostate cancer with 177Lu-Labeled PSMA-617. J Nucl Med. 2016;57(8): 1170–1176. 81. Heck MM, Retz M, D’Alessandria C, et al. Systemic radioligand therapy with (177)Lu labeled prostate specific membrane antigen ligand for imaging and therapy in patients with metastatic castration resistant prostate cancer. J Urol. 2016;196(2):382–391. 82. Kulkarni HR, Singh A, Schuchardt C, et al. PSMA-based radioligand therapy for metastatic castration-resistant prostate cancer: the Bad Berka experience since 2013. J Nucl Med. 2016;57(suppl 3): 97S–104S. 83. Baum RP, Kulkarni HR, Schuchardt C, et al. 177Lu-labeled prostatespecific membrane antigen radioligand therapy of metastatic castrationresistant prostate cancer: safety and efficacy. J Nucl Med. 2016;57(7):1006–1013. 84. Fendler WP, Reinhardt S, Ilhan H, et al. Preliminary experience with dosimetry, response and patient reported outcome after 177Lu-PSMA617 therapy for metastatic castration-resistant prostate cancer. Oncotarget. 2017;8(2):3581–3590. 85. Hofman MS, Violet J, Hicks RJ, et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825–833. 86. Kratochwil C, Bruchertseifer F, Giesel FL, et al. 225Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57(12):1941–1944.

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106. Jurcic JG. Alpha-particle immunotherapy for acute myeloid leukemia (AML) with Bismuth-213 and Actinium-225. Cancer Biother Radiopharm. 2006;21(4):396. 107. Tempero M, Leichner P, Baranowska-Kortylewicz J, et al. High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial. Clin Cancer Res. 2000;6(8):3095–3102. 108. DeNardo GL, DeNardo SJ. Evaluation of a cathepsin-cleavable peptide linked radioimmunoconjugate of a panadenocarcinoma MAb, m170, in mice and patients. Cancer Biother Radiopharm. 2004;19(1):85–92. 109. Beeson C, Butrynski JE, Hart MJ, et al. Conditionally cleavable radioimmunoconjugates: a novel approach for the release of radioisotopes from radioimmunoconjugates. Bioconjug Chem. 2003;14(5):927–933. 110. Chappell LL, Dadachova E, Milenic DE, et al. Synthesis, characterization, and evaluation of a novel bifunctional chelating agent for the lead isotopes 203Pb and 212Pb. Nucl Med Biol. 2000;27(1):93–100. 111. Macklis RM, Kaplan WD, Ferrara JL, et al. Alpha particle radioimmunotherapy: animal models and clinical prospects. Int J Radiat Oncol Biol Phys. 1989;16(6):1377–1387. 112. Dadachova E. Cancer therapy with alpha-emitters labeled peptides. Semin Nucl Med. 2010;40(3):204–208. 113. Borchardt PE, Yuan RR, Miederer M, et al. Targeted actinium-225 in vivo generators for therapy of ovarian cancer. Cancer Res. 2003;63(16):5084–5090. 113a. Wulbrand C, Seidl C, Gaertner FC, et al. Alpha-particle emitting 213Bi-anti-EGFR immunoconjugates eradicate tumor cells independent of oxygenation. PLoS One. 2013;8(5):e64730. 114. Baidoo KE, Yong K, Brechbiel MW. Molecular pathways: targeted alpha-particle radiation therapy. Clin Cancer Res. 2013;19(3): 530–537. 115. Allen BJ, Singla AA, Rizvi SM, et al. Analysis of patient survival in a Phase I trial of systemic targeted alpha-therapy for metastatic melanoma. Immunotherapy. 2011;3(9):1041–1050. 116. Zalutsky MR, Reardon DA, Akabani G, et al. Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6. J Nucl Med. 2008;49(1):30–38. 117. Hultborn R, et al. Pharmacokinetics and dosimetry of (211)At-MX35 F(AB’)(2) in therapy of ovarian cancer - preliminary results from an ongoing phase I study. Cancer Biother Radiopharm. 2006;21(4):1. 118. Birnbaum ER, et al. The Road to Large Scale Production of Ac-225. 8th International Symposium on Targeted Alpha Therapy; 2013; Oak Ridge, TN. 119. Meredith RF, LoBuglio AF, Plott WE, et al. Pharmacokinetics, immune response, and biodistribution of iodine-131-labeled chimeric mouse/ human IgG1,k 17-1A monoclonal antibody. J Nucl Med. 1991;32(6):1162–1168. 120. Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood. 2002;100(4):1233–1239. 121. Rosenblat TL, McDevitt MR, Mulford DA, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16(21):5303–5311. 122. Jurcic JG, et al. Phase I trial of the targeted alpha-particle nanogenerator actinium-225 (225Ac)-lintuzumab (anti-CD33; HuM195) in actue myeloid leukemia (AML). Blood. 2011;118:1. 123. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–223. 124. Bruland OS, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res. 2006;12(20 Pt 2):6250s–6257s. 125. Finlay IG, Mason MD, Shelley M. Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol. 2005;6(6):392–400. 125a. Parker C, Heidenreich A, Nilsson S, Shore N. Current approaches to incorporation of radium-223 in clinical practice. Prostate Cancer Prostatic Dis. 2018;21(1):37–47.

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CHAPTER 25 169. Behr TM, Sharkey RM, Juweid ME, et al. Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG. J Nucl Med. 1997;38(6):858–870. 170. Juweid M, Swayne LC, Sharkey RM, et al. Prospects of radioimmunotherapy in epithelial ovarian cancer: results with iodine-131-labeled murine and humanized MN-14 anticarcinoembryonic antigen monoclonal antibodies. Gynecol Oncol. 1997;67(3):259–271. 171. Ychou M, Pelegrin A, Faurous P, et al. Phase-I/II radio-immunotherapy study with Iodine-131-labeled anti-CEA monoclonal antibody F6 F(ab’)2 in patients with non-resectable liver metastases from colorectal cancer. Int J Cancer. 1998;75(4):615–619. 172. Behr TM, Salib AL, Liersch T, et al. Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver: preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study. Clin Cancer Res. 1999;5(10 suppl): 3232s–3242s. 173. Juweid ME, Hajjar G, Swayne LC, et al. Phase I/II trial of (131) I-MN-14F(ab)2 anti-carcinoembryonic antigen monoclonal antibody in the treatment of patients with metastatic medullary thyroid carcinoma. Cancer. 1999;85(8):1828–1842. 174. Steffens MG, Boerman OC, de Mulder PH, et al. Phase I radioimmunotherapy of metastatic renal cell carcinoma with 131I-labeled chimeric monoclonal antibody G250. Clin Cancer Res. 1999;5(10 suppl):3268s–3274s. 175. Chen S, Yu L, Jiang C, et al. Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer. J Clin Oncol. 2005;23(7):1538–1547. 176. Meredith RF, Khazaeli MB, Liu T, et al. Dose fractionation of radiolabeled antibodies in patients with metastatic colon cancer. J Nucl Med. 1992;33(9):1648–1653. 177. Weiden PL, Breitz HB, Seiler CA, et al. Rhenium-186-labeled chimeric antibody NR-LU-13: pharmacokinetics, biodistribution and immunogenicity relative to murine analog NR-LU-10. J Nucl Med. 1993;34(12):2111–2119. 178. Murray JL, Macey DJ, Kasi LP, et al. Phase II radioimmunotherapy trial with 131I-CC49 in colorectal cancer. Cancer. 1994;73(3 suppl):1057–1066. 179. Welt S, Divgi CR, Kemeny N, et al. Phase I/II study of iodine 131-labeled monoclonal antibody A33 in patients with advanced colon cancer. J Clin Oncol. 1994;12(8):1561–1571. 180. Wheeler RH, et al. A phase II trial of IL-1 + radioimmunotherapy (RIT) in patients (pts) with metastatic colon cancer (meeting abstract). Proc Annu Meet Am Soc Clin Oncol. 1994;(13):1. 181. Meredith RF, Khazaeli MB, Plott WE, et al. Initial clinical evaluation of iodine-125-labeled chimeric 17-1A for metastatic colon cancer. J Nucl Med. 1995;36(12):2229–2233. 182. Mulligan T, Carrasquillo JA, Chung Y, et al. Phase I study of intravenous Lu-labeled CC49 murine monoclonal antibody in patients with advanced adenocarcinoma. Clin Cancer Res. 1995;1(12):1447–1454. 183. Deb N, Goris M, Trisler K, et al. Treatment of hormone-refractory prostate cancer with 90Y-CYT-356 monoclonal antibody. Clin Cancer Res. 1996;2(8):1289–1297. 184. Yu B, Carrasquillo J, Milenic D, et al. Phase I trial of iodine 131-labeled COL-1 in patients with gastrointestinal malignancies: influence of serum carcinoembryonic antigen and tumor bulk on pharmacokinetics. J Clin Oncol. 1996;14(6):1798–1809. 185. Juweid M, Sharkey RM, Swayne LC, et al. Pharmacokinetics, dosimetry and toxicity of rhenium-188-labeled anti-carcinoembryonic antigen monoclonal antibody, MN-14, in gastrointestinal cancer. J Nucl Med. 1998;39(1):34–42. 186. Kahn D, Austin JC, Maguire RT, et al. A phase II study of [90Y] yttrium-capromab pendetide in the treatment of men with prostate cancer recurrence following radical prostatectomy. Cancer Biother Radiopharm. 1999;14(2):99–111. 187. Colnot DR, Quak JJ, Roos JC, et al. Phase I therapy study of 186Re-labeled chimeric monoclonal antibody U36 in patients with

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205. Wong JY, Somlo G, Odom-Maryon T, et al. Initial clinical experience evaluating Yttrium-90-chimeric T84.66 anticarcinoembryonic antigen antibody and autologous hematopoietic stem cell support in patients with carcinoembryonic antigen-producing metastatic breast cancer. Clin Cancer Res. 1999;5(10 suppl):3224s–3231s. 206. Juweid ME, Hajjar G, Stein R, et al. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR. J Nucl Med. 2000;41(1):93–103. 207. Meredith RF, Khazaeli MB, Plott WE, et al. Phase I trial of iodine-131chimeric B72.3 (human IgG4) in metastatic colorectal cancer. J Nucl Med. 1992;33(1):23–29. 208. Divgi CR, Scott AM, Gulec S, et al. Pilot radioimmunotherapy trial with I-131-labeled murine monoclonal antibody CC49 and deoxyspergualin in metastatic colon carcinoma. Clin Cancer Res. 1995;1(12):1503–1510. 209. Meredith RF, Khazaeli MB, Plott WE, et al. Phase II study of dual 131I-labeled monoclonal antibody therapy with interferon in patients with metastatic colorectal cancer. Clin Cancer Res. 1996;2(11):1811–1818. 210. Macey DJ, Grant EJ, Kasi L, et al. Effect of recombinant alpha-interferon on pharmacokinetics, biodistribution, toxicity, and efficacy of 131I-labeled monoclonal antibody CC49 in breast cancer: a phase II trial. Clin Cancer Res. 1997;3(9):1547–1555. 211. Slovin SF, Scher HI, Divgi CR, et al. Interferon-gamma and monoclonal antibody 131I-labeled CC49: outcomes in patients with androgenindependent prostate cancer. Clin Cancer Res. 1998;4(3):643–651. 212. Meredith RF, Khazaeli MB, Macey DJ, et al. Phase II study of interferonenhanced 131I-labeled high affinity CC49 monoclonal antibody therapy in patients with metastatic prostate cancer. Clin Cancer Res. 1999;5(10 suppl):3254s–3258s. 213. Meyer T, Gaya AM, Dancey G, et al. A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas. Clin Cancer Res. 2009;15(13):4484–4492. 214. Bodel-Milin C, et al. Toxicity and efficacy of combined radioimmunotherapy and bevacizumab (avastin) in mouse model of medullary thyroid carcinoma. Cancer Biother Radiopharm. 2008; 23(4):1. 215. Markoe AM, Brady LW, Woo D, et al. Treatment of gastrointestinal cancer using monoclonal antibodies. Front Radiat Ther Oncol. 1990;24:214–224, discussion 225-217. 216. Buchegger F, Allal AS, Roth A, et al. Combined radioimmunotherapy and radiotherapy of liver metastases from colorectal cancer: a feasibility study. Anticancer Res. 2000;20(3B):1889–1896. 217. Order SE, Stillwagon GB, Klein JL, et al. Iodine 131 antiferritin, a new treatment modality in hepatoma: a Radiation Therapy Oncology Group study. J Clin Oncol. 1985;3(12):1573–1582. 218. Order SE, Klein JL, Leichner PK, et al. 90Yttrium antiferritin–a new therapeutic radiolabeled antibody. Int J Radiat Oncol Biol Phys. 1986;12(2):277–281. 219. Stillwagon GB, Order SE, Klein JL, et al. Multi-modality treatment of primary nonresectable intrahepatic cholangiocarcinoma with 131I anti-CEA–a Radiation Therapy Oncology Group Study. Int J Radiat Oncol Biol Phys. 1987;13(5):687–695. 220. Emrich JG, Brady LW, Quang TS, et al. Radioiodinated (I-125) monoclonal antibody 425 in the treatment of high grade glioma patients: ten-year synopsis of a novel treatment. Am J Clin Oncol. 2002;25(6):541–546. 221. Reardon DA, Akabani G, Coleman RE, et al. Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol. 2002;20(5):1389–1397. 222. Goetz C, Rachinger W, Poepperl G, et al. Intralesional radioimmunotherapy in the treatment of malignant glioma: clinical and experimental findings. Acta Neurochir Suppl. 2003;88:69–75. 223. Carabasi M, et al. Autologous stem cell transplantation for breast and prostate cancer after combined modality therapy with radioimmunotherapy plus external beam radiation. Blood. 1999;94(10 suppl 1):1.

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CHAPTER 25 245. Whitlow M, Bell BA, Feng SL, et al. An improved linker for single-chain Fv with reduced aggregation and enhanced proteolytic stability. Protein Eng. 1993;6(8):989–995. 246. Holliger P, Prospero T, Winter G. "Diabodies." Small bivalent and dispecific antibody fragments. Proc Natl Acad Sci USA. 1996;90:5. 247. Forero A, Meredith RF, Khazaeli MB, et al. A novel monoclonal antibody design for radioimmunotherapy. Cancer Biother Radiopharm. 2003;18(5):751–759. 248. Meredith RF, et al. Radioimmunotherapy of colon cancer with an imporvised humanized monoclonal antibody design. Int J Radiat Oncol Biol Phys. 2002;54(2 suppl). 249. Jain RK. Haemodynamic and transport barriers to the treatment of solid tumours. Int J Radiat Biol. 1991;60(1–2):85–100. 250. Philben VJ, Jakowatz JG, Beatty BG, et al. The effect of tumor CEA content and tumor size on tissue uptake of indium 111-labeled anti-CEA monoclonal antibody. Cancer. 1986;57(3):571–576. 251. Wong JY, Williams LE, Demidecki AJ, et al. Radiobiologic studies comparing Yttrium-90 irradiation and external beam irradiation in vitro. Int J Radiat Oncol Biol Phys. 1991;20(4):715–722. 252. Buras R, Williams LE, Beatty BG, et al. A method including edge effects for the estimation of radioimmunotherapy absorbed doses in the tumor xenograft model. Med Phys. 1994;21(2):287–292. 253. O’Donoghue JA, Bardies M, Wheldon TE. Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J Nucl Med. 1995;36(10):1902–1909. 254. Behr TM, Sharkey RM, Juweid ME, et al. Variables influencing tumor dosimetry in radioimmunotherapy of CEA-expressing cancers with anti-CEA and antimucin monoclonal antibodies. J Nucl Med. 1997;38(3):409–418. 255. De Bree R, et al. The impact of tumour volume and other characteristics on uptake and radiolabelled monoclonal antibodies in tumour tissue of head and neck cancer patients. Eur J Nucl Med. 1998;25:4. 256. Liersch T, Meller J, Bittrich M, et al. Update of carcinoembryonic antigen radioimmunotherapy with (131)I-labetuzumab after salvage resection of colorectal liver metastases: comparison of outcome to a contemporaneous control group. Ann Surg Oncol. 2007;14(9):2577–2590. 257. Sahlmann CO, Homayounfar K, Niessner M, et al. Repeated adjuvant anti-CEA radioimmunotherapy after resection of colorectal liver metastases: safety, feasibility, and long-term efficacy results of a prospective phase 2 study. Cancer. 2017;123(4):638–649. 258. Cahan B, Leong L, Wagman L, et al. Phase I/II trial of anticarcinoembryonic antigen radioimmunotherapy, gemcitabine, and hepatic arterial infusion of fluorodeoxyuridine postresection of liver metastasis for colorectal carcinoma. Cancer Biother Radiopharm. 2017;32(7):258–265. 259. Karacay H, Sharkey RM, Gold DV, et al. Pretargeted radioimmunotherapy of pancreatic cancer xenografts: TF10-90YIMP-288 alone and combined with gemcitabine. J Nucl Med. 2009;50(12):2008–2016. 260. Gold DV, Schutsky K, Modrak D, Cardillo TM. Low-dose radioimmunotherapy ((90)Y-PAM4) combined with gemcitabine for the treatment of experimental pancreatic cancer. Clin Cancer Res. 2003;9(10 Pt 2):3929S–3937S. 261. Graves SS, Dearstyne E, Lin Y, et al. Combination therapy with Pretarget CC49 radioimmunotherapy and gemcitabine prolongs tumor doubling time in a murine xenograft model of colon cancer more effectively than either monotherapy. Clin Cancer Res. 2003;9(10 Pt 1):3712–3721. 262. DeNardo SJ, Kukis DL, Kroger LA, et al. Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: efficacy and toxicity in breast cancer xenografts. Proc Natl Acad Sci USA. 1997;94(8):4000–4004. 263. O’Donnell RT, DeNardo SJ, Miers LA, et al. Combined modality radioimmunotherapy with Taxol and 90Y-Lym-1 for Raji lymphoma xenografts. Cancer Biother Radiopharm. 1998;13(5):351–361. 264. Kievit E, Pinedo HM, Schluper HM, Boven E. Addition of cisplatin improves efficacy of 131I-labeled monoclonal antibody 323/A3 in experimental human ovarian cancer. Int J Radiat Oncol Biol Phys. 1997;38(2):419–428.

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265. Remmenga SW, Colcher D, Gansow O, et al. Continuous infusion chemotherapy as a radiation-enhancing agent for yttrium-90radiolabeled monoclonal antibody therapy of a human tumor xenograft. Gynecol Oncol. 1994;55(1):115–122. 266. Kinuya S, Yokoyama K, Tega H, et al. Efficacy, toxicity and mode of interaction of combination radioimmunotherapy with 5-fluorouracil in colon cancer xenografts. J Cancer Res Clin Oncol. 1999;125(11):630–636. 267. Blumenthal RD, et al. Multimodal preclinical radioimmunotherapy (RAIT) in combination with chemotherapy of human colonic tumors. Selection between 5-fluorouracil (5-FU) and irinotecan (CPT-11). Proc Am Assoc Cancer Res. 2002;43. 268. Behr TM, Wulst E, Radetzky S, et al. Improved treatment of medullary thyroid cancer in a nude mouse model by combined radioimmunochemotherapy: doxorubicin potentiates the therapeutic efficacy of radiolabeled antibodies in a radioresistant tumor type. Cancer Res. 1997;57(23):5309–5319. 269. Buchsbaum DJ, Khazaeli MB, Davis MA, Lawrence TS. Sensitization of radiolabeled monoclonal antibody therapy using bromodeoxyuridine. Cancer. 1994;73(3 suppl):999–1005. 270. Roffler SR, Chan J, Yeh MY. Potentiation of radioimmunotherapy by inhibition of topoisomerase I. Cancer Res. 1994;54(5):1276–1285. 271. Ng B, Kramer E, Liebes L, et al. Radiosensitization of tumor-targeted radioimmunotherapy with prolonged topotecan infusion in human breast cancer xenografts. Cancer Res. 2001;61(7):2996–3001. 272. Langmuir VK, Mendonca HL. The combined use of 131I-labeled antibody and the hypoxic cytotoxin SR 4233 in vitro and in vivo. Radiat Res. 1992;132(3):351–358. 273. Blumenthal RD, Taylor A, Osorio L, et al. Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia. Int J Cancer. 2001;94(4):564–571. 274. Lee FT, Mountain AJ, Kelly MP, et al. Enhanced efficacy of radioimmunotherapy with 90Y-CHX-A’ ’-DTPA-hu3S193 by inhibition of epidermal growth factor receptor (EGFR) signaling with EGFR tyrosine kinase inhibitor AG1478. Clin Cancer Res. 2005;11(19 Pt 2):7080s–7086s. 275. van Gog FB, et al. Perspectives of combined radioimmunotherapy and anti-EGFR antibody therapy for the treatment of residual head and neck cancer. Int J Cancer. 1998;77(1):6. 276. Herbertson RA, Tebbutt NC, Lee FT, et al. Targeted chemoradiation in metastatic colorectal cancer: a phase I trial of 131I-huA33 with concurrent capecitabine. J Nucl Med. 2014;55(4):534–539. 277. Ocean AJ, Pennington KL, Guarino MJ, et al. Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: a phase 1 trial. Cancer. 2012;118(22):5497–5506. 278. Picozzi VJ, Ramanathan RK, Lowery MA, et al. (90)Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: a phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies. Eur J Cancer. 2015;51(14):1857–1864. 279. Sharkey RM, Hajjar G, Yeldell D, et al. A phase I trial combining high-dose 90Y-labeled humanized anti-CEA monoclonal antibody with doxorubicin and peripheral blood stem cell rescue in advanced medullary thyroid cancer. J Nucl Med. 2005;46(4):620–633. 280. DeNardo SJ, Richman CM, Albrecht H, et al. Enhancement of the therapeutic index: from nonmyeloablative and myeloablative toward pretargeted radioimmunotherapy for metastatic prostate cancer. Clin Cancer Res. 2005;11(19 Pt 2):7187s–7194s. 281. Richman CM, Denardo SJ, O’Donnell RT, et al. High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody. Clin Cancer Res. 2005;11(16):5920–5927. 282. Meredith RF, Alvarez RD, Partridge EE, et al. Intraperitoneal radioimmunochemotherapy of ovarian cancer: a phase I study. Cancer Biother Radiopharm. 2001;16(4):305–315. 283. David KA, Milowsky MI, Kostakoglu L, et al. Clinical utility of radiolabeled monoclonal antibodies in prostate cancer. Clin Genitourin Cancer. 2006;4(4):249–256.

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SECTION II

Techniques and Modalities

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CHAPTER 25 lock method for use in cancer targeting. Proc Natl Acad Sci USA. 2006;103(18):6841–6846. 325. Ugrin M, Stojiljkovic M, Zukic B, et al. Functional analysis of an (A) gamma-globin gene promoter variant (HBG1: g.-225_-222delAGCA) underlines its role in increasing fetal hemoglobin levels under erythropoietic stress. Hemoglobin. 2016;40(1):48–52. 326. Rowlinson G, Snook D, Busza A, Epenetos AA. Antibody-guided localization of intraperitoneal tumors following intraperitoneal or intravenous antibody administration. Cancer Res. 1987;47(24 Pt 1):6528–6531. 327. Colcher D, Esteban J, Carrasquillo JA, et al. Complementation of intracavitary and intravenous administration of a monoclonal antibody (B72.3) in patients with carcinoma. Cancer Res. 1987;47(15):4218–4224. 328. Ward BG, Mather SJ, Hawkins LR, et al. Localization of radioiodine conjugated to the monoclonal antibody HMFG2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration. Cancer Res. 1987;47(17):4719–4723. 329. Chatal JF, Saccavini JC, Gestin JF, et al. Biodistribution of indium-111labeled OC 125 monoclonal antibody intraperitoneally injected into patients operated on for ovarian carcinomas. Cancer Res. 1989;49(11):3087–3094. 330. Nicholson S, Gooden CS, Hird V, et al. Radioimmunotherapy after chemotherapy compared to chemotherapy alone in the treatment of advanced ovarian cancer: a matched analysis. Oncol Rep. 1998;5(1):223–226. 331. Verheijen RH, Massuger LF, Benigno BB, et al. Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol. 2006;24(4):571–578. 332. Oei AL, Verheijen RH, Seiden MV, et al. Decreased intraperitoneal disease recurrence in epithelial ovarian cancer patients receiving intraperitoneal consolidation treatment with yttrium-90-labeled murine HMFG1 without improvement in overall survival. Int J Cancer. 2007;120(12):2710–2714. 333. Meredith R, You Z, Alvarez R, et al. Predictors of long-term outcome from intraperitoneal radioimmunotherapy for ovarian cancer. Cancer Biother Radiopharm. 2012;27(1):36–40. 334. Cokgor I, Akabani G, Kuan CT, et al. Phase I trial results of iodine-131labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas. J Clin Oncol. 2000;18(22):3862–3872. 335. Bigner DD, Brown MT, Friedman AH, et al. Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results. J Clin Oncol. 1998;16(6):2202–2212. 336. Reardon DA, Zalutsky MR, Akabani G, et al. A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost. Neuro Oncol. 2008;10(2):182–189. 337. Reardon DA, Quinn JA, Akabani G, et al. Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results. J Nucl Med. 2006;47(6):912–918. 338. Riva P, Arista A, Franceschi G, et al. Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with 131I: comparison of the results obtained in recurrent and newly diagnosed tumors. Cancer Res. 1995;55(23 suppl):5952s–5956s. 339. Riva P, Franceschi G, Arista A, et al. Local application of radiolabeled monoclonal antibodies in the treatment of high grade malignant gliomas: a six-year clinical experience. Cancer. 1997;80(12 suppl):2733–2742. 340. Riva P, Franceschi G, Frattarelli M, et al. Loco-regional radioimmunotherapy of high-grade malignant gliomas using specific monoclonal antibodies labeled with 90Y: a phase I study. Clin Cancer Res. 1999;5(10 suppl):3275s–3280s. 341. Goetz C, Riva P, Poepperl G, et al. Locoregional radioimmunotherapy in selected patients with malignant glioma: experiences, side effects and survival times. J Neurooncol. 2003;62(3):321–328.

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SECTION II

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534. Weiss B, Vora A, Huberty J, et al. Secondary myelodysplastic syndrome and leukemia following 131I-metaiodobenzylguanidine therapy for relapsed neuroblastoma. J Pediatr Hematol Oncol. 2003;25(7):543–547. 535. Hobbs RF, McNutt T, Baechler S, et al. A treatment planning method for sequentially combining radiopharmaceutical therapy and external radiation therapy. Int J Radiat Oncol Biol Phys. 2011;80(4):1256–1262. 536. Stabin MG. Uncertainties in internal dose calculations for radiopharmaceuticals. J Nucl Med. 2008;49(5):853–860. 537. Bolch WE. alpha-Particle emitters in radioimmunotherapy: new and welcome challenges to medical internal dosimetry. J Nucl Med. 2001;42(8):1222–1224. 538. Limits for intakes of radionuclides by workers. Ann ICRP. 1979;3(1–4):i–ii. 539. Sgouros G, Roeske JC, McDevitt MR, et al. MIRD Pamphlet No. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. J Nucl Med. 2010;51(2):311–328. 540. Hobbs RF, Howell RW, Song H, et al. Redefining relative biological effectiveness in the context of the EQDX formalism: implications for alpha-particle emitter therapy. Radiat Res. 2014;181(1):90–98. 541. Stabin MG. Radiotherapy with internal emitters: what can dosimetrists offer? Cancer Biother Radiopharm. 2003;18(4):611–617. 542. Siegel JA, Lee RE, Pawlyk DA, et al. Sacral scintigraphy for bone marrow dosimetry in radioimmunotherapy. Int J Rad Appl Instrum B. 1989;16(6):553–559. 543. Sgouros G. Bone marrow dosimetry for radioimmunotherapy: theoretical considerations. J Nucl Med. 1993;34(4):689–694. 544. Lassmann M, Hanscheid H, Chiesa C, et al. EANM Dosimetry Committee series on standard operational procedures for pretherapeutic dosimetry I: blood and bone marrow dosimetry in differentiated thyroid cancer therapy. Eur J Nucl Med Mol Imaging. 2008;35(7):1405–1412. 545. Minarik D, Sjogreen-Gleisner K, Linden O, et al. 90Y Bremsstrahlung imaging for absorbed-dose assessment in high-dose radioimmunotherapy. J Nucl Med. 2010;51(12):1974–1978. 546. Fisher DR, Shen S, Meredith RF. MIRD dose estimate report No. 20: radiation absorbed-dose estimates for 111In- and 90Y-ibritumomab tiuxetan. J Nucl Med. 2009;50(4):644–652. 547. Wiseman GA, Leigh BR, Erwin WD, et al. Radiation dosimetry results from a Phase II trial of ibritumomab tiuxetan (Zevalin) radioimmunotherapy for patients with non-Hodgkin’s lymphoma and mild thrombocytopenia. Cancer Biother Radiopharm. 2003;18(2):165–178. 548. Verel I, Visser GW, Boellaard R, et al. Quantitative 89Zr immuno-PET for in vivo scouting of 90Y-labeled monoclonal antibodies in xenograftbearing nude mice. J Nucl Med. 2003;44(10):1663–1670. 549. Hobbs RF, Wahl RL, Lodge MA, et al. 124I PET-based 3D-RD dosimetry for a pediatric thyroid cancer patient: real-time treatment planning and methodologic comparison. J Nucl Med. 2009;50(11):1844–1847. 550. Larson SM, Pentlow KS, Volkow ND, et al. PET scanning of iodine124-3F9 as an approach to tumor dosimetry during treatment planning for radioimmunotherapy in a child with neuroblastoma. J Nucl Med. 1992;33(11):2020–2023. 551. Stillebroer AB, Franssen GM, Mulders PF, et al. ImmunoPET imaging of renal cell carcinoma with (124)I- and (89)Zr-labeled anti-CAIX monoclonal antibody cG250 in mice. Cancer Biother Radiopharm. 2013;28(7):510–515. 552. Brouwers A, Verel I, Van Eerd J, et al. PET radioimmunoscintigraphy of renal cell cancer using 89Zr-labeled cG250 monoclonal antibody in nude rats. Cancer Biother Radiopharm. 2004;19(2):155–163. 553. Breitz HB, Fisher DR, Weiden PL, et al. Dosimetry of rhenium-186labeled monoclonal antibodies: methods, prediction from technetium99m-labeled antibodies and results of phase I trials. J Nucl Med. 1993;34(6):908–917. 554. Press OW, Appelbaum FR, Eary JF, Bernstein ID. Radiolabeled antibody therapy of lymphomas. Important Adv Oncol. 1995;157–171. 555. Eary JF, Press OW, Badger CC, et al. Imaging and treatment of B-cell lymphoma. J Nucl Med. 1990;31(8):1257–1268. 556. Dewaraja YK, Frey EC, Sgouros G, et al. MIRD pamphlet No. 23: quantitative SPECT for patient-specific 3-dimensional dosimetry in internal radionuclide therapy. J Nucl Med. 2012;53(8):1310–1325.

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CHAPTER 25 557. Sgouros G, Squeri S, Ballangrud AM, et al. Patient-specific, 3-dimensional dosimetry in non-Hodgkin’s lymphoma patients treated with 131I-anti-B1 antibody: assessment of tumor dose-response. J Nucl Med. 2003;44(2):260–268. 558. Tsui BMW. Quantitative SPECT. In: Henkin RE, et al, eds. Nuclear Medicine. St. Louis: Mosby-Year Book; 1996. 559. Stabin MG. Developments in the internal dosimetry of radiopharmaceuticals. Radiat Prot Dosimetry. 2003;105(1–4): 575–580. 560. Howell RW, Wessels BW, Loevinger R, et al. The MIRD perspective 1999. Medical Internal Radiation Dose Committee. J Nucl Med. 1999;40(1):3S–10S. 561. Maynard MR, Geyer JW, Aris JP, et al. The UF family of hybrid phantoms of the developing human fetus for computational radiation dosimetry. Phys Med Biol. 2011;56(15):4839–4879. 562. Long DJ, Lee C, Tien C, et al. Monte Carlo simulations of adult and pediatric computed tomography exams: validation studies of organ doses with physical phantoms. Med Phys. 2013;40(1):013901. 563. Bolch WE, Bouchet LG, Robertson JS, et al. MIRD pamphlet No. 17: the dosimetry of nonuniform activity distributions–radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee. J Nucl Med. 1999;40(1):11S–36S. 564. Stabin MG, Siegel JA. Physical models and dose factors for use in internal dose assessment. Health Phys. 2003;85(3):294–310. 565. Jokisch DW, Rajon DA, Bahadori AA, Bolch WE. An image-based skeletal model for the ICRP reference adult male-specific absorbed fractions for neutron-generated recoil protons. Phys Med Biol. 2011;56(21):6857–6872. 566. Hurtado JL, Lee C, Lodwick D, et al. Hybrid computational phantoms representing the reference adult male and adult female: construction and applications for retrospective dosimetry. Health Phys. 2012;102(3):292–304. 567. Lee C, Kim KP, Long DJ, Bolch WE. Organ doses for reference pediatric and adolescent patients undergoing computed tomography estimated by Monte Carlo simulation. Med Phys. 2012;39(4):2129–2146. 568. Moteabbed M, Geyer A, Drenkhahn R, et al. Comparison of whole-body phantom designs to estimate organ equivalent neutron doses for secondary cancer risk assessment in proton therapy. Phys Med Biol. 2012;57(2):499–515. 569. Wayson M, Lee C, Sgouros G, et al. Internal photon and electron dosimetry of the newborn patient–a hybrid computational phantom study. Phys Med Biol. 2012;57(5):1433–1457. 570. Meredith RF, Johnson TK, Plott G, et al. Dosimetry of solid tumors. Med Phys. 1993;20(2 Pt 2):583–592. 571. Siegel JA, Thomas SR, Stubbs JB, et al. MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med. 1999;40(2):37S–61S. 572. Huang S, et al. A Geant4-based internal dosimetry tool of 131I-meaiodobenzylguanidine (MIBG) targeted radionuclide therapy for neuroblastoma using 124I-MIBG PET/CT. J Nucl Med. 2013;54(suppl 2). 573. Johnson TK, McClure D, McCourt S. MABDOSE. II: validation of a general purpose dose estimation code. Med Phys. 1999;26(7):1396–1403. 574. Mirzaei S, Sohlberg A, Knoll P, et al. Easy-to-use online software package for internal dose assessment after radionuclide treatment in clinical routine. Clin Nucl Med. 2013;38(9):686–690. 575. Back T, et al. Alpha Camera Imaging in Targeted Alpha Therapy for Evaluation of Small-Scale-Activity and Dose Distributions in Tumors and Normal Tissues. 8th Interantional Symposium on Targeted Alpha Therapy; 2013; Oak Ridge, TN. 576. Baechler S, Hobbs RF, Boubaker A, et al. Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy. Med Phys. 2012;39(10):6118–6128. 577. Hobbs RF, Song H, Watchman CJ, et al. A bone marrow toxicity model for (2)(2)(3)Ra alpha-emitter radiopharmaceutical therapy. Phys Med Biol. 2012;57(10):3207–3222. 578. Rajon D, Bolch WE, Howell RW. Lognormal distribution of cellular uptake of radioactivity: Monte Carlo simulation of irradiation and cell

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killing in 3-dimensional populations in carbon scaffolds. J Nucl Med. 2011;52(6):926–933. 579. Ljungberg M, Frey E, Sjogreen K, et al. 3D absorbed dose calculations based on SPECT: evaluation for 111-In/90-Y therapy using Monte Carlo simulations. Cancer Biother Radiopharm. 2003;18(1):99–107. 580. Yoriyaz H, Stabin MG, dos Santos A. Monte Carlo MCNP-4B-based absorbed dose distribution estimates for patient-specific dosimetry. J Nucl Med. 2001;42(4):662–669. 581. Allen BJ, Hobbs RF, Roeske JC, et al. Alpha-particle dosimetry. In: Sgouros G, ed. MIRD Monograph-Radiobiology and Dosimetry for Radiopharmaceutical Therapy. Reston, VA: Society of Nuclear Medicine and Molecular Imaging; 2015. 582. Back T, Jacobsson L. The alpha-camera: a quantitative digital autoradiography technique using a charge-coupled device for ex vivo high-resolution bioimaging of alpha-particles. J Nucl Med. 2010;51(10):1616–1623. 583. Miller BW, et al. Digital autoradiography with the iQID alpha camera. 8th International Symposium on Targted Alpha Therapy; 2013; Oak Ridge, TN. 584. Chouin N, Lindegren S, Frost SH, et al. Ex vivo activity quantification in micrometastases at the cellular scale using the alpha-camera technique. J Nucl Med. 2013;54(8):1347–1353. 585. Griffith MH, et al. Direct dose confirmation of quantitative autoradiography with micro-TLD measurements for radioimmunotherapy. J Nucl Med. 1988;29(11). 586. Scarantino CW, Beyer GP. The Dose Verification System (DVS) for cancer patients receiving radiation therapy. Expert Rev Med Devices. 2008;5(6):679–685. 587. Wiseman GA, Kornmehl E, Leigh B, et al. Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin’s lymphoma: combined data from 4 clinical trials. J Nucl Med. 2003;44(3):465–474. 588. Zelenetz AD. A clinical and scientific overview of tositumomab and iodine I 131 tositumomab. Semin Oncol. 2003;30(2 suppl 4):22–30. 589. Helisch A, Forster GJ, Reber H, et al. Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA-Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advanced neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2004;31(10):1386–1392. 590. Shen S, Meredith RF, Duan J, et al. Improved prediction of myelotoxicity using a patient-specific imaging dose estimate for non-marrow-targeting (90)Y-antibody therapy. J Nucl Med. 2002;43(9):1245–1253. 591. Wilderman SJ, Roberson PL, Bolch WE, Dewaraja YK. Investigation of effect of variations in bone fraction and red marrow cellularity on bone marrow dosimetry in radio-immunotherapy. Phys Med Biol. 2013;58(14):4717–4731. 592. Koral KF, Kaminski MS, Wahl RL. Correlation of tumor radiationabsorbed dose with response is easier to find in previously untreated patients. J Nucl Med. 2003;44(9):1541–1543, author reply 1543. 593. Dewaraja YK, Schipper MJ, Shen J, et al. Tumor-absorbed dose predicts progression-free survival following (131)I-tositumomab radioimmunotherapy. J Nucl Med. 2014;55(7):1047–1053. 594. Schipper MJ, Koral KF, Avram AM, et al. Prediction of therapy tumor-absorbed dose estimates in I-131 radioimmunotherapy using tracer data via a mixed-model fit to time activity. Cancer Biother Radiopharm. 2012;27(7):403–411. 595. Wahl RL. The clinical importance of dosimetry in radioimmunotherapy with tositumomab and iodine I 131 tositumomab. Semin Oncol. 2003;30(2 suppl 4):31–38. 596. Cremonesi M, Botta F, Di Dia A, et al. Dosimetry for treatment with radiolabelled somatostatin analogues. A review. Q J Nucl Med Mol Imaging. 2010;54(1):37–51. 597. Tuttle RM, Leboeuf R, Robbins RJ, et al. Empiric radioactive iodine dosing regimens frequently exceed maximum tolerated activity levels in elderly patients with thyroid cancer. J Nucl Med. 2006;47(10): 1587–1591. 598. Tuttle RM, Lopez N, Leboeuf R, et al. Radioactive iodine administered for thyroid remnant ablation following recombinant human thyroid

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SECTION II

Techniques and Modalities

stimulating hormone preparation also has an important adjuvant therapy function. Thyroid. 2010;20(3):257–263. 599. Bentzen SM, Dorr W, Gahbauer R, et al. Bioeffect modeling and equieffective dose concepts in radiation oncology–terminology, quantities and units. Radiother Oncol. 2012;105(2):266–268. 600. Chiesa C, Botta F, Di Betta E, et al. Dosimetry in myeloablative (90) Y-labeled ibritumomab tiuxetan therapy: possibility of increasing administered activity on the base of biological effective dose evaluation. Preliminary results. Cancer Biother Radiopharm. 2007;22(1): 113–120. 601. Cremonesi M, Ferrari M, Grana CM, et al. High-dose radioimmunotherapy with 90Y-ibritumomab tiuxetan: comparative dosimetric study for tailored treatment. J Nucl Med. 2007;48(11):1871–1879. 602. Rajendran JG, Gopal AK, Fisher DR, et al. Myeloablative 131I-tositumomab radioimmunotherapy in treating non-Hodgkin’s lymphoma: comparison of dosimetry based on whole-body retention and dose to critical organ receiving the highest dose. J Nucl Med. 2008;49(5):837–844. 603. Cremonesi M, Ferrari M, Bodei L, et al. Dosimetry in Peptide radionuclide receptor therapy: a review. J Nucl Med. 2006;47(9):1467–1475. 604. Kurizaki T, Okazaki S, Sanderson SD, et al. Potentiation of radioimmunotherapy with response-selective peptide agonist of human C5a. J Nucl Med. 2002;43(7):957–967. 605. Behr TM, Liersch T, Greiner-Bechert L, et al. Radioimmunotherapy of small-volume disease of metastatic colorectal cancer. Cancer. 2002;94(4 suppl):1373–1381. 606. Liersch T. Repeated anti-CEA-radioimmunotherapy (RAIT) with 131 iodine-labetuzumab (phase II study) versus single dose RAIT after salvage resection of colorectal liver metastases (CRC-LM). J Clin Oncol. 2008;26:198s. 607. Sultana A, Shore S, Raraty MG, et al. Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I(131) KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma. BMC Cancer. 2009;9:66. 608. Divgi CR, Scott AM, Dantis L, et al. Phase I radioimmunotherapy trial with iodine-131-CC49 in metastatic colon carcinoma. J Nucl Med. 1995;36(4):586–592. 609. Welt S, Scott AM, Divgi CR, et al. Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer. J Clin Oncol. 1996;14(6):1787–1797. 610. Gulec SA, Cohen SJ, Pennington KL, et al. Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial. Clin Cancer Res. 2011;17(12):4091–4100. 611. Sharkey RM, Goldenberg DM, Vagg R, et al. Phase I clinical evaluation of a new murine monoclonal antibody (Mu-9) against colon-specific antigen-p for targeting gastrointestinal carcinomas. Cancer. 1994;73(3 suppl):864–877. 612. Chen S, Li B, Xie H, et al. Phase I clinical trial of targeted therapy using 131I-Hepama-1 mAb in patients with hepatocellular carcinoma. Cancer Biother Radiopharm. 2004;19(5):589–600. 613. Divgi CR, Bander NH, Scott AM, et al. Phase I/II radioimmunotherapy trial with iodine-131-labeled monoclonal antibody G250 in metastatic renal cell carcinoma. Clin Cancer Res. 1998;4(11):2729–2739. 614. Brouwers AH, Mulders PF, de Mulder PH, et al. Lack of efficacy of two consecutive treatments of radioimmunotherapy with 131I-cG250 in patients with metastasized clear cell renal cell carcinoma. J Clin Oncol. 2005;23(27):6540–6548. 615. Muselaers CH, Rijpkema M, Bos DL, et al. Radionuclide and fluorescence imaging of clear cell renal cell carcinoma using dual labeled anti-carbonic anhydrase IX antibody G250. J Urol. 2015;194(2):532–538. 616. DeNardo SJ, Mirick GR, Kroger LA, et al. The biologic window for chimeric L6 radioimmunotherapy. Cancer. 1994;73(3 suppl):1023–1032. 617. Carrasquillo JA, Krohn KA, Beaumier P, et al. Diagnosis of and therapy for solid tumors with radiolabeled antibodies and immune fragments. Cancer Treat Rep. 1984;68(1):317–328.

618. Klein M, Lotem M, Peretz T, et al. Safety and efficacy of 188-rheniumlabeled antibody to melanin in patients with metastatic melanoma. J Skin Cancer. 2013;2013:828329. 619. Lamborn KR, DeNardo GL, DeNardo SJ, et al. Treatment-related parameters predicting efficacy of Lym-1 radioimmunotherapy in patients with B-lymphocytic malignancies. Clin Cancer Res. 1997;3(8):1253–1260. 620. Vose JM, Colcher D, Gobar L, et al. Phase I/II trial of multiple dose (131)iodine-MAb LL2 (CD22) in patients with recurrent non-Hodgkin’s lymphoma. Leukemia Lymphoma. 2000;38(1–2):91–101. 621. Shibata S, Raubitschek A, Leong L, et al. A phase I study of a combination of yttrium-90-labeled anti-carcinoembryonic antigen (CEA) antibody and gemcitabine in patients with CEA-producing advanced malignancies. Clin Cancer Res. 2009;15(8):2935–2941. 622. Anderson P. A phase I safety and imaging study using radiofrequency ablation (RFA) followed by 131 I-chTNT-1/B radioimmunotherapy adjuvant treatment of hepatic metastases. Cancer Ther. 2003;1:283–291. 623. Wygoda Z, Kula D, Bierzynska-Macyszyn G, et al. Use of monoclonal anti-EGFR antibody in the radioimmunotherapy of malignant gliomas in the context of EGFR expression in grade III and IV tumors. Hybridoma (Larchmt). 2006;25(3):125–132. 624. Chatal JF, Campion L, Kraeber-Bodere F, et al. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol. 2006;24(11):1705–1711. 625. Schoffelen R, Boerman OC, Goldenberg DM, et al. Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results. Br J Cancer. 2013;109(4):934–942. 626. Breitz H. Pretargeted radioimmunotherapy with antibody-streptavidin and Y-90 DOTA-biotin (Avidin). Result of a dose escalation study. J Nucl Med. 1998;39(5):71. 627. Forero-Torres A, Shen S, Breitz H, et al. Pretargeted radioimmunotherapy (RIT) with a novel anti-TAG-72 fusion protein. Cancer Biother Radiopharm. 2005;20(4):379–390. 628. Paganelli G, Grana C, Chinol M, et al. Antibody-guided three-step therapy for high grade glioma with yttrium-90 biotin. Eur J Nucl Med. 1999;26(4):348–357. 629. Stewart JS, Hird V, Snook D, et al. Intraperitoneal yttrium-90-labeled monoclonal antibody in ovarian cancer. J Clin Oncol. 1990;8(12):1941–1950. 630. Hird V, Maraveyas A, Snook D, et al. Adjuvant therapy of ovarian cancer with radioactive monoclonal antibody. Br J Cancer. 1993;68(2):403–406. 631. Meredith R. Intraperitoneal radioimmunotherapy for refractory epithelial ovarian cancer with 177 Lu-CC49. Minerva Biotecnologica. 1998;10(3):100–107. 632. Rosenblum MG, Verschraegen CF, Murray JL, et al. Phase I study of 90Y-labeled B72.3 intraperitoneal administration in patients with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics and toxicity. Clin Cancer Res. 1999;5(5):953–961. 633. Muto MG, Finkler NJ, Kassis AI, et al. Intraperitoneal radioimmunotherapy of refractory ovarian carcinoma utilizing iodine-131-labeled monoclonal antibody OC125. Gynecol Oncol. 1992;45(3):265–272. 634. Mahe MA, Fumoleau P, Fabbro M, et al. A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma. Clin Cancer Res. 1999;5(10 suppl):3249s–3253s. 635. Jacobs AJ, Fer M, Su FM, et al. A phase I trial of a rhenium 186-labeled monoclonal antibody administered intraperitoneally in ovarian carcinoma: toxicity and clinical response. Obstet Gynecol. 1993;82(4 Pt 1):586–593. 636. Crippa F, Bolis G, Seregni E, et al. Single-dose intraperitoneal radioimmunotherapy with the murine monoclonal antibody I-131 MOv18: clinical results in patients with minimal residual disease of ovarian cancer. Eur J Cancer. 1995;31A(5):686–690. 637. Riva P, Marangolo M, Tison V, et al. Treatment of metastatic colorectal cancer by means of specific monoclonal antibodies conjugated with iodine-131: a phase II study. Int J Rad Appl Instrum B. 1991;18(1):109–119.

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CHAPTER 25 638. Buckman R, De Angelis C, Shaw P, et al. Intraperitoneal therapy of malignant ascites associated with carcinoma of ovary and breast using radioiodinated monoclonal antibody 2G3. Gynecol Oncol. 1992;47(1):102–109. 639. Reardon DA, Akabani G, Coleman RE, et al. Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results. J Clin Oncol. 2006;24(1):115–122. 640. Riva P, Franceschi G, Frattarelli M, et al. 131I radioconjugated antibodies for the locoregional radioimmunotherapy of high-grade malignant glioma–phase I and II study. Acta Oncol. 1999;38(3):351–359. 641. Pizer BL, et al. Meningeal leukemia and medulloblastoma. Preliminary experience with intrathecal radioimmunothearpy. Antibody Immunoconj Radiopharm. 1991;4(4):9.

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642. DeNardo GL, DeNardo SJ. Treatment of B-lymphocyte malignancies with 131I-Lym-1 and 67Cu-2IT-BAT-Lym-1 and opportunities for improvement. In: Goldenberg DM, ed. Cancer Therapy With Radiolabeled Antibodies. Boca Raton, FL: CRC Press; 1994:217. 643. Davis T. Long-term results of a randomized trial comparing Tositumomab and Iodine-131 Tositumomab (BEXXAR®) with Tositumomab alone in patients with relapsed or refractory low-grade (LG) or transformed low grade (T-LG) non-Hodgkin’s Lymphoma (NHL). Blood. 2003;102(11):405a. 644. Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, et al. Targeting, toxicity, and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and 131I-labeled bivalent hapten in a phase I optimization clinical trial. J Nucl Med. 2006;47(2):247–255.

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26 Immunotherapy With Radiotherapy Andrew G. Brandmaier and Silvia C. Formenti

EMERGENCE OF IMMUNOTHERAPY Immunotherapy encompasses a class of biologic substrates including peptides, recombinant antibodies, and cells that are administered to target the immune system and treat disease. In the field of oncology, immunotherapy has old origins (like the use of bacilli Calmette-Guérin [BCG] in bladder cancer), and it has recently re-emerged as a promising treatment paradigm to expand the repertoire of therapeutic options beyond traditional approaches with surgery, radiation therapy, and chemotherapy. Decades of discoveries uncovering the molecular targets of fundamental immunologic processes are translating to therapeutic success in clinical trials. Multiple immunotherapeutic strategies for treating the full spectrum of solid and hematologic malignancies are under active investigation. To date the progress of immunotherapy has primarily manifested with the use of monoclonal antibodies that block checkpoint inhibitors, which are regulatory receptors on T cells. Checkpoint blockade facilitates generalized T-cell activation in the host and revives exhausted T cells in the tumor microenvironment, thus facilitating their antitumor activity. Mobilization of activated antitumor T cells has been the central strategy of most modern immunotherapy endeavors. This chapter will provide an overview of immunologic properties of T cells in tumor immunology, review the tumor immune microenvironment, and examine the emerging role of radiotherapy as an adjuvant modality to immunotherapy.

T-CELL RECOGNITION OF TUMORS Self-Nonself and Danger The immune system is composed of a diverse population of cells spanning the hematopoietic lineage. Through their specialized functions, they collectively carry out the following processes: sensing danger stimuli, secreting paracrine molecules to recruit and activate partner cells, presenting peptide fragments, recognizing antigenic epitopes, and mediating engulfment and lysis of targets. A foundational principle of immune recognition was proposed by immunologists Burnet and Medawar, who later won the Nobel Prize, as the Self-Nonself Model (SNS): Immune cells are driven to recognize and attack “Nonself ” antigens.1 This model succinctly explained how microbes and infected or aberrant cells possess protein epitopes that are recognized as “Nonself” and targeted for elimination, whereas normal tissues of the host “Self ” are protected from immune attack. SNS provides insight on fundamental patterns of immune function, including specificity of antigen recognition and the development of the host T- and B-cell repertoires.2 Novel T-cell clones systematically differentiate in the lymphoid compartment, and clones that recognize self-antigens are deleted from the lymphocyte pool. However, the SNS model was incomplete in explaining important phenomena such as tumor immunity. The “Danger Model” later emerged as a paradigm for interpreting immune activation as driven by the

composite of innate immune signals in the tissue microenvironment. This theory provides a useful framework to interpret fundamental concepts in the field of tumor immunology.3 It explains the role of costimulation as a necessary signal for T-cell activation as well as the regulatory impact of checkpoint molecules. In tumor immunology, these factors account for the limitations of the immune system in preventing cancer incidence and progression. Antitumor T-cell responses are constrained by homeostatic regulatory processes and suppressive mechanisms within the tumor microenvironment.

T Cells in Immunity αβ T cells, which are central mediators of the adaptive immune response, play a critical role in antitumor immunity. Each T-cell clone expresses a unique cell membrane-bound T-cell receptor (TCR), which is a dimer of α and β immunoglobulin-like subunits. TCRs interact with major histocompatibility complex (MHC):peptide complexes displayed on adjacent antigen-presenting cells (APCs). Most cells across all tissue types present MHC class I peptide complexes that can be recognized by CD8+ T cells. MHC class II complexes are primarily expressed by professional APCs, such as dendritic cells and macrophages, and are recognized by CD4+ T cells. When the TCR of a T cell binds an MHC:peptide complex with sufficient affinity, the TCR is activated, and it initiates downstream signaling cascades that direct the effector function of the cell. CD8+ T cells secrete cytokines, such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), and also release cytotoxic granules containing perforin and granzyme, which lyse the antigenic target cell.4 Activated CD4+ T cells perform helper functions including releasing cytokines in accordance with their particular helper subtype and expressing CD40 ligand, which transmits an activating signal by binding CD40 on neighboring APCs. In particular, type I CD4+ helper T cells (Th1) contribute to antitumor immunity by releasing IFN-γ, which potently activates class I and class II antigen presentation and further exposes tumor cells to immune recognition by CD8+ cytotoxic T cells.5 Th1 cells also secrete IL-2, which supports the proliferation of neighboring T cells. Altogether, these mechanisms amplify immune activity in the tissue microenvironment and mediate destruction of antigen-containing cells.

T-Cell Repertoire The T-cell repertoire consists of the global population of T-cell clones in the host immune system and the corresponding antigens they recognize. Each T-cell clone possesses specific antigen recognition capability via its TCR, and the novelty of an individual receptor is largely attributable to complementarity determining region 3 (CDR3) in the variable region. Diversity in CDR3 is generated through random rearrangements of the TCR α and β chain genes.6 Recombination activating gene enzymes cut and splice variable region fragments, thereby creating a sequence that translates a unique protein confirmation at the receptor interface. This process takes place within the thymus where developing progenitor T cells

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CHAPTER 26

Immunotherapy With Radiotherapy

439

A

B T-Cell Activation

C

Fig. 26.1 T-cell Development and Activation. (A) The thymus contains a network of cortical and medullary epithelial cells that guide the maturation of developing thymocytes. Positive selection in the cortex promotes survival of clones with T-cell receptors (TCRs) that recognize novel major histocompatibility complex (MHC):peptide complexes. Negative selection is mediated by medullary epithelial cells and dendritic cells that present host antigens and trigger apoptosis of clones with TCRs that recognize self-peptides. (B) In the periphery, immature antigen-present cells (APCs) present peptides from the surrounding milieu without costimulation. Engagement of naïve T cells in this manner promotes anergy and helps maintain peripheral tolerance in the absence of danger signals by limiting spontaneous immunity. (C) Danger signals, such as high mobility group box 1 (HMGB1) from dying cells, activate dendritic cells to express costimulatory molecules and proinflammatory cytokines. The combination of these signals with TCR stimulation potently activates naïve T cells. Following activation, naïve T cells differentiate into effector and memory subtypes. CD8+ T cells can recognize and lyse target cells displaying an antigenic MHC:peptide complex.

(known as thymocytes) generate a custom TCR that is subjected to positive and negative selection processes.7 Epithelial cells of the thymic cortex express a thymoproteasome that generates unique peptide epitopes for presentation by MHC.8 Clones with TCRs that are able to recognize one of these MHC complexes are positively selected to survive, having demonstrated functional competence. Subsequently, a crucial step of negative selection occurs in the medulla. Medullary thymic epithelial cells promiscuously express tissue-restricted proteins and, together with dendritic cells, present an array of epitopes representative of the host’s own (self) protein

milieu (Fig. 26.1A).9 Thymocytes expressing TCRs that bind with high affinity to one of these self-antigen MHC peptide complexes are induced to undergo apoptosis, thus removing potentially autoreactive clones from the functional repertoire. Thymocytes surviving negative selection are ultimately released from the thymus into the peripheral circulation. In accordance with the SNS paradigm, positive and negative selection sculpt the T-cell repertoire down to the 1% to 5% of thymocytes from the original pool that are able to recognize host MHC:peptide complexes and are not predisposed to elicit autoimmunity against the host.

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T-Cell Activation and Regulation Following release from the thymus and prior to their first antigenic encounter, T-cell clones maintain a “naive” phenotype. The context surrounding their initial TCR stimulation is critical for their function and fate. TCR engagement without costimulation has a tolerizing effect and induces T-cell anergy, which stifles proliferation and IL-2 secretion (Fig. 26.1B).10 According to the Danger Model, immune responses are triggered by inducible alarm signals from distressed or injured cells. The toll-like receptors (TLRs) comprise a major family of innate danger sensors for APCs, and TLR binding can stimulate their maturation. Professional APCs, such as dendritic cells (DCs), that have been matured by environmental danger stimuli upregulate expression of B7-1 and B7-2 and provide costimulation by engaging CD28 on naïve T cells.11 A combination of Signal 1 from TCR stimulation and Signal 2 from costimulation induces changes in the naïve T cell. The TCR signaling machinery is reorganized for more sensitive responses to future antigen encounters, and CD25 is expressed to facilitate large-scale proliferation in response to IL-2. The activated T cell is thus equipped to leave the draining lymph node, proliferate into effector and memory progeny, and effectively attack antigenic targets in peripheral tissues (Fig. 26.1C). Dendritic cell maturation turns on essential processes for T-cell priming such as phagocytosis of dead cells, antigen presentation, and secretion of stimulatory cytokines.12 In the tumor microenvironment, danger-associated molecular patterns (DAMPs), which will be discussed in detail later, can activate TLRs on DCs to induce their maturation. A subset of basic leucine zipper ATF-like transcription factor 3 (BAFT-3)-dependent CD103+ DCs have demonstrated high efficiency for endocytosing tumor cell debris and subcellular vesicles, such as exosomes, and transporting these cargo from tumors to draining lymph nodes.13 The DCs then process tumor antigens for cross-presentation on MHC class I molecules and efficient prime antitumor T cells. For DCs to be mobilized effectively to prime antitumor T cells, it is critical that sufficient DAMP signals are present within the tumor microenvironment. The immune system relies on multiple programmed regulatory signals to prevent overactive T-cell responses in order to maintain tissue homeostasis. Checkpoint molecules are a class of receptors and ligands that modulate the duration and strength of T-cell activation. In vivo models have characterized the role of two prominent targets for immunotherapy, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is expressed at elevated levels on the T-cell plasma membrane after MHC:peptide stimulation of the TCR. Whereas CD80 and CD86 on APCs provide costimulation to T cells by binding CD28, they can also bind CTLA-4 to transmit regulatory signals. This signal diminishes the amplitude of response in early stages of T-cell activation. Also, T regulatory cells (Tregs), an immunosuppressive CD4+ T-cell population, utilize CTLA-4 to remove functional molecules from the surface of DCs. Mice with a genetic knockout of the CTLA-4 gene develop a fatal syndrome of generalized autoimmunity mediated by widespread T-cell activation, which illustrates the potent regulatory contribution of this signal in immune homeostasis. PD-1 expression increases on T cells following activation and plays a role in regulating their involvement in tissue inflammation and autoimmunity. Its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), are expressed on cancer cells and suppressive immune cells. PD-1 signaling inhibits kinases involved in T-cell activation and leads to an “exhausted” T-cell phenotype characterized by limited activity or apoptosis. As with CTLA-4 deficiency, PD-1 knockout mice develop tissuespecific autoimmunity, although not as severe. Collectively, the checkpoint molecules provide a counterbalance to immune activation and help protect the host against autoimmunity. Likewise, they are also exploited in the tumor microenvironment as a means to suppress antitumor immunity.

Tumor Immunosurveillance and Tumor-Associated Antigens The tumor immunosurveillance model postulates that the immune system detects and eliminates most neoplastic cells before they form tumors. In this paradigm, genetic and cellular alterations that arise in malignant cells are recognized and attacked when antigenic peptides are presented to circulating T cells. For tumors that escape such surveillance, identification of viable antigens represents a potential therapeutic target. Gubin et al.14 classified three primary categories of tumor antigens: tumor-associated antigens, cancer/germline testis antigens, and tumorspecific antigens. Tumor-associated antigens include functional or differentiation molecules that may be expressed at aberrant levels, such as pigment-related proteins in melanoma (MART-1 and GP100) and HER2/neu in breast cancer. Germline antigens, such as MAGE-A and NY-ESO-1, are normally restricted to gonadal tissue, so their presentation in peripheral tumor cells can be detected as antigenic. Finally, tumorspecific antigens are nonsynonymous gene mutations that generate novel protein epitopes completely unique from the self milieu. With whole genome sequencing and mass spectroscopy data incorporated into informatics algorithms, new methods are emerging to predict which of these “neoantigens” will be recognized by T cells. Such approaches have been validated with studies identifying epitope-specific clones among tumor-infiltrating lymphocytes.15 Furthermore, incorporation of predicted neoantigens into peptide and RNA vaccines for cancer therapy has demonstrated measurable antitumor responses.16 In the clinical setting, tumors with a high mutational load, such as with defective mismatch repair, are more responsive to immunotherapies, presumably owing to their tendency to generate neoantigens. Further advances in interpreting the antigenic profile of individual patient tumors will inform future immunotherapy applications.

TUMOR IMMUNE ESCAPE Cancer Immunoediting Despite ongoing immunosurveillance targeting neoplastic cells, tumors are manifestly able to avoid rejection. Immune evasion is recognized as one of Hanahan and Weinberg’s hallmarks of cancer.17 Mittal et al.18 established a framework for how tumors ultimately bypass the host’s immune system consisting of three phases: Elimination, Equilibrium, and Escape. Malignant cells are recognized by T cells and eliminated owing to aberrant expression levels of specific antigenic proteins or the production of mutated neoantigens. However, through genetic instability and clonal selection, poorly immunogenic malignant clones survive to form small tumors that remain in equilibrium with the immune system; as cells continue to mutate and undergo clonal selection, the more immunogenic clones are eliminated and nonimmunogenic progeny persist. Sustained proliferation and selection enable the tumor ultimately to adapt to a favorable genotype/phenotype that avoids immune attack. Through this stepwise “cancer immunoediting” the tumor modifies its antigenic profile to become unrecognizable by αβ T cells. Immunoediting happens by genetic alterations, including deletion and promoter methylation, which serve to minimize expression of antigenic proteins or reduce presentation of MHC molecules by tumor cells. Ultimately, a critical mass of evolved, resistant cancer cells escapes immune surveillance and manifests as a clinically detectable cancer. A fundamental discovery in the field of immunoediting came from mouse models of chemically induced cancers. Tumor cells generated in hosts lacking T cells were more easily rejected when isolated and injected into wild-type mice than ones from immunocompetent hosts.19 This important finding supported the conclusion that the adaptive immune system ultimately selects for resistant cancer cell clones. The

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CHAPTER 26 practical implications of cancer immunoediting have also been observed clinically. A case study of a patient with a melanoma tumor expressing the well-characterized NY-ESO-1, MAGE-C1, and Melan-a antigens reported that treatment with NY-ESO-1 vaccination resulted in outgrowth of tumors that expressed MAGE-C1 and Melan-a but not NY-ESO-1. Furthermore, studies have shown that a range of tumor types have the ability to silence MHC class I expression, which is associated with adverse clinical outcomes. Loss of MHC molecule expression has been correlated with a reduction in disease-free interval and survival in head and neck squamous cell carcinoma, breast carcinoma, small cell lung carcinoma, bladder carcinoma, cervical carcinoma, and cutaneous melanoma.20 Overall, the cancer immunoediting model illustrates the dynamic interplay between developing tumors and the host immune system. Although many cancer cells are eliminated before becoming clinically apparent, neoplastic cells can evolve to resist surveillance.

Immunosuppressive Tumor Microenvironment In addition to tumor escape via immunoediting, cancers also actively suppress host immunity and thwart antitumor responses. The cumulative history of unsuccessful immunotherapy trials, including multiple vaccination studies, has demonstrated that even exogenous stimulation of the host immune system with tumor antigens often fails to reach a threshold to achieve therapeutic efficacy.21 Histologic evaluation shows that the tumor microenvironment is often populated by a variety of cell types, including stromal fibroblasts, myeloid lineage cells, and tumor-associated vascular endothelium (Fig. 26.2A). As a result of the selection process described above, tumor cells and fibroblasts evolve to generate an immunosuppressive profile that shares many parallels with an unhealed wound. They sustain this milieu by secreting cytokines, such as vascular endothelial growth factor (VEGF), chemokine ligand 2 (CCL2), granulocytemacrophage colony-stimulating factor (GM-CSF), G-CSF, and M-CSF. These factors promote recruitment of immature myeloid cells which differentiate into myeloid-derived suppressor cells (MDSCs) and macrophages within the tumor where they suppress APCs and T cells. A high frequency of polymorphonculear MDSCs in patients with cancer has been shown to correlate with radiographic progression and poor prognosis, which underscores their potent suppression of antitumor immunity. MDSCs produce reactive oxygen species, which suppress antigen-specific CD8+ T cells through downregulation of the TCR zeta chain and disruption of IL-2 receptor signaling. They also deplete nutrients, such as arginine, which attenuates the function of the TCR complex and limits proliferation of antigen-activated T cells. MDSCs, tumor-associated macrophages, and Tregs secrete IL-10 and TGF-β. IL-10 inhibits DC activation and downregulates expression of MHC class II and CD86 by macrophages. TGF-β activates and expands the intratumoral Treg population, promotes differentiation of naive CD4+ T cells to induced Tregs, and inhibits cytotoxic activity of CD8+ T cells. It also inhibits DC activation and skews macrophages toward a suppressor phenotype. DCs in the tumor microenvironment can upregulate indoleamine 2,3-dioxygenase, an enzyme that catabolizes available tryptophan to kynurenine products. Low tryptophan levels sensitize activated T cells to apoptosis, and kynurenines promote Treg cell differentiation. Tumor hypoxia promotes expression of hypoxia-inducible factor 1α (HIF1-α), which promotes tumor expression of PD-L1 and VEGF. The surrounding tumor stroma and vasculature can also aggressively suppress T cell activity. Cancer-associated fibroblasts are able to form a physical layer around the periphery of the tumor. Through production of a collagen matrix, they can physically block lymphocytes from accessing the tumor microenvironment. Increased levels of HIF1-α and associated VEGF expression increase tumor vascularization and promote endothelial cell expression of Fas ligand. As a result, approaching T cells that attempt to cross the endothelial wall are induced to undergo apoptosis, which

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preempts their entry into the tumor. Overall, an extensive network of cells and signals supports tumor growth and creates a significant barrier to adaptive antitumor T-cell responses.

RADIATION AS AN IMMUNE ADJUVANT Classic radiobiology attributes the therapeutic efficacy of radiation to cytocidal DNA damage imparted directly to tumor cells. Cells that have accumulated a lethal damage load commonly undergo mitotic death, which occurs as they attempt to divide in the mitotic phase of the cell cycle. Without appropriate repair and checkpoint processes in place to ensure that chromosomes are intact for spindle alignment, the process is aborted, and cell death often follows. Radiation can also neutralize tumor cells through other mechanisms such as apoptosis and senescence.22 Survival measurements, such as clonogenic assays, model the therapeutic efficacy of different dose and fractionation combinations. Clinical radiotherapy dose and fractionation regimens are designed with the objective of achieving a high kill percentage within the tumor while sufficiently sparing surrounding normal tissue. However, more recent data have elucidated how radiation also has a transformative impact on the tumor immune microenvironment. Experimental mouse models have demonstrated in vivo that ionizing radiation can stimulate antitumor immune rejection in a synergistic fashion, when administered with immunomodulatory drugs. The formation of DNA strand breaks and induction of tumor cell death by radiation also imparts signals that activate innate immune receptors and promote T-cell activation. These phenomena, which will be described below, explain how radiation stimulates tumor immunity and why it can be a useful adjuvant in combinatorial approaches with immunotherapy.

Immunogenic Cell Death For radiation to enhance immunosurveillance of tumors, how target cells die is just as consequential as how many die. Kroemer et al. discovered that some cell death processes cause release of DAMPS, which signals the immune system to recognize danger and mount an adaptive T-cell response against antigens from the dying cells. Cell death in this manner is categorized as “immunogenic cell death” (ICD).23 ICD has important implications for selecting treatment modalities aimed at promoting antitumor immunity. A fundamental approach to assess the propensity of therapeutic agents to induce ICD in tumors entails vaccination and rechallenge: tumor cells are treated in vitro with a test treatment, then injected into mice. After sufficient time for immune priming, the host is rechallenged with live tumor cells of the same line. Failure of tumor engraftment after rechallenge is evidence of antitumor immunity. It can be inferred that the test treatment used on the initially injected cells induced ICD and the dead tumor cells primed an adaptive immune response in the mouse. Although performing vaccination/ rechallenge is useful for assessing bona fide ICD, measuring characteristic biomarkers offers a simpler approach. Three important DAMPs have been conventionally associated with cells undergoing ICD24: 1. Calreticulin, an endoplasmic reticulum protein, is exposed on the cell surface. Translocation of calreticulin is associated with endoplasmic reticulum stress, and it signals CD91 on DCs and macrophages to phagocytose the dying cell.25 2. HGMB1, a nonhistone chromatin binding factor, is passively released and binds to TLR4 on DCs, which promotes maturation with expression of costimulatory molecules, endocytic activity, and cross-presentation of exogenous antigens.26 3. Adenosine triphosphate (ATP) is secreted that recruits APCs and promotes IL-1β release by DCs, which stimulates antigen cross-presentation. Collectively, the ICD DAMPs trigger recruitment and activation of APCs, phagocytosis of dead tumor cells, and effective processing and cross-presentation of antigens to prime antitumor T cells.

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A

B Fig. 26.2 Tumor Microenvironment. (A) Tumors can foster an immunosuppressive microenvironment by secreting anti-inflammatory cytokines, such as IL-10 and tumor growth factor-β (TGF-β), and recruiting regulatory cells with chemokines, such as CCL22. Myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) suppress T effector cells. Dendritic cells (DCs) can secrete metabolic byproducts that also suppress T effector cells. Tumor-associated fibroblasts create a collagen matrix that blocks T cell entry into the tumor. Also, tumor endothelial cells can express Fas-L, which induces apoptosis of approaching T cells. (B) Tumor radiation induces immunogenic cell death, which enhances immune activation in the local microenvironment. Endoplasmic reticulum stress leads to external calreticulin exposure on injured cells. Antigen-presenting cells (APCs) recognize calreticulin via CD91 and internalize dying cells. Dying cells also release high mobility group box 1 (HMGB1), which binds TLR4 and matures APCs effectively to cross-present antigens and costimulate effector T cells. Secreted adenosine triphosphate (ATP) recruits APCs and activates the inflammasome, which promotes antigen cross-presentation. Type I interferon is produced following cGas-STING signaling, which promotes DC activation and cross-presentation. Chemokines secreted by radiated tumors can recruit effector T cells and myeloid-derived suppressor cells (MDSCs). Upregulation of vascular cell adhesion molecule (VCAM) by the tumor vasculature facilitates T-cell entry. MHC, major histocompatibility complex; VEGF, vascular endothelial growth factor.

Elucidation of ICD has generated interest in categorizing antineoplastic therapies according to their ability to elicit immune responses. In vitro and in vivo studies of several types of chemotherapy have found that anthracyclines, oxaliplatin, and cylcophosphamide cause ICD of tumor cells.27 Importantly, radiation therapy has also been shown to

promote ICD. Early evidence of this came from vaccination/rechallenge assays where immunocompetent mice were injected with lethally irradiated tumor cells. The mice were able to reject a subsequent tumor challenge, thus illustrating a vaccination effect from the initial exposure. Notably, this finding was not observed in immunodeficient mice, further

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CHAPTER 26 substantiating a causal role of host immunity in the response to radiated tumor cells. Golden et al.28 demonstrated that radiation of tumor cells generates ICD-associated DAMPs with the release of ATP and high mobility group box 1 as well as surface translocation of calreticulin in a dose-dependent manner.28 Thus radiation is able to elicit key danger signals that promote immune priming.

MHC Presentation and Type I Interferon Expression Radiation of tumors also enhances their presentation of MHC:peptide molecules. Reits et al.29 demonstrated that treatment of human melanoma cell lines with radiation in vitro upregulated surface expression of MHC class I molecules in a dose-dependent manner. A similar effect was also observed for in vivo radiation of normal tissues.29 Newcomb et al.30 confirmed these findings in the GL261 syngeneic murine glioma model by demonstrating that whole-brain radiotherapy upregulated MHC-I expression on tumors cells, enhancing the effectiveness of peripheral vaccination. Radiation also activates mammalian target of rapamycin, which increases degradation of proteins into peptides and increases synthesis of new proteins, leading to an expanded intracellular peptide pool. A related study showed that radiation of different types of human tumor cells increased expression of cancer-testis antigens known to be immunogenic, such as MAGE-A1 and NY-ESO-1, with corresponding activation of specific T cells. Thus, radiation promotes T-cell recognition of tumors by enhancing antigenic display. Importantly, radiotherapy also stimulates a type I interferon response. When tumor cells sustain double-strand DNA breaks and then progress through mitosis, they generate micronuclei containing chromosome fragments. These micronuclei activate the intrinsic cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway leading to inflammatory gene expression.31 The expression of IFN-β resulting from this process plays a key role in activating DCs to cross prime CD8+ T cells and promote adaptive antitumor responses.32 Combination treatment with immunotherapy and tumor radiation relies on IFN-β recruitment and activation of BATF-3–dependent DCs to achieve systemic tumor regression successfully. Studies in a mouse breast cancer model incorporating CTLA-4 blockade with radiation demonstrated that tumor doses above 12 to 15 Gy per fraction yielded diminishing antitumor immunity. The higher doses of radiation upregulated Trex1, a nuclease, which digested cytosolic DNA and attenuated IFN-β induction.33 These findings show that radiation dose may need to be calibrated for protocols incorporating immunotherapy to optimize type I interferon production.

Radiation Induces Targetable Regulatory Signals Although radiation therapy generates immunogenic signals within the tumor microenvironment, its downstream pathways promote some of the previously described immunoregulatory processes exploited by tumors. HIF1-α upregulation, transforming growth factor-β (TGF-β) secretion, and recruitment and activation of Tregs, MDSCs, and macrophages are all enhanced by tumor radiation. Research efforts have explored strategies to tip the balance by employing combinatorial therapy using radiation together with immunomodulatory drugs. An early preclinical model utilizing this approach incorporated the Flt-3 ligand, which stimulates DC proliferation, to generate more APCs capable of cross-presenting tumor antigens. Mice challenged with footpad injection of Lewis Lung carcinoma were treated with leg radiation, Flt-3 ligand alone, or a combination of both therapies.34 Monotherapy resulted in limited survival owing to lung metastases, whereas a combination of radiation therapy followed by Flt-3 ligand injection demonstrated reduced pulmonary metastases and increased overall survival. This provided early evidence of a synergistic immune response with clinical benefit. Going further, Demaria et al.35 demonstrated a bona fide abscopal

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response with this approach. Using mice with bilateral flank tumors of 67NR mammary carcinoma, they showed that radiation of a single tumor followed by Flt-3 ligand therapy limited the growth rate of the distant tumor.35 Moreover, the treatment effect was abrogated in nude mice (which lack mature αβ T cells), further substantiating the central role of immunity in this phenomenon. Blockade of immune regulatory signals has proven to be a useful adjunct with radiation. The underlying strategy is to exploit immunogenic stimuli radiation creates and simultaneously “release the brakes” of suppressive signals that are also generated. TGF-β is a potent immunosuppressive cytokine, and the active form of the molecule is increased by radiation. It suppresses cross-priming by APCs, diminishes activation of CD8+ T cells, and increases Treg cells. In a 4T1 breast cancer model, a combination of radiation and TGF-β blockade enhanced priming of antitumor CD8+ T cells, inhibited tumor growth and metastases, and improved survival of tumor challenged mice.36 A corresponding randomized prospective trial examined this approach for metastatic breast cancer. Patients were treated with three doses of 7.5 Gy of radiation to one lesion and randomized to either low- or high-dose anti-TGF-β antibody. Patients in the higher-dose cohort showed a boost in their memory CD8+ T-cell pool and improved survival.37 Targeting of suppressive signals induced by radiation also showed efficacy with the chemokine receptor 2 (CCR2) pathway. Radiation activation of cGas-STING increases production of chemokine ligands for CCR2, which promotes tumor recruitment of MDSCs. Tumor-challenged mice treated with radiation together with CCR2 blockade showed improved rates of CD8+ T-cellmediated tumor rejection compared with radiation alone.38 In summary, radiation has dual effects of inducing immunostimulatory and suppressive processes. Rational targeting of regulatory molecules together with radiation can effectively promote antitumor immune responses.

RADIATION AND IMMUNE CHECKPOINT INHIBITORS Immune Checkpoint Inhibition The success of checkpoint inhibitors in treating a variety of cancers has established immunotherapy as a mainstream modality in oncology. Clinical trials continue to expand applications for these molecules, with a current focus on metastatic and locally advanced malignancies. The idea of targeting CTLA-4 to achieve disinhibition of T cells and elicit antitumor immunity was initially investigated by Leach et al.39 They found that mice challenged with immunogenic tumors demonstrated significant enhancement of tumor rejection when CTLA-4 blockade was administered.39 A subsequent in vivo model of melanoma showed that CTLA-4 blockade improved tumor immunity by the combination of enhancing effector T-cell function and inhibiting Treg cell activity.40 Although the first studies using anti-CTLA4 therapy in immunogenic mouse tumor models showed striking therapeutic success, additional investigation with poorly immunogenic tumors, such as the melanoma line B16-BL6, showed minimal effect on tumor growth.41 However, combination treatment with anti-CTLA4 and an immunogenic vaccine of irradiated B16-BL6 cells genetically expressing the cytokine GM-CSF was able to achieve effective eradication of established tumors. These findings suggested that combining a checkpoint inhibitor with additional immunomodulation could be a viable strategy to improve responses against poorly immunogenic tumors. Following the success of anti-CTLA-4 therapy, the PD-1/PD-L1 checkpoint pathway emerged as another viable target for tumor immunotherapy. Whereas CTLA-4 is prominently involved in regulating the initial stage of T-cell priming and costimulation, expression of PD-L1 can be upregulated in a variety of human tumor types including carcinomas of lung, ovary, and colon as well as melanomas to suppress

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activated T cells.42 Additionally, MDSCs in the tumor microenvironment often express PD-L1.43 When PD-L1 binds PD-1 on effector T cells, it induces an exhausted phenotype and neutralizes cell activity. The ability of checkpoint inhibitors to revive effector T cells and promote antitumor responses represents a breakthrough in oncology. They now have indications for patients with advanced melanoma, NSCLC, and head and neck and urothelial cancers. However, despite these successes, a large proportion of patients do not achieve significant disease response with checkpoint blockade. Strategies to enhance the proportion of responders are warranted: radiation has shown promise.

Synergy of Immune Checkpoint Inhibitors and Radiation Radiation therapy has been associated with off-target tumor response (abscopal effect) in limited case reports since the 1950s. Patients treated with radiotherapy for melanoma, renal cell carcinoma, and lymphoma have demonstrated regression of distant site tumors with no clear underlying mechanism.44–46 The apparent systemic response generated by radiation in these instances can now be considered in the context of its impact on tumor immunity. As previously described, radiation conditions the tumor microenvironment and is able to elicit an in situ vaccination effect, which makes it a potent adjuvant for immunotherapy. Several preclinical models have reported the success of combinations of radiation with checkpoint inhibition.47 Demaria et al.48 showed that mice challenged with the poorly immunogenic breast carcinoma, 4T1, derived negligible benefit from treatment with either radiation or anti-CTLA-4 monotherapy. However, combined therapy of subcutaneous tumor radiation together with anti-CTLA-4 therapy achieved a significant improvement in survival and a reduction in lung metastases.48 Synergy of radiation with checkpoint inhibition has been demonstrated with both CTLA-4 and PD-1 in several additional tumor models as well as diverse anatomic sites. For example, in mice with intracranial glioma, combination of a PD-1 inhibitor and tumor radiation of 10 Gy in a single fraction achieved significant improvement in survival compared with either therapy alone.49 In a landmark study, Twyman-Saint et al.50 evaluated a combination of dual checkpoint inhibition (anti-PD1 and anti-CTLA4) with radiation for the treatment of murine B16 melanoma and demonstrated superior efficacy with all three therapies combined because they contributed non-redundant and complementary immune stimulation. Radiation therapy increased the diversity of the antitumor TCR repertoire. Blocking CTLA-4 decreased Tregs, whereas blocking PD-L1 reinvigorated exhausted CD8+ T cells; thus combined checkpoint inhibition increased the CD8/Treg cell ratio.50 Furthermore, Rudqvist et al.51 reported that combination treatment of tumor-challenged mice with radiation and anti-CTLA-4 synergized to broaden the TCR repertoire. Analysis of tumor infiltrating lymphocytes showed an increase in the number and diversity of CDR3 motifs.51 Together, these preclinical findings have established a foundation for treating tumors with combinations of radiation and checkpoint inhibitors (Fig. 26.3). The promising results from preclinical studies have propelled new trials investigating the efficacy of combinatorial regimens with radiation and immunotherapy. Most of the findings at present include anecdotal case reports and small cohort studies. One prominent case report described a patient with melanoma with systemic disease progression after an initial response to ipilimumab. Palliative radiation of 28.5 Gy in three fractions was prescribed for a paraspinal metastasis. The lesion responded, and within three months, distant hilar lymphadenopathy and multiple splenic lesions regressed, leaving the patient with minimal disease.52 Similar instances of abscopal effects have been noted in other cases of melanoma as well as NSCLC treated with ipilimumab.53 Two patients were reported from a Phase II study treating advanced Merkel cell carcinoma with pembrolizumab. Following disease progression, they received a course of palliative radiation and subsequently demonstrated

marked tumor regression outside of the treatment field.54 Additionally, Twyman-Saint et al.50 conducted a Phase I clinical trial treating 22 patients with melanoma with multiple metastases with hypofractionated radiation (two to three fractions) to a single lesion followed by four cycles of ipilimumab. Evaluation of the nonirradiated lesions per RECIST criteria showed 18% of patients experienced a partial response, 18% had stable disease, and 64% had progressive disease. With just more than one-third of patients showing significant clinical response, the study highlighted significant room for improvement with this approach, including the possibility of adding dual checkpoint blockade or modifying the dose and fractionation of radiotherapy. As new trials mature, fundamental questions remain regarding how most effectively to prescribe radiation in combination with immunotherapy.50

Dose, Fractionation and Sequencing Preclinical studies have demonstrated antitumor synergy with the combination of radiation and immunotherapy, but several treatment parameters are undefined. Optimal dose and fractionation comprise a central question. Many of the previously described case reports administered a hypofractionated course, yet no standard prescription has been adopted. Data from preclinical studies also favor hypofractionation, although the utility of ablative doses is less clear. For B16 melanoma, a single ablative dose of 20 Gy induced a CD8+ T cell-mediated antitumor response that was lost in a comparison cohort receiving 5 Gy times four daily fractions.55 However, Vanpouille-Box’s TSA breast carcinoma model combining radiation with anti-CTLA4 showed that a course of 8 Gy times three daily fractions yielded better systemic antitumor rejection and survival outcomes compared with 20 Gy in a single fraction. Fractional doses exceeding 12 Gy attenuated the type I interferon response, which limited dendritic cell cross-presentation.33 To this end, early-phase clinical trials are utilizing different radiation dose levels in combinatorial protocols. A Phase I trial conducted by Luke et al.56 enrolled patients with progressive, metastatic solid tumors treated with pembrolizumab combined with SBRT doses ranging from 30 to 50 Gy. The trial demonstrated the feasibility of this approach with a favorable toxicity profile. However, the objective response rate was limited to 13.2%, comparable to that of prembrolizumab alone in a similar unselected cohort of metastatic patients, with a median progression-free survival of 3.1 months.56 Alternatively, a preliminary Phase II report from the Netherlands Cancer Institute used a subablative radiation dose for patients with metastatic NSCLC who had already failed first-line therapy. Patients were randomized to pembrolizumab alone or pembrolizumab in conjunction with upfront radiation of a single metastatic lesion to a dose of 8 Gy times three daily fractions. In the control arm, 19% of patients achieved an objective response compared with 41% in the combined treatment arm with. Median progression-free survival was 1.8 versus 6.4 months, respectively.57 These preliminary clinical results suggest superior efficacy when pembrolizumab is combined with a subablative radiotherapy, possibly owing to fractional doses that do not induce three prime repair exonuclease 1. Additional parameters being examined include how best to sequence radiation with immunotherapy. Preclinical data have shown that when combining anti-CTLA-4 with radiation, upfront checkpoint blockade achieves the greatest tumor treatment efficacy. This approach depletes Tregs, which allows maximum CD8+ T-cell priming when radiation is delivered.58 Clinical studies generally support overlapping or close sequencing of radiation and checkpoint blockade. Patients with melanoma brain metastases treated with anti-PDL1 and anti-CTLA4 followed by stereotatic radiosurgery had greater median reduction in lesion volume if radiation was administered within four weeks of immunotherapy.59 Also, an analysis of the Phase III Pacific trial suggests that patients who received chemoradiation followed by immunotherapy had improved progression free survival if

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CHAPTER 26

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Fig. 26.3 Anti-CTLA-4 and anti-PD-1 immunotherapy activate non-redundant mechanisms that promote clonal expansion of T cells and revive exhausted effector cells. Tumor radiation enhances major histocompatibility complex (MHC) antigen presentation and increases the diversity of the antitumor T-cell repertoire. Clinical trials are exploring optimal paradigms for combining immunotherapy with tumor radiation to synergistically activate and expand antitumor T cells that mediate systemic tumor rejection. DC, Dendritic cell; TCR, T-cell receptor.

durvalumab was given within two weeks versus a longer interval.60 As more trials are reported, the relative success of various dose and fractionation schemes, as well as optimal timing for checkpoint inhibitors, will become clearer.

Circulating Lymphocytes as an Organ at Risk When using radiation as an adjuvant with immunotherapy, its impact on the host T-cell pool is highly relevant to treatment response. Preclinical studies have evaluated the impact of including tumor-draining lymph nodes in the target field. Marciscano et al.61 challenged mice with flank tumors and treated them with 12 Gy combined with either CTLA-4 or PD-1 checkpoint inhibition. The mice were divided into two radiation target groups: tumor alone versus tumor and draining lymph nodes. They

showed that adding nodal irradiation diminished immune infiltration of tumors and adversely affected survival.61 Peripheral blood circulating through the tumor target is also affected by radiation, and lymphocytes are sensitive, with a D50 of approximately 2 Gy. Fractionated radiation courses protracted over several weeks generally induce some degree of lymphopenia, such as in patients with glioblastoma treated with a six-week course to an often sizable brain volume. Yovino et al.62 developed a model to investigate radiation dose to circulating lymphocytes. A single fraction was calculated to deliver 0.5 Gy to 5% of circulating cells, whereas a 30-fraction course delivered 0.5 Gy or more to 99% of circulating blood. These findings support lymph node sparing and hypofractionated (versus protracted) radiation courses as crucial objectives to protect the host lymphocyte pool when attempting to stimulate antitumor immune responses.

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SUMMARY Immunotherapy is transforming the practice of oncology and creating new treatment paradigms. The utility of radiotherapy as an adjuvant with immunotherapy is being evaluated based on its conditioning effect on the tumor microenvironment. Preclinical models have demonstrated how tumor radiation releases danger signals that foster creation of an in situ vaccine. Tipping the balance by adding immunomodulators, such as checkpoint inhibitors, can create a synergistic effect that promotes therapeutic antitumor T-cell responses. The results of ongoing clinical trials will measure the translational success of this approach in patients. New data regarding dose, timing, and targeting are needed to establish optimal parameters for combinatorial protocols in order to standardize clinical trial design and successfully utilize these therapies in the clinic.

CRITICAL REFERENCES 1. Ribatti D. Peter Brian Medawar and the discovery of acquired immunological tolerance. Immunol Lett. 2015;167(2):63–66. 3. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566):301–305. 4. Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity. 2011;35(2):161–168. 5. Borst J, Ahrends T, Babala N, et al. CD4(+) T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18(10): 635–647. 12. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–680. 14. Gubin MM, Artyomov MN, Mardis ER, Schreiber RD. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest. 2015;125(9):3413–3421. 22. Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol. 2010;31(4):363–372. 27. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39(1):74–88. 28. Golden EB, Frances D, Pellicciotta I, et al. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014;3:e28518. 31. Harding SM, Benci JL, Irianto J, et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548(7668):466–470. 35. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58(3):862–870.

37. Formenti SC, Lee P, Adams S, et al. Focal irradiation and systemic TGFbeta blockade in metastatic breast cancer. Clin Cancer Res. 2018;24(11):2493–2504. 38. Liang H, Deng L, Hou Y, et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun. 2017;8(1):1736. 39. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–1736. 40. Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206(8):1717–1725. 47. Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 2015;1(9):1325–1332. 48. Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11(2 Pt 1): 728–734. 50. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–377. 51. Rudqvist NP, Pilones KA, Lhuillier C, et al. Radiotherapy and CTLA-4 blockade shape the TCR repertoire of tumor-infiltrating T cells. Cancer Immunol Res. 2018;6(2):139–150. 52. Postow MA, Callahan MK, Barker CA, et al. Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma. N Engl J Med. 2012; 366(10):925–931. 56. Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 2018;36(16):1611–1618. 57. Theelen W, Peulen H, Lalezari F, et al. Randomized phase II study of pembrolizumab after stereotactic body radiotherapy (SBRT) versus pembrolizumab alone in patients with advanced non-small cell lung cancer: The PEMBRO-RT study. Abstract presented at: ASCO Annual Meeting 2018; Chicago, IL. 58. Young KH, Baird JR, Savage T, et al. Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS ONE. 2016;11(6):e0157164. 59. Qian JM, Yu JB, Kluger HM, Chiang VL. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer. 2016;122(19):3051–3058. 61. Marciscano AE, Ghasemzadeh A, Nirschl TR, et al. Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy. Clin Cancer Res. 2018;24(20):5058–5071.

A full list of references can be found online at ExpertConsult.com.

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CHAPTER 26

REFERENCES 1. Ribatti D. Peter Brian Medawar and the discovery of acquired immunological tolerance. Immunol Lett. 2015;167(2):63–66. 2. Medzhitov R, Janeway CA Jr. Decoding the patterns of self and nonself by the innate immune system. Science. 2002;296(5566):298–300. 3. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566):301–305. 4. Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity. 2011;35(2):161–168. 5. Borst J, Ahrends T, Babala N, et al. CD4(+) T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18(10):635–647. 6. Robins HS, Campregher PV, Srivastava SK, et al. Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood. 2009;114(19):4099–4107. 7. Shah DK, Zuniga-Pflucker JC. An overview of the intrathymic intricacies of T cell development. J Immunol. 2014;192(9):4017–4023. 8. Sasaki K, Takada K, Ohte Y, et al. Thymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells. In. Nat Commun. 2015;6:7484. 9. Kondo K, Takada K, Takahama Y. Antigen processing and presentation in the thymus: implications for T cell repertoire selection. Curr Opin Immunol. 2017;46:53–57. 10. Appleman LJ, Boussiotis VA. T cell anergy and costimulation. Immunol Rev. 2003;192:161–180. 11. Lanzavecchia A, Sallusto F. Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells. Science. 2000;290(5489):92–97. 12. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–680. 13. Sanchez-Paulete AR, Teijeira A, Cueto FJ, et al. Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy. Ann Oncol. 2017;28(suppl_12):xii74. 14. Gubin MM, Artyomov MN, Mardis ER, Schreiber RD. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest. 2015;125(9):3413–3421. 15. Pasetto A, Gros A, Robbins PF, et al. Tumor- and neoantigen-reactive T-cell receptors can be identified based on their frequency in fresh tumor. Cancer Immunol Res. 2016;4(9):734–743. 16. Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547(7662):222–226. 17. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 18. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases–elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16–25. 19. Shankaran V, Ikeda H, Bruce AT, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410(6832):1107–1111. 20. Chang CC, Campoli M, Ferrone S. Classical and nonclassical HLA class I antigen and NK Cell-activating ligand changes in malignant cells: current challenges and future directions. Adv Cancer Res. 2005;93:189–234. 21. Rosenberg SA, Sherry RM, Morton KE, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigenspecific CD8+ T cells in patients with melanoma. J Immunol. 2005;175(9):6169–6176. 22. Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol. 2010;31(4):363–372. 23. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72. 24. Gebremeskel S, Johnston B. Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies. Oncotarget. 2015;6(39):41600–41619. 25. Wiersma VR, Michalak M, Abdullah TM, et al. Mechanisms of Translocation of ER Chaperones to the Cell Surface and Immunomodulatory Roles in Cancer and Autoimmunity. Front Oncol. 2015;5:7.

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26. Pathak SK, Skold AE, Mohanram V, et al. Activated apoptotic cells induce dendritic cell maturation via engagement of Toll-like receptor 4 (TLR4), dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)grabbing nonintegrin (DC-SIGN), and beta2 integrins. J Biol Chem. 2012;287(17):13731–13742. 27. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39(1):74–88. 28. Golden EB, Frances D, Pellicciotta I, et al. Radiation fosters dosedependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014;3:e28518. 29. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203(5):1259–1271. 30. Newcomb EW, Demaria S, Lukyanov Y, et al. The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas. Clin Cancer Res. 2006;12(15):4730–4737. 31. Harding SM, Benci JL, Irianto J, et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548(7668):466–470. 32. Deng L, Liang H, Xu M, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41(5):843–852. 33. Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. 34. Chakravarty PK, Alfieri A, Thomas EK, et al. Flt3-ligand administration after radiation therapy prolongs survival in a murine model of metastatic lung cancer. Cancer Res. 1999;59(24):6028–6032. 35. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58(3):862–870. 36. Vanpouille-Box C, Diamond JM, Pilones KA, et al. TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 2015;75(11):2232–2242. 37. Formenti SC, Lee P, Adams S, et al. Focal irradiation and systemic TGFbeta blockade in metastatic breast cancer. Clin Cancer Res. 2018;24(11):2493–2504. 38. Liang H, Deng L, Hou Y, et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun. 2017;8(1):1736. 39. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–1736. 40. Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206(8): 1717–1725. 41. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190(3):355–366. 42. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800. 43. Ballbach M, Dannert A, Singh A, et al. Expression of checkpoint molecules on myeloid-derived suppressor cells. Immunol Lett. 2017;192:1–6. 44. Kingsley DP. An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol. 1975;48(574):863–866. 45. Wersall PJ, Blomgren H, Pisa P, et al. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol. 2006;45:493–497. 46. Robin HI, AuBuchon J, Varanasi VR, Weinstein AB. The abscopal effect: demonstration in lymphomatous involvement of kidneys. Med Pediatr Oncol. 1981;9(5):473–476.

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47. Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 2015;1(9):1325–1332. 48. Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11(2 Pt 1): 728–734. 49. Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343–349. 50. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–377. 51. Rudqvist NP, Pilones KA, Lhuillier C, et al. Radiotherapy and CTLA-4 blockade shape the TCR repertoire of tumor-infiltrating T cells. Cancer Immunol Res. 2018;6(2):139–150. 52. Postow MA, Callahan MK, Barker CA, et al. Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma. N Engl J Med. 2012;366(10):925–931. 53. Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1(6):365–372. 54. Xu MJ, Wu S, Daud AI, et al. In-field and abscopal response after short-course radiation therapy in patients with metastatic Merkel cell carcinoma progressing on PD-1 checkpoint blockade: a case series. J Immunother Cancer. 2018;6(1):43. 55. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–595.

56. Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 2018;36(16):1611–1618. 57. Theelen W, Peulen H, Lalezari F, et al. Randomized phase II study of pembrolizumab after stereotactic body radiotherapy (SBRT) versus pembrolizumab alone in patients with advanced non-small cell lung cancer: The PEMBRO-RT study. Abstract presented at: ASCO Annual Meeting 2018; Chicago, IL. 58. Young KH, Baird JR, Savage T, et al. Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS One. 2016;11(6):e0157164. 59. Qian JM, Yu JB, Kluger HM, Chiang VL. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer. 2016;122(19): 3051–3058. 60. Wang Y, Deng W, Li N, et al. Combining immunotherapy and radiotherapy for cancer treatment: current challenges and future directions. Front Pharmacol. 2018;9:185. 61. Marciscano AE, Ghasemzadeh A, Nirschl TR, et al. Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy. Clin Cancer Res. 20182018;24(20):5058–5071. 62. Yovino S, Kleinberg L, Grossman SA, et al. The etiology of treatmentrelated lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest. 2013;31(2):140–144.

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27 Stereotactic Irradiation: CNS Tumors Christopher D. Abraham, Brian D. Kavanagh, and Jason P. Sheehan

The term radio-surgery was possibly first used in a medical context more than 90 years ago, when Dr. Francis Hernaman-Johnson described in a lecture to the Royal Society of Medicine an assortment of indications where x-ray therapy might be combined with surgery for benign and malignant indications. From the modern perspective, Dr. HernamanJohnson’s oration is quaint but wonderfully lyrical, at times invoking Biblical metaphors and Greek fables.1 Prophetically, though, he concluded with the message that “no human mind can compass the whole field of medicine. Hence the hope of the future lies in specialism [sic] tempered by co-operation.” Fast-forward to the mid-20th century, and with the loss of a hyphen along the way, the term radiosurgery was repurposed to describe the procedure now widely used as treatment for a variety of benign and malignant intracranial neoplasms as well as a few selected functional disorders. Applying principles of stereotactic surgery and harnessing the tissue- and tumor-ablative potential of ionizing radiation, the Swedish neurosurgeon Lars Leksell designed the first prototype unit for stereotactic radiosurgery (SRS), opening up new clinical opportunities and launching a Hernaman-Johnsonian interspecialty cooperation between neurosurgeons and radiation oncologists that continues to provide valuable clinical service to patients and new insights into tumor and normal tissue biology. In this chapter we review the distinct technical aspects of SRS, the current understanding of SRS radiobiology, and clinical outcomes after SRS for common indications.

DEFINITION AND TECHNICAL PRINCIPLES OF SRS In the half-century following Leksell’s pioneering work in SRS, numerous other investigators around the world made important contributions to the technical development of SRS. Whereas Leksell eventually settled on a design involving a hemispherical pattern of multiple cobalt-60 sources shielded and arranged so that their output gamma rays would converge on the target, in the 1980s and 1990s various linear acceleratorbased SRS platforms were also developed.2,3 Many of these newer commercially available systems are also capable of delivering other forms of radiotherapy, and there was a period when the commonly used terminology describing SRS and non-SRS forms of radiotherapy were somewhat loosely interchanged. Ultimately, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, and the American Society for Radiation Oncology (ASTRO) agreed that a uniform description of SRS was required to avoid confusion, and the consensus definition is as follows.4 SRS is a distinct discipline that uses externally generated ionizing radiation in certain cases to inactivate or eradicate a defined target or

targets in the head or spine without the need to make an incision. The target is defined by high-resolution stereotactic imaging. To assure quality of patient care, the procedure involves a multidisciplinary team consisting of a neurosurgeon, radiation oncologist, and medical physicist. SRS typically is performed in a single session, using a rigidly attached stereotactic guiding device, other immobilization technology, and/or a stereotactic image-guidance system, but can be performed in a limited number of sessions, up to a maximum of five. Technologies that are used to perform SRS include linear accelerators, particle beam accelerators and multisource cobalt-60 units. To enhance precision, various devices may incorporate robotics and real time imaging. Contained within this definition are references to several essential ingredients of SRS. The treatment is noninvasive and involves external radiation sources or beams. As it is also elaborated in other ASTRO statements concerning SRS,5 the adjective stereotactic implies that the target lesion is localized relative to a fixed three-dimensional spatial coordinate system, using either a rigid head frame or reliable internal fiducial markers (bony landmarks or implanted markers). And, most important, SRS is a multidisciplinary endeavor in which the quality of patient care is of paramount importance. Appropriate patient selection, treatment delivery, and follow-up care including complication management is best accomplished by a multidisciplinary team. Regarding the issue of patient safety, in 2011, ASTRO issued a white paper concerning quality and safety considerations for SRS and the extracranial application of high dose-per-fraction irradiation, stereotactic body radiation therapy (SBRT).6 This report highlights structure and process elements that are essential for establishing and operating a clinical program with the proper recognition of the risks involved and attention to detail that maximizes the chance for successful treatment while minimizing the chance of error. As for any clinical activity involving radiation therapy, developing a culture of safety is crucial.7 Collegiality and a nonjudgmental atmosphere can contribute to an environment that fosters proactive recognition of ways to avoid systematic problems that might produce potentially harmful errors. In the context of SRS, mistakes can be magnified beyond what might be seen in conventionally fractionated radiotherapy treatments. That an entire treatment course is delivered in only a single or perhaps a few fractions means that a targeting inaccuracy greatly increases the odds of tumor progression via geographic miss. Furthermore, that each treatment involves a large amount of ionizing radiation dose deposition means that the risk of injury to normal tissue may be escalated beyond an acceptable range if the delivered dose hotspots drift into adjacent normal brain parenchyma rather than remain in the target volume. A thorough discussion of quality assurance methods in SRS is outside the scope of the present chapter. Among the high-priority

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tasks are accurate initial commissioning and periodic calibration of the treatment delivery technology, proper personnel training, and various patient-specific preparation routines.6 Common to all delivery technology for SRS is the use of multiple nonopposed radiation beams that converge on a target in the brain, thus avoiding a high dose to normal tissues in the entrance and exit paths of the beams while depositing an ablative dose within the target volume. The ideal treatment delivery plan achieves a high level of conformality, implying that the volume receiving the prescription dose closely approximates the target volume, thus minimizing the volume of normal tissue exposed to a high dose (Fig. 27.1). Unlike the case in some applications of conventionally fractionated radiation therapy, wherein dose homogeneity within the target volume is clinically valuable for cosmetic or other endpoints,8 for SRS it is generally advantageous to allow for a dose hotspot to be present within the target volume, both for the purpose of increasing the intensity of therapeutic effect and steepening the gradient of dose falloff into surrounding normal tissues in the brain. This latter goal in particular is often best achieved under the conditions whereby the beam’s-eye view of the tumor nearly surrounds the contour of the target itself, perhaps with even a “negative

margin” where the beam is slightly smaller than the target in cross section—effectively exploiting that the maximum slope of dose falloff outside the beam is generally at the midpoint of the lateral penumbra, a consideration also applicable in SBRT.9

THE RADIOBIOLOGY OF SRS Upon recall of the classic “4 Rs” of radiobiology, it is readily apparent that SRS involves considerations that depart from the traditional views of conventionally fractionated radiotherapy. For a single treatment course, the interfraction processes of repair, repopulation, redistribution, and reoxygenation are not relevant realities. Furthermore, for single or extremely hypofractionated regimens, the utility of the popular linearquadratic model of radiobiological potency has been challenged given the lack of agreement with some preclinical observations and emerging awareness of dose threshold effects that affect tumor and normal tissue responses via vasculature-related events. By the 1980s, SRS had become appreciated as a safe and effective therapy for arteriovenous malformations (AVMs),10,11 and efforts were initiated to understand the nature of the therapeutic histologic effect

A

B

C

D

Fig. 27.1 Example of a stereotactic radiosurgery treatment of a right parietal lesion to a prescription dose of 20 Gy, illustrating good conformality. The target is outlined in red and shaded in pink. The 20-Gy prescription isodose volume is outlined in yellow and is shown on (A) axial, (B) sagittal, and (C) coronal planes through the center of the lesion, in all views tightly surrounding the target. The treatment was delivered on a linear accelerator; (D) is a coronal view showing the angles through which the arcs passed (yellow lines). The beam angles were achieved by table rotations. A separately treated left-sided lesion is also seen in red in that panel, and several normal tissue structures are also outlined.

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CHAPTER 27 on blood vessels in particular. Interestingly, a wide variety of animal models (e.g., goat, baboon, cat) of SRS have been used to study normal tissue effects.12–14 Some of these early reports included experimental single fraction doses on the order of 150 to 200 Gy, and thus their relevance to modern clinical practice, which frequently uses doses an order of magnitude smaller, is uncertain. However, using a dose more closely in line with current human clinical practice, Acker et al. at Duke University studied the pial vasculature in a rat using a window chamber model that allowed for repeated direct visual inspection of the in vivo microcirculation.15 The experimental setup at Duke included a 4-MV LINAC fitted with a 2.2-mm diameter collimator. Doses in the range of 15 to 30 Gy were administered in a single exposure, and serial observations were made to characterize the effect on blood flow, vessel density, and leukocyte-endothelial cell interactions. Acute reductions in vessel length density and blood flow were observed at 24 hours postirradiation and continued to become more pronounced 30 days after exposure, without a suggestion of dose dependence above the level of a 15-Gy dose. Notably foreshadowing a future area of intense focus by others, morphological changes that included extensive sections of endothelial cell loss were also observed within weeks after irradiation. The authors found this apparently apoptotic effect to be somewhat curious, speculating on its relationship to changes observed in white blood cell interactions with the vessel walls and hypothesizing that platelet-activating factor might play an important role. This possibility that the tumor vasculature is an important target of radiotherapy is not an especially modern concept and was suggested at least as long ago as 1930, when James Ewing commented that with regard to certain tumors whose cells were thought to be relatively radioresistant, “it seems to me highly probable that the influence is mainly upon the blood vessels, which eventually shrink and cut off the blood supply.”16 There was rather limited investigation into this topic specifically between that statement and the SRS-inspired work of the late 20th and early 21st centuries. Many of these studies are cataloged in a review by Park et al., who concluded that there appears to be a suggestion of a threshold effect occurring at a fraction size on the order of 10 Gy, above which there appears to be substantial vascular damage that contributes indirectly to a tumoricidal effect.17 Perhaps best exemplifying these studies, while also adding fundamental mechanistic insights, is the work of Garcia-Barros et al. from Memorial Sloan-Kettering Cancer Center.18 In the experiments reported in 2003, these investigators implanted MCA/129 fibrosarcomas and B16F1 melanomas into mice that were either genetically wild type or deficient in acid sphingomyelinase (ASMase), an enzyme needed for endothelial cell apoptosis. For both tumor cell types, host ASMase deficiency was associated with radioresistance as evidenced by significantly enhanced tumor growth delay after a single dose of 15 Gy. Confirmatory assays of endothelial apoptosis reported in the same paper demonstrated that the effect occurs acutely, peaking within 3 to 6 hours after exposure. Additionally, there is an apparent threshold dose for inducing endothelial apoptosis between 7 Gy, where essentially zero apoptosis was seen, and 11 Gy, where the percentage of apoptotic cells in ASMase wild type jumped up to approximately 20%. There was a continued increase in percentage of apoptotic endothelial cells up to approximately 60% with a dose of 25 Gy, the upper limit of dose evaluated in this study. As will be discussed, the profound vascular effects of SRS are also well-illustrated clinically by the frequently successful obliteration of complex intracranial AVMs when using single-fraction doses in the upper range of what was tested here preclinically. For fractionated radiotherapy, the most frequently applied mathematical model to relate radiation dose to expected tumor cell kill is the linear-quadratic (LQ) model, based on a formula that first appeared

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in Lea and Catcheside’s description of the relationship between radiation dose and incidence of chromosomal translocations, using a plant model.19 Although this model has been the most popular in recent decades and is discussed in Chapter 1, sometimes overlooked in the original publication by Lea and Catcheside is recognition that for high-dose exposure, there would in principle need to be a correction applied to the LQ model that accounted for a decaying effect when the dose is delivered over a prolonged interval, presumably related to what amounts to intrafractional repair as some radiation-induced single-stranded breaks recombine without translocation. Experimental data supporting this possibility in mammalian cells may be found in the work of Eley et al., who used a glioma cell line and modeled SRS-type dose effects, comparing radiosensitivity when the same 12-Gy dose was given either in a single brief exposure or else in a series of smaller exposures spread out over 1 hour.20 The intent was to simulate SRS treatments that might be delivered clinically using multiple beam angle and table position changes, effectively prolonging the time of dose delivery. The results revealed that the cells underwent detectable cell-cycle arrest at the G2/M after the first subfraction in intermittent exposure conditions and that this effect was associated with relative radioresistance, consistent with the Lea-Catcheside predictions. In view of the vascular threshold dose effects and possible intrafraction repair effects, among other differences from fractionated radiotherapy, an argument can be made that alternatives to the LQ model are needed.21 Indeed, numerous groups have proposed alternative models to characterize the relationship between radiation dose and tumor cell kill when doses in the realm used for SRS or SBRT are used. For example, Guerrero and Li proposed a modified LQ model based largely on the lethalpotentially lethal model of Curtis,22 except they proposed a new term, δ, to account for repair kinetics related to dose rate. In a model that combines elements of LQ formalism and a multitarget model, Park et al. at the University of Texas–Southwestern Medical Center have described a “universal survival curve” that involves a step function: LQ estimates apply below a certain dose per fraction, but above a transition dose, DT, there is a correction that effectively straightens the curve to maintain a linear relationship between dose and log cell kill above DT.23 The purpose of this construct is to match the true relationship between high-dose exposure and log cell kill, which tends to be overestimated by the LQ model. The universal survival curve model may be used to derive a convenient index of radiobiological potency, the single fraction equivalent dose (SFED), by which different SRS or SBRT regimens might be compared. When the dose per fraction, d, exceeds DT, SFED is calculated as follows: SFED = D − (n − 1)Dq where D is the total dose, D0 is the dose required to reduce the surviving fraction of cells to 37%, n is the total number of fractions, and Dq is the quasi-threshold dose of the multitarget model. The SFED metric has been demonstrated to describe a dose-control relationship for a variety of tumor types treated with SBRT.24,25 To gauge the true dose-related normal tissue toxicity risk in clinical settings, even the best predictive mathematical models are not a substitute for careful analyses of actual clinical data. The Quantitative estimates of Normal Tissue Effects in the Clinic (QUANTEC) project was sponsored jointly by the American Association of Physicists in Medicine and ASTRO. Medical physicists, radiobiologists, and radiation oncologists from across North America, Europe, and Asia participated. The group’s charge was to catalog, review, analyze, and summarize all published literature concerning the quantitative relationship between dose of ionizing radiation and injury to normal tissues, with the intent of identifying practical guidelines for normal tissue dose constraints based not on

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Techniques and Modalities

models but on actual patient observations. Of direct relevance to SRS are the QUANTEC reports on radiation effects in the brain, brainstem, and optic nerves and chiasm.26–28 In each case, there are acknowledged limitations concerning the quantitative data available for analysis; nevertheless, the QUANTEC papers do offer dose-volume parameters that are clinically useful in the design and evaluation of SRS treatment plans for individual patients. Largely influenced by the synthesis of numerous reports involving the treatment of AVMs and subsequent risk of radionecrosis, the authors of the QUANTEC brain paper concluded that toxicity increases rapidly once the volume of the brain exposed to >12 Gy is >5 cm3 to 10 cm3.26 An added caveat is that eloquent areas of the brain such as the brainstem or corpus callosum require extra caution. The QUANTEC brainstem summary is mainly concerned with tolerance to fractionated radiotherapy, given the larger number of studies available for that setting relative to the setting of brainstem SRS and, in particular, the paucity of long-term reports after SRS to brainstem metastases.27 One clinical indication for SRS in which long-term follow-up is typically available is for the treatment of acoustic schwannomas, a benign condition with negligible risk of mortality to the patient. Here, the dose to the brainstem is primarily just a glancing focus of scattered dose away from the actual target; a maximum point dose of less than 12.5 Gy is associated with a low risk of new cranial neuropathy in that setting. Regarding injury to the optic nerves or chiasm, the QUANTEC reviewers found that the risk of radiation-induced optic neuropathy in the more modern context of magnetic resonance imaging–aided planning is low, with a maximum point dose of ≤12 Gy to the optic apparatus.28 Fig. 27.2 provides an illustration of a patient treated with SRS where the tumor approached the chiasm, necessitating caution with the optic chiasm dose.

CLINICAL OUTCOMES In Leksell’s report describing the first 762 cases treated with SRS at the Karolinska Institute, the three most common diagnoses were AVMs, Cushing disease, and acoustic neuromas.29 No brain metastases were treated, and a large percentage of the cases were functional disorders such as trigeminal neuralgia, intractable pain elsewhere in the body, or pituitary tumors. Nowadays, the most common indication for SRS is brain metastases. Although many of the diagnoses treated in the early years by Leksell are still managed by SRS today, others such as Parkinson disease, anxiety, or obsessive-compulsive disorder are more frequently managed with other interventions.

Pituitary Tumors It is difficult to summarize the full spectrum of literature on SRS, primarily because there have been so many papers involving so many patients. In an encyclopedic review of recent series, Sheehan et al. identified 25 separate reports published between 2002 and 2013 concerning SRS for nonfunctioning pituitary tumors alone.30 A representative series, which is also the largest published experience, would be the multicenter retrospective study of the North American Gamma Knife Consortium.31 Among 512 patients with nonfunctional pituitary adenomas, 94% had prior resection and 7% had prior fractionated radiotherapy, and the median age at the time of SRS was 53 years. Most patients had some degree of baseline pre-SRS hypopituitarism. The median SRS dose to the tumor margin was 16 Gy. The actuarial rate of tumor control, assessed radiographically, was 95% and 85% at 5 and 10 years post-SRS, respectively. New or worsened hypopituitarism after SRS was noted in 21% of patients, most commonly manifest as thyroid or cortisol deficiencies. Prior fractionated radiotherapy and higher tumor dose were associated with a higher risk of endocrinopathy.

Summary of Selected Recent Series of Stereotactic Radiosurgery for Cushing Disease or Acromegaly

TABLE 27.1

SRS FOR CUSHING DISEASE

No. Patients

Mean or Median Follow-Up, Mo

Mean or Median Margin Dose (Gy)

Endocrine Remission (%)

Castinetti60

40

54.7

29.5

42.5

Jagannathan61

90

45

23

54

Petit62

33

62

20

52

63

68

67.3

23

27.9

Sheehan64

82

31

24

54

Author and Reference

Wan

SRS FOR ACROMEGALY 61

Jagannathan

95

57

22

53

Losa65

83

69

21.5

60.2

Wan63

103

67.3

21.4

36.9

130

31

24

53

103

71

22.5

60.7

Sheehan Franzin66

64

Modified from Sheehan JP, Yen C-Y, Lee C-C, Loeffler JS. Cranial stereotactic radiosurgery: current status of the initial paradigm shifter. J Clin Oncol. 2014;32(26):2836–2846.

New or progressive cranial nerve deficits occurred in 70, age < 65 years, and controlled primary tumor) patients have a better median prognosis of 7 months. Class 2 (KPS < 70, age > 65 years, or uncontrolled primary tumor) patients have a median prognosis of 4 months. Class 3 (KPS < 70, age > 65 years, and uncontrolled primary tumor) patients have a median prognosis of 2 months. Other factors, such as histology of the tumor and number and size of metastases, are important in the initial evaluation. Treatment options are evolving and now include whole brain radiotherapy (WBRT), surgical resection, and radiosurgery (linear accelerator or gamma knife). Patients with a single brain metastasis in recursive partitioning analysis (RPA) Class 1 are treated aggressively with either surgical resection followed by SRS or WBRT or SRS alone. Multiple metastases from any RPA class may receive standard WBRT alone or SRS. Patients with up to three metastases in Class 1 or 2 usually are considered for local modality surgery or SRS. In some institutions, patients with 10 or greater metastases that are good candidates are treated with SRS or fractionated SRS.

Whole Brain Radiotherapy WBRT is the treatment of choice for many patients because of the high incidence of multiple metastatic brain sites.139,145,146 The goal of WBRT is to limit tumor progression; sterilize microscopic disease, preventing future brain metastasis147; and to limit corticosteroid dependency. Classically, WBRT is thought to have some response in around 50% of patients and is histology dependent, with small-cell and breast cancers being the most sensitive. Renal cell and melanoma histologies are thought to be the most resistant. A study by Nieder et al.148 reported that complete remission was observed in 37% of metastases from small-cell carcinoma, 35% of those from breast cancer, 25% of those from squamous cell carcinoma, and 14% of those from nonbreast adenocarcinoma. The rate was 52% for metastases < 0.5 cm3 and 0% for those > 10 cm3. Sneed et al.149 showed that WBRT for patients with unresected brain metastases results in symptomatic response in about 50% of patients and improvement in median survival from 3 to 6 months compared with historical controls. The optimal dose of radiation is unknown, but in clinical practice, the range is 20 Gy in 5 fractions over 1 week to 40 Gy in 20 fractions over 4 weeks.139 Complications of treatment include alopecia, transient worsening of neurological symptoms, and otitis. Continuing use of corticosteroids during WBRT may limit the incidence of most side effects. Long-term side effects—such as memory loss, dementia, and decreased concentration— are possible in survivors but are not expected to materialize in the majority of poor-prognosis patients. At our institutions, WBRT is becoming less commonly employed in patients with one to three metastatic lesions. Studies by Aoyama et al.147 and Chang et al.150 have shown that WBRT does not add to survival in this subset of patients and may even be detrimental compared with SRS alone, as shown in the study by Chang et al.150 The authors attributed this finding to patients treated with WBRT receiving less salvage treatment and less systemic therapy. In the Chang et al.150 study, there was a greater risk of significant decline in learning and memory function at 4 months in the SRS with WBRT group compared with SRS alone. Because of this association between WBRT and cognitive decline, RTOG 0933, a single-arm Phase II study, looked at hippocampal-sparing WBRT using IMRT technique compared with a historical control of WBRT without hippocampal avoidance. The dose received by the entirety of the hippocampus did not exceed 10 Gy, and the maximum dose did not exceed 17 Gy. The results showed that avoidance of the hippocampus during WBRT is associated with memory preservation at 4 and 6 months. Only 4.5% of patients had progression in the hippocampal-avoidance region.151 The preliminary results showing time to neurocognitive failure was significantly longer in favor of hippocampal avoidance-WBRT+memantine versus WBRT+memantine.151a The RTOG is accruing a study of hippocampal-sparing prophylactic cranial irradiation in patients with small-cell lung cancer. Further study is needed to define the role and optimization of WBRT and hippocampal-sparing WBRT in the modern era. Technique of WBRT. The patient undergoes simulation for palliative treatment and therefore should be conscious and cooperative. Agitated or unresponsive patients should be stabilized before this step to decrease the risk of injury. Simulation is done in a supine position with a headrest, and immobilization is achieved with a custom mask or at least tape between the forehead and table. CT simulation requires the use of a mask. Portal films with the gantry at 90 degrees and 270 degrees will give parallel-opposed lateral fields. The collimator should be rotated to allow the inferior border to parallel the base of the skull. The field borders

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CHAPTER 29

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Metastatic Disease: Bone, Spinal Cord, Brain, Liver, and Lung

TABLE 29.12

WBRT Alone or Plus Surgical Resection in the Management of Brain

Trial

Treatment

Radiotherapy Schedule

n

Biopsy + WBRT S + WBRT

36 Gy/12 36 Gy/12

23 25

4.2 10

< 0.01

Vecht et al.152

WBRT S + WBRT

40 Gy/10 bid 40 Gy/10 bid

31 32

6.5 10.8

NA

Mintz et al.153

WBRT S + WBRT

30 Gy/10 30 Gy/10

43 41

6.3 5.9

0.24

Metastases Patchell et al.

143

Median Survival (mo)

p Value

NA, Not applicable; S, surgery; WBRT, whole-brain radiotherapy.

should go beyond the skull anterior, superior, and posterior bony limits by 2 cm to allow dosimetric homogeneity. The inferior border can be set from the bony canthus to the C1 to C2 intervertebral space and should cover the base of skull with a 1-cm margin. CT simulation is now commonly used with the same parameter but allows for a customblock design to avoid irradiation of the lens and facial structures. All fields are treated daily. Megavoltage energy of 4 MV to 6 MV is used.

Surgical Resection The role of surgery has evolved over the past decade. Three randomized controlled trials comparing WBRT alone versus surgery plus WBRT in patients with a single brain metastasis have been published.143,152,153 Two demonstrated a survival advantage of the combined modalities over WBRT alone (Table 29.12). All three trials addressed the issue of single metastasis—the results cannot be extrapolated to multiple lesions. The negative results of Mintz contradict those of others, but this trial also contained a large crossover rate, poor KPS patients, lower complete surgical resection rate, and lower WBRT dose.153 These trials established the increased effectiveness of combination therapy of WBRT and surgical resection. Patchell et al.154 examined the effectiveness of postoperative WBRT after complete resection in patients with a single brain metastasis. They found that, although whole brain did not improve survival in this group of patients, it did improve local control at the site of resection, decreased the risk of general brain recurrence, and decreased the risk of dying from neurological causes. Patients who undergo surgical resection of a single brain metastasis have about a 50% risk of local recurrence at the surgical site within the next 6 months, with larger size of metastasis increasing the risk of local recurrence.154,155 SRS, SRT, and postoperative WBRT have all been shown to significantly reduce the risk of local failure postresection. In addition to local control, WBRT also reduces the risk of distant brain failure by about 40%.155 Postoperative SRS and SRT have become the more favored approach over postoperative standard WBRT due to studies demonstrating decreased neurocognitive decline with these approaches without a detriment to survival.156 Stereotactic techniques are dependent on accurate identification of the cavity and leptomeninges at risk, whereas local control with WBRT is less operator dependent and easily able to extensively cover postsurgical contaminated leptomeninges. Dose and fractionation of stereotactic radiation is tailored based on factors that balance the risk of radiation necrosis and local control. These factors include size of the cavity, location, and histology.

Radiosurgery Numerous papers have been published showing the efficacy of SRS with excellent survival and local control in patients with one to three brain metastases. SRS does not require WBRT154 to achieve excellent local control at the metastatic site, likely because of the penumbra

dose beyond the periphery of the metastatic lesion sterilizing microscopic disease. In our institution, surgical resection of a single brain metastasis is trending toward being reserved for symptomatic tumors resistant to steroid treatment, larger lesions more than 4 cm in which giving an ablative dose of radiation using a stereotactic technique would be deleterious, and establishing diagnosis of metastatic disease when indicated. Stereotactic radiosurgery is an accepted alternative to resection in patients with limited metastatic lesions that meet size criteria. SRS may be offered to patients with one to three brain metastases and 4 cm or less in size.157–172 RTOG 9508 study randomized 333 patients with 1 to 3 brain metastases to WBRT (37.5 Gy in 2.5-Gy fractions) versus WBRT plus SRS within 1 week of completing WBRT.161 All metastases were ≤ 4 cm, and only one metastasis could be > 3 cm. The dose was dependent on the lesion size based on the RTOG 9005 Phase I study 2: 24 Gy to lesions ≤ 2 cm, 18 Gy for lesions > 2 to ≤ 3 cm, and 15 Gy to lesions > 3 Gy to ≤ 4 cm. In both RTOG 9005 and RTOG 9508, the prescription dose covering the gross tumor was the 50% to 90% isodose line, equating to central doses of 1.1 to 2 times the prescription dose. The RTOG 9508 trial demonstrated a significant survival advantage with the use of SRS in patients with a single unresectable metastasis, with a median survival of 4.9 versus 6.5 months (p = 0.0393). The addition of SRS resulted in improved performance status and reduced extent of steroid use. The authors conclude that SRS should be used for patients with an unresectable solitary metastasis and considered for patients with one to three metastases. SRS alone (without WBRT) in patients with one to three unresectable brain metastases is an alternative approach that remains actively investigated.173,174 In retrospective studies, the 1-year local control rate is generally on the order of 80% to 95% with WBRT with SRS,158,163,165,167,168,170 versus 80% to 90% with SRS alone.165,170–172 At 2 years, local control is on the order of 80% to 85% versus 50% to 70%. Thus, WBRT does lower the risk of brain failure; the equivalence in survival likely reflects the need for more salvage therapy in the patients who underwent SRS only. In a study published by the University of Alabama (Birmingham, AL), the risk of new brain metastases in 100 patients treated with SRS alone was significantly correlated to the number of brain metastases: in patients with > 3 metastases, a hazard ratio (HR) of 3.3 (p = 0.004), poorly controlled extracranial disease (HR, 2.16; p = 0.04), and melanoma histology (p = 2.14, p = 0.02).175 Retrospective data suggest similar local control, overall survival, and neurological death with SRS alone versus resection with WBRT.176,177 Interestingly, in some series, the reported local control with SRS is greater than that after resection,178,179 probably reflecting the radiosurgical penumbra dose around the tumor periphery that treats microscopic disease.180

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Techniques and Modalities

A multi-institutional, pooled retrospective analysis examined 569 patients treated with SRS alone compared with SRS with WBRT.160 Among the patients treated with SRS alone, 37% underwent salvage therapy at a median of 5.7 months after SRS versus 7% after a median of 8 months following WBRT with SRS. This study did not differentiate between salvage for local failures and distant central nervous system (CNS) failures. Survival was not significantly different (~ 8-month median survival in both arms). In a randomized study from M. D. Anderson Cancer Center (MDACC; Houston, TX), 58 patients were randomized to receive SRS alone versus SRS plus WBRT.150 Patients treated with SRS alone had a significantly inferior 1-year tumor control (67% vs. 100%, p = 0.012) and distant brain tumor control (45% vs. 73%, p = 0.020) but had a significantly improved 1-year survival (63% vs. 21%, p = 0.003), with a > 2 HR of death from neurological as well as systemic causes. Postulated reasons for the improved survival of the SRS-only group is the earlier administration of systemic therapy and high rate of salvage therapy (87%) for brain metastases. Avoiding WBRT can potentially prevent acute and late toxicity from WBRT and allow WBRT to be used as salvage therapy if needed. During WBRT, patients acutely experience alopecia and may develop skin erythema and mild desquamation. Less commonly, otitis media may develop. More concerning is the late toxicity from WBRT, occurring months to years after radiation, which may be relevant in the population of patients with a solitary metastasis who have a potential for cure. Late toxicity includes cataract formation, dry eye, and neurocognitive defects, such as memory loss and dementia.181–183 The extent to which WBRT causes neurocognitive defects is not well reported.184 Neurocognitive decline may in part be because of the poor function of many patients who present with brain metastases and the general deterioration of patients whose cancer progresses.185,186 In the randomized study from Japan on SRS versus WBRT with SRS, there was not a significant difference in the posttreatment change in neurocognitive function between the two study groups, although those patients in the SRS-alone group experienced a more rapid decline in neurocognitive function, presumably as a consequence of brain failure (local failure or distant brain failure).187 Patients treated with WBRT experienced a continued decline in neurocognitive function, as a result of tumor recurrence or effects from WBRT. In the previously discussed trial from MDACC, Chang et al. employed the most sophisticated cognitive testing to date in a randomized trial. The trial was prematurely closed because of the significantly greater likelihood of decline in learning and memory function for patients undergoing WBRT with SRS versus SRS alone.

LIVER METASTASES Liver metastases are a common cause of morbidity and mortality. They can occur in patients with tumors of many common cancer types, are difficult to treat, and often lead to short survival periods. The liver is also protected from some cytotoxic agents because of its natural detoxification function and its relative hypoxic state. In contrast to the 80% perfusion of the normal liver by the portal venous system, most liver tumors obtain blood flow almost exclusively through the hepatic arterial system. This phenomenon necessitates novel interventional radiological techniques. Likewise, advances in imaging have allowed for more definitive anatomic localization of liver metastases, leading to new minimally or noninvasive treatments for these tumors.

Clinical Manifestations and Patient Evaluation Common symptoms of liver metastasis include nausea, vomiting, changes in bowel habits, distension, and bloating associated with ascites, jaundice, and pain as a result of distension of the liver capsule. Some patients experience petechia, night sweats, and weight loss.

Diagnosis Most liver metastases are discovered with routine metastatic surveys. Biphasic and triphasic helical CT is the optimal method for the detection of liver metastases. During the portal venous phase of the scan, the tumor is hypointense because of its dependence on hepatic arterial perfusion, while tumors can be enhanced on arterial-phase images. Approximately 90% of lesions greater than 1 cm are detected by portalphase images alone; approximately 10% more lesions are detected when the arterial images are used in combination.188 These imaging characteristics are also useful for distinguishing metastatic disease from many other benign small lesions commonly seen in the liver, including cysts and hemangiomas.189 An MRI can also help detect liver metastases and offer fine soft-tissue differentiation that may help describe anatomic involvement of the biliary tree and vasculature. However, MRIs are expensive and can have motion artifacts. They are generally employed when a patient has a contraindication to a contrast CT scan or when a CT is inconclusive. MRI can distinguish solid hepatic metastasis from fatty change, cysts, and hemangiomas. On T1-weighted images, hepatic metastases have low signal intensity, whereas on T2-weighted images, tumors have inhomogeneously high signal intensity. Other methods of tumor detection include ultrasound and incidental detection during procedures done for benign diagnoses.

Treatment Colorectal histology is the most common primary in patients with liver metastases. A small percentage of patients, less than 10%, with liver metastases are thought to be curative. Not being able to achieve oncological negative margins, the extent of liver involvement and extrahepatic disease remain considerations regarding the curative nature of patients with colorectal primary liver metastases. Most treatments for liver metastases are systemic. Liver metastasis can respond well to chemotherapy and hormone therapy, but most remissions are short lived. The response to these treatments can be mixed, with some tumors progressing while others subside. Aggressive local treatments for liver metastases can also provide substantial benefits. Although liver transplantation is not recommended, resection of lesions can lead to long-term survival, particularly among patients who respond to chemotherapy.190,191 Benefits for patients who respond to chemotherapy occur even among those who were initially unresectable because of nodes, number or location of lesions, or lesion size.191 Generally, resections are limited to patients with disease in a single lobe peripheral to the portal region. This limitation is also true for many other localized techniques, including radiofrequency ablation and cryotherapy. Chemoablation has arisen as an effective form of therapy. In this invasive radiological technique, the artery feeding the tumor is infused with chemotherapy, usually after an injection of contrast material defined by the tumor vasculature, followed by vascular ablation to trap the drug and asphyxiate the tumor.192–196 Chemoablation is suitable for patients with a limited number of tumors and for whom vascular access is possible.

Irradiation Technique and Doses Radiation techniques for liver metastases include whole-liver radiation, stereotactic liver radiation, and selective internal radiotherapy methods. Radiotherapy is often used to palliate liver-capsule pain and treat patients with chemotherapy-resistant disease. In addition, it can be used on patients with poor liver function who have an expected survival of more than 3 months. Whole-liver irradiation. Normal liver has poor tolerance to EBRT if the entire liver is irradiated, and clinical liver failure can arise from low to moderate doses of whole-liver radiation (20 to 30 Gy in 1.8- to 2-Gy fractions). Higher doses have not been shown to be superior to

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CHAPTER 29

Metastatic Disease: Bone, Spinal Cord, Brain, Liver, and Lung

lower doses. Care is taken to avoid exposure of the kidneys. Radiation has not had a significant role in the treatment of liver metastases in most institutions. It should be noted, however, that the risk for radiationinduced liver disease (RILD) is low if the whole liver dose is restricted to 30 Gy or less in fractions of 2 Gy or less. Liver radiation for metastatic disease can be of palliative benefit, as found in an RTOG Phase II trial of 100 patients in whom palliation of pain was noted in 55%.197 Survival for more than 6 months was significantly correlated with colorectal primary, good initial performance status, and lack of extrahepatic metastases. Median survival, however, even when these criteria are employed, is only 4 to 4.5 months.198 Addition of chemotherapy provides little if any additional benefit.199 Bydder used 5 Gy × 2 fractions and found improvement at 6 weeks in abdominal pain (63%), distention (30%), night sweats (63%), and nausea (44%).200 This abbreviated treatment provided results similar to those seen with more protracted courses and may be recommended for patients with poor performance status. Selective internal radiotherapy (SIRT). Liver metastases can be treated with one of several embolization techniques, in which microscopic spheres (microspheres) are administered via the liver’s arterial supply. Specific techniques include “bland embolization,” in which the microspheres are not embedded with cytotoxic agents; transarterial chemotherapy embolization (TACE), in which the microspheres are embedded with chemotherapeutic agents; and SIRT, in which the microspheres are embedded with radioactive Yttrium-90 (Y-90). It remains controversial as to which embolization technique is preferred for any given patient. Y-90–labeled microspheres have also been used in the treatment of hepatocellular carcinoma.201 Specifically, radioembolization is a highly conformal method of delivering radiation using the radioactive beta emitter, isotope Y-90 embedded in a glass or in resin microspheres. An interventional radiologist delivers these microspheres using the hepatic artery; the microsphere size allows it to become embedded in the tortuous vasculature of metastatic liver tumors. The high stopping power of the beta particle (maximum energy 2.28 MeV, average energy 0.94 MeV) allows for an average penetration range of about 2.5 mm in soft-tissue. SIR-Spheres (SIRTeX, Sydney, Australia), Y-90–labeled biocompatible resin microspheres (20 to 40 μm in diameter), are the only Y-90 radioembolization product approved in the United States for the treatment of unresectable liver metastases from primary colorectal cancer. A study from Northwestern University (Chicago, IL) investigated 137 patients who underwent 227 administrations of Y-90–labeled microspheres for chemotherapy refractory liver metastases.202 Of the patients, 59% had > 4 tumors. Most patients (> 80%) had < 25% of the liver involved. For all lesions in all patients, 87% experienced a biological response. Toxicity was acceptable. Fifty-one patients had colorectal cancer; their median survival was about 15 months. Another study from Northwestern University demonstrated the safety and efficacy of Y-90–labeled microspheres in patients with liver metastases.203 In an early study from Australia of patients mostly with hepatic colorectal metastases, the combination of a single injection of Y-90– labeled microspheres plus regional hepatic artery chemotherapy was substantially more effective in increasing tumor responses and progression-free survival (PFS) than the same regimen of hepatic artery chemotherapy alone. Clinical tumor response, carcinoembryonic antigen (CEA) level, and survival were all significantly improved with the addition of Y-90–labeled microspheres.204 In another study by the same group, adding Y-90–labeled microspheres to systemic therapy yielded improved response rates and acceptable toxicity.205 A Phase III trial published in 2010 comparing protracted intravenous fluorouracil infusion with or without Y-90 resin microsphere radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy showed

475

that Y-90 microspheres plus fluorouracil is well tolerated and improves time to liver progression 2.1 versus 5.5 (p = 0.003).206 A pooled analysis combined 19 studies that specifically investigated patients receiving Y-90–labeled microspheres for liver metastases from colorectal cancer. The reported median survival ranged from 10.8 to 29.4 months.201 Liver metastases from neuroendocrine tumors also appear to be effectively treated with Y-90–labeled microspheres. In the study from Northwestern University, 19 patients had neuroendocrine carcinomas. Among these patients, the median survival was 26 months and the 2-year survival rate was 69%.202 In a multi-institutional report, 148 patients with liver metastases from neuroendocrine tumors underwent 185 administrations of Y-90 microspheres.139 After treatment, 23% had stable disease, 61% partial response, 3% complete response, and 5% progressive disease. The 2-year survival was ~ 75%, and the median survival was ~ 70 months. In another multi-institutional study, 42 patients underwent Y-90 microspheres for liver metastases from neuroendocrine tumors.207 Greater than 90% achieved stable disease or a partial response. The median survival was on the order of 2 years. In an Australian study, 34 patients with liver metastases from neuroendocrine tumors were treated with Y-90 microspheres. Radiological liver responses were observed in 50% of patients and included 6 (18%) complete responses and 11 (32%) partial responses; the mean overall survival was 29 months. Symptoms from the tumor were improved in 50%. The differences in survival between these studies demonstrate a heterogeneous patient population. Also, the survival without Y-90– labeled microspheres treatment cannot be determined in these patients, with a condition that is often slowly progressive. Only one of these studies addressed the potential of Y-90 microspheres treatment to alleviate symptoms from carcinoid tumors. Evidence is accumulating supporting Y-90 use for hepatic metastatic tumor treatment in a wide variety of primary cancer histologies including breast, pancreatic, lung, renal, esophageal, ovarian, and intrahepatic cholangiocarcinoma.208,209 Because of the expense and limited data at this time, Y-90 is usually reserved for unresectable liver–dominant metastatic hepatic disease with a projected life expectancy of at least 3 months. The preworkup of this procedure is relatively intensive and includes a pretreatment planning angiogram, microsphere angiography of the liver, and a 99m-Tc macroaggregated albumin scan that demonstrates lung shunting or flow to the gastrointestinal tract. A consensus statement addressing patient eligibility for Y-90–labeled microspheres states, “Patients considered for radioembolization therapy would include those with (1) unresectable hepatic primary or metastatic cancer, (2) liver-dominant tumor burden, and (3) a life expectancy of at least 3 months … Contraindications for radioembolization therapy may include (1) pretreatment 99m-Tc macro-aggregated albumin (MAA) scan demonstrating the potential of ≥30 Gy radiation exposure to the lung or flow to the gastrointestinal tract resulting in extrahepatic deposition of 99m-Tc MAA that cannot be corrected by catheter embolization techniques, (2) excessive tumor burden with limited hepatic reserve, (3) elevated total bilirubin level (≥2 mg/dL) in the absence of a reversible cause, and (4) compromised portal vein, unless selective or superselective radioembolization can be performed. Patients with prior radiotherapy involving the liver should be carefully reviewed on a case-by-case basis. It is unclear whether capecitabine chemotherapy treatments represent a contraindication to Y90 treatment.”210 SBRT. Because the liver’s regenerative powers make localized highdose radiation achievable with minimal toxicity, SBRT has become popular for patients with a limited number of metastases and minimal extrahepatic tumors.12,13,211,212 As with most SBRT approaches, respiratory arrest or gating is preferred, but four-dimensional CT has also achieved good results. Large and portal lesions can be treated safely, and most studies show local control rates of more than 70%.213,214 No clear dose

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476

SECTION II

Techniques and Modalities

response has been measured, but all radiation doses and schedules have produced similar results. Liver tolerance. Although lethal RILD can occur when the median liver dose exceeds 37 Gy in standard fractionation, little or no toxicity is seen when more than 50% to 70% of the liver is maintained under 30 Gy.213,214 Patients primarily report decreased appetite and gastritis; moreover, patients with cirrhosis may experience exacerbation of hepatitis, and those with subdiaphragmatic tumors can have asymptomatic right pleural effusions. After radiation, tumors often become hypointense on CT scans, and surrounding hepatic damage may correspond to the 37-Gy isodose line. These radiographic changes can be confused with tumor progression because tumors reach a maximum size at 6 weeks to 3 months after irradiation and recover at 6 to 9 months. The contralateral lobe of the liver commonly hypertrophies to compensate for the lost liver mass; however, total liver volume usually maintains normal levels.

fraction sizes do not necessarily produce higher control rates for metastases, but grade 3 to grade 5 toxicity is most common with larger fraction sizes and central tumor locations.218 Rusthoven et al.220 report on patients with one to three metastases with a cumulative diameter under 7 cm who were given 48 to 60 Gy in 3 fractions: 63 lesions were treated in 38 patients with a local control rate of 96% at 2 years and 8% grade 3 and no grade 4 toxicity. Okunieff et al.217 report local failures in 8 of 125 lesions (local control rate of 94%) treated and followed for a minimum of 1 year. Tumors were up to 7.7 cm, and the dose was 50 Gy in 10 fractions. The PFS was 16% at 2 years. Grade 3 toxicity was seen in only 2% of patients; there was no grade 4 toxicity. Most patients have already failed several courses of standard chemotherapy before being offered SBRT. Nevertheless, excellent tumor control with minimal toxicity and unexpectedly high rates of PFS suggest that SBRT improves morbidity and mortality.

LUNG METASTASES

CRITICAL REFERENCES

Disease can occur in the parenchyma and in mediastinal or hilar nodes. Metastases in the lung bases are more common than in upper regions.11 Although peripheral lesions are often asymptomatic, central tumors can cause airway obstruction. Other signs and symptoms include cough, respiratory discomfort, shortness of breath, superior vena cava syndrome, and, in severe cases, hemoptysis or dysphagia. High-speed helical CT allows for high-precision detection of lung tumors smaller than 1 cm. Malignancy can be confirmed using PET/CT for glucose-avid tumor types, including colorectal, lung, and breast cancers.

65. Stopeck AT1, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–5139. 88. Chow E, Zeng L, Salvo N, et al. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012;24(2):112–124. 107. Cox BW, Spratt DE, Lovelock M, et al. International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012;83(5):e597–e605. 108. Redmond KJ, Robertson S, Lo SS, et al. Consensus contouring guidelines for postoperative stereotactic body radiation therapy for metastatic solid tumor malignancies to the spine. Int J Radiat Oncol Biol Phys. 2016;97(1):64–74. 154. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280(17):1485–1489. 155. Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;1040–1048. 156. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC⋅3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;1049–1060. 203. Lewandowski RJ, Thurston KG, Goin JE, et al. 90Y microsphere (TheraSphere) treatment for unresectable colorectal cancer metastases of the liver: response to treatment at targeted doses of 135–150 Gy as measured by [18F]fluorodeoxyglucose positron emission tomography and computed tomographic imaging. J Vasc Interv Radiol. 2005;16:1641–1651. 204. Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12:1711–1720. 205. Van Hazel G, Blackwell A, Anderson J, et al. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004;88:78–85. 206. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010;28:3687–3694. 207. Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg. 2008;247:1029–1035.

Treatment Standard treatment for pulmonary metastases is systemic chemotherapy. Tumor response to chemotherapy can be substantial, but it is usually short lived and often results in eventual recurrence. Minimally invasive surgical techniques paired with advanced imaging of the lung have made it possible to remove many small lesions. Although rarely employed for adult cancers, resection by open or minimally invasive techniques is commonly used for many childhood malignancies.215,216 As with liver metastases, radiofrequency ablation and radiosurgical techniques are also employed.

Stereotactic Body Radiotherapy Use of pulmonary SBRT for metastasis to the lung has greatly increased with the advent of imaging technologies capable of identifying very small metastatic tumors. The more widespread availability of PET/CT has improved our ability to distinguish these small tumors from benign nodules. The incremental gain for patients, as with metastectomy, has been difficult to prove; still, as with surgical approaches, local control rates are consistently higher than 80% or 90%. New metastases in the lungs are also commonly low, and quality of life is improved with maintenance of pulmonary function. Additionally, most studies show increased long-term and disease-free survival, which indicates the potential for a cure. The ability to give hypofractionated ablative doses of radiation relies on decreasing the size of the planned treatment volume (PTV) to spare normal tissue from damaging penumbra. In the lung, the most severe limitation of a parsimonious PTV that covers the lesion is respiratory motion. Several methods for increased PTV accuracy include real-time imaging of the lesion during respiration, gating, and methods to decrease the severity of motion (breath hold, quiet breathing, real-time breathing feedback, and diaphragmatic immobilization). Radiation doses range from 30 to 66 Gy given in 3 to 10 fractions to 48 to 60 Gy given in 10 to 12 fractions.217–220 Despite the wide variation in dose and fractionation, the results have been uniformly excellent, with high control rates. Higher

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208. Coldwell D, Sangro B, Salem R, et al. Radioembolization in the treatment of unresectable liver tumors: experience across a range of primary cancers. Am J Clin Oncol. 2012;35(2):167–177. 209. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres–safety, efficacy, and survival. Radiology. 2008;247(2):507–515. 210. Kennedy A, Nag S, Salem R, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys. 2007;68:13–23. 211. Dawood O, Mahadevan A, Goodman KA. Stereotactic body radiation therapy for liver metastases. Eur J Cancer. 2009;45:2947–2959. 212. Lo SS, Fakiris AJ, Teh BS, et al. Stereotactic body radiation therapy for oligometastases. Expert Rev Anticancer Ther. 2009;9:621–635. 213. Lee MT, Kim JJ, Dinniwell R, et al. Phase I study of individualized stereotactic body radiotherapy of liver metastases. J Clin Oncol. 2009;27:1585–1591. 214. Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat Oncol. 2005;15:279–283.

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215. Aljubran AH, Griffin A, Pintilie M, et al. Osteosarcoma in adolescents and adults: survival analysis with and without lung metastases. Ann Oncol. 2009;20:1136–1141. 216. Horan TA, Santiago FF, Araujo LM. The benefit of pulmonary metastectomy for bone and soft tissue sarcomas. Int Surg. 2000;85:185–189. 217. Okunieff P, Petersen AL, Philip A, et al. Stereotactic body radiation therapy (SBRT) for lung metastases. Acta Oncol. 2006;45:808–817. 218. Chi A, Liao Z, Nguyen NP, et al. Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non–small-cell lung cancer: clinical implications. Radiother Oncol. 2010;94:1–11. 219. Joyner M, Salter BJ, Papanikolaou N, et al. Stereotactic body radiation therapy for centrally located lung lesions. Acta Oncol. 2006;45:802–807. 220. Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi-institutional phase I/ II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol. 2009;27:1579–1584.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 29

Metastatic Disease: Bone, Spinal Cord, Brain, Liver, and Lung

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Techniques and Modalities

146. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745–751. 147. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295:2483–2491. 148. Nieder C, Berberich W, Schnabel K. Tumor-related prognostic factors for remission of brain metastases after radiotherapy. Int J Radiat Oncol Biol Phys. 1997;39:25–30. 149. Sneed PK, Larson DA, Wara WM. Radiotherapy for cerebral metastases. Neurosurg Clin N Am. 1996;7(3):505–515. 150. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10:1037–1044. 151. Gondi V, Mehta M, Pugh S, et al. Memory preservation with conformal avoidance of the hippocampus during whole-brain radiotherapy (WBRT) for patients with brain metastases: primary endpoint results of RTOG 0933. Int J Radiat Oncol Biol Phys. 2013;87:LBA1. 151a. Gondi V, Deshmukh S, Brown PD, et al. Preservation of neurocognitive function (NCF) with conformal avoidance of the hippocampus during whole-brain radiotherapy (HA-WBRT) for brain metastases: preliminary results of Phase III trial NRG oncology CC001. Int J Radiat Oncol Biol Phys. 2018;102(5):1607. 152. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33:583–590. 153. Mintz AH, Kestle J, Rathbone MP, et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer. 1996;78:1470–1476. 154. Patchell RA, Tibbs PA, Regine WF. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280:1485–1489. 155. Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;1040–1048. 156. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC⋅3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;1049–1060. 157. Kondziolka D, Patel A, Lunsford LD, et al. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys. 1999;45: 427–434. 158. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47:291–298. 159. Sanghavi SN, Miranpuri SS, Chappell R, et al. Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys. 2001;51:426–434. 160. Sneed PK, Suh JH, Goetsch SJ, et al. A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys. 2002;53:519–526. 161. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363:1665–1672. 162. Kondziolka D, Martin JJ, Flickinger JC, et al. Long-term survivors after gamma knife radiosurgery for brain metastases. Cancer. 2005;104:2784–2791. 163. Mehta MP, Tsao MN, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review

of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys. 2005;63:37–46. 164. Schomas DA, Roeske JC, Macdonald RL, et al. Predictors of tumor control in patients treated with linac-based stereotactic radiosurgery for metastatic disease to the brain. Am J Clin Oncol. 2005;28:180–187. 165. Varlotto JM, Flickinger JC, Niranjan A, et al. The impact of whole-brain radiation therapy on the long-term control and morbidity of patients surviving more than one year after gamma knife radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys. 2005;62:1125–1132. 166. Fuentes R, Bonfill X, Exposito J. Surgery versus radiosurgery for patients with a solitary brain metastasis from non–small cell lung cancer. Cochrane Database Syst Rev. 2006;(1):CD004840. 167. Vogelbaum MA, Angelov L, Lee SY, et al. Local control of brain metastases by stereotactic radiosurgery in relation to dose to the tumor margin. J Neurosurg. 2006;104:907–912. 168. Auchter RM, Lamond JP, Alexander E, et al. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys. 1996;35: 27–35. 169. Shiau CY, Sneed PK, Shu HK, et al. Radiosurgery for brain metastases: relationship of dose and pattern of enhancement to local control. Int J Radiat Oncol Biol Phys. 1997;37:375–383. 170. Chidel MA, Suh JH, Reddy CA, et al. Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases. Int J Radiat Oncol Biol Phys. 2000;47:993–999. 171. Pirzkall A, Debus J, Lohr F, et al. Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. J Clin Oncol. 1998;16:3563–3569. 172. Shehata MK, Young B, Reid B, et al. Stereotatic radiosurgery of 468 brain metastases < or = 2 cm: implications for SRS dose and whole brain radiation therapy. Int J Radiat Oncol Biol Phys. 2004;59:87–93. 173. Hasegawa T, Kondziolka D, Flickinger JC, et al. Brain metastases treated with radiosurgery alone: an alternative to whole brain radiotherapy? Neurosurgery. 2003;52:1318–1326. 174. Sneed PK, Lamborn KR, Forstner JM, et al. Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys. 1999;43:549–558. 175. Sawrie SM, Guthrie BL, Spencer SA, et al. Predictors of distant brain recurrence for patients with newly diagnosed brain metastases treated with stereotactic radiosurgery alone. Int J Radiat Oncol Biol Phys. 2008;70:181–186. 176. Muacevic A, Kreth FW, Horstmann GA, et al. Surgery and radiotherapy compared with gamma knife radiosurgery in the treatment of solitary cerebral metastases of small diameter. J Neurosurg. 1999;91:35–43. 177. Rades D, Bohlen G, Pluemer A, et al. Stereotactic radiosurgery alone versus resection plus whole-brain radiotherapy for 1 or 2 brain metastases in recursive partitioning analysis class 1 and 2 patients. Cancer. 2007;109:2515–2521. 178. O’Neill BP, Iturria NJ, Link MJ, et al. A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys. 2003;55:1169–1176. 179. Schoggl A, Kitz K, Reddy M, et al. Defining the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases. Acta Neurochir (Wien). 2000;142:621–626. 180. Baumert BG, Rutten I, Dehing-Oberije C, et al. A pathology-based substrate for target definition in radiosurgery of brain metastases. Int J Radiat Oncol Biol Phys. 2006;66:187–194. 181. Sawaya R. Considerations in the diagnosis and management of brain metastases. Oncology (Williston Park). 2001;15:1144–1148. 182. Wen PY, Loeffler JS. Management of brain metastases. Oncology (Williston Park). 1999;13:941–961. 183. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39:789–796. 184. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341:476–484.

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CHAPTER 29

Metastatic Disease: Bone, Spinal Cord, Brain, Liver, and Lung

185. Meyers CA, Smith JA, Bezjak A, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol. 2004;22:157–165. 186. Regine WF, Scott C, Murray K, et al. Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. acceleratedhyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group Study 91-04. Int J Radiat Oncol Biol Phys. 2001;51:711–717. 187. Aoyama H, Tago M, Kato N, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys. 2007;68:1388–1395. 188. Hollett MD, Jeffrey RB Jr, Nino-Murcia M, et al. Dual-phase helical CT of the liver: value of arterial phase scans in the detection of small (< or = 1.5 cm) malignant hepatic neoplasms. AJR Am J Roentgenol. 1995;164:879–884. 189. Jones EC, Chezmar JL, Nelson RC, et al. The frequency and significance of small (less than or equal to 15 mm) hepatic lesions detected by CT. AJR Am J Roentgenol. 1992;158:535–539. 190. Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg. 2004;240:438–447. 191. Tanabe K. Emerging therapies for metastatic carcinoma to the liver. Commun Oncol. 2006;3(9):567–573. 192. Pwint TP, Midgley R, Kerr DJ. Regional hepatic chemotherapies in the treatment of colorectal cancer metastases to the liver. Semin Oncol. 2010;37:149–159. 193. Vogl TJ, Zangos S, Eichler K, et al. Colorectal liver metastases: regional chemotherapy via transarterial chemoembolization (TACE) and hepatic chemoperfusion: an update. Eur Radiol. 2007;17:1025–1034. 194. Martin RC, Robbins K, Tomalty D, et al. Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report. World J Surg Oncol. 2009;7:80. 195. You YT, Changchien CR, Huang JS, et al. Combining systemic chemotherapy with chemoembolization in the treatment of unresectable hepatic metastases from colorectal cancer. Int J Colorectal Dis. 2006;21:33–37. 196. Giroux MF, Baum RA, Soulen MC. Chemoembolization of liver metastasis from breast carcinoma. J Vasc Interv Radiol. 2004;15:289–291. 197. Borgelt BB, Gelber R, Brady LW, et al. The palliation of hepatic metastases: results of the Radiation Therapy Oncology Group pilot study. Int J Radiat Oncol Biol Phys. 1981;7:587–591. 198. Russell AH, Clyde C, Wasserman TH, et al. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol. Int J Radiat Oncol Biol Phys. 1993;27:117–123. 199. Mohiuddin M, Chen E, Ahmad N. Combined liver radiation and chemotherapy for palliation of hepatic metastases from colorectal cancer. J Clin Oncol. 1996;14:722–728. 200. Bydder S, Spry NA, Christie DR, et al. A prospective trial of shortfractionation radiotherapy for the palliation of liver metastases. Australas Radiol. 2003;47:284–288. 201. Vente MA, Wondergem M, van der Tweel I, et al. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol. 2009;19:951–959. 202. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres—safety, efficacy, and survival. Radiology. 2008;247:507–515. 203. Lewandowski RJ, Thurston KG, Goin JE, et al. 90Y microsphere (TheraSphere) treatment for unresectable colorectal cancer metastases of the liver: response to treatment at targeted doses of 135–150 Gy as measured by [18F]fluorodeoxyglucose positron emission tomography and computed tomographic imaging. J Vasc Interv Radiol. 2005;16:1641–1651.

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204. Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12:1711–1720. 205. Van Hazel G, Blackwell A, Anderson J, et al. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004;88:78–85. 206. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010;28:3687–3694. 207. Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg. 2008;247:1029–1035. 208. Coldwell D, Sangro B, Salem R, et al. Radioembolization in the treatment of unresectable liver tumors: experience across a range of primary cancers. Am J Clin Oncol. 2012;35(2):167–177. 209. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres–safety, efficacy, and survival. Radiology. 2008;247(2):507–515. 210. Kennedy A, Nag S, Salem R, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys. 2007;68:13–23. 211. Dawood O, Mahadevan A, Goodman KA. Stereotactic body radiation therapy for liver metastases. Eur J Cancer. 2009;45:2947–2959. 212. Lo SS, Fakiris AJ, Teh BS, et al. Stereotactic body radiation therapy for oligometastases. Expert Rev Anticancer Ther. 2009;9:621–635. 213. Lee MT, Kim JJ, Dinniwell R, et al. Phase I study of individualized stereotactic body radiotherapy of liver metastases. J Clin Oncol. 2009;27:1585–1591. 214. Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat Oncol. 2005;15:279–283. 215. Aljubran AH, Griffin A, Pintilie M, et al. Osteosarcoma in adolescents and adults: survival analysis with and without lung metastases. Ann Oncol. 2009;20:1136–1141. 216. Horan TA, Santiago FF, Araujo LM. The benefit of pulmonary metastectomy for bone and soft tissue sarcomas. Int Surg. 2000;85:185–189. 217. Okunieff P, Petersen AL, Philip A, et al. Stereotactic body radiation therapy (SBRT) for lung metastases. Acta Oncol. 2006;45:808–817. 218. Chi A, Liao Z, Nguyen NP, et al. Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non–small-cell lung cancer: clinical implications. Radiother Oncol. 2010;94:1–11. 219. Joyner M, Salter BJ, Papanikolaou N, et al. Stereotactic body radiation therapy for centrally located lung lesions. Acta Oncol. 2006;45:802–807. 220. Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi-institutional phase I/ II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol. 2009;27:1579–1584. 221. Press MF, Jones LA, Godolphin W, et al. HER-2/neu oncogene amplification and expression in breast and ovarian cancers. Prog Clin Biol Res. 1990;354A:209–221. 222. Okawa T, Kita M, Goto M, et al. Randomized prospective clinical study of small, large and twice-a-day fraction radiotherapy for painful bone metastases. Radiother Oncol. 1988;13:99–104. 223. Madsen EL. Painful bone metastasis: efficacy of radiotherapy assessed by the patients: A randomized trial comparing 4 Gy × 6 versus 10 Gy × 2. Int J Radiat Oncol Biol Phys. 1983;9:1775–1779. 224. Steenland E, Leer JW, van Houwelingen H, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol. 1999;52:101–109. 225. Sze WM, Shelley MD, Held I, et al. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy—a systematic review of randomised trials. Clin Oncol (R Coll Radiol). 2003;15:345–352.

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226. Fitzpatrick PJ. Wide-field irradiation of bone metastasis. In: Weiss L, Gilbert HA, eds. Bone Metastasis. Boston: G. K. Hall Medical Publishers; 1981:83–113. 227. Rowland CG, Bullimore JA, Smith PJ, et al. Half-body irradiation in the treatment of metastatic prostatic carcinoma. Br J Urol. 1981;53:628–629. 228. Qasim MM. Half body irradiation (HBI) in metastatic carcinomas. Clin Radiol. 1981;32:215–219. 229. Salazar OM, Rubin P, Hendrickson FR, et al. Single-dose half-body irradiation for palliation of multiple bone metastases from solid tumors. Final Radiation Therapy Oncology Group report. Cancer. 1986;58:29–36.

230. Wilkins MF, Keen CW. Hemi-body radiotherapy in the management of metastatic carcinoma. Clin Radiol. 1987;38:267–268. 231. Landaw SA. Acute leukemia in polycythemia vera. Semin Hematol. 1986;23:156–165. 232. Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol. 1994;31:33–40. 233. Ahonen A, Joensuu H, Hiltunen J, et al. Samarium-153-EDTMP in bone metastases. J Nucl Biol Med. 1994;38:123–127.

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PART A

Central Nervous System Tumors

30 Overview Minesh P. Mehta and Rupesh R. Kotecha

Central nervous system (CNS) tumors account for fewer than 3% of all neoplasms. For a number of very specific anatomic, physiological, pharmacological, immunological, and functional considerations, they pose challenges that are unique in all of oncology. Unlike most organ systems, the CNS extends its reach very broadly through large swathes of the body. Therefore, the clinical presentations are diffuse and varied, and highly dependent on anatomic location. A patient with a sacrococcygeal tumor, for example, might present with long-standing nerve or bone pain, whereas another with a cortical tumor might present with seizures. Similarly, a bulbar tumor may cause a cranial nerve palsy, a hypothalamic tumor might produce an endocrinopathy, and an occipital tumor could lead to visual problems. The immense variation in tumor growth rates adds to the complexity of clinical presentations, especially when factoring in patient age. For example, bulging fontanelles might represent a neoplasm in an infant, whereas the same tumor in an older child might manifest as gait disturbance or even nonspecific symptoms of increased intracranial pressure. A malignant tumor would be expected to have rapid growth with a corresponding degree of therapeutic resistance. Yet some of the most rapidly proliferating neoplasms of the CNS—such as germ cell tumors, medulloblastomas, and primary CNS lymphomas—are, in fact, highly treatment sensitive and, in specific instances, highly curable. Contrast these with slowly proliferating low-grade astrocytomas, which are eventually relentless in their progression, recurrence, and malignant transformation. These malignancies are associated with longer survival but high morbidity and eventual mortality. One expects mitotically active neoplasms to respond dramatically to antineoplastic therapy; yet, a low-grade oligodendroglioma, a mitotically nearly quiescent tumor, demonstrates dramatic chemo- and radiosensitivity, underscoring the biological sensitivity driven by specific genetic alterations. Therefore, the physician needs to be anatomically and biologically astute as well as clinically highly sophisticated when managing patients with CNS malignancies. The wide variety of cell types in the CNS gives rise to an immense range of tumor histologies and grades, with a dizzying array of names— some archaic, some historic, and some current—which have only recently been formulated into an internationally accepted histopathological classification promulgated by the World Health Organization (WHO). The considerable evolution in nomenclature over time has resulted in a generation of literature that is subject to the vagaries of time as new terms and classifications rapidly make older ones redundant.

Compounding this is the issue of inter- and intraobserver variability in arriving at a histopathological diagnosis, with substantial variability among pathologists regarding terminology and molecular-diagnostic evaluations. The emergence of neuro-oncologic pathology as a crucial subspecialty has led to increasing uniformity in diagnosis, but because the vast majority of patients still undergo initial evaluation at smaller primary institutions, often without a neuropathologist, the need for central review by an experienced neuropathologist is critical to the diagnosis and subsequent management of many patients with CNS tumors. Perhaps the most relevant current development is the routine incorporation of molecular markers in classifying CNS neoplasms. We have long known about the prognostic significance of several of these markers, but only recently have they become entrenched in the new WHO classification schema. The enormous variety of tumors, their vast range of clinical behaviors, considerable diagnostic uncertainty in their classification, and limited available tissue for thorough evaluation had previously limited genomic, proteomic, and metabolomic assessments of these tumors for the most part. In the last decade or so, there has been a clear fundamental shift for several tumor types, for which important molecular markers have now been identified. These include promoter region methylation of MGMT for glioblastoma (GBM) and other gliomas, 1p19q deletions or translocations for tumors of oligodendroglial lineage, IDH1 mutations for astrocytic tumors, a proangiogenic genetic signature for GBM, coexpression of mutant EGFR and wild-type PTEN for recurrent malignant glioma, H3K27M mutations in midline gliomas, such as diffuse intrinsic pontine gliomas, BRAF mutations in pilocytic astrocytomas, and hypermutational signatures in rare cases of glioblastoma, to name a few. This is a rapidly evolving field that holds the promise of identifying targeted therapies for select subsets of patients, an area that, while adding diagnostic clarity, consequently poses numerous clinical trial challenges. The current WHO classification is the first step of many to come in the future, providing a key focus on the importance of molecular diagnostics. The surgical challenges in the CNS are immense. Unlike other anatomic sites, the concept of “redundant” tissue simply does not exist in the brain or spinal cord. Therefore, every surgical procedure is technically risky, and en-bloc oncologically complete resections with wide margins are almost impossible. Prior to the advent of pre- and intraoperative neuronavigation with three-dimensional (3D) navigational capabilities, intraoperative microscopes, the availability of brilliant illumination, chemically fluorescent tumor edge visualization, improved

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instrumentation and techniques for hemostatsis, and neuroanesthetic advances, aggressive resections with an intent to remove all visible disease were undertaken infrequently. The consequences of this were multiple. First, many tumors remained “imaging and clinically diagnosed,” for example, skull base meningiomas, vestibular schwannomas, brainstem gliomas, and presumed pineal germ cell tumors. Inclusion of these tumors, with uncertain diagnoses, as well as uncertain clinical behaviors, made interpretation of generalized treatment results inaccurate. Second, a tendency toward “small” biopsies was very common, adding to diagnostic uncertainty. Third, and most important, although level 1 evidence is sparse, an increasing body of literature suggests that more complete resections are important for almost all CNS neoplasms, a trend that has clearly increased in practice. However, we do not have a national registry program in place to ensure that such an approach of maximal resection in the safest possible manner in the hands of vastly experienced multidisciplinary teams for all CNS tumor patients is available, something that is being considered in some European nations and controversially proposed to be linked with payment for service. Rapid advances in technology have essentially resulted in magnetic resonance imaging (MRI) becoming the de facto standard for diagnosing most CNS neoplasms. Although this has supplanted computed tomography (CT) imaging to a large extent, the latter still retains a significant role in specific situations and is the workhorse for dose calculation in radiotherapy planning. In spite of the superb detail provided by today’s high-resolution, high-field magnets, a major limitation of imaging, especially for infiltrative neoplasms, is defining the true extent and range of disease spread, something that no established imaging technique even comes close to estimating with precision. The success of local therapies, such as surgery and radiotherapy, is highly dependent on the accurate estimation of tumor extent. CNS neoplasms can spread along extremely complicated pathways, such as along fiber tracts, along subependymal planes, through the CSF, by exhibiting “skipping” and “multifocality,” and in the context of antiangiogenic therapeutic pressure by using the presumed phenomenon of “co-option.” Several studies have now demonstrated that currently available imaging is simply inadequate for detecting these complex pathways of microscopic infiltration. Moreover, the unusual phenomena of pseudoprogression, pseudoresponse, and therapeutically induced inflammatory changes, rarely seen outside the CNS, pose commonly encountered diagnostic conundrums. More sophisticated, biologically based imaging platforms are critically needed to evaluate the true extent of disease at diagnosis, detect biologically aggressive areas of disease, elucidate the “true” response to therapy, and provide early signals of response or failure. Radiomics, an emerging field, might provide guidance for resection and radiotherapy field design in the future, but as of now remains in its infancy, with no current convincing evidence to support it as a superior tool above and beyond conventional imaging. Metabolic imaging, at least for meningiomas, appears much more mature, with novel positron emission tomography isotopes approved in some countries for identification of tumors prior to their detection on routine imaging studies, classification of biologically aggressive tumors, and tumor margin delineation. Advances in radiotherapeutic techniques over the last decade have had a major impact in neuro-oncology. Because the majority of cell populations within the CNS have a low mitotic index and proliferate slowly, they are the prototypical “late-responding tissues” of conventional radiobiological literature. Consequently, the effects of CNS radiation are sometimes not apparent for years; even then, the historical approach has assumed that “all brain is equally sensitive,” with a nascent appreciation of compartment and cell-type specific radiosensitivity. This, too, is changing rapidly; the advent of 3D conformal, stereotactic, intensitymodulated radiotherapy (IMRT), image-guided radiation therapy (IGRT)

and proton solutions now offer unique opportunities for altering the therapeutic index in CNS tumors. Some elegant and practical examples include the avoidance of the optic apparatus during stereotactic radiosurgery (SRS) to prevent blindness, cochlear sparing with IMRT in children with posterior fossa tumors to spare hearing, minimizing the dose to the hypothalamic-pituitary axis to avoid endocrinopathies, and the emerging hypothesis of compartmental stem cell sparing to retain neurogenesis and, hence, spare memory. Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) provides a new dataset for normal tissue tolerance. Although still limited in scope, it represents a substantial improvement over what was available just a few years ago for the treating physician, which should help standardize dose-selection practices. In radiotherapy, technological advances are the hallmark of new developments, which pose challenging clinical and societal questions. Some of the most exciting developments in this regard come from recent randomized trials. One, from India, demonstrates convincingly that excluding normal brain tissue from unnecessary low-dose exposure provides categorical neurological, neurofunctional, and neuroendocrine benefits, something the practicing radiation oncologist has long assumed to be true. Now, however, we have level 1 evidence to support this premise; yet, we often have to battle insurance companies for IMRT and intensity-modulated proton therapy (IMPT) authorization for such patients. How many patients do we have to harm before we can all agree that unnecessary radiation to the normal brain is not a good thing? Unfortunately, these insurance companies frequently rely on our per-case reimbursed professional colleagues who get to make judgment calls regarding advanced technology utilization. Can we imagine a scenario in which fee-per-case utilization review radiologists would determine who can have an MRI versus a CT and ask for randomized data demonstrating a survival advantage to back up an MRI request? Of course not…it is, unfortunately, predominantly in the field of radiation oncology that we face this scourge! Recent randomized data from NRG trials demonstrate that hippocampal avoidance decreases cognitive decline in brain metastasis patients. Should we now conduct hippocampal avoidance trials in a hundred other brain tumor types or can we accept technological advances based on demonstrated dosimetric and biological superiority in one tumor type? The most exciting focus in neuro-oncology in the last decade has been the emergence of robust long-term data from large significant clinical trials, which are beginning to change the standard of care based on level 1 evidence, especially on the basis of multimodality focus on translational biology. Examples include the substantial survival improvement seen in lower-grade gliomas with combinatorial chemoradiotherapy, especially in IDH-mutant and 1p19q co-deleted tumors. Unfortunately, the era of antiangiogenic therapies and singleagent agnostic use of receptor kinase inhibitors has come and gone without much substance. Preliminary data from the use of immune checkpoint inhibitors in primary gliomas have so far proven to be negative, with the exception of highly selected mutationally hyperactive cases. Vaccine-based approaches, at least to date, have largely failed, the CAR-T cell approach for CNS neoplasms is very much in its infancy, and the last decade marked the demise of the first generation of intratumoral catheter-based therapeutics. This is a large corpus of negative trials—we clearly have to reflect on the failures to improve the likelihood of success in the future. In the series of elegant chapters that follow, a team of internationally acclaimed authors, infused with this newfound enthusiasm in neurooncology, review the issues highlighted here in considerable detail, providing the treating physician with an up-to-date resource that is practical, comprehensive, and thoroughly referenced, which we hope will ultimately serve our patients’ needs.

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31 Low-Grade Gliomas Hugues Duffau, Charles Eberhart, Matthew D. Hall, and Yazmin Odia

KEY POINTS Epidemiology The estimated incidence of low-grade gliomas (LGG) is approximately 2,000 cases per year, comprising 5-10% of newly diagnosed primary brain tumors. Biological Characteristics Molecular characterization has emerged as a critical element in the diagnosis, prognosis, and management of LGG. WHO grade II tumors are subdivided into three classes: (1) oligodendroglioma (1p/19q codeleted, IDH-mutated tumors), (2) IDH-mutated non-1p/19q codeleted astrocytoma, and (3) IDH wild-type astrocytoma. The diagnosis of WHO grade I tumors remains primarily based on histology, but presence of mutations of interest (in particular BRAF mutations and fusions) may guide treatment and predict survival. Staging Evaluation LGG most commonly present in patients between 20-50 years of age. In contrast to glioblastoma multiforme, the incidence of low grade astrocytoma decreases with increasing age. Presenting symptoms directly result from the anatomical location of the tumor and may slowly progress over months to years. On imaging, selected LGG such as pilocytic astrocytoma, ganglioglioma, and DNET are typically well circumscribed while the remainder, including most grade II tumors, are infiltrative. Diffuse astrocytomas are often nonenhancing, T1 hypointense tumors, which are best seen on T2- or FLAIR-weighted MRI sequences. Primary Therapy and Results Maximum surgical resection is associated with improved overall survival. Surgery is essential to confirm the diagnosis, differentiate tumor subtypes, and define the grade and molecular profile of tumors. Biopsies (even when guided by metabolic imaging) have a high probability of underrating tumor grade, and should be proposed only for diffuse tumors that cannot be removed safely or when surgical resection is contraindicated. WHO grade I tumors are generally observed following gross total resection (GTR). Observation may be reasonable in selected low risk patients with WHO grade II tumors (Age 8 mm/y) allows the diagnosis of a “false LGG,” which behaves as a high-grade glioma. In the postoperative period, VDE is a useful monitoring tool and serves to evaluate tumor response/stability to adjuvant treatments.30 Whereas oligodendrogliomas have calcifications in 70% to 90% of cases31 and also tend to have cortical involvement, structural MRI alone cannot reliably distinguish between low-grade oligodendrogliomas and astrocytomas. However, advances in imaging, such as the MR spectroscopic evaluation of IDH-related metabolites, may help to refine the diagnosis.32

Advanced Imaging/Metabolic Imaging Spectroscopy-MRI (SRM) measures the main metabolites in the tumor. A typical spectrum for an LGG shows an increased choline peak, which reflects an increase of the membrane turnover; a decrease of the N-acetylaspartate peak, reflecting neuronal loss, and an increase of the myoinositol peak, indicating glial proliferation. However, these metabolic abnormalities are also noted in some nonneoplastic lesions. Although the presence of lactates and lipids (suggesting necrosis) is associated with higher proliferative activity and more aggressive behavior,33 it is not possible to determine the tumor grading on the sole basis of SRM. Despite these limitations, SRM can be helpful for guiding a surgical biopsy in inoperable LGG and for monitoring the tumor in response to treatment.30,34 Dynamic susceptibility contrast (DSC) imaging perfusion MRI helps calculate relative cerebral blood volume (rCBV), which is correlated with microvascularization. Increased rCBV in LGG is a marker of malignant transformation prior to development of enhancement.35 Of

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note, this is true only for astrocytomas, as rCBV is significantly higher in oligodendroglioma than in low-grade astrocytoma.36 Dynamic contrast-enhanced (DCE) MRI measures permeability of the blood-brain barrier by calculating a transfer coefficient (K trans), which is correlated to the tumor grading, even though this correlation is weaker compared with rCBV.37 Regarding diffusion MRI, values of apparent diffusion coefficient (ADC) are lower and more variable in low-grade oligodendrogliomas than in low-grade astrocytomas. There is no significant correlation between ADC and the choline peak.38 Finally, quantitative MRI in oligodendrogliomas shows more heterogeneous T1 and T2 signal abnormalities, poorly delineated margin, and an increased rCBV compared with noncodeleted tumors.31 [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) has limited value, because LGGs have weak uptake compared with normal brain cortex. Its interest is only in the detection of malignant transformation in low-grade astrocytomas and in differentiating between radionecrosis and tumor relapse after treatment.39 11C-methionine (MET) PET offers the advantage of MET uptake correlated with the proliferative activity of tumor cells. MET uptake by normal brain tissue is lower than FDG uptake, allowing for superior contrast and delineation of glioma. Oligodendroglial tumors exhibit increased MET uptake. MET-PET can be useful for distinguishing LGG from nonneoplastic lesions, for guiding stereotactic biopsy in unresectable tumors, and for monitoring treatment response.40 However, a cyclotron is necessary, limiting access to MET-PET in many departments. Recently, 18F-fluoro-ethyl-L-tyrosine (FET)-PET has been used for guiding biopsy for treatment planning in gliomas.41 A longer half-life than MET enables the preparation of FET at institutions with a cyclotron and its transportation to other departments. Even if FET and MET seem to have similar uptake and distribution in brain tumors, the actual experience with FET remains limited.

Clinical Presentation Anatomic Distributions

The anatomic distributions of low-grade (WHO grade 1 or 2) gliomas depend on morphological and molecular classification as well as age. Pilocytic astrocytomas predominantly occur in the infratentorial brain in or near the cerebellum. Other common locations include the optic nerve, especially in patients with neurofibromatosis, as well as other central supratentorial regions—such as the hypothalamus, basal ganglia, thalamus, and tectum—and can extend into the ventricles. Pilocytic astrocytomas less frequently arise within the spinal cord.42 The molecular profile of pilocytic astrocytomas is also linked to the anatomic distribution (Fig. 31.1).43 Pleomorphic xanthoastrocytomas (PXAs) generally arise in superficial regions within the cerebrum in up to 98% of cases and may occur along the leptomeningeal surface. The temporal lobes are the most common location, though rare cases have been reported in the cerebellum, spinal cord, and retina.42 SEGAs, by definition, are rare tumors that arise from the walls of the lateral ventricles near the foramen of Monro. Choroid gliomas of the third ventricle are adult tumors arising exclusively from the third ventricle, mostly the anterior portion, but rarely extend into the hypothalamus. Angiocentric gliomas typically arise within the cerebral cortex, often extending via parenchymal vessels into the subpial zone. Astroblastomas, currently unclassified by WHO grade, arise predominantly from the cerebrum, though 19% involve the infratentorial brain and rarely occur in the spinal cord.42 Ganglioglioma, DNET, desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG), papillary glioneuronal tumor (PGNT), and rosette-forming glioneuronal tumor (RFGNT) are rare mixed

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Cerebral hemispheres

Diencephalon

Posterior fossa

KIAA1549:BRAF Other RAF fusion BRAF mut KRAS mut FGFRml mut/fus/dup NTRK fusion NF1 (germline) None identified Fig. 31.1 Pie charts summarizing the estimated frequency of particular mitogen-activated protein kinase pathway alterations in different anatomic locations (posterior fossa, diencephalon and cerebral hemispheres), calculated from a total of 188 pilocytic astrocytomas. (Modified from Collins VP, Jones DT, Giannini C. Pilocytic astrocytoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129(6):775–788.)

neuronal-glial tumors with stereotypic, if not pathognomonic, anatomic distributions. DNETs arise predominantly from the cerebral cortex, mainly in the mesial temporal (67.3%) and frontal (16.3%) lobes, with 16.4% occurring in other diencephalic or brainstem locations. Gangliogliomas arise in the temporal lobes in 70% of cases but may occur throughout the CNS from the cerebrum to the spinal cord as well as pituitary and pineal glands. DIAs and DIGs exclusively arise in multiple cerebral lobes, often frontal and parietal, followed by temporal and occipital regions. PGNTs also often arise in the cerebral hemispheres, are often periventricular, and can even extend intraventricularly. RFGNTs are characteristically midline, typically within the fourth ventricle and/or aqueduct extending into the nearby brainstem, cerebellar vermis, pineal gland, or thalamus.42 Infiltrative low-grade astrocytomas and oligodendrogliomas (WHO grade 2) arise throughout the neuroaxis, but the anatomic distribution varies greatly by molecular profile. 1p/19q-codeleted oligodendrogliomas and IDH-mutant astrocytomas arise in the frontal cerebral subcortical white matter or cortex in 50% of cases, but occur in decreasing frequency in the temporal, parietal, and occipital lobes. Rare sites include the brainstem, cerebellum, basal ganglia, and—in rare cases—the spinal cord. Leptomeningeal spread has been reported.42 IDH wild-type astrocytomas also predominantly arise in the supratentorial regions and often involve multiple hemispheres or deep gray matter structures (gliomatosis cerebri). IDH wild-type gliomas are further subclassified by BRAF and H3-K27M mutational status. Astrocytomas harboring K27M mutations in either H3F3A or HIST1H3B/C mainly arise from midline structures. While strictly classified as WHO grade 4, these tumors may express WHO grade 2 histologic features, but behave aggressively, consistent with their grade 4 stratification. In children, the brainstem is the predominant location, while the thalamus and spinal cord are more commonly involved in adults. H3-K27M mutated tumors have also been reported in the third ventricle, hypothalamus, pineal region, and cerebellum.42

Clinical Presentation Presenting symptoms directly result from the anatomic location of the tumor. Intraventricular or periventricular tumors—such as pilocytic

astrocytomas, PGNT, RFGNT, SEGA, or choroid gliomas of the third ventricle—often present with signs and symptoms of obstructive hydrocephalus and elevated intracranial pressure, such as headaches, nausea and emesis, and progressive lethargy. Seizures are far less common but are the hallmark of temporal lobe and cortical predominant histologies, like DNET, gangliogliomas, DIA/DIG, and PXA. Infiltrative gliomas have the most varied clinical presentations owing to their distribution throughout the CNS, though seizures, weakness, gait instability, cognitive deficits, and headaches are common depending on the anatomic location.

PATHOLOGY Histopathology and World Health Organization 2016 Classification One broad way to categorize gliomas is based on their tendency to diffusely infiltrate the brain. Infiltrating gliomas are most common in adults, and include astrocytic lesions of increasing grades (diffuse astrocytoma, WHO grade 2, anaplastic astrocytoma, WHO grade 3 and GBM, WHO grade 4) as well as analogous oligodendroglial tumors (oligodendroglioma, WHO grade 2 and anaplastic oligodendroglioma, WHO grade 3). Brisk mitotic activity is required for a diagnosis of anaplastic astrocytoma, WHO grade 3, while necrosis and/or microvascular proliferation define GBM. In oligodendroglioma, anaplasia is characterized by brisk mitotic activity or microvascular proliferation. “Mixed” gliomas with microscopic oligodendroglial and astrocytic components can now generally be distinguished molecularly as one or the other, and the diagnosis of oligoastrocytoma is strongly discouraged in the 2016 WHO classification scheme.42 When molecular testing is not possible or is inconclusive, a “not otherwise specified” (NOS) designation can be used. Compact, largely noninfiltrative gliomas include PXA, pilocytic astrocytoma, and other rarer lesions. Pilocytic astrocytomas are generally characterized by a combination of loose, somewhat microcystic and denser piloid growth patterns, with Rosenthal fibers and eosinophilic granular bodies often found in the latter regions. However, significant regions with an oligodendroglial appearance can also be present. As their name suggests, neoplastic astrocytes in PXA can contain large pleomorphic nuclei and cells with variably foamy or xanthomatous cytoplasm. Many tumors with both glial and neuronal components, such as gangliogliomas and DIG, also have a relatively compact pattern of growth.

Molecular Profiling Molecular changes define many glial neoplasms of the CNS in the 2016 WHO classification. Infiltrating astrocytomas grades 2, 3, and 4 are now separated into IDH mutant and IDH wild-type groups, which have different age distributions and clinical outcomes. Bona fide oligodendrogliomas are now required to have both IDH mutations and loss of chromosomal arms 1p and 19q. Lesions previously classified as diffuse intrinsic pontine glioma are now designated “diffuse midline glioma, H3 K27M-mutant, WHO grade 4,” and the group was expanded to include other infiltrating midline gliomas with this signature molecular change.42 While these H3 mutant gliomas are most often found in children, they are increasingly being recognized in adults, and it is not clear that the impact on survival is as negative in this older population.44 Some signature molecular changes found in gliomas, including BRAF V600E mutations, represent attractive targets for therapeutic intervention. It has been suggested that IDH wild-type infiltrating astrocytomas, which are histopathologically grade 2 and 3 but have molecular changes characteristic of GBM, may also merit a grade 4 designation.45 Amplification of epidermal growth factor receptor (EGFR), gain of chromosome

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CHAPTER 31 7, loss of chromosome 10, or mutation of the TERT promoter are the changes that would qualify. The proposed designation is “diffuse astrocytic glioma, IDH wild-type, with molecular features of GBM, WHO grade 4.” This is not currently an official WHO entity, but it further highlights the potential of molecular profiles to define new diagnostic groups.

SURGICAL MANAGEMENT Circumscribed Astrocytomas In pilocytic astrocytoma, gross total resection (GTR) is the greatest predictor of recurrence-free survival in the pediatric population.46 Similarly, in adults, an analysis of the Surveillance, Epidemiology, and End Results (SEER) program database reviewed outcomes in 865 patients (age > 19 years) and reported that GTR was a significant predictor of survival compared with subtotal resection or biopsy (hazard ratio [HR], 0.3; 95% confidence interval [CI], 0.1-0.4).47 Postoperative tumor relapse rates were as high as 42%, especially after subtotal resection. Therefore, the aim of surgery should always be GTR when feasible.48 In ganglioglioma, surgery is also the first therapeutic option. Because these tumors are in essence noninfiltrative and well demarcated from the normal tissue, GTR is often feasible. In the SEER series, 92% of patients had surgery, with 68% achieving a GTR.49 GTR is the best predictor of prolonged OS and progression-free survival (PFS).50 The outcome of surgical resection for DNET is excellent.25 Even though some series have reported an aggressive behavior, requiring reoperation,51 long-term clinical follow-up usually reveals no evidence of relapse, especially after complete resection. In addition, total tumor resection yields long-term epilepsy control: seizure-free status is noted in 70% to 90% of patients.52

Infiltrative Low-Grade Gliomas Maximizing Outcomes

Early and maximal safe surgical resection for diffuse LGG has three main goals: 1. To provide tumor tissue for histological and molecular analysis 2. To increase OS by minimizing the risk of malignant transformation 3. To preserve or even to improve the quality of life (QoL), especially by controlling seizures53 First, surgery is necessary in all cases to confirm the diagnosis of glioma, to differentiate tumor subtypes (astrocytoma vs. oligodendroglioma), and to define the grade and molecular profile. Of note, because gliomas are very heterogeneous, biopsies (even if performed in stereotactic condition guided by metabolic imaging) have a high risk of underrating tumor grade, which could result in inappropriate management.54,55 Thus, biopsies should be proposed only in the case of very diffuse LGG that cannot be removed (such as gliomatosis-like) or when surgical resection is contraindicated for other medical issues.56 Second, although the oncological benefit of surgery in LGG was debated for many decades, efficacy analyses were limited due to the lack of objective calculation of the extent of resection (EOR) on postoperative MRI. Even in recent randomized trials, EOR was evaluated only on the basis of the subjectivity of surgeons.57 Because diffuse LGG is not well delineated, the postoperative residual tumor is regularly underestimated if it is not volumetrically calculated on the T2/FLAIRweighted MRI. Recent series with rigorous evaluation of EOR showed that more extensive resection was associated with a significant improvement of OS in comparison with simple debulking or biopsy.58 In two near-randomized investigations that studied OS in populationbased parallel cohorts of LGG from departments with distinct surgical attitudes, early surgical excision, especially with a residual tumor volume of < 15 cc, was correlated with better OS compared with biopsy and a wait-and-see strategy.59,60 In a large surgical series with more than 1000

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LGGs, both EOR and postsurgical residual volume were independent prognostic factors significantly associated with longer OS.61 These results have been confirmed in a surgical experience with 1509 LGGs, leading to OS around 13 years since first surgery and around 15 years since first symptoms,62 that is, about double compared with the survival reported in series with no attempted resection19,63 or with a simple biopsy.59,60 Several studies revealed that surgical excision was also an independent prognostic factor correlated with increased malignant PFS,64,65 suggesting that the surgical impact on OS may be explained by the fact that surgery delays histological upgrading. Third, a more extensive resection is also associated with better seizure control, particularly in patients with preoperative intractable epilepsy and in case of insular gliomas.62,66 In this setting, surgery can dramatically improve QoL. The use of intraoperative brain mapping by means of direct electrostimulation increases the rate of total resection while significantly decreasing the risk of postoperative severe permanent defects.67,68 To this end, awake surgery is a well-tolerated procedure that permits (1) increased feasibility of maximal resection for gliomas located in so-called “eloquent” areas; (2) mapping and preservation of cortical and subcortical structures essential for brain functions, such as movement, language, cognition, and emotion; (3) optimizing EOR68,69; and (4) increasing OS.70 When functionally possible, awake surgery can be used to perform resection according to critical neural networks in order to take a margin beyond the signal abnormality visible on preoperative FLAIR-weighted MRI and achieve a supratotal resection. In a recent series of supramarginal removal of LGG, with a long-term follow-up of 11 years, no anaplastic transformation has been observed (without adjuvant chemotherapy in all cases but one).71 Of note, by using imaging-guided resection techniques, such as intraoperative MRI, the rate of complete resection is only about 36%,72 with a rate of new persistent deficit of about 13%.73 Because tumor relapse is frequent in LGG, the value of repeated surgeries has been investigated: reoperation was an independent prognostic factor significantly correlated with prolonged survival in two series.61,74 Interestingly, when the resection was not complete during the first surgery for functional reasons, EOR could be increased during subsequent surgery while preserving QoL owing to mechanisms of neuroplasticity,75 allowing for a multistage therapeutic approach.76 In summary, early and maximal safe resection is the first treatment in LGG according to current recommendations.77,78 Surgery should be proposed early for incidentally discovered LGG.79

Impact of Molecular Subtypes In the era of molecular biology, some suggest that the value of EOR may depend on molecular subtypes.80,81 However, others have shown that greater EOR and OS are not correlated with the molecular pattern of LGG. Indeed, although one could argue that longer OS after surgery could be due to the fact that diffuse LGG amenable to radical removal have more favorable genetic markers—for example, IDH mutation or 1p19q codeletion—a series with 200 consecutive diffuse LGGs revealed that the effect of better surgical resection was independent of the molecular profile.82 A recent cohort with IDH wild-type low-grade astrocytomas surgically removed also showed that only 16% of patients died at a median time from radiological diagnosis of 3.5 years (range, 2.6-4.5 years), whereas survival from diagnosis was 77.3% at 5 years. Of note, no patients who survived for more than 5 years died.83 Jakola et al. demonstrated that the beneficial effect of surgery on OS persisted after adjusting for genetic prognostic markers.60 In addition, when only partial resection can be achieved because of the invasion of critical structures by tumor cells, neoadjuvant chemotherapy can be considered in order to allow glioma shrinkage and subsequent surgery with a greater EOR.84 Tumor shrinkage is not just dependent on the molecular profile.85

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Consequently, the individualized therapeutic management of diffuse LGG must not rely solely on routine genetic markers but must also take into account patient-specific clinical and radiological criteria.86

RADIOTHERAPY Indications

Adjuvant Radiotherapy Alone Three Phase III trials provide the best “evidence” regarding the indications for and dosing of RT in WHO grade 2 gliomas. In EORTC 22845, 314 patients were randomized to immediate postoperative RT to 54 Gy or delayed RT at progression. A statistically significant improvement in PFS was associated with early RT, 5.3 versus 3.4 years (p < 0.0001), but no difference was observed in median survival, 7.4 versus 7.2 years.87 In EORTC 22844, 379 patients were randomized to 45 Gy versus 59.4 Gy. With a median follow-up of 74 months, OS (58% vs. 59%) and PFS (47% vs. 50%) were similar.88 In an Intergroup study, 203 patients were randomized to 50.4 Gy versus 64.8 Gy. Again, there was no significant difference in PFS or OS.89 To assess the impact on OS and cause-specific survival (CSS) of early adjuvant RT following resection of supratentorial LGG, 2021 adult patients (age 16-65 years) treated from 1988 to 2007 in the SEER database were evaluated. Of the 2021 patients, 871 (43%) received early adjuvant RT while 1150 (57%) did not. In this analysis, early adjuvant RT was associated with worse OS and CSS on multivariate analysis; however, propensity score and instrumental variable analyses suggested that an imbalance in prognostic factors and confounding variables may explain this discordance.90 Based on these data, the benefit of adjuvant RT alone remains highly controversial in light of the completed randomized trials and is generally not supported as monotherapy. The vast majority of these trials included astrocytoma, oligoastrocytoma, and oligodendroglioma without molecular stratification. Therefore, extrapolating the conclusions to molecularly defined subgroups remains challenging. Patients with large, symptomatic, or incompletely resected WHO grade 2 gliomas likely benefit from adjuvant therapy, while observation may be reasonable in very-low-risk patients with completely resected tumors. In EORTC 22845, patients treated with immediate RT had significantly fewer seizures at 1 year than those who were observed (25% vs. 41%).91 While ongoing trials may better define treatment strategies by molecular subtype, level 1 evidence now exists to support the use of adjuvant RT and chemotherapy in grade 2 gliomas.

Adjuvant Radiotherapy and Chemotherapy RTOG 9802 evaluated RT alone versus RT followed by adjuvant vincristine (PCV) chemotherapy (procarbazine, lomustine [CCNU], and vincristine). In this trial, all patients at high risk for recurrence (age ≥ 40 years or any patient after STR) were randomized to adjuvant RT with or without 6 cycles of PCV. Patients with astrocytoma, oligoastrocytoma, and oligodendroglioma were eligible. With a median follow-up of 11.9 years, 10-year PFS was 21% with RT alone compared with 51% with RT plus PCV. Median survival was 7.5 years with RT alone and was not reached in the RT-plus-PCV arm. Ten-year OS was 40% in patients treated with RT alone compared with 60% with RT plus PCV (HR, 0.59; 95% CI, 0.42-0.83; p = 0.003).57 Because RTOG 9802 was conducted prior to routine molecular evaluation of these tumors, doubts persist as to whether RT plus PCV chemotherapy should be the de facto standard for all patients. Bell and colleagues performed comprehensive combinatorial genomic and clinical prognostic factor analysis on 114 patients (out of 251 enrolled) in the RTOG 9802 protocol who had tissue available for molecular typing. Of the tumors profiled, 75% had IDH1/2 mutations, 40% in the TERT

promoter, 28% in TP53, 24% in ATRX, 22% in CIC, 7% in FUBP1, and 37% expressed 1p/19q codeletions. On multivariate analysis, IDH1/2 mutations (HR, 0.42; 95% CI, 0.23-0.77; p = 0.005), CIC mutations (HR, 0.24; 95% CI, 0.08-0.76; p = 0⋅01), and 1p/19q codeletions (HR, 0.21; 95% CI, 0.09-0.46; p < 0.001) were significantly associated with longer OS. IDH1/2 mutations and 1p/19q codeletions were also significantly associated with improved PFS. On subgroup analysis, both PFS and OS were significantly improved in all three key molecular subgroups with the addition of PCV (IDH mutant and 1p/19q codeleted, IDH mutant and 1p/19q noncodeleted, and IDH wild-type).92 The data suggest that while all subgroups likely benefitted from adjuvant PCV, with the greatest PFS and OS advantages observed in oligodendroglioma patients. Several trials have demonstrated that both temozolomide and PCV are effective in newly diagnosed and recurrent LGG patients. To date, no direct randomized comparison has been reported in the literature. RTOG 0424 reported a 3-year OS of 73.1% (95% CI, 65.3%-80.8%) in high-risk LGG patients treated with RT with concurrent and adjuvant temozolomide, which was higher than historical controls.93 While all high-risk patients received adjuvant therapy after STR in RTOG 9802, delaying RT until progression may be reasonable in selected patients with minimal or no symptoms after STR if they are very young, have biologically less aggressive tumors, and can be followed routinely with MRI. One reason often provided to delay RT is concern for postradiation malignant transformation of the tumor. In the EORTC 22845 trial, no significant difference was observed in malignant transformation with early use of RT (66% with observation vs. 72% with RT); however, the high rates of malignant transformation underscore two concerns. First, the high observed rate of malignant transformation suggests that malignant progression is common in the natural history of this disease. Second, it has been hypothesized that this high rate is driven by astrocytic and IDH wild-type tumors, although the impact of IDH status on post-therapeutic malignant transformation remains unknown. Until further evidence arises to modify this paradigm, the current level 1 evidence supports the use of adjuvant RT and chemotherapy in high-risk LGG patients of all molecular subtypes, and observation following STR should not be routinely recommended in this population.

Dose/Fractionation LGGs are treated with limited RT fields. Gross tumor volume (GTV) includes the postoperative tumor bed and should encompass all FLAIR abnormalities on MRI. Clinical tumor volumes (CTVs) generally comprise a 0.5- to 1.0-cm anatomically constrained expansion. The use of MRI with and without contrast for radiation treatment planning is essential to delineate both the target volume and critical organs at risk. Dose largely remains a matter of preference. In the United States, the total dose is typically 54 Gy in 30 fractions at 1.8 Gy per daily fraction. In Europe, based on the lack of benefit using higher doses, 45 Gy in 25 fractions is frequently employed. Much higher doses lead to a slightly greater risk of cerebral radionecrosis without meaningful clinical benefit.

Reirradiation/Salvage Many LGG patients, particularly those with diffuse infiltrative subtypes, develop recurrent disease. This can lead to radiographic progression and/or worsening neurological symptoms, and up to 72% of patients may develop malignant transformation.94 Treatment options include surgery, chemotherapy, and reirradiation with external beam RT, brachytherapy, or stereotactic radiosurgery (SRS). None of the treatments is curative, although for some favorable subsets, prolonged survival is still feasible. Management should be pursued on a case-by-case basis

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CHAPTER 31 considering tumor extent and location, prior therapies, and the time interval since prior therapies.

Toxicities

Radionecrosis and Pseudoprogression After cranial RT, radiographic changes on MRI can develop in areas receiving high-dose irradiation due to pseudoprogression, radionecrosis, and tumor progression. Pseudoprogression generally appears at a median of 12 months but may be observed greater than 5 years following RT. The pathogenesis of this condition is an interruption in myelin synthesis secondary to oligodendrocyte injury, which is often transient and can lead to spontaneous recovery without intervention. In a large retrospective series, the incidence of pseudoprogression following RT in LGG was 20%, with all examples occurring within the volume receiving greater than 45 Gy.95 Cerebral radionecrosis also can occur months to years following cranial RT96 and is a rare but potentially injurious toxicity owing to vascular injury.97 Analysis of histological specimens collected in radionecrosis cases demonstrate calcification, vascular hyalinization, and endothelial thickening within the affected white matter, consistent with necrosis.98,99 Both pseudoprogression and radionecrosis can lead to MR signal changes, space-occupying lesions with mass effect, and worsening neurological symptoms, which often obligate clinicians to identify and manage the underlying cause of these findings. The findings for these entities are often similar on conventional MRI. It is further important to note that even upon histopathological evaluation, radionecrosis admixed with active tumor is commonly observed. Diffusion tensor imaging (DTI), MR perfusion, MR spectroscopy, and PET can help to differentiate between recurrent tumor and radionecrosis. Restricted diffusion and an elevated rCBV are much more frequently observed in recurrent tumor compared with radionecrosis.100 In regular practice, diffusion-weighted imaging and perfusion images should be included with conventional MRI to aid in evaluation during routine follow-up, with additional studies ordered based on radiographic findings and clinical circumstances.

Delayed Neurocognitive and Neuroendocrine Deficits Neurocognition remains an important consideration for all patients with brain tumors, significantly affecting QoL and function. Brown and colleagues reviewed Mini-Mental Status Examination (MMSE) results for 203 adult LGG patients treated with RT and reported that most maintained stable neurocognitive status after RT. In addition, patients with abnormal baseline results were more likely to experience improvement rather than deterioration in cognition after RT.101 Formal neurocognitive testing further suggests that the tumor itself may have more deleterious effects on cognition than subsequent medical interventions, with RT remaining the most feared.102 In EORTC 22033-26033, high-risk LGG patients were randomized to RT versus dose-dense temozolomide. No difference was found between the two treatment groups in PFS, the primary endpoint, but also no difference between health-related QoL and global cognitive functioning during 3 years of follow-up.103 The authors concluded that cognition was not inferior following RT compared to temozolomide, at least at 3 years. Moreover, patients with IDH1/2 mutant, 1p/19q non-codeleted tumors had improved 5-year PFS with RT compared with temozolomide, while no difference was observed for other molecular subgroups. Grades 3 to 4 hematological toxicity was also significantly increased in the chemotherapy arm (9% vs. < 1%). Rates of moderate to severe fatigue were also diminished in the RT arm.104 It is important to note that RT alone cannot be considered standard of care in high-risk LGG given the dramatic survival advantage reported in RTOG 9802. Long-term neurocognitive impairment following RT for benign or low-grade adult brain tumors could be associated with hippocampal

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dose. Dose to 40% of the bilateral hippocampi (D40) > 7.3 Gy was associated with long-term impairment in list-learning delayed recall.105 In a randomized trial evaluating limited margin RT, Jalali and colleagues reported that LGG patients treated with smaller fields (and, consequently, lower doses to critical organs) had significantly superior mean Full-Scale and performance intelligence quotient (IQ) scores and lower incidence of new neuroendocrine dysfunction at 5 years after RT without compromising survival.106 Reducing dose to normal tissues—in particular, the hippocampus and temporal lobes for neurocognition and the hypothalamic-pituitary axis for neuroendocrine function—is associated with reduction in late effects. Advanced RT techniques, including proton therapy, may reduce cognitive deficits and other treatment-related adverse effects.

Advanced Radiotherapy Modalities Proton therapy spares uninvolved brain tissues from exposure to low-dose radiation compared with traditional photon techniques. Proton therapy has been safely used in the treatment of brain tumors, including WHO grade 2 gliomas, with low toxicity rates and excellent disease control. Whereas initial clinical studies have established preliminary evidence for its efficacy, it is not categorically known whether reduction in dose delivered to normal brain tissues through proton therapy is associated with improved cognitive function or reduction in overall symptom burden in LGG patients. Shih et al. reported results from a prospective trial that enrolled patients with grade 2 gliomas. In addition to reporting excellent disease control rates, they assessed cognitive function and QoL following proton therapy. Twenty patients were enrolled, all with supratentorial tumors. With a median follow-up of 5.1 years, cognitive function remained stable to improved, with no patients experiencing cognitive failure.107 Early results from the University of Heidelberg reporting on 19 patients treated for LGG with pencil-beam scanning proton therapy suggest high rates of tumor control and favorable toxicity rates.108 Badiyan and colleagues reported on 28 patients with LGG treated with pencil-beam scanning proton therapy between 1997 and 2014, 71% of whom were younger than 18 years of age. Median age was 12.3 years (range, 2.2-53.0 years). Eight QoL domains in 16 patients were prospectively assessed. In this series, no grade 3 or higher acute toxicities were observed and no appreciable change in QoL scores was noted in any of the eight domains at any time point.109 To further evaluate the value of proton therapy in this population, the NRG Oncology Group initiated a randomized trial comparing proton versus photon therapy for IDH-mutated WHO grades 2 and 3 gliomas (NRG BN005). Beyond neurocognition, proton therapy can also reduce other late effects compared with photon therapy. In a report from Boston, 32 pediatric patients with LGG were treated with proton therapy from 1995 to 2007 with a median dose of 52.2 Gy relative biological effectiveness (RBE; range 48.6-54). Sixteen patients received at least 1 chemotherapy regimen before definitive RT. With a median follow-up of 7.6 years, 8-year PFS and OS were 82.8% and 100%, respectively. In patients who received serial neurocognitive testing, no significant declines were observed in Full-Scale IQ in the entire cohort (p = 0.80) at a median neurocognitive testing interval of 4.5 years. Subgroup analysis demonstrated measurable declines in neurocognition in particularly young children (< 7 years) and those receiving higher doses to the left temporal lobe and hippocampus. Endocrinopathy incidence correlated with a mean dose of greater than or equal to 40 Gy to the hypothalamus or pituitary gland.110 The major critique of proton therapy is the lack of prospective evidence that dosimetric sparing is associated with clinical benefits in patients despite the fact that late effects require years of concerted follow-up to observe. This gap continues to be filled by ongoing clinical

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488

SECTION III

Disease Sites

investigations. Pulsifer et al. prospectively measured cognitive and adaptive functioning at baseline and during follow-up for 155 pediatric brain tumor patients treated with proton therapy between 2002 and 2017. Mean age was 8.9 years; 61% of patients were treated with focal proton therapy while 39% received craniospinal irradiation (CSI). With a mean follow-up of 3.6 years, mean Full-Scale IQ scores demonstrated a small but statistically significant decline in the total sample from 105.4 to 102.5 (p < 0.01). This decline, however, was only observed in patients younger than 6 years of age receiving CSI, whereas no significant change was observed in older patients receiving CSI or patients of all ages treated with focal fields. Processing speed and working memory scores were significantly lower for patients treated with CSI regardless of age but were not different in patients receiving focal therapy. Adaptive functioning scores for performance reasoning and verbal comprehension were also stable across all ages and treatment field groups.111 These reports on late effects in LGG patients after proton therapy are encouraging. While data continue to mature, radiation oncologists are encouraged to consider advanced radiotherapy modalities in LGG patients with favorable clinical outcomes, especially when the tumor location allows for increased sparing of the left temporal lobe, hippocampus, and hypothalamic-pituitary axis. Fig. 31.2 illustrates a dosimetric comparison between intensitymodulated radiotherapy and proton therapy in a young adult patient with oligodendroglioma following STR. Owing to tumor location within the left temporal lobe, the ipsilateral temporal lobe and hippocampus received near prescription dose in both plans. Proton therapy significantly reduced the contralateral temporal lobe and hippocampus, hypothalamus, pituitary gland, and the total integral dose to normal brain.

SYSTEMIC THERAPY At present, no established standard of care exists for the initial treatment of WHO grade 2 infiltrative gliomas. Surgery followed by observation,

RT, chemotherapy, or combined chemoradiation therapy are all accepted treatments. IDH-mutant and 1p/19q-codeleted oligodendrogliomas and, to a lesser degree, IDH-mutant astrocytomas are often treated with procarbazine, CCNU, and vincristine (PCV) initially or at recurrence,57,112,113 whereas IDH wild-type astrocytomas are treated with temozolomide initially and/or recurrence and a nitrosourea (BCNU or CCNU) at recurrence.114 Bevacizumab, while approved for recurrent WHO grade 4 GBM, has little role and no clear proven benefit in LGG. At the time of recurrence, treatment options are limited, with no accepted standard of care and reduced benefit for both IDH mutant and wild-type tumors.115 The standard care of all WHO grade 1 gliomas involves maximal safe resection, as GTR is often curative. For residual or unresectable tumors, malignant transformation, or recurrent tumors, involved field radiation is the standard of care. Systemic therapy is reserved for recurrent tumors or malignant transformation based on approved treatment for infiltrative gliomas. There is no accepted standard of care for salvage systemic therapy, but options include temozolomide, nitrosourea, platinum, vincristine, and etoposide-containing regimens.116 Various molecularly targeted therapies—for example, directed at BRAF mutations in PXA, H3-K27M mutations in midline gliomas, IDH mutations in diffuse astrocytomas, or oligodendrogliomas—are in early phase trials with none yet approved or proven beneficial.117

PROGNOSIS AND FUTURE DIRECTIONS LGGs are heterogeneous primary CNS tumors with variable natural histories, prognoses, and preferred treatment paradigms. When feasible, maximal safe resection remains the standard of care and is often curative in WHO grade 1 gliomas. Many gliomas, however, harbor a diffuse infiltrative growth pattern that precludes complete surgical extirpation. Grade 2 oligodendroglioma has the most favorable outcomes among LGG patients. While observation can be considered in selected low-risk patients (age < 40 years and GTR), this population is rather uncommon.

Fig. 31.2 Comparative treatment plans in a young adult patient with WHO grade 2 oligodendroglioma following subtotal resection. Compared to intensity-modulated radiotherapy, the proton therapy plan delivers comparable target volume coverage with a significant reduction in low and intermediate doses to the brain and more distant organs at risk, including the contralateral hippocampus and temporal lobes.

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CHAPTER 31 For most patients, adjuvant RT and chemotherapy should be considered following maximal safe resection based on the results of RTOG 9802. In addition, the favorable prognosis of this population suggests that advanced RT modalities, including proton therapy, should be considered in order to reduce late adverse effects of RT with long-term survivorship.118 While the results of RTOG 9802 suggest a benefit in all grade 2 LGG patients regardless of molecular subtype, survival is significantly shortened in patients with IDH1/2 mutant, 1p/19q noncodeleted tumors, and IDH wild-type tumors, the latter of which demonstrate survival akin to GBM. Clinical trials are ongoing to identify superior and novel treatment strategies in these molecularly less favorable tumors. In the future, detailed molecular characterization of LGG may help to better predict which patients may benefit from earlier therapy and determine which patients can be “safely” observed at diagnosis until progression. To date, prospective validation of these strategies is lacking and molecular findings are not commonly used for clinical decisionmaking. Future trials may help to better personalize therapies in LGG patients. The optimal chemotherapy regimen may be clarified by ongoing randomized trials.

CRITICAL REFERENCES 2. Mehta MP, Buckner JC, Sawaya R, Cannon G. Neoplasms of the central nervous system. In: DeVita V, Lawrence TS, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. 4. Sahm F, Reuss D, Koelsche C, et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 2014;128:551–559. 5. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–820. 8. Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015;372:2499–2508. 19. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985–990. 22. Murphy ES, Leyrer CM, Parsons M, et al. Risk factors for malignant transformation of low-grade glioma. Int J Radiat Oncol Biol Phys. 2018;100(4):965–971. 42. Louis DN, Ohgaki H, Wiestler OD, et al, eds. WHO Classification of Tumors of the Central Nervous System. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2016:16–23, 60–69, 80–97, 116–122. 45. Brat DJ, Aldape K, Colman H, et al. cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol. 2018;136(5):805–810. 53. Duffau H. Surgery for diffuse low-grade gliomas (DLGG) oncological outcomes. In: Duffau H, ed. Diffuse Low-Grade Gliomas in Adults. 2nd ed. London: Springer; 2017. 57. Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016;374(14):1344–1355. 60. Jakola AS, Skjulsvik AJ, Myrmel KS, et al. Surgical resection versus watchful waiting in low grade gliomas. Ann Oncol. 2017;28:1942–1948.

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63. Pignatti F, van den Bent M, Curran D, et al. Prognostic factors for survival in adult patients with cerebral low grade glioma. J Clin Oncol. 2002;20:2076–2084. 64. Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term outcome of low grade hemispheric gliomas. J Clin Oncol. 2008;26:1338–1345. 71. Duffau H. Long-term outcomes after supratotal resection of diffuse low grade gliomas: a consecutive series with 11-year follow-up. Acta Neurochir (Wien). 2016;158:51–58. 72. Claus EB, Horlacher A, Hsu L, et al. Survival rates in patients with low grade glioma after intraoperative magnetic resonance image guidance. Cancer. 2005;103(6):1227–1233. 75. Picart T, Herbet G, Moritz-Gasser S, et al. Iterative surgical resections of diffuse glioma with awake mapping: how to deal with cortical plasticity and connectomal constraints? Neurosurgery. 2018;doi:10.1093/neuros/ nyy218. Epub ahead of print. 77. Weller M, van den Bent M, Tonn JC, et al. European Association for Neuro-Oncology (EANO) Task Force on Gliomas. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 2017;18(6):e315–e329. 81. Wijnenga MMJ, French PJ, Dubbink HJ, et al. The impact of surgery in molecularly defined low grade glioma: an integrated clinical, radiological, and molecular analysis. Neuro Oncol. 2018;20:103–112. 88. Karim AB, Maat B, Hatlevoll R, et al. A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys. 1996;36:549–556. 89. Shaw E, Arusell R, Scheithauer B, et al. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol. 2002;20:2267–2276. 93. Fisher BJ, Hu C, Macdonald DR, et al. Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: preliminary results of Radiation Therapy Oncology Group 0424. Int J Radiat Oncol Biol Phys. 2015;91(3):497–504. 105. Gondi V, Hermann BP, Mehta MP, et al. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic RT for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85:348–354. 106. Jalali R, Gupta T, Goda JS, et al. Efficacy of stereotactic conformal radiotherapy vs conventional radiotherapy on benign and low-grade brain tumors: a randomized clinical trial. JAMA Oncol. 2017;3(10):1368–1376. 107. Shih HA, Sherman JC, Nachtigall LB, et al. Proton therapy for low-grade gliomas: results from a prospective trial. Cancer. 2015;121(10):1712–1719. 111. Pulsifer MB, Duncanson H, Grieco J, et al. Cognitive and adaptive outcomes after proton radiation for pediatric patients with brain tumors. Int J Radiat Oncol Biol Phys. 2018;102(2):391–398. 112. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31:344–350.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 31

REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. 2. Mehta MP, Buckner JC, Sawaya R, Cannon G. Neoplasms of the central nervous system. In: DeVita V, Lawrence TS, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. 3. Reifenberger G, Kros JM, Burger PC, et al. Oligodendroglioma. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. 2nd ed. Lyon, France: IARC Press; 2000:56–61. 4. Sahm F, Reuss D, Koelsche C, et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 2014;128:551–559. 5. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–820. 6. Horbinski C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta Neuropathol. 2013;125:621–636. 7. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–773. 8. Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015;372:2499–2508. 9. Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000;343:1350–1354. 10. Houillier C, Wang X, Kaloshi G, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010;75:1560–1566. 11. Sansom M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27:4150–4154. 12. Louis DN, Giannini C, Capper D, et al. cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol. 2018;135(4):639–642. 13. Burger PC, Minn AY, Smith JS, et al. Losses of chromosomal arms 1p and 19q in the diagnosis of oligodendroglioma: a study of paraffinembedded sections. Mod Pathol. 2001;14:842–853. 14. van den Bent MJ, Looijenga LH, Langenberg K, et al. Chromosomal anomalies in oligodendroglial tumors are correlated with clinical features. Cancer. 2003;97(5):1276–1284. 15. Sahm F, Reuss D, Koelsche C, et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol. 2014;128:551–559. 16. Fine VH, Barker GF II, Markert MJ, et al. Neoplasms of the central nervous system. In: DeVita VT Jr, Hellman S, Steven A, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia: JB Lippincott; 2005. 17. Mork SJ, Lindegaard KF, Halvorsen TB, et al. Oligodendroglioma: incidence and biological behavior in a defined population. J Neurosurg. 1985;63(6):881–889. 18. Mehta MP, Bucker JC, Sawaya R, Cannon G. Neoplasms of the central nervous system. In: DeVita V, Lawrence TS, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. 19. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985–990. 20. Ginsberg LE, Fuller GN, Hashmi M, et al. The significance of lack of MR contrast enhancement of supratentorial brain tumors in adults: histopathological evaluation of a series. Surg Neurol. 1998;49:436–440. 21. Chaichana KL, McGirt MJ, Laterra J, et al. Recurrence and malignant degeneration after resection of adult hemispheric low-grade gliomas. J Neurosurg. 2010;112:10–17.

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22. Murphy ES, Leyrer CM, Parsons M, et al. Risk factors for malignant transformation of low-grade glioma. Int J Radiat Oncol Biol Phys. 2018;100(4):965–971. 23. Nakano Y, Yamamoto J, Takahashi M, et al. Pilocytic astrocytoma presenting with atypical features on magnetic resonance imaging. J Neuroradiol. 2015;42(5):278–282. 24. Trehan G, Bruge H, Vinchon M, et al. MR imaging in the diagnosis of desmoplastic infantile tumor: retrospective study of six cases. AJNR Am J Neuroradiol. 2004;25(6):1028–1033. 25. Stanescu CR, Varlet P, Beuvon F, et al. Dysembrioblastic neuroepithelial tumors: CT, MR findings and imaging follow-up: a study of 53 cases. J Neuroradiol. 2001;28:230–240. 26. Sanders WP, Chistoforidis GA. Imaging of low grade primary brain tumors. In: Rock JP, Rosenblum ML, Shaw EG, Cairncross JG, eds. The Practical Management of Low Grade Primary Brain Tumors. 1st ed. Philadelphia: Lippincott Williams & Wilkins; 1999. 27. Pallud J, Capelle L, Taillandier L, et al. Prognostic significance of imaging contrast enhancement for WHO grade II gliomas. Neuro Oncol. 2009;11:176–182. 28. Gozé C, Blonski M, Le Maistre G, et al. Imaging growth and isocitrate dehydrogenase 1 mutation are independent predictors for diffuse low grade gliomas. Neuro Oncol. 2014;16(8):1100–1109. 29. Pallud J, Blonski M, Mandonnet E, et al. Velocity of tumor spontaneous expansion predicts long-term outcomes for diffuse low grade gliomas. Neuro Oncol. 2013;15(5):595–606. 30. Guillevin R, Menuel C, Taillibert S, et al. Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy. Br J Cancer. 2011;104:1854–1861. 31. Jenkinson MD, du Plessis DG, Smith TS, et al. Histological growth patterns and genotype in oligodendroglial tumours: correlation with MRI features. Brain. 2006;129:1884–1891. 32. Zonari P, Baraldi P, Crisi G. Multimodal MRI in the characterization of glial neoplasms: the combined role of single-voxel MR spectroscopy, diffusion imaging and echo-planar perfusion imaging. Neuroradiology. 2007;49:795–803. 33. Guillevin R, Menuel C, Duffau H, et al. Proton magnetic resonance spectroscopy predicts proliferative activity in diffuse low grade gliomas. J Neurooncol. 2008;87:181–187. 34. Reijneveld JC, van der Grond J, Ram LM, et al. Proton MRS imaging in the follow-up of patients with suspected low grade gliomas. Neuroradiology. 2005;47:887–891. 35. Danchaivijitr N, Waldman AD, Tozer DJ, et al. Low grade gliomas: do changes in rCBV measurements at longitudinal perfusion-weighted MR imaging predict malignant transformation? Radiology. 2008;247:170–178. 36. Saito T, Yamasaki F, Kajiwara Y, et al. Role of perfusion-weighted imaging at 3T in the histopathological differentiation between astrocytic and oligodendroglial tumors. Eur J Radiol. 2012;81(8):1863–1869. 37. Law M, Yang S, Babb JS, et al. Comparison of cerebral blood volume and vascular permeability from dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade. AJNR Am J Neuroradiol. 2004;25:746–755. 38. Khayal IS, Crawford FW. Saraswathy S. Relationship between choline and apparent diffusion coefficient in patients with gliomas. J Magn Reson Imaging. 2008;27:718–725. 39. Minn H. PET and SPECT in low grade gliomas. Eur J Radiol. 2005;56:171–178. 40. Jacobs AH, Thomas A, Kracht LW, et al. 18F-fluoro- L-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors. J Nucl Med. 2005;46:1948–1958. 41. Smits A, Baumert BG. The clinical value of PET with amino acid tracers for gliomas WHO grade II. Int J Mol Imaging. 2011;2011:372509. 42. Louis DN, Ohgaki H, Wiestler OD, et al, eds. WHO Classification of Tumors of the Central Nervous System. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2016:16–23, 60–69, 80–97, 116–122. 43. Collins VP, Jones DT, Giannini C. Pilocytic astrocytoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129(6):775–788.

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489.e2

SECTION III

Disease Sites

44. Ebrahimi A, Skardelly M, Schuhmann MU, et al. High frequency of H3 K27M mutations in adult midline gliomas. J Cancer Res Clin Oncol. 2019;doi:10.1007/s00432-018-02836-5. Epub ahead of print. 45. Brat DJ, Aldape K, Colman H, et al. cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. Acta Neuropathol. 2018;136(5):805–810. 46. Dodgshun AJ, Maixner WJ, Hansford JR, Sullivan MJ. Low rates of recurrence and slow progression of pediatric pilocytic astrocytoma after gross-total resection: justification for reducing surveillance imaging. J Neurosurg Pediatr. 2016;17:569–572. 47. Johnson DR, Brown PD, Galanis E, Hammack JE. Pilocytic astrocytoma survival in adults: analysis of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. J Neurooncol. 2012;108:187–193. 48. Bond KM, Hughes JD, Porter AL, et al. Adult pilocytic astrocytoma: an institutional series and systematic literature review for extent of resection and recurrence. World Neurosurg. 2018;110:276–283. 49. Dudley RWR, Torok MR, Gallegos DR, et al. Pediatric Low grade Ganglioglioma/gangliocytoma: epidemiology, treatments, and outcome analysis on 348 children from the SEER database. Neurosurgery. 2015;76(3):313–320. 50. Zentner J, Wolf HK, Ostertun B, et al. Gangliogliomas: clinical, radiological, and histopathological findings in 51 patients. J Neurol Neurosurg Psychiatry. 1994;57(12):1497–1502. 51. Mano Y, Kumabe T, Shibahara I, et al. Dynamic changes in magnetic resonance imaging appearance of dysembryoplastic neuroepithelial tumor with or without malignant transformation. J Neurosurg Pediatr. 2013;11(5):518–525. 52. Bonney PA, Boettcher LB, Conner AK, et al. Review of seizure after surgical resection of dysembryoplastic neuroepithelial tumors. J Neurooncol. 2016;126:1–10. 53. Duffau H. Surgery for diffuse low-grade gliomas (DLGG) oncological outcomes. In: Duffau H, ed. Diffuse Low-Grade Gliomas in Adults. 2nd ed. London: Springer; 2017. 54. Jackson RJ, Fuller GN, Abi-Said D, et al. Limitations of stereotactic biopsy in the initial management of gliomas. Neuro Oncol. 2001;3:193–200. 55. Muragaki Y, Chernov M, Maruyama T, et al. Low grade glioma on stereotactic biopsy: how often is the diagnosis accurate? Minim Invasive Neurosurg. 2008;51:275–279. 56. Sanai N, Chang S, Berger MS. Low grade gliomas in adults. J Neurosurg. 2011;115(5):948–965. 57. Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016;374(14):1344–1355. 58. Sanai N, Berger MS. Surgical oncology for gliomas: the state of the art. Nat Rev Clin Oncol. 2018;15:112–125. 59. Roelz R, Strohmaier D, Jabbarli R, et al. Residual tumor volume as best outcome predictor in low grade glioma - A nine-years near-randomized survey of surgery vs. biopsy. Sci Rep. 2016;6:32286. 60. Jakola AS, Skjulsvik AJ, Myrmel KS, et al. Surgical resection versus watchful waiting in low grade gliomas. Ann Oncol. 2017;28:1942–1948. 61. Capelle L, Fontaine D, Mandonnet E, et al. Spontaneous and therapeutic prognostic factors in adult hemispheric WHO grade II gliomas: a series of 1097 cases. J Neurosurg. 2013;118:1157–1168. 62. Pallud J, Audureau E, Blonski M, et al. Epileptic seizures in diffuse low grade gliomas in adults. Brain. 2014;137:449–462. 63. Pignatti F, van den Bent M, Curran D, et al. Prognostic factors for survival in adult patients with cerebral low grade glioma. J Clin Oncol. 2002;20:2076–2084. 64. Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term outcome of low grade hemispheric gliomas. J Clin Oncol. 2008;26:1338–1345. 65. Chaichana KL, McGirt MJ, Laterra J, et al. Recurrence and malignant degeneration after resection of adult hemispheric low grade gliomas. J Neurosurg. 2010;112:10–17. 66. Chang EF, Potts MB, Keles GE, et al. Seizure characteristics and control following resection in 332 patients with low grade gliomas. J Neurosurg. 2008;108:227–235.

67. Duffau H, Lopes M, Arthuis F, et al. Contribution of intraoperative electrical stimulations in surgery of low grade gliomas: a comparative study between two series without (1985-96) and with (1996-2003) functional mapping in the same institution. J Neurol Neurosurg Psychiatry. 2005;76:845–851. 68. De Witt Hamer PC, Robles SG, Zwinderman AH, et al. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol. 2012;30:2559–2565. 69. De Benedictis A, Moritz-Gasser S, Duffau H. Awake mapping optimizes the extent of resection for low grade gliomas in eloquent areas. Neurosurgery. 2010;66:1074–1084. 70. Chang EF, Clark A, Smith JS, et al. Functional mapping-guided resection of low grade gliomas in eloquent areas of the brain: improvement of long-term survival. J Neurosurg. 2011;114:566–573. 71. Duffau H. Long-term outcomes after supratotal resection of diffuse low grade gliomas: a consecutive series with 11-year follow-up. Acta Neurochir (Wien). 2016;158:51–58. 72. Claus EB, Horlacher A, Hsu L, et al. Survival rates in patients with low grade glioma after intraoperative magnetic resonance image guidance. Cancer. 2005;103(6):1227–1233. 73. Senft C, Bink A, Franz K, et al. Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol. 2011;12(11):997–1003. 74. Martino J, Taillandier L, Moritz-Gasser S, et al. Re-operation is a safe and effective therapeutic strategy in recurrent WHO grade II gliomas within eloquent areas. Acta Neurochir (Wien). 2009;151(5):427–436. 75. Picart T, Herbet G, Moritz-Gasser S, et al. Iterative surgical resections of diffuse glioma with awake mapping: how to deal with cortical plasticity and connectomal constraints? Neurosurgery. 2018;doi:10.1093/neuros/ nyy218. Epub ahead of print. 76. Duffau H, Taillandier L. New concepts in the management of diffuse low grade glioma: proposal of a multistage and individualized therapeutic approach. Neuro Oncol. 2015;17:332–342. 77. Weller M, van den Bent M, Tonn JC, et al. European Association for Neuro-Oncology (EANO) Task Force on Gliomas. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 2017;18(6):e315–e329. 78. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Central Nervous System Cancers. Version 2; 2018. Available at: http://www.nccn.org/professionals/physician_gls/f_ guidelines.asp. Accessed December 15, 2018. 79. de Oliveira Lima GL, Duffau H. Is there a risk of seizures in “preventive” awake surgery for incidental diffuse low grade gliomas? J Neurosurg. 2015;122:1397–1405. 80. Morshed RA, Young JS, Hervey-Jumper SL. Sharpening the surgeon’s knife: value of extent of resection for glioma in molecular age. World Neurosurg. 2018;117:350–352. 81. Wijnenga MMJ, French PJ, Dubbink HJ, et al. The impact of surgery in molecularly defined low grade glioma: an integrated clinical, radiological, and molecular analysis. Neuro Oncol. 2018;20:103–112. 82. Cordier D, Gozé C, Schädelin S, et al. A better surgical resectability of WHO grade II gliomas is independent of favorable molecular markers. J Neurooncol. 2015;121:185–193. 83. Poulen G, Gozé C, Rigau V, et al. Huge heterogeneity in survival data in a subset of adult IDH wild type lower-grade astrocytomas surgically removed. J Neurosurg. 2018;1–10. doi:10.3171/2017.10.JNS171825. Epub ahead of print. 84. Blonski M, Taillandier L, Herbet G, et al. Combination of neoadjuvant chemotherapy followed by surgical resection as a new strategy for WHO grade II gliomas: a study of cognitive status and quality of life. J Neurooncol. 2012;106:353–366. 85. Blonski M, Pallud J, Gozé C, et al. Neoadjuvant chemotherapy may optimize the extent of resection of World Health Organization grade II gliomas: a case series of 17 patients. J Neurooncol. 2013;113:267–275. 86. Duffau H. Paradoxes of evidence-based medicine in lower-grade glioma: to treat the tumor or the patient? Neurology. 2018;91(14):657–662.

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CHAPTER 31 87. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985–990. 88. Karim AB, Maat B, Hatlevoll R, et al. A randomized trial on doseresponse in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys. 1996;36:549–556. 89. Shaw E, Arusell R, Scheithauer B, et al. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol. 2002;20:2267–2276. 90. Gondi V, Eickhoff J, Tome W, et al. Absence of survival benefit from early adjuvant radiotherapy (EART) for resected supratentorial low-grade glioma (SLGG) in adults: a SEER database analysis. Int J Radiat Oncol Biol Phys. 2011;S270:Abstract# 2120. 91. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985–990. 92. Bell EH, McElroy JP, Fleming J, et al. Comprehensive mutation analysis in NRG Oncology/RTOG 9802: a phase III study of RT vs RT + PCV in high-risk low-grade gliomas (LGGs). J Clin Oncol. 2016;34(15_suppl):2017. 93. Fisher BJ, Hu C, Macdonald DR, et al. Phase 2 study of temozolomidebased chemoradiation therapy for high-risk low-grade gliomas: preliminary results of Radiation Therapy Oncology Group 0424. Int J Radiat Oncol Biol Phys. 2015;91(3):497–504. 94. van den Bent MJ, Afra D, de Witte O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985–990. 95. van West SE, de Bruin HG, van de Langerijt B, et al. Incidence of pseudoprogression in low-grade gliomas treated with radiotherapy. Neuro Oncol. 2017;19(5):719–725. 96. Parvez K, Parvez A, Zadeh G. The diagnosis and treatment of pseudoprogression, radiation necrosis and brain tumor recurrence. Int J Mol Sci. 2014;15:11832–11846. 97. Laack NN, Brown PD. Cognitive sequelae of brain radiation in adults. Semin Oncol. 2004;31(5):702–713. 98. Reinhold HS, Calvo W, Hopewell JW, van der Berg AP. Development of blood vessel-related radiation damage in the fimbria of the central nervous system. Int J Radiat Oncol Biol Phys. 1990;18:37–42. 99. Schultheiss TE, Kun LE, Ang KK, Stephens LC. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys. 1995;31:1093–1112. 100. Shah R, Vattoth S, Jacob R, et al. Radiation necrosis in the brain: imaging features and differentiation from tumor recurrence. Radiographics. 2012;32(5):1343–1359. 101. Brown PD, Buckner JC, Uhm JH, et al. The neurocognitive effects of radiation in adult low-grade glioma patients. Neuro Oncol. 2003;5:161–167. 102. Laack NN, Brown PD, Ivnik RJ, et al. Cognitive function after RT for supratentorial low-grade glioma: a North Central Cancer Treatment

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Group prospective study. Int J Radiat Oncol Biol Phys. 2005;63:1175–1183. 103. Reijneveld JC, Taphoorn MJ, Coens C, et al. Lancet Oncol. 2016;17(11):1533–1542. 104. Baumert BG, Hegi ME, van den Bent MJ, et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016;17(11):1521–1532. 105. Gondi V, Hermann BP, Mehta MP, et al. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic RT for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85:348–354. 106. Jalali R, Gupta T, Goda JS, et al. Efficacy of stereotactic conformal radiotherapy vs conventional radiotherapy on benign and low-grade brain tumors: a randomized clinical trial. JAMA Oncol. 2017;3(10):1368–1376. 107. Shih HA, Sherman JC, Nachtigall LB, et al. Proton therapy for low-grade gliomas: results from a prospective trial. Cancer. 2015;121(10):1712–1719. 108. Hauswald H, Rieken S, Ecker S, et al. First experiences in treatment of low-grade glioma grade I and II with proton therapy. Radiat Oncol. 2012;7:189. 109. Badiyan SN, Ulmer S, Ahlhelm FJ, et al. Clinical and radiologic outcomes in adults and children treated with pencil-beam scanning proton therapy for low-grade glioma. Int J Radiat Oncol Biol Phys. 2017;3(4):450–460. 110. Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2014;89:1060–1068. 111. Pulsifer MB, Duncanson H, Grieco J, et al. Cognitive and adaptive outcomes after proton radiation for pediatric patients with brain tumors. Int J Radiat Oncol Biol Phys. 2018;102(2):391–398. 112. van den Bent MJ, Brandes AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31: 344–350. 113. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27:5874–5880. 114. Chammas M, Saadeh F, Maaliki M, Assi H. Therapeutic interventions in adult low-grade gliomas. J Clin Neurol. 2019;15(1):1–8. 115. van den Bent MJ, Chang SM. Grade II and III oligodendroglioma and astrocytoma. Neurol Clin. 2018;36(3):467–484. 116. Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009;24(11):1397–1408. 117. Hargrave D. Paediatric high and low grade glioma: the impact of tumour biology on current and future therapy. Br J Neurosurg. 2009;23(4):351–363. 118. Shih HA, Sherman JC, Nachtigall LB, et al. Proton therapy for low-grade gliomas: results from a prospective trial. Cancer. 2015;121(10):1712–1719.

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32 High-Grade Gliomas Dror Limon, Michal Raz, Andrew B. Lassman, and Benjamin W. Corn

KEY POINTS Incidence There are approximately 75,000 new cases of brain tumors diagnosed in the United States each year. Gliomas now account for nearly 75% of malignant brain tumors. Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor.1 Biological Characteristics The World Health Organization (WHO) classification of brain tumors was revised and published in 2016, introducing a new classification incorporating molecular parameters such as IDH mutational status and 1p/19q co-deletion. Still, better prognosis is associated with grade 3 tumors when compared with grade 4 tumors (i.e., GBM). IDH1/2 mutant gliomas, including astrocytoma without 1p/19q co-deletion and 1p/19q co-deleted oligodendroglioma, are associated with longer survival than IDH wild-type gliomas, with oligodendroglioma considered most favorable. MGMT gene promoter methylation predicts for increased sensitivity to DNA alkylating agents such as temozolomide and is prognostic for overall survival (OS) in patients with GBM, especially older patients, nearly all of which are IDH wild type. Staging Evaluation Optimal imaging is carried out with contrast-enhanced magnetic resonance imaging (MRI). Computed tomography (CT) scans are primarily used as an infrastructure for radiation treatment planning (a function of the tissue electron density that characterizes CT technology, a parameter required for accurate dose computation) before fusion

with MRI images. Early in the postoperative period, ideally within 48 hours, an MRI should be obtained to evaluate the extent of resection and as a basis for radiation treatment planning. Extracranial staging is not performed routinely because gliomas almost never metastasize outside the CNS. Primary Therapy and Results The standard of care for the definitive treatment of newly diagnosed GBM in patients aged 18 to 70 years is the delivery of approximately 60 Gy of fractionated partial brain radiotherapy following maximal safe surgical debulking. Irradiation (most commonly administered with conformal strategies) should be accompanied by concurrent temozolomide chemotherapy. Adjuvant temozolomide is also administered for at least 6 months following the end of radiotherapy unless disease progression occurs. Adjuvant alternating electric field therapy (Optune; Novocure, Portsmouth, NH) also prolongs survival. Special considerations apply to elderly patients and those with poor performance status. Initial results from a prospective trial assessing the role of temozolomide in newly diagnosed WHO grade III gliomas, without 1p/19q co-deletion, has also established its role in this group of patients. Locally Advanced Disease and Recurrence Bevacizumab has been approved for salvage of failures following definitive therapy for GBM. If chemotherapeutic options are not available in the setting of recurrence, creative radiotherapeutic strategies (e.g., reirradiation, radiosurgery, brachytherapy) may be considered.

High-grade gliomas (HGGs) are almost universally fatal. Although recent combined-modality approaches have prolonged survival, many patients succumb relatively quickly, and cure remains elusive for the majority. Progress in the management of brain tumor is glacial. For more than a decade, major changes have not been made in the standard treatment protocol, consisting of temozolomide and radiotherapy. Bevacizumab prolongs progression-free survival (PFS) in the recurrent setting but not survival in newly diagnosed or recurrent disease in randomized studies. Recently, a new treatment modality with alternating electric field therapy has emerged and shows improved survival as first-line therapy in GBM. Molecular profiling of gliomas has also advanced, which may allow tailoring of the treatment of patients diagnosed with HGG in the future.

such as anaplastic astrocytoma and anaplastic oligodendroglioma.2 Other, rarer primary malignant brain tumors discussed elsewhere include anaplastic ependymomas (also a type of glioma), some meningiomas, and primary central nervous system (CNS) lymphoma. Men are more commonly affected than women by HGG. The peak incidence occurs in the age range of 65 to 75 years, and the median survival time is inversely proportional to age. These findings have prompted a redoubling of efforts in elderly subpopulations.1 There has been concern for cancer development following exposure to electromagnetic fields, but definitive evidence is still lacking. The use of cellular telephones has been studied extensively in Europe, but its importance as a risk factor for causing brain tumors has not been established.3 Although a recent meta-analysis suggested an increased risk for glioma with long-term use of mobile phones,4 the real impact of mobile phones on glioma incidence still needs further elucidation. In terms of chemical exposure, nitrosamines have long been regarded as culpable, but causality is far from proven.5 The only accepted environmental risk factor for development of brain tumors

ETIOLOGY AND EPIDEMIOLOGY Most malignant brain tumors are HGGs, and most of these are GBMs, a WHO grade 4 tumor. The remaining HGGs are WHO grade 3 tumors,

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CHAPTER 32

A

B

C

D

High-Grade Gliomas

491

Fig. 32.1 (A) Mitotically active anaplastic oligodendroglioma. (B) Glioblastoma, pleomorphic tumor cells with necrosis. (C) Immunohistochemistry for H3K27M in diffuse midline glioma. (D) Immunohistochemistry for IDH1R132H, in IDH-mutant glioma.

is previous exposure to ionizing radiation5; however, the absolute risk is low. Most gliomas are sporadic, but genetic susceptibility is suspected based on the occurrence of multiple brain tumors in families with germline mutation of the TP53 suppressor gene and patients with neurofibromatosis type 1 as well as the rare patients who have been diagnosed with Turcot’s syndrome. A heritable syndrome contributes to less than 5% of GBMs.6

PREVENTION AND EARLY DETECTION No viable strategy for screening or early detection of glial tumors has been developed. There is also no convincing evidence demonstrating either improved survival when HGGs are found early or a clear rationale for prophylactic strategies to reduce the incidence of these aggressive tumors.5

PATHOLOGY AND PATHWAYS OF SPREAD The WHO classification system for brain tumors is derived in part from the correlation between histological findings and survival rates observed by Bailey and Cushing and published in the early 1900s. In current parlance, “low grade” refers to WHO grades 1 to 2 tumors, and “high grade” to WHO grades 3 and 4 tumors (Fig. 32.1). “Anaplastic” in the context of gliomas refers to WHO grade 3 tumors such as anaplastic astrocytoma and anaplastic oligodendroglioma. WHO grade 4 refers to GBM. The 2016 WHO classification of CNS tumors promotes a nosological shift to a classification based on both phenotype and genotype (Fig. 32.2).2 Generally, infiltrating gliomas are divided first based on their IDH status (wild-type or mutant) and second on the presence (oligodendroglioma) or absence (astrocytoma) of 1p/19q co-deletion, which occurs in a subset of those with IDH mutation. Since all gliomas may be molecularly classified as either astrocytoma or oligodendroglioma, the diagnosis of

a mixed tumor is discouraged and, therefore, was removed from the 2016 classification. Morphological characteristics such as mitotic activity still guide grading, while the presence of microvascular proliferation or necrosis in an infiltrating astrocytic tumor lead to the diagnosis of GBM. GBM is further classified as IDH-mutant or IDH-wild type. The 2016 classification scheme does account for another less common grade 4 infiltrating glioma, the H3K27M-mutant diffuse midline glioma. “Gliomatosis cerebri,” no longer a diagnostic entity, is now regarded as a clinical pattern of extensive CNS involvement. WHO grades 2 to 4 gliomas are characterized by a tendency to directly infiltrate adjacent brain tissue. Lesions with direct access to the corpus callosum may extend across the midline and configure themselves in a classic butterfly pattern (Fig. 32.3). MRI underestimates the extent of invasive disease, and the diffusely infiltrative nature of these tumors makes complete removal of all tumor cells impossible. This “misleading appearance of enucleability” was described more than 90 years ago.7 Leptomeningeal spread occurs occasionally (Fig. 32.4). Hematogenous and lymphatic spread are exceedingly uncommon, which explains the rarity of extra-CNS metastasis. An exception to this rule is seen in patients who received an organ donation from a glioma patient and continue to develop metastatic glioma, suggesting that circulating tumor cells do exist but are generally suppressed and fail to overtly develop metastatic disease.8

BIOLOGICAL CHARACTERISTICS AND MOLECULAR BIOLOGY Investigators around the world are searching for the molecular biological characteristics of gliomas in an effort to improve therapy. For example, work by the Cancer Genome Atlas Research Network9 and others10,11 suggests that at least three molecular subclasses of GBM exist with potential therapeutic and prognostic implications. Mouse modeling has also demonstrated the oncogenic importance of abnormalities in

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492

SECTION III

Histology

Astrocytoma

IDH status

1p/19q and other genetic parameters

Disease Sites Oligoastrocytoma

IDH mutant

ATRX loss* TP53 mutation*

Glioblastoma

Oligodendroglioma

IDH wild-type

IDH wild-type

IDH mutant

Glioblastoma, IDH mutant 1p/19q co-deletion Glioblastoma, IDH wild-type

Diffuse astrocytoma, IDH mutant Genetic testing not done or inconclusive

Oligodendroglioma, IDH mutant and 1p/19q co-deleted

After exclusion of other entities: Diffuse astrocytoma, IDH wild-type Oligodendroglioma, NOS

* = characteristic but not

Diffuse astrocytoma, NOS Oligodendroglioma, NOS Oligoastrocytoma, NOS Glioblastoma, NOS

required for diagnosis Fig. 32.2 Simplified algorithm to classify the diffuse gliomas as a function of histological and genetic features. Of note, the diagnostic flow does not necessarily proceed from histology to molecular genetic features since molecular signatures may outweigh histological characteristics in achieving an integrated diagnosis. NOS, Not otherwise specified. (Redrawn from Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820.)

Fig. 32.3 “Butterfly” glioblastoma (long arrow); a separate satellite lesion in the right parietal lobe (short arrow) is also apparent. The contrast enhancement with central necrosis is classic for a glioblastoma, which was histologically confirmed by biopsy.

receptor signaling (e.g., epidermal growth factor receptor [EGFR] and platelet-derived growth factor receptor [PDGFR]), signal transduction cascades (e.g., RAS and AKT), and cell-cycle regulation.12 In the early 1990s, it was recognized that deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) occurred in most tumors that were characterized histologically as oligodendrogliomas.13 Since then, 1p/19q co-deletion has become a diagnostic marker of oligodendroglioma2 and is also now recognized as prognostic for longer survival.14–16 Until recently, however, controversy existed as to whether this finding should alter therapy.17 It is now recognized that an unbalanced chromosomal translocation underlies 1p/19q co-deletion,18,19 but the specific genes involved and their mechanism of action remain elusive. Thus, co-deletion remains “a marker not a mechanism” (J. Gregory Cairncross, MD, personal communication). Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes, occurring most often in low-grade gliomas but also in a minority of WHO grades 3 and 4 tumors, have been described20,21 and are also prognostic for longer survival.16,20,22,23 Mutations in the chromatin regulator gene, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) gene are typically present with IDH1/2 mutations and TP53 mutations in IDH-mutant astrocytomas24 and are mutually exclusive with 1p/19q co-deletion in IDH-mutant tumors. ATRX alterations are associated with an alternative lengthening of telomeres (ALT) phenotype and are thought to represent a subgroup of patients with better prognosis.25 In a subset of diffuse midline gliomas, characteristically thalamic and brainstem tumors in young patients, a mutation in the histone protein

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CHAPTER 32

Fig. 32.4 T1 contrast-enhanced sagittal view from a magnetic resonance image showing rare leptomeningeal spread from a glioblastoma surrounding the spinal cord.

High-Grade Gliomas

493

The typical imaging appearance of a GBM is a ring-enhancing or heterogeneously enhancing lesion. The differential diagnosis may include stroke, brain metastasis, primary CNS lymphoma, demyelination, and even infectious or other inflammatory diseases. If a brain metastasis is suspected, it is prudent to perform an appropriate extracranial evaluation to identify the primary malignant tumor. If there is a high index of suspicion for primary CNS lymphoma, such as in multifocal, periventricular, or homogenously enhancing lesions,28 corticosteroids should be withheld preoperatively unless herniation is imminent because their use may confound the histological diagnosis. Nearly all GBMs demonstrate contrast enhancement. However, up to 17% of anaplastic gliomas will not manifest such a pattern on imaging.29 Focal enhancement is a predictor of better survival than diffuse enhancement pattern.29 Background uptake in the brain (an organ with an inherent avidity for glucose) significantly compromises the use of glucose-based positron emission tomography (PET) as a diagnostic tool for HGGs. Other radiotracers are sometimes in use for brain PET scans, such as F-DOPA, methionine, and more. These alternatives, however, are still not in widespread clinical use. An algorithm for the evaluation and management of patients with GBM is shown in Fig. 32.5.

PRIMARY THERAPY Prognostic and Predictive Factors

H3K27M is found, which defines a specific grade 4 glioma with worse prognosis.26 Methylation of the MGMT promoter (see the section on chemotherapy, “Systemic Therapy”) is a potential but imperfect predictive and prognostic factor in the treatment of newly diagnosed GBMs. It is not yet clear how to best incorporate molecular data into the treatment of individual patients other than alkylator chemotherapy before or after radiotherapy in patients with newly diagnosed anaplastic gliomas harboring 1p/19q co-deletion. Detailed discussions of the biological characteristics of glioma and their clinical relevance are beyond the scope of this chapter and can be found elsewhere.27 In summary, there is a new paradigm of CNS tumor classification that leads to precision diagnostics. The updated taxonomy enables us to more precisely define tumor types. Presumably, the new system is also more reproducible and, therefore, can impact patient care as well as clinical research. There is a new role for pathologists and the endeavor of clinical decision-making has become more complex. The pathologist is now charged with the provision of diagnostic and actionable targets. The very nature of the neuro-oncology tumor board has been altered since not only neurosurgeons, neuro-oncologists and/or medical oncologists, and radiation oncologists occupy seats around the table, but also room must be made for diagnostic and informatics specialists. Consensus can thereby be reached in order to improve diagnosis, prognosis, and treatment. A new genomic understanding of primary brain tumors will help us with patient care today and will also assist in precisely defining the next generation of clinical trials.

CLINICAL MANIFESTATIONS, PATIENT EVALUATION, AND STAGING No specific symptom constellation is pathognomonic of HGG. Typically, patients present with some combination of headaches, neurological deficits, nausea, and vomiting depending on tumor size and location. It is not unusual for patients to present with or subsequently develop seizures. Tissue for pathological diagnosis can be obtained via stereotactic biopsy, open biopsy, or gross resection in the context of craniotomy. More complete resection improves diagnostic accuracy, provides additional tissue for molecular analyses, and is increasingly thought to improve OS.

Historically, all HGGs were lumped together in clinical trials, confounding results because of maldistribution of patients with differing prognoses. In 1993, Curran et al.30 published a landmark paper describing a prognostic classification scheme based on clinical variables. Data from three Radiation Therapy Oncology Group (RTOG) trials that enrolled nearly 1600 patients with high-grade glioma from 1974 to 1989 were used. This recursive partitioning analysis (RPA) methodology builds decision trees to model predictors by examining all possible cut points for all variables included in the model. Patients were segmented into six distinct groups with different survival outcomes. The key variables included patient age, performance status, histological tumor type (i.e., anaplastic astrocytoma vs. GBM), mental status, symptom duration antecedent to diagnosis, extent of resection, neurological function, and radiotherapy dose. This data predated the temozolomide era but the European Organization for Research and Treatment of Cancer (EORTC) demonstrated that the prior RTOG RPA classification remained valid among patients treated with radiation and temozolomide.31 Simplification of the model was subsequently introduced also in alignment with current treatment strategies.32 The original RPA classification also lacked molecular markers, but a recent nomogram introduced MGMT protein levels and c-Met expression into the classification.33 The median survival was 21.9 months for class 1, 16.6 months for class 2 and 9.4 months for class 3. One of the more controversial factors in the setting of HGGs has been the extent of surgical resection. Bailey and Cushing observed longer survival following resection in their 1926 publication,7 as did others in the 1960s.34 Numerous series since then also support more complete resection as a prognostic factor.35–39 One of the largest involved more than 400 patients at the M. D. Anderson Cancer Center (MDACC) and demonstrated improved median survival (13 vs. 8.8 months; p < 0.0001) following at least 98% resection as defined by postoperative MRI scans,40 although the importance of a specific threshold remains unclear. A systematic review and meta-analysis of 37 trials evaluating this question found decreased mortality for gross tumor resection compared with subtotal resection and for subtotal resection when compared to biopsy only.41 Use of 5-aminolevulinic acid fluorescence intraoperatively improves the likelihood of gross total resection,39 but the effect on

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494

SECTION III

Disease Sites Treatment schema for glioblastoma Suspected GBM: History and PE MRI Maximal surgical resection (if feasible)

Postoperative treatment: 60 Gy partial brain RT plus concurrent and adjuvant temozolomide (with or without TTF) Consider clinical trial Follow-up History and PE MRI Suspected PD on MRI: Differentiate from pseudoprogression (RANO criteria, advanced imaging studies) Recurrent disease: Second-line systemic therapy Surgery (with or without BCNU wafers) Reirradiation Consider clinical trial Fig. 32.5 Algorithm for diagnosis and treatment of glioblastoma. See text for details. BCNU, Carmustine; GBM, glioblastoma, MRI, magnetic resonance imaging; PD, progressive disease; PE, physical examination; RANO, Response Assessment in Neuro-Oncology; RT, radiotherapy; TMZ, temozolomide; TTF, tumor-treating fields.

survival has been debated. Retrospective analyses have been criticized by the potential for selection bias; that is, patients who were treated with more aggressive surgery may have had other favorable prognostic factors preoperatively. Nonetheless, maximal safe surgical resection is now widely considered standard of care and is associated with improved survival relative to less extensive attempts at tumor extirpation.

Surgery Patients often undergo a craniotomy, in which the goal is the safe removal of the largest possible volume of tumor to establish a diagnosis and relieve mass effect. HGGs are not surgically curable because of their extensive infiltration into the brain. If biopsy rather than resection is pursued, choices include stereotactic options with CT or MRI guidance or open craniotomy and biopsy. Some have employed metabolic imaging, such as magnetic resonance spectroscopy (MRS) to better select the biopsy sites most likely to contain the most aggressive portions of the tumor, but this is not widely used. Usually, stereotactic biopsy can be performed using either frame-based or frameless neuronavigation systems. The pathologist can review the frozen section to make an immediate preliminary diagnosis and confirm tissue adequacy. When craniotomy is contemplated, meticulous planning is invested in the scalp incision and flap design. Special care must be taken to preserve the vascular supply of the scalp. The bony opening is devised to be sufficiently large to facilitate resection without needlessly exposing adjacent brain to the risk of injury. After opening the scalp, burr holes are placed and connected with a craniotomy. The bone flap is removed and the dura mater is opened. As a rule, the bone flap is reattached at the end of the resection, although some surgeons prefer not to reattach the bone flap. Although tumors on the brain surface are immediately visible after exposure, subcortical lesions are harder to discern. Frameless image-guided

neuronavigation systems are employed to localize subcortical tumors along with intraoperative ultrasound and MRI. Tumors that are situated near “eloquent” areas of cortex, such as those harboring motor and speech function, are mapped intraoperatively via electrical cortical stimulation to achieve maximal tumor debulking without operative morbidity. This technique of “awake craniotomy” was shown to allow aggressive resection with language preservation and even verbal improvement.42 Occasionally, tumors may be removed en bloc via circumferential dissection, but more frequently, resection is effected in piecemeal fashion. A cavitational ultrasonic surgical aspirator (CUSA) facilitates removal of a firm, adherent, or calcified tumor. Patients are routinely monitored in an intensive care unit following a craniotomy. The first MRI is obtained within 24 to 48 hours after surgery before postoperative changes set in to determine the extent of resection.

External Beam Radiotherapy External beam radiotherapy (EBRT) has historically been the cornerstone of the therapeutic approach to HGGs for the past half-century, and its use in brain tumors was already described by the 1920s.43 By the 1970s and early 1980s, categorical level 1 data became available from several studies,44 including prospective Phase III trials conducted by the Brain Tumor Study Group (BTSG; Table 32.1).45,46 The radiotherapeutic approach to HGG has evolved. Initially, large opposed lateral fields were employed to cover the entire brain volume. In 1989, Shapiro et al.47 published data from Brain Tumor Cooperative Group trial 80-01, in which the randomization was altered during the trial to compare partial brain irradiation with whole-brain radiotherapy (WBRT). No difference in OS or change in the patterns of failure was seen. Accordingly, WBRT is generally not advocated, except perhaps in the scenario of a widespread intracranial process such as gliomatosis cerebri.

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CHAPTER 32

495

High-Grade Gliomas

Positive Phase III Trials Evaluating the Role of Radiotherapy, Chemotherapy, or Chemoradiotherapy in the Treatment of Malignant Gliomas

TABLE 32.1 Study BTSG 69-01

a,45

BTSG 72-01b,46

EORTC/NCI-Cc,80,81,87

No. Patients

Treatment Arm

Median (mo)

18 mo

24 mo

5y

VSG 31 51 68 72

Observation Carmustine Radiotherapy Radiotherapy plus carmustine

— 3.2 4.3 8.3 7.9

0 4 4 19

0 0 1 5

0 0 NA NA

VSG 81 94 92 91

Semustine Radiotherapy Radiotherapy plus carmustine Radiotherapy plus semustine

— 4.8 8.3 11.8 9.7

10 15 27 23

8 10 15 12

NA NA NA NA

286 287

Radiotherapy Radiotherapy plus temozolomide

12.1 14.6

21 39

11 27

2 10

p = 0.001 for radiotherapy versus observation/supportive care and radiotherapy plus carmustine versus observation/supportive care. p ≤ 0.003 for radiotherapy, radiotherapy plus carmustine, and radiotherapy plus semustine versus semustine alone. c p < 0.0001. Most patients randomized to radiotherapy alone crossed over to temozolomide at time of relapse or progression. BTSG, Brain Tumor Study Group; EORTC, European Organization for Research and Treatment of Cancer; NA, not available; NCI-C, National Cancer Institute of Canada; VSG, valid study group. a

b

Several lines of evidence have influenced the trend to treat the gross tumor volume along with a margin of approximately 2 cm. In a classic paper published in 1980, Hochberg and Pruitt48 used CT scans to determine that nearly 90% of GBM recurrences occurred within 2 cm of the primary tumor site (although this may be changing with the use of bevacizumab). Wallner et al.49 assessed the patterns of recurrence in 32 patients with unifocal malignant gliomas who were treated with primary surgery and postoperative irradiation. Nearly 80% of patients manifested recurrence or progression within 2 cm of the original tumor. Even when 80 Gy of partial brain irradiation was used in a prospective Phase I trial, 90% of patients failed within the high-dose region.50 It has been demonstrated on biopsy and autopsy studies that the abnormality detected on T2 or fluid-attenuated inversion-recovery (FLAIR) images harbors microscopic tumor extension. Accordingly, 45 to 50 Gy is generally delivered in 1.8- to 2-Gy fractions to the T2/ FLAIR abnormality seen on the image, followed by a boost to raise the total dose to 60 Gy based on the T1-enhancing abnormality. The MRI abnormalities, however, remain quite nonspecific in terms of histopathological confirmation, and even when novel strategies such as MRS are used for radiotherapy planning, there can be over- or underestimation of the true extent of microscopic disease spread.51 Various strategies to reduce and adjust the volume of radiation have been tested. One approach is the MDACC technique, that uses clinical target volume (CTV) of the resection cavity + 2-cm margin (excluding edema expansion) + 5-mm planning target volume (PTV) to 50 Gy and resection cavity + 5-mm PTV to 60 Gy.52 This approach, when compared with the classic RTOG protocol (published only in abstract form) showed similar recurrence patterns with better overall survival and quality of life for the smaller fields.53 Other strategies use functional or advanced imaging to define areas with higher risk for recurrence. One approach looked into the dose to neuroprogenitor cells in the subventricular zone (SVZ). High dose (> 40 Gy) in the ipsilateral SVZ was associated with a significantly improved PFS and OS.54,55 An ongoing trial is comparing standard radiation fields with or without SVZ dose (NCT02177578).

Rationale for Current Total Irradiation Dose A pooled analysis of three successive randomized trials conducted by the BTSG (66-01, 69-01, and 72-01) generated data to support doses in excess of 50 Gy.56 A stepwise improvement in survival was observed with doses ranging from less than 45 to 60 Gy, consistent with dose response. A comparison of 70 versus 60 Gy demonstrated no survival or local control advantage for the 70-Gy dose.57,58 These results established 60 Gy as the standard of care. Dose escalation has remained an important investigational option because there is still a pattern of failure characterized by local progression or recurrence. There are now multiple techniques for dose escalation, including three-dimensional conformal irradiation, radiosurgery, and brachytherapy, but these have not yielded higher rates of disease control or survival. An ongoing randomized Phase II trial by NRG Oncology is evaluating dose escalation with temozolomide, but the highly anticipated results of this trial are pending (NCT02179086).

Altered Fractionation The RTOG has systematically and rigorously studied hyperfractionation for HGGs. In RTOG 83-02, patients were randomized to one of four dose arms (64.8 Gy, 72 Gy, 76.8 Gy, or 81.6 Gy) using twice-daily fractions of 1.2 Gy. Initial results suggested the superiority of 72 Gy,59 but a subsequent Phase III trial did not confirm this finding.60 Prados et al.61 used an elegant randomization to assess not only a hyperfractionation schedule but also to determine the activity of difluoromethylornithine (DFMO), a compound that inhibits sublethal and potentially lethal damage repair. Unfortunately, neither intervention improved survival.

Stereotactic Irradiation The role of stereotactic radiosurgery (SRS) in the treatment of malignant gliomas has not been clearly defined. Two provocative small-scale experiences prompted the design of Phase III trials to formally evaluate SRS for HGGs.62,63 Loeffler et al. reported on 37 patients treated with 59.4 Gy of fractionated radiotherapy followed by an SRS boost to a

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496

SECTION III

Disease Sites

median dose of 12 Gy. After a median follow-up period of 19 months, a 76% survival rate was reported.62 Sarkaria et al. described 115 patients with HGG who received conformal radiation therapy and an SRS boost; median survival time was 96 weeks.63 These results called into question whether there was a benefit from SRS or simply selection bias. RTOG 93-05 compared conformal irradiation plus carmustine with or without an SRS boost for newly diagnosed GBM. No differences were observed in terms of OS (median, approximately 13 months in each arm) or quality of life.64 Of note, the patients in that prospective trial had relatively large tumors, which may have overridden the potential efficacy of SRS. In the face of that negative prospective trial, interest in radiosurgical options was shunted to the setting of recurrent disease.

Brachytherapy Brachytherapy, the use of implanted radioactive material at the site of the tumor, offers a mechanism for focal dose escalation. Both permanent and temporary radioactive implants have been used. Early positive results by Gutin et al.65 suggested a potential survival benefit in a Phase II trial. These findings were not reproduced in subsequent randomized trials.66,67 Interest in this modality was rekindled when the GliaSite radiation therapy system (Proxima Therapeutics, Alpharetta, GA) received approval by the US Food and Drug Administration (FDA) in 2001. This intracavitary device is implanted at the time of tumor debulking, and a solution of iodine-125 (125I) is injected into an expandable closed-catheter balloon. A retrospective study suggested reasonable safety and promising efficacy68; a Phase I study was subsequently conducted.69 However, the implant induces changes in imaging that complicate determination of disease progression.70

Systemic Therapy Early randomized trials of chemotherapy were individually negative, but meta-analysis of these trials showed that 15% to 20% of patients treated with EBRT and nitrosoureas survived at least 18 months versus 5% to 15% treated with radiotherapy alone (see Table 32.1).45,46,71,72 Nitrosoureas, especially carmustine, were the most commonly used drugs, although procarbazine was also used extensively.73 The combination of procarbazine, lomustine (CCNU), and vincristine (PCV)74 had no clear benefit (yet much greater toxicity) versus carmustine for anaplastic astrocytoma.75 This regimen has been largely abandoned for nonoligodendroglial tumors. Intratumoral delivery of chemotherapy for residual postoperative disease is most commonly in the form of carmustine-eluting (Gliadel, Chemocare, Cleveland, OH) wafers. Patients undergoing wafer implantation during surgery for recurrent GBM survived approximately 2 months longer than patients without wafers in one study (p = 0.02).76 Treatment of newly diagnosed disease also yielded a 2-month prolongation of average survival.77,78 However, this was not statistically significant when the analysis was restricted to patients with GBM histology. Of note, wafer delivery of carmustine versus systemic administration has not been compared for safety or efficacy. Gliadel does, however, carry an FDA label for implantation during resection of recurrent GBM and newly diagnosed malignant glioma. Attempts to treat residual visible or microscopic disease with other local chemotherapies delivered through implanted catheters and using convection-enhanced migration of drug have generally failed.79 Currently, the most widely used chemotherapeutic agent is temozolomide. Whether it is more effective than nitrosoureas has not been investigated, but it is unquestionably better tolerated, with significant myelosuppression in less than 20% of patients.80,81 Temozolomide was first approved for use in the United States in recurrent anaplastic astrocytomas following a Phase II study.82 A randomized study also demonstrated superior efficacy to procarbazine in recurrent GBM.83

Temozolomide for newly diagnosed GBM has been studied both when given before radiotherapy (RT)84 and when combined with RT in various dosing schedules.85,86 Its role for newly diagnosed GBM was established by Stupp et al.80,81 on the basis of the EORTC 26981/22981 and NCIC CE.3 trials (see Fig. 32.5). In this Phase III multicenter study, 573 patients with newly diagnosed GBM received EBRT alone or EBRT with concurrent temozolomide followed by six adjuvant cycles of temozolomide. The patients who received the combined-modality regimen had significantly longer OS and PFS without significantly more toxicity (see Table 32.1). The 5-year OS was 10% among those receiving temozolomide versus 2% among those receiving RT alone (p < 0.0001).81 Patients in the most favorable RPA class had a 5-year OS rate of 28% following combined therapy.81 In a companion paper, Hegi et al.87 reported that promoter methylation for the O6-methylguanine DNA methyltransferase (MGMT) gene, which encodes the DNA repair enzyme O6-alkylguanine DNA alkyltransferase (AGT or AGAT, but now commonly also referred to as MGMT), correlated with prolonged survival and patients with MGMT methylated tumors benefited the most from temozolomide. MGMT repairs DNA damage induced by temozolomide, and methylation of the MGMT promoter silences expression of the protein, thereby accentuating the antineoplastic effects of temozolomide. However, the mechanism by which MGMT-promoter methylation leads to an improved outcome is more complex. For example, some patients with tumors that did not demonstrate MGMT methylation also benefited from temozolomide although it is increasingly recognized that the initial test probably scored some methylated tumors as either unmethylated or unknown.80,81,87 Accordingly, it remains unclear whether MGMT analysis should categorically alter treatment, although this situation remains somewhat fluid. In addition, patients with tumors harboring methylated MGMT survived longer following treatment with RT alone than patients who did not have tumors harboring methylated MGMT treated identically.80,81 Others reported similar findings in GBM88 and other malignant gliomas.89 Moreover, MGMT protein expression by immunostaining does not predict outcome.90 Several groups have explored intensifying the temozolomide dosing schedule in an attempt to overcome MGMT-mediated resistance.91,92 The intensified regimens are designed to deplete MGMT activity as suggested by previous studies.93 RTOG 0525 was a Phase III randomized, placebo-controlled study that compared standard temozolomide dosing following completion of radiotherapy (150-200 mg/m2 body surface area days 1 to 5 of 28) versus an intensified regimen (75-100 mg/m2 body surface area days 1 to 21 of 28). This prospectively validated MGMT-promoter methylation as a favorable prognostic factor regardless of treatment.94 However, dose-dense temozolomide was more toxic than standard dosing and did not significantly alter PFS or OS regardless of MGMT status.94 Therefore, MGMT-promoter methylation is prognostic but the mechanism remains unclear. In addition, there are several different methodologies to test for MGMT-promoter methylation, which may lead to discordant results.95 It is possible that MGMT is a marker of more global hypermethylation and is only one of multiple genes mechanistically involved in resistance to alkylator chemotherapy and prognosis in tumors harboring the recently described glioma CpG island methylator phenotype (G-CIMP).96,97 Therefore, a practical approach to determine MGMT promotor methylation testing results should be implemented, as it might determine the test interpretation and have an impact on clinical decisions.98 Treatment duration with temozolomide is also a subject of controversy. The original EORTC protocol used 6 months of adjuvant treatment.80 However, common practice showed that prolonged use of temozolomide for a longer period had an acceptable safety profile,

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CHAPTER 32 although lacking proof of efficacy.99,100 Notwithstanding, retrospective comparisons of 6 months of temozolomide with longer treatment durations did not reveal an OS advantage,101,102 although the larger study did show an advantage in PFS for the prolonged use, especially in the MGMT methylated group.101 Another major area of investigation has been the use of vascular endothelial growth factor receptor (VEGFR) signaling inhibitors. Bevacizumab is a monoclonal antibody against VEGF that competitively inhibits binding of the ligand to VEGFR and targets tumor vascularity. It is the most widely studied of these antiangiogenic strategies. Based on encouraging response rates and prolongation of PFS in recurrent GBM,103,104 two major Phase III studies—RTOG 0825 and Avastin in Glioblastoma (AVAglio), sponsored by F. Hoffmann La Roche—were launched nearly simultaneously. Following maximal safe surgical resection, both studies randomized patients to receive RT and temozolomide plus either bevacizumab or placebo. Although there were subtle differences in trial design with respect to extent of resection (e.g., biopsy-only patients not permitted in RTOG 0825 but allowed in AVAglio, timing of treatment, and so on), both demonstrated prolongation of PFS (median, 10.7 vs. 7.3 months, p = 0.007 for RTOG 0825; median, 8.4 vs. 4.3 months, p < 0.001 for AVAglio).105,106 However, neither demonstrated a difference in OS (median, 15.7 vs. 16.1 months, p = 0.21 for RTOG 0825; median, 16.8 months vs. 16.7 months for AVAglio, p = 0.10). Both permitted crossover from placebo to bevacizumab that was offered as part of the study design to participants in RTOG 0825 and permitted but not offered routinely in AVAglio. These results have not categorically settled the issue of whether bevacizumab should be used for newly diagnosed GBM. In RTOG 0825, the prolongation of PFS did not meet the prespecified statistical level (30% reduction in hazard, p = 0.004 required for significance), whereas it did for AVAglio (23% improvement, p = 0.01 required for significant difference in PFS). In addition, quality of life (QOL) measures in RTOG 0825 did not demonstrate a net clinical benefit. In fact, it was worse for those who received bevacizumab, whereas stabilization of QOL during the PFS period was observed in AVAglio.105–107 In the context of these results, some practitioners consider using bevacizumab for patients with unresectable large, deep tumors with surrounding edema, especially patients with poor performance status, but such patients would have been excluded from the Phase III trials. Other antiangiogenic therapies also have not improved survival. For example, the integrin inhibitor cilengitide was tested in a Phase III trial in combination with temozolomide and radiotherapy but failed to improve results.108 Two systemic reviews that evaluated the efficacy of antiangiogenic agents in HGGs also failed to identify improved survival.109,110 Two studies have evaluated antiangiogenic therapy in particular for patients with MGMT unmethylated tumors. The CORE (Cilengitide in patients with newly diagnosed glioblastoma multifoRme and unmethylated MGMT genE promoter) trial randomized such patients to EBRT and temozolomide with or without cilengitide but failed to improved survival.111 The German GLARIUS Phase II trial randomized cases with ummethyalted MGMT 2 : 1 to EBRT and concurrent bevacizumab followed by maintenance bevacizumab and irinotecan or EBRT with concurrent and adjuvant temozolomide for six cycles.112 The primary endpoint was 6-month PFS. As was seen with other bevacizumab trials, PFS was improved but not OS. These results suggest that there is a group of patients that may benefit from antiangiogenic therapy. Thus far, however, this group has not been clearly identified.

Immunotherapy GBM has long been thought to hold immunosuppressive features.113 A few mechanisms were suggested to play a role in this local immunosuppression

High-Grade Gliomas

497

as transforming growth factor-β (TGF-β) secretion by tumor microglia cells,114 PD-L1 overexpression by macrophages of GBM patients,115 downregulation of sphingosine 1-phosphate receptor 1 (S1P1),116 indoleamine 2,3-deoxygenase (IDO) expression by GBM cells,117 and more. Attempts to recruit the immune system for treating GBM has been ongoing for several decades, using various strategies with only anecdotal successes.118 Over the past decade, there have been encouraging results, although the hints of benefit still have not been incorporated into routine daily practice. A few modalities have been developed and tested over the years: dendritic cell–mediated vaccinations, immune checkpoint inhibitors, oncolytic viral therapies, and chimeric antigen receptor T-cell (CART) therapy. Addressing the full extent of this subject is beyond the scope of this chapter. Therefore, we choose to briefly focus on a few important examples. The first published Phase III trial119 used a peptide vaccine, called rindopepimut, which targets the epidermal growth factor receptor variant III (EGFRvIII), a mutant receptor formed by the deletion of exons 2 to 7, which is expressed in about 20% of GBM patients.120 In this trial, EGFRvIII-positive patients were treated by standard first-line therapy with temozolomide and EBRT and were randomized to add the vaccine or a control injection (which was the vaccine conjugate only). The study was terminated for futility after a preplanned analysis that did not show any survival difference (~ 20 months in both arms).119 Immune checkpoint inhibitors have been a subject of extensive research over the past decade. Although initial results from the use of the PD-1 inhibitor pembrolizumab in CNS tumors were discouraging,121 current trials are examining checkpoint inhibitors’ role in newly diagnosed and recurrent GBM. An initial report from the CheckMate 143 trial, comparing bevacizumab to the PD-L1 inhibitor nivolumab for recurrent disease, did not meet the primary endpoint of OS difference with ~ 10 months in both arms.122 The effect of checkpoint inhibitors with radiotherapy is still not well established, and current trials are ongoing in newly diagnosed patients combined with EBRT (NCT02617589 and NCT02667587). Encouraging results are seen with another treatment strategy that uses genetically modified T-cells, which are manipulated to present a T-cell-activating receptor to tumor-specific antigens. These cells are called chimeric antigen receptor T (CART) cells. The most prominent report concerned the use of IL13Rα2-targeted CARTs123 that were infused into a patient with recurrent multifocal GBM and induced regression of all tumor sites. A current trial with IL13Rα2-targeted CARTs is ongoing (NCT02208362). First results from a Phase III trial that tested an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax-L, Northwest Biotherapeutics, Bothell, WA) for newly diagnosed glioblastoma were recently reported.124 Following surgery and concurrent EBRT + temozolomide, patients were randomized (2 : 1) to receive adjuvant temozolomide with the vaccine or placebo. The study allowed for all patients to receive the vaccine upon disease progression, which was eventually given to nearly 90% of patients. The study arms are still blinded; however, the median survival was 23.1 months for all for the intent-to-treat population and 34.7 months for the MGMT methylated population124 when pooling patients from both arms. These results are superior to historical controls. Whether the vaccine itself prolongs survival remains to be determined. The use of oncolytic viruses was also reported in early-phase clinical trials.125 Recent Phase I results from Duke University described the treatment of recurrent GBM with recombinant poliovirus.126 Patients received infusion of the manipulated virus through a convection-enhanced delivery catheter and were assessed with increasing doses for toxicity and survival. Grade 3 toxicity and higher was reported in 19% of patients. Median survival was 12.5 months, not meaningfully superior to 11.3 months in

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498

SECTION III

Disease Sites

RT

Maximal surgical resection

AG without 1p–19q combined loss

RT ! Concurrent TMZ R RT

Adjuvant TMZ

RT ! Concurrent and adjuvant TMZ Fig. 32.7 Schema from the CATNON study (Intergroup Phase III, EORTC 26-53, RTOG 0834).135 AG, Anaplastic glioma; R, randomization; RT, radiotherapy; TMZ, temozolomide.

The most recent addition to the armamentarium against HGG is alternating electric field therapy (Optune; Novocure, Portsmouth, NH). This technology is a wearable device that contains transducer arrays that attach to the scalp. A connection is made to an electric field generator; a lightweight battery pack is carried by the patient and worn for at least 18 hours a day (Fig. 32.6). The transducer arrays deliver alternating electric fields that have been dubbed tumor-treating fields (TTF), which have theoretical potential to disrupt mitosis. A Phase III randomized trial (study EF-14) of 695 patients with newly diagnosed GBM treated with TTF in addition to maintenance temozolomide had a statistically significant benefit in OS (median survival time of 21 vs. 16 months; p < 0.001) when compared with those treated by standard therapy (surgery, radiochemotherapy, and maintenance temozolomide).127 There was no significant difference between the two arms in the overall frequency of adverse events (48% vs. 44%); however, mild to moderate scalp dermatitis under the transducer arrays occurred in 52% of those randomized to TTF. A detailed secondary endpoint assessment of health-related quality of life (HRQoL) scales completed by patients128 showed no significant differences between the treatment arms of study EF-14 in an area under the curve analysis. The trial has been criticized for flawed randomization (e.g., a sham device was not used) as well as variance in follow-up between the intervention group and the group getting the standard (Stupp) regimen. Moreover, TTF constitutes a radical departure from standard of care and there is documented reluctance of physicians to incorporate new technologies.129 Studies are being designed to assess earlier use of TTF by combining the technology with the radiochemotherapy that follows surgical resection with early safety results recently reported.130

whether chemotherapy or EBRT was used first among patients with anaplastic astrocytomas, oligodendrogliomas, and mixed tumors.16 However, time to progression following RT was longer than after chemotherapy, and initial RT achieved more complete and partial responses than initial chemotherapy, suggesting the superiority of EBRT.131 Long-term results confirmed the initial report; further analysis by histology and various molecular subgroups—oligodendroglioma, astrocytoma, CpG island methylator phenotype (CIMP), 1p/19q deletion, and IDH—did not demonstrate an advantage to either one of the treatment arms.132 Regarding chemotherapy, Combs et al.133 reviewed the outcomes of 191 patients with grade 3 astrocytic tumors treated at the University of Heidelberg with either EBRT alone or EBRT in combination with temozolomide during a 20-year period (from 1988 to 2007). In this retrospective study, no significant advantage in rates of OS or PFS could be attributed to the combination. The RTOG 9813 trial randomized patients with anaplastic astrocytomas (or oligoastrocytomas) to EBRT with concurrent nitrosourea (carmustine or lomustine) or with temozolomide.134 The study was terminated prematurely since it did not meet the target accrual rate. No OS or PFS differences were seen, with median survival around 4 years in both arms. However, combination with nitrosourea was more toxic than temozolomide. The other finding was that IDH-mutated patients had better survival than IDH-wt (7.9 years vs. 2.8 years, p = 0.004).134 The EORTC 26053-22054 trial, also called CATNON—Concurrent vs. Adjuvant Temozolomide for NON 1p/19q co-deleted anaplastic gliomas—randomized patients to receive postoperative EBRT alone (59.4 Gy in 33 fractions), concurrent temozolomide and EBRT without adjuvant temozolomide, EBRT (without concurrent temozolomide) followed by 12 cycles of adjuvant temozolomide, or EBRT with both concurrent and adjuvant temozolomide (Fig. 32.7).135 The study recruited WHO grade 3 gliomas without 1p/19q co-deletion. Interim analysis of 748 patients shows improved survival for the adjuvant temozolomide arms compared with EBRT alone (median survival not reached vs. 41.1 months). The impact of concurrent temozolomide was not yet reported.135 Therefore, as NOA-04 demonstrated that survival following initial chemotherapy alone was at best equivalent to initial EBRT alone132 and CATNON demonstrated that combined radiochemotherapy (with temozolomide) was superior to EBRT alone, by extrapolation, combinedmodality therapy is likely superior to temozolomide alone.135

Anaplastic Gliomas

Anaplastic Oligodendroglial Tumors

Anaplastic astrocytomas and anaplastic oligodendrogliomas represent the most common WHO grade 3 tumors.1,2 In anaplastic gliomas, resection appears to improve survival relative to biopsy, as it does for GBM.

Long-term follow-up is now available for patients enrolled in the RTOG 94-0214,136 and EORTC 26951 trials.15,137 In these studies, EBRT was compared with EBRT with PCV chemotherapy. The RTOG trial entailed administration of chemotherapy before EBRT (intensified PCV138 for up to four cycles in the combined-modality arm) whereas the reverse sequence (i.e., EBRT alone vs. EBRT followed by up to six cycles of standard-dose PCV) was used in the EORTC trial. With median follow-up

Fig. 32.6 This figure depicts components of the Optune system, as described in the text. (Courtesy Novocure, Portsmouth, NH.)

an institutional historical control. The OS rate was 21% after 24 and 36 months, better than historical control but also possibly the result of selection bias.126 A randomized study has not been completed.

Tumor-Treating Fields

Anaplastic Astrocytic Neoplasms It is generally accepted that EBRT should be administered postoperatively for astrocytomas. In a German study (NOA-04), survival was equivalent

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CHAPTER 32 in excess of 10 years in both studies, there was a dramatic improvement in OS associated with combined chemotherapy and radiotherapy (irrespective of sequence) among patients with anaplastic oligodendroglioma or anaplastic mixed oligoastrocytoma whose tumors contain allelic loss of chromosomes 1p and 19q compared with EBRT alone. For example, in RTOG 9402, median survival was 14.7 years versus 7.3 years (p = 0.03, hazard ratio [HR], 0.59 for chemoradiotherapy; 95% confidence interval [CI], 0.37-0.95; p = 0.03) and in EORTC 26951, the median survival was not reached versus 9.3 years (p = 0.0594, HR, 0.56 for chemoradiotherapy; 95% confidence interval [CI], 0.31-1.03). In addition, patients with IDH mutant but not 1p/19q co-deleted tumors also benefited from chemotherapy in RTOG 9402, although the magnitude was lower than for those with tumors that harbored both co-deletion and IDH mutation.139 Those with MGMT-promoter methylation95 or ATRX retention139 may also benefit regardless of 1p/19q deletion status. The applicability of these findings in an era in which PCV is no longer popular remains debatable, especially because temozolomide has almost entirely replaced PCV in routine practice140 despite the lack of a clear efficacy equivalence. On the contrary, the NOA-04 shows a PFS benefit for PCV over temozolomide in the CIMP co-deleted population.132 What is clear, however, is that EBRT alone is inadequate for treatment of patients with co-deleted tumors and likely those with IDH1- or IDH2-mutated tumors, regardless of deletion status. In addition, the role of RT for newly diagnosed anaplastic oligodendroglioma is becoming the subject of controversy because of the tumor’s reported sensitivity to chemotherapy,138 especially tumors with 1p/19q co-deletion.141 Neither RTOG 9402 nor EORTC 26951 used chemotherapy alone, which was recommended by 42% of clinicians (typically with temozolomide)17 and used in 55% of patients from 2005 to 2007 in a retrospective series of co-deleted tumors, without prospective data supporting such usage.140 The ongoing CODEL (for 1p/19q CODELeted tumors) trial now randomizes patients with low-grade or anaplastic 1p/19q co-deleted tumors to RT followed by PCV versus EBRT plus concurrent and adjuvant temozolomide (NCT00887146), which is hoped will provide an answer. The approach of postponing EBRT for the chemotherapy-sensitive tumors such as 1p/19q co-deleted oligodendroglioma is especially appealing if one also takes into account the long-term cognitive effect of brain RT.142 Current trials are expected to provide some answers to these debatable issues, such as a study in France of PCV versus EBRT and PCV for 1p/19q co-deleted anaplastic oligodendroglial tumors with survival without neurocognitive deterioration as the primary endpoint (NCT02444000). However, as discussed earlier, NOA-04 results would suggest that deferring EBRT will shorten OS132 relative to EBRT and PCV.

Special Topics

Elderly Patients With GBM The highest incidence of GBM occurs in patients older than 65 years.1 One of the few shortcomings of the landmark trial published by Stupp et al. from the EORTC and Canadian Cancer Trials Group (CCTG) in 2005 was the investigators’ decision to exclude patients older than 70 years of age.80 Thus, following the publication of the study, a dilemma arose since a new standard for grade 4 glioma had emerged, but clinicians were not certain that the results were applicable to the elderly. The question was compounded when a post-hoc analysis of the aforementioned study showed that the subgroup of patients aged 65 to 70 years had less survival benefit from the addition of temozolomide to radiotherapy.143 Several small studies have attempted to sort through these issues. The Association of French-Speaking Neuro-Oncologists conducted a randomized trial comparing EBRT alone (50 Gy in conventional fractionation) versus supportive care among patients older than 70 years.144 The trial was discontinued after 85 patients were registered

High-Grade Gliomas

499

when it became apparent that RT was associated with a statistically advantageous outcome (median survival time, 29 vs. 17 weeks; p = 0.002). Efforts to abbreviate the duration of EBRT have also been conducted. For example, a randomized study in patients older than age 60 years demonstrated that 40 Gy in 15 fractions was not inferior to 60 Gy in 30 fractions.145 A later Phase III trial for the elderly (age ≥ 65 years) and/or frail (Karnofsky Performance Status [KPS] 50%-70%) patients with newly diagnosed GBM compared the abbreviated course of 40 Gy with a shorter course of 25 Gy in 5 fractions.146 The trial showed noninferiority of the 25-Gy course, with comparable OS, PFS, and QOL. A Phase II study of temozolomide alone in 32 patients older than age 70 years with newly diagnosed GBM demonstrated a response rate of 31%, median PFS time of 5 months, and median survival time of 6.4 months, comparable to EBRT alone.147,148 A single-arm 77-patient Phase II study for those older than age 70 with poor performance status (KPS < 70) demonstrated median survival of approximately 6 months, with 26% becoming functionally independent (KPS at least 70).149 As always, it is perilous to compare results across trials and physicians are often left with the duty of making a clinical decision on a per-case basis or by establishing a somewhat arbitrary policy in a given institution. In the NOA-08 trial, patients older than 65 years (who had a KPS of at least 60) showed noninferiority of dose-dense temozolomide when compared with standard RT of 60 Gy (median OS 8.6 months for temozolomide and 9.6 months for EBRT, p for noninferiority = 0.033) but superiority of temozolomide treatment when compared with RT in MGMT-methylated patients.150 The Nordic trial randomly assigned patients (initially older than 60 years and, subsequently, older than 65 years) to standard-dose temozolomide versus hypofractionated RT (34 Gy in 10 fractions) versus standard RT (60 Gy in 30 fractions).151 The results showed that in patients older than 70 years, temozolomide alone and hypofractionation were associated with longer survival compared with standard RT (9 months for temozolomide, 7 months for hypofractionation vs. 5.2 months for standard RT, p < 0.0001 for temozolomide and p = 0.02 for hypofractionation both vs. standard EBRT). Once again, there was a clear benefit for temozolomide among patients whose tumors had MGMT promotor methylation. Considerable attention has also been given to another trial led by the CCTG wherein hypofractionated RT (40 Gy in 15 fractions) was tested with or without concurrent and adjuvant temozolomide, in a protocol similar to the Stupp regimen, for “fit” elderly patients (e.g., age ≥ 65, Eastern Cooperative Oncology Group [ECOG] score of 0-2).152 The trial showed good tolerability and a survival advantage to the temozolomide arm (median OS of 9.3 months vs. 7.6 months, p < 0.001). This is the first randomized evidence showing the actual benefit of adding temozolomide to EBRT in this population of patients. A reasonable clinical stance may be to offer the latter CCTG regimen to older patients with good performance status and to recommend temozolomide alone to older patients with MGMT-methylated tumors while proposing hypofractionated RT alone to older patients with MGMT-unmethylated tumors. Another void in the literature pertains to nonelderly patients with poor functional status. There is overlap between these populations—one wonders if there is sufficient similarity to make some clinical inferences. While many assume that it is clinically sound to apply the principles learned from older patients to young patients with poor functional status, it must be remembered that this ostensibly logical reasoning does not have an evidence base.

Pseudoprogression Pseudoprogression confounds interpretation of imaging performed in the first several months following completion of EBRT. Descriptions of pseudoprogression appeared as early as 1979, when Hoffman et al.153

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500

SECTION III

Disease Sites

described patients treated with EBRT and carmustine. Among patients thought to have experienced disease progression immediately following irradiation, nearly half were shown to have improvement or at least stabilization on subsequent brain imaging. A report in 2004 indicated that approximately one-third of patients with gliomas stabilized or improved with no change in management.154 Chamberlain et al.155 reported histologically proven treatment injury rather than disease progression in approximately 50% of patients with symptomatic resectable lesions felt to represent worsening disease following concurrent EBRT and temozolomide. There is concern that the incidence of pseudoprogression is higher following concurrent EBRT and temozolomide than that following EBRT alone, although supportive evidence is equivocal.156 The incidence of pseudoprogression has been reported to be as high as 75% in selected subsets of patients with GBM.92,157,158 Pseudoprogression rather than “true” progression may also correlate with MGMT-promoter methylation,157 and IDH mutation159 and improved survival, although this has not yet been prospectively validated. Multiple imaging techniques have been explored to delineate radiographic pseudoprogression from true progression.157,160–162 However, at this time, histological analysis is the only validated method of distinguishing the two diagnoses, and even that has its limitations because of sampling issues and difficulty in interpreting tumor cell viability posttreatment.163 One interesting technique that was histologically validated uses highresolution treatment response assessment maps (TRAMs), based on MRI contrast accumulation, to distinguish real progression from pseudoprogression, with a positive predictive value of 96%.164 One approach to dealing with this issue was proposed by the RANO (Response Assessment in Neuro-Oncology) Working Group with further modifications and involves using the MRI study done following EBRT as a new baseline, unless there is surgical documentation of recurrent disease or clear worsening outside of the EBRT field (80% isodose line). This remains an area of active study.165,166 This issue is further complicated with the introduction of immunotherapy into clinical trials and was addressed by the RANO Working Group, making the diagnosis of progression also based on clinical status and time from initiation of immunotherapy.167 The issue of pseudoprogression requires further research and refinement.

RECURRENT DISEASE It is axiomatic that nearly all patients with GBM will manifest recurrence after treatment. Assuming there is true progression, rather than pseudo-progression, and that the patient has relatively good functional status, several therapeutic options are available. If, on the other hand, the patient has poor functional status then best supportive care may be more appropriate than an aggressive intervention. The array of options available to the clinician is a testimony to the fact that there is no solitary solution to the problem of recurrent GBM. Therefore, there is equipoise among neuro-oncologists to offer clinical trials to this poor-prognostic group.

Surgery Repeat resection, depending on the size and location of the lesion, can achieve cytoreduction and corroborate the diagnosis of true rather than pseudoprogression. Given today’s analytic capability, surgery is not merely a tool to verify that there is active tumor but also enables the identification of targetable mutations. The latter is a prerequisite for accrual to many clinical trials. Several small retrospective series from centers of neuro-oncologic excellence168,169 have suggested that there may be a survival advantage to gross total re-resection in comparison to subtotal re-resection but,

of course, resectability may simply be a surrogate for favorable features such as small tumor volume. One controversial study suggested that surgery for recurrent GBM is associated with shorter rather than longer survival.170

Reirradiation

Brachytherapy Focal RT approaches are often employed with limited volume recurrences. In a retrospective analysis of 95 patients with recurrent gliomas treated with brachytherapy, using the GliaSite device (Proxima Therapeutics, Inc., Alpharetta, GA), the median survival time was 36 weeks.171,172 However, whether this is a function of true benefit or patient selection has not been determined. At large, brachytherapy treatment in recurrent disease has not been extensively used or studied.

Radiosurgery Another form of focal EBRT, single-fraction SRS, may have a role in the treatment of recurrent disease, particularly if a focal region of recurrence can be well defined. However, this has not been tested in prospective trials. A previous report showed a PFS of 4.6 months following SRS for recurrent GBM and better survival than historical control.173 The main complication was radionecrosis, reported in 24% of patients. A recent report by Bokstein et al.174 examined 55 SRS procedures among 47 patients with HGG (70% GBM; 30% grade 3 glioma) that was locally progressive. The median prescription dose was 18 Gy (range: 14-24 Gy) and the median target volume was 2.5 cc (range, 0.2-9.5 cc). In 22 cases, chemotherapies (usually temozolomide) or biological therapies (usually bevacizumab) were added. Comparison was made to a matched cohort (by histology, age, and KPS) with recurrent HGG treated with bevacizumab alone. Median survival was significantly longer for the SRS-treated patients compared with those treated by bevacizumab only (12.6 months vs. 7.3 months; p = 0.0102). The authors speculated that judicious application of SRS in the setting of minimalvolume recurrences has merit. Further prospective data is needed to better define the targeted patient population and real impact of this modality as a single or combined therapy.

Fractionated EBRT Fractionation and hypofractionation to treat larger-volume recurrent disease has also been employed. Although there has been speculation from animal studies that neural tissue will recover from previous irradiation to a large extent once some time has elapsed (e.g., 1-3 years),175 no firm data quantify the degree to which one can assume that a “dose discount” exists. It is most likely that the damage from reirradiation is underestimated because the majority of patients do not live long enough to express clinical sequelae from such damage. A Phase I dose escalation trial176 for reirradiation following a previous dose of 60 Gy found a dose-related response (response rate ~ 80%) with no major toxicity when using doses of 30 to 35 Gy in 10 fractions. A small study showed good short-term tolerance to intensity-modulated radiation therapy (IMRT) delivered in six daily fractions of 5 Gy each.177 A single-arm trial from the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated reasonable safety and efficacy of combined bevacizumab and reirradiation (5 Gy × 6 fractions) for small recurrent malignant gliomas.178 A follow-up study also showed that this approach may be useful179—no radionecrosis was observed and survival appeared to be prolonged relative to historical controls, suggesting that bevacizumab may not only treat radionecrosis180 but might protect against it. In terms of efficacy, there is no prospective randomized data. A recent systematic review, presented as an abstract only,181 found a 1-year survival rate of 39%, which might be higher with concurrent use of systemic therapy. Prospective data is expected form the RTOG 12-05 trial, a Phase II

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CHAPTER 32 study that compares concurrent bevacizumab plus reirradiation (using a hypofractionated RT—35 Gy in 10 fractions) with bevacizumab alone (NCT01730950). As mentioned, no standard protocol exists for the dose and scheme of reirradiation, nor for the combination of systemic therapy. Most trials use hypofractionation protocols, ranging from 30 to 35 Gy in 5 to 10 fractions.182 There is also some variability in the definition of the target volumes.182 The gross target volume (GTV) in usually defined as the T1-enhancing lesion. Most trials did not add a CTV, while some included the peritumoral edema. The RTOG 1205 protocol allows a CTV expansion of up to 5 mm for lesions measuring < 3.5 cm or new lesions; otherwise, no expansion can also be used. Planning target volume (PTV) expansion, as always, is localization dependent and can range from 1 to 5 mm.

Systemic Therapy Efforts to treat recurrent disease with single agents, either cytotoxics or molecular-targeted agents, have generally been unsuccessful, at least in part because of the innate resistance, poor drug penetrability, and molecular complexity of the disease.183 If the treatment-free interval between the conclusion of maintenance chemotherapy and recurrence is relatively long, and disease progression did not occur during temozolomide previously, patients can be rechallenged with temozolomide. There is no consensus regarding the optimal disease-free interval or dosing of temozolomide in this context. For instance, Weller et al. stewarded the DIRECTOR trial (Dose Intensified Re-challenge with Temozolomide)184 but could not identify an impact on survival when comparing a schedule of 21 days on and 7 days off with a schedule of 1 week on followed by 1 week off. For patients who recur in the wake of a short treatment-free interval after completing temozolomide, or those who experience progression during the administration of adjuvant temozolomide, the nitrosoureas have made a comeback. Although this family of agents is associated with higher rates of adverse events (e.g., interstitial lung disease as well as hepatic, hematological, and renal toxicity), the dire nature of the clinical scenario of recurrence behooves a relatively high level of risk taking. Various single agents—lumustine, carmustine, and fotemustine—have demonstrated 6-month PFS ranging between 13% and 20%. In the favorable subset of patients with first progression, the 6-month PFS rates can be as high as 60% and median overall survival time can approach 1 year.185 Considerable excitement was generated following the accelerated approval of bevacizumab for recurrent glioblastoma by the FDA in 2009. Since then, skepticism has arisen and investigators have realized that the desperate nature of recurrent disease allowed a relatively low threshold for countenancing this biological agent. The BRAIN trial was a noncomparative Phase II study for recurrent GBM that randomized 167 patients to either bevacizumab alone or bevacizumab combined with irinotecan.104 The 6-month PFS was 43% with bevacizumab and 50% with bevacizumab plus irinotecan. Similar results were seen in a single-arm Phase II study conducted by the National Cancer Institute (NCI; United States).103 None of these trials, however, provided categorical evidence of improved OS. Follow-up trials have also failed to demonstrate a significant impact of bevacizumab on survival outcomes with median OS times generally ranging between 6 and 9 months.186 Investigators have also attempted to combine nitrosoureas and bevacizumab. For example, lomustine was conjoined with bevacizumab in the Phase II BELOB trial (BEvacizumab vs. LOmustine in glioBlastoma).187 That protocol provided a hint of a survival benefit for the combination in comparison with either of the agents given alone. However, that survival benefit could not be corroborated in a subsequent Phase III trial, with medians of approximately 9 months with either lomustine + bevacizumab or lomustine alone.188

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In assessing the therapeutic ratio of bevacizumab, alone or in combination, one must also take into account its association with impaired wound healing, blood clot risks and hypertension. Conversely, one of the redeeming features of bevacizumab is the ameliorating effect that the drug can have on peritumoral edema. In the absence of a proven standard therapy, an appealing approach that has benefited patients with other solid tumors is the use of targeted therapy driven by individual tumor profiling, using genomic sequencing. An early report suggested, for example, increased tumor response to EGFR tyrosine kinase inhibitors in patients co-expressing EGFRvIII and PTEN.189 However, more recent experience with treating patients according to genomic sequencing has shown very disappointing results, although targetable mutations were found in 95% of patients.190 This deflating outcome might be a result of major tumor heterogenicity and may call for a different approach with the use of targeted therapy in GBM. A potential approach that might overcome tumor heterogenicity lies with the use of immunotherapy in this setting, described earlier in this chapter, which showed encouraging results in recurrent disease.123,126

Tumor-Treating Fields Finally,TTF has also been explored in the recurrent setting. A Phase III trial, in the context of recurrent disease, suggested noninferiority when compared with any one of several possible physician-chosen chemotherapy regimens.191 This was true for both PFS and OS (median survival 6.6 months vs. 6.0 months, p = 0.27; 6-month PFS 21.4% vs. 15.1%, p = 0.13) with less toxicity than chemotherapy.191

IRRADIATION TECHNIQUES AND TOXICITIES WBRT has been replaced with partial brain techniques by consensus for almost all gliomas. Although the dose computation component of treatment planning requires CT imaging, effective image registration with MRI has made this the modality of choice for contouring. The notion of a dedicated MRI simulator has also been proposed as a valuable adjunct in the radiotherapeutic management of HGGs.192 However, treatment plans based only on MRI are not able to take into account tissue electron-density variations, which may lead to slightly inaccurate dose calculations. Advances in this field with more accurate electrondensity assignment algorithms, while using MRI scans, lead to MRI-CT concordance in the upper 80th percentile.193 Patients are usually simulated after surgical wound apposition is reasonably stable and free of infection (generally, 10-14 days after the operation). An immobilization mask is fashioned to reduce motion during and between fractions. The planning CT scan is extended to encompass the head and neck region to allow sufficient anatomic areas for proper image fusion and generation of high-quality digitally reconstructed radiographs (DRRs) and to permit the introduction of noncoplanar beams. Ideally, the slice thickness should match that of the MRI used for fusion. For HGGs, especially GBM, T1 contrast-enhanced sequences are used to define the GTV and the T2 or FLAIR sequences plus a margin to define the microscopic disease extent or CTV, which reflects the bulk of microscopic infiltration. The CTV may be further modified to exclude normal tissue in areas where gliomas are unlikely to infiltrate. Anatomic barriers such as the temporal bone can serve as a border to impede tumor spread; failure is likely to be seen in less than 5% of cases even when the customary 2-cm margins are not added to the abnormalities seen on MRI (Fig. 32.8).194 To arrive at a PTV, both organ motion and setup error must be taken into account. Organ motion in the brain is quite minimal during therapy (e.g., < 1 mm). In general, there are two major schools of thought (with numerous institutional variations based on these) that provide guidance for

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502

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Disease Sites

Radiotherapy Volume Used in Recent Clinical Trials

TABLE 32.2 RT Dose

Dosimetry Margin

Source for RT Dose

46 Gy 14 Gy

T2 + 2 cm T1 + 2 cm

RTOG/NRG

60 Gy

T1 + 2-3 cm

EORTC

EORTC, European Organization for Research and Treatment of Cancer; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group.

Fig. 32.8 Lesion that could be treated without a full complement of margins because of anatomic barrier of the temporal bone.

the prescription of the radiation regimen. The RTOG approach is a biphasic technique that includes an initial PTV (PTV1) followed by a second PTV (PTV2) that represents the cone down. In the lexicon of the RTOG, postoperative MRI scans are used, the PTV1 includes GTV1 that delineates the T2 or FLAIR changes, then a margin of 2 cm is used to define CTV1. This volume (CTV1) should be cropped to exclude expansions beyond anatomic boundaries, such as bones, flax, ventricles, brain cisterns, and so on. The PTV1 is created with further margins of 3 to 5 mm and is treated with 46 Gy in 2-Gy fractions. The PTV2 includes the T1-enhancing GTV2 with a margin of 2 cm to create CTV2 and is treated with an additional 14 Gy. PTVs can be altered where proximity to organs at risk (OARs) prevents treatment delivery while maintaining OAR constraints. In contrast, the EORTC recommends a single-phase technique using one treatment volume throughout the course of therapy. The GTV is then defined as the postoperative enhancing T1 lesion, 2- to 3-cm margins are added to create the CTV and 3 to 5 mm for the PTV, which is treated with 60 Gy. Table 32.2 shows the partial brain volumes advocated by EORTC and RTOG cooperative groups for the successive phases of partial brain irradiation. Fig. 32.9 shows a comparison of treatment plans made according to the two approaches. With the advent of functional imaging tools (e.g., functional MRI [fMRI]) it may be possible to specifically modify irradiation doses to functional brain areas. Fig. 32.10 displays a treatment plan in which the region governing motor control (e.g., finger tapping) is delineated to enable an accounting for dose deposition. In this case, this region in the right hemisphere (i.e., governing tapping by the left upper extremity) is included in the high-dose region but the contralateral side is well spared; a major caveat here is that the dose-response relationships for various functional subvolumes in the brain are largely unknown. Therefore, this information is of little practical dosimetric usefulness at this point in time. In RTOG 08-25, it was noteworthy that approximately 80% of patients, irrespective of treatment arm, received IMRT. Lorentini et al.195 performed a meticulous comparison of IMRT and three-dimensional (3D) conformal irradiation among patients treated for GBM. The IMRT plans consistently provided better target coverage than their 3D-conformal counterparts and yielded a statistically significant dose reduction to the healthy brain.

The authors suggested that IMRT represents the superior technique when there are more than two regions of overlap between OARs and the PTV. However, clinical data supporting improved outcomes from IMRT in HGGs is essentially nonexistent. Table 32.3 summarizes the tolerance of various OARs according to the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines. Lawrence et al.196 postulated that the original estimates of Emami et al.,197 suggesting a 5% risk of chronic brain damage at 5 years when one-third of the brain is irradiated to 60 Gy, were overly conservative. Instead, they hypothesized (Fig. 32.11) that the dose correlated with a 5% risk of damage at 5 years following conventionally fractionated irradiation to the partial brain of 72 Gy, but data regarding subvolumes and substructures sensitivity (i.e., motor cortex, basal ganglia, and so on) are not included in the QUANTEC assessment. They also suggest higher brain sensitivity when using fractional doses over 2 Gy,196 a factor that should be considered when treating with hypofractionation (e.g., elderly patients), although the practical meaning of this consideration is not clear. There may sometimes be a tendency to overlook structures that, if damaged, would have led to noncatastrophic sequelae. For instance, although it is true that radiation-induced cataracts are easily repairable,198 avoidance of entrance and exit dose to the eye may be a relatively simple means of preventing not only cataracts but also conjunctivitis and dry eye by sparing the lacrimal gland. Similarly, when one contours the ear canals, there is now a greater awareness of the risks of developing otitis externa as well as otitis media. Avoiding the parotid glands should also be considered when treating temporal lesions to reduce the risk for xerostomia. Overall, the aim is to achieve the treatment plan that most closely approximates the defined volumes and thereby produces the most conformal plans.

Toxicities of Radiotherapy Acute radiation morbidity includes fatigue, erythema, alopecia, headache, and, rarely, nausea with or without vomiting; these are generally not severe and are usually self-limiting. Some have cautioned that the combination of cranial EBRT and phenytoin as well as other anticonvulsants could give rise to the Stevens-Johnson syndrome,199,200 but this dermatological emergency is an exceedingly rare event and the causal association between the two has not been established. Fatigue is a common symptom among patients with primary brain tumors, reported in 40% to 70% of patients during the course of their illness201 and exacerbated during EBRT.202 The underlying mechanism is unknown, while various theories were proposed, for example, a dose-dependent effect to the brainstem and posterior fossa, reported in head and neck cancer patients.203 Pharmacological interventions for ameliorating this phenomenon are generally disappointing204 with armodafinil being the most investigated drug.205 The lack of data prevents specific recommendations from being made for dose constraints and calls for further study.

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CHAPTER 32

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503

Patient 1

A

B

Patient 2 B

A

Fig. 32.9 Comparison of treatment plans between EORTC (plan A) versus RTOG/NRG (plan B) guidelines. Of note, differences are prominent when there is a large T2 component (e.g., as seen in patient 2, whereas T2 changes are nil in patient 1 and, therefore, the respective plans are practically superimposable). EORTC, European Organization for Research and Treatment of Cancer; RTOG, Radiation Therapy Oncology Group.

Late effects of radiation (e.g., somnolence and, especially, cognitive impairments) are more worrisome and may become manifest many years later.142 The impact of partial brain irradiation on neurocognitive decline continues to be a hotly debated topic. The confounding factor is always the extent to which there is baseline cognitive impairment or decreased mentation secondary to tumor. Hippocampal sparing may emerge as a method to reduce the risks of neurocognitive injury as it appears to do in the treatment of brain metastases with WBRT.206 Feasibility trials revealed that this strategy can at least be implemented for the contralateral hippocampus.207,208 Brain necrosis is a serious and uncommon late toxicity to which bevacizumab can be used as a treatment option, reported in GBM and brain metastases.178,180 We currently estimate the risk of normal tissue damage based on the most sensitive 5% of the population. Accordingly, we bias our recommendations in a manner that is not germane to most individuals; preliminary efforts at predicting the likelihood of toxicities based on individual risk are ongoing.209,210

Radiotherapy for Grade 3 Gliomas Guidelines for tumor delineation and dose selection for WHO grade 3 gliomas are less well developed. In general, the same considerations as for GBM are implemented here. The FLAIR and T2 compartments are regarded as containing microscopic disease and, therefore, constitute the CTV. The typical dose is 59.4 or 60 Gy in 1.8- to 2-Gy fractions.

TREATMENT ALGORITHM, CONTROVERSIES, CHALLENGES, AND FUTURE POSSIBILITIES Treatment Algorithm Fig. 32.5 illustrates the current standard of care for adults younger than 70 years who are diagnosed with GBM, while further details about treatment decisions with imaging changes and disease progression can be found earlier in this chapter. For newly diagnosed anaplastic gliomas, choosing the timing for EBRT and/or chemotherapy is a bigger challenge, which takes into account the tumor histology and molecular parameters, as mentioned earlier.

Controversies

Elderly Patients Treatment for elderly patients (variably defined as older than 60, 65, or 70 years, depending on the study) remains a subject of dispute. Since not all elderly patients are alike, we propose a practical approach based on geriatric assessment of these patients. This can be done with the more extensive Comprehensive Geriatric Assessment (CGA)211 or with the use of an abbreviated tool, such as the G8 questionnaire.212 Based on this assessment, patients can be divided into 3 categories—good, intermediate, and poor—and different treatment strategies can be offered to each group. In addition, patients can be further divided according to MGMT methylation status, based on previously discussed trials145,150–152 and illustrated in Fig. 32.12.

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504

SECTION III

Disease Sites

Left SMA

Right SMA Left SMA

Right SMA

Right SMA Left SMA CTV1

CTV1 Fig. 32.10 Treatment planning based on a functional magnetic resonance imaging. Note delineation of the clinical target volume (CTV) as well as left and right somatomotor areas (SMA) controlling hand movements of the right and left upper extremities, respectively.

Selected Organs at Risk for Treatment Planning of Malignant Glioma

TABLE 32.3

Dose Limit– Dmax

Organ 196

Comments

Brain parenchyma

72 Gy

Brain appears to be more sensitive to fraction size > 2 Gy and to twice-daily radiotherapy.

Optic apparatus216

55-60 Gy

Risk of optic neuropathy is rare under 55 Gy and increases to 3%-7% between 55 and 60 Gy

Brainstem217

54 Gy

59 Gy if small volumes (i.e., 1-10 mL)

Retina218

45-50 Gy

Cochlea219

Mean dose, 45 Gy

Challenges Local control of HGGs remains a vexing problem. The increased recognition of pseudoprogression following chemoradiation as well as immunotherapy213 and the possibility of pseudoresponse to antiangiogenic therapy such as bevacizumab214 complicate matters further. Revised consensus criteria were developed in part to address some of these issues.165,167 Certainly, correlative clinical follow-up to provide the proper perspective on the health status of the patient will never be abandoned, because imaging will always represent an imperfect surrogate for survival. Although new developments in diagnostic imaging continue to hold

promise for resolution of the diagnostic dilemmas faced by the neurooncology team, to date, even the most sophisticated imaging studies (e.g., PET-MRI and MRS) have not provided a consistently reliable solution to these and other problems.

Future Possibilities Prior dose-escalation trials for GBM, all conducted in the pretemozolomide era, have been uniformly negative beyond 60 Gy. However, it is conceivable that the notion of dose escalation now needs to be revisited in the context of control of microscopic disease by temozolomide enhancing the effect of focal dose-escalation as well as the potential radioprotection offered by bevacizumab.178 Incorporating new treatment strategies, such as including molecular and genomic data in the treatment algorithm, should be further explored. This statement is also true for the use of immunotherapy, which, after many years of research, has started to yield consistently improved results. The 5-year OS from the EORTC-NCIC study of patients with GBM treated with EBRT and temozolomide was approximately 10%; for patients with favorable prognostic factors, it approached 30%.81 Moreover, a patient who lived more than 20 years following the diagnosis of GBM was described, perhaps the longest documented survivor.215 He had been treated with surgery and partial brain irradiation with no concurrent or maintenance chemotherapy (59 Gy in conventional fractionation delivered via a shrinking-field technique). The authors speculated that the outcome may have stemmed from the fact that he had a favorable molecular profile (e.g., methylated MGMT promoter, PTEN wild-type, and p53 positive, which the authors termed “triple positive,” resembling the nomenclature of breast cancer). Whether this explained the prolonged survival time is unclear. The authors have cared for similar relatively long survivors without favorable biomarkers. Perhaps more importantly, these observations prove that one may strive to create and sustain hope for patients diagnosed with HGGs.

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CHAPTER 32 Standard Fractionation (daily, d ! 2.5 Gy)

30

n " 160-120

n " 160-120

25

n # 120

Radiation necrosis (%)

Radiation necrosis (%)

n ! 60

20 15 10

n # 120 20 15 10

5

5

0

0 25

50

75

100

125

150

175

200 220

0

25

50

75

B

BED (Gy)

100

125

150

175

BED (Gy)

Twice-Daily Fractionation

50 n ! 60

45

n " 160-120

40 Radiation necrosis (%)

0

A

505

Larger Fractions (daily, d " 2.5 Gy)

30

n ! 60 25

High-Grade Gliomas

n # 120

35 30 25 20 15 10 5 0 0

25

50

75

100

125

150

175

200 220

C BED (Gy) Fig. 32.11 Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) data for central nervous system tolerance based on the study in Lawrence et al. Relationship between biologically effective dose (BED) and radiation necrosis after fractionated radiotherapy. The Lawrence figure was done with a nonlinear least-squares algorithm using MATLAB software (MathWorks, Natick, MA). The nonlinear function chosen was the probit model (similar functional form to the Lyman model). Dotted lines represent 95% confidence levels; each dot represents data from a specific study (Lawrence Table 2); n = patient numbers as shown. (A) Fraction size less than 2.5 Gy. (B) Fraction size 2.5 Gy or larger (data too scattered to allow plotting of “best-fit” line). (C) Twice-daily radiotherapy. (Redrawn from Lawrence YR, Li XA, Naqa I, et al. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys. 2010;76:S20–S27.)

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200 220

506

SECTION III

Disease Sites Treatment schema for elderly HGG

Age ≥ 70 years

Good

Combined chemo-RT (hypofractionation + TMZ)

Methylated

Temozolomide only

Prognostic / geriatric assessment

Intermediate

MGMT status

Unmethylated

Frail

Consider hypofractionation

BSC

Unknown

Radiotherapy hypofractionation

Radiotherapy hypofractionation

Fig. 32.12 Proposed management algorithm for elderly patients according to guidelines described in the text. BSC, Best supportive care; HGG, high-grade gliomas; RT, radiotherapy; TMZ, temozolomide.

CRITICAL REFERENCES 1. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19(suppl_5):v1–v88. doi:10.1093/neuonc/nox158. 2. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–820. doi:10.1007/ s00401-016-1545-1. 9. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–1068. doi:10.1038/nature07385. 13. Reifenberger J, Reifenberger G, Liu L, et al. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol. 1994;145(5):1175–1190. http://www.ncbi.nlm.nih.gov/ pubmed/7977648. 20. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 Mutations in Gliomas. N Engl J Med. 2009;360(8):765–773. doi:10.1056/NEJMoa0808710. 30. Curran WJ, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst. 1993;85(9):704–710. http:// www.ncbi.nlm.nih.gov/pubmed/8478956. 45. Walker MD, Alexander E, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978;49(3):333–343. doi:10.3171/ jns.1978.49.3.0333. 46. Walker MD, Green SB, Byar DP, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303(23):1323–1329. doi:10.1056/ NEJM198012043032303. 57. Chang CH, Horton J, Schoenfeld D, et al. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer. 1983;52(6):997–1007. http://www.ncbi.nlm.nih.gov/pubmed/6349785.

80. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. doi:10.1056/NEJMoa043330. 81. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466. doi:10.1016/S1470-2045(09)70025-7. 87. Hegi ME, Diserens A-C, Gorlia T, et al. MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma. N Engl J Med. 2005;352(10):997–1003. doi:10.1056/NEJMoa043331. 94. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32):4085–4091. doi:10.1200/JCO.2013.49.6968. 105. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708. doi:10.1056/NEJMoa1308573. 106. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy– temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–722. doi:10.1056/NEJMoa1308345. 119. Weller M, Butowski N, Tran DD, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373–1385. doi:10.1016/S1470-2045(17)30517-X. 122. Reardon DA, Omuro A, Brandes AA, et al. Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro Oncol. 2017;19(suppl_3):iii21. doi:10.1093/neuonc/nox036.071. 124. Liau LM, Ashkan K, Tran DD, et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16(1):142. doi:10.1186/ s12967-018-1507-6. 126. Desjardins A, Gromeier M, Herndon JE, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med. 2018;doi:10.1056/ NEJMoa1716435. NEJMoa1716435. 127. Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on

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CHAPTER 32 survival in patients with glioblastoma a randomized clinical trial. JAMA. 2017;318(23):2306–2316. doi:10.1001/jama.2017.18718. 150. Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13(7):707–715. doi:10.1016/S1470-2045(12)70164-X. 151. Malmström A, Grønberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13(9):916–926. doi:10.1016/ S1470-2045(12)70265-6. 152. Perry JR, Laperriere N, O’Callaghan CJ, et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017;376(11):1027–1037.

High-Grade Gliomas

507

176. Hudes RS, Corn BW, Werner-Wasik M, et al. A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys. 1999;43(2):293–298. http://www.ncbi.nlm.nih.gov/ pubmed/10030252. 181. Vellayappan B, Kazmi F, Lim K, et al. Re-irradiation for recurrent glioblastoma multiforme (GBM): systematic review and meta-analysis. Int J Radiat Oncol. 2017;99(2):E114. doi:10.1016/j.ijrobp.2017.06.868.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 32

REFERENCES 1. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19(suppl_5):v1–v88. doi:10.1093/neuonc/nox158. 2. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–820. doi:10.1007/ s00401-016-1545-1. 3. Myung S-K, Ju W, McDonnell DD, et al. Mobile phone use and risk of tumors: a meta-analysis. J Clin Oncol. 2009;27(33):5565–5572. doi:10.1200/JCO.2008.21.6366. 4. Yang M, Guo W, Yang C, et al. Mobile phone use and glioma risk: a systematic review and meta-analysis. PLoS ONE. 2017;12(5):e0175136. doi:10.1371/journal.pone.0175136. 5. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of brain tumors. Neurol Clin. 2007;25(4):867–890, vii. doi:10.1016/j. ncl.2007.07.002. 6. Farrell CJ, Plotkin SR. Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin. 2007;25(4):925–946, viii. doi:10.1016/j. ncl.2007.07.008. 7. Bailey P, Cushing H. A Classification of the Tumors of the Glioma Group on a Histogenetic Basis With a Correlated Study of Prognosis. Philadelphia: J.B. Lippincott Co.; 1926. 8. Collignon FP, Holland EC, Feng S. Organ donors with malignant gliomas: an update. Am J Transplant. 2004;4(1):15–21. doi:10.1046/j.1600-6143.2003.00289.x. 9. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–1068. doi:10.1038/nature07385. 10. Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157–173. doi:10.1016/j.ccr.2006.02.019. 11. Verhaak RGW, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. doi:10.1016/j.ccr.2009.12.020. 12. Lassman AB, Holland EC. Molecular biology and genetic models of gliomas and medulloblastomas. In: McLendon RE, Rosenblum MK, Bigner DD, eds. Russell & Rubinstein’s Pathology of Tumors of the Nervous System. 7th ed. London: CRC Press; 2006:1039–1091. 13. Reifenberger J, Reifenberger G, Liu L, et al. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol. 1994;145(5):1175–1190. http://www.ncbi.nlm.nih.gov/ pubmed/7977648. 14. Intergroup Radiation Therapy Oncology Group Trial 9402, Cairncross G, Berkey B, et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006;24(18):2707–2714. doi:10.1200/JCO.2005.04.3414. 15. van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006;24(18):2715–2722. doi:10.1200/JCO.2005.04.6078. 16. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27(35):5874–5880. doi:10.1200/JCO.2009.23.6497. 17. Abrey LE, Louis DN, Paleologos N, et al. Survey of treatment recommendations for anaplastic oligodendroglioma. Neuro Oncol. 2007;9(3):314–318. doi:10.1215/15228517-2007-002. 18. Jenkins RB, Blair H, Ballman K V, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of

19.

20. 21.

22.

23.

24.

25.

26.

27. 28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

High-Grade Gliomas

507.e1

patients with oligodendroglioma. Cancer Res. 2006;66(20):9852–9861. doi:10.1158/0008-5472.CAN-06-1796. Griffin CA, Burger P, Morsberger L, et al. Identification of der(1;19) (q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol. 2006;65(10):988–994. doi:10.1097/01.jnen.0000235122.98052.8f. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 Mutations in Gliomas. N Engl J Med. 2009;360(8):765–773. doi:10.1056/NEJMoa0808710. Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469–474. doi:10.1007/s00401-009-0561-9. van den Bent MJ, Dubbink HJ, Marie Y, et al. IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res. 2010;16(5):1597–1604. doi:10.1158/1078-0432.CCR-09-2902. Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27(25):4150–4154. doi:10.1200/JCO.2009.21.9832. Jiao Y, Killela PJ, Reitman ZJ, et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget. 2012;3(7):709–722. doi:10.18632/oncotarget.588. Wiestler B, Capper D, Holland-Letz T, et al. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol. 2013;126(3):443–451. doi:10.1007/s00401-013-1156-z. Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44(3):251–253. doi:10.1038/ng.1102. Siegal T. Clinical impact of molecular biomarkers in gliomas. J Clin Neurosci. 2015;22(3):437–444. doi:10.1016/j.jocn.2014.10.004. Bühring U, Herrlinger U, Krings T, et al. MRI features of primary central nervous system lymphomas at presentation. Neurology. 2001;57(3):393– 396. http://www.ncbi.nlm.nih.gov/pubmed/11515505. Wang Y, Wang K, Wang J, et al. Identifying the association between contrast enhancement pattern, surgical resection, and prognosis in anaplastic glioma patients. Neuroradiology. 2016;58(4):367–374. doi:10.1007/s00234-016-1640-y. Curran WJ, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst. 1993;85(9):704–710. http:// www.ncbi.nlm.nih.gov/pubmed/8478956. Mirimanoff R-O, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006;24(16):2563–2569. doi:10.1200/JCO.2005.04.5963. Li J, Wang M, Won M, et al. Validation and simplification of the Radiation Therapy Oncology Group recursive partitioning analysis classification for glioblastoma. Int J Radiat Oncol Biol Phys. 2011;81(3):623–630. doi:10.1016/j.ijrobp.2010.06.012. Bell EH, Pugh SL, McElroy JP, et al. Molecular-based recursive partitioning analysis model for glioblastoma in the temozolomide era: a correlative analysis based on NRG oncology RTOG 0525. JAMA Oncol. 2017;3(6):784–792. doi:10.1001/jamaoncol.2016.6020. Jelsma RK, Bucy PC. The treatment of glioblastoma multiforme. Trans Am Neurol Assoc. 1967;92:90–93. http://www.ncbi.nlm.nih.gov/ pubmed/4329419. Devaux BC, O’Fallon JR, Kelly PJ. Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome. J Neurosurg. 1993;78(5):767–775. doi:10.3171/ jns.1993.78.5.0767. Keles GE, Anderson B, Berger MS. The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surg Neurol. 1999;52(4):371–379. http://www.ncbi.nlm.nih.gov/pubmed/10555843. Laws ER, Parney IF, Huang W, et al. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from

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507.e2

SECTION III

Disease Sites

the Glioma Outcomes Project. J Neurosurg. 2003;99(3):467–473. doi:10.3171/jns.2003.99.3.0467. 38. Vuorinen V, Hinkka S, Färkkilä M, Jääskeläinen J. Debulking or biopsy of malignant glioma in elderly people - a randomised study. Acta Neurochir (Wien). 2003;145(1):5–10. doi:10.1007/s00701-002-1030-6. 39. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392–401. doi:10.1016/S1470-2045(06)70665-9. 40. Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190–198. doi:10.3171/ jns.2001.95.2.0190. 41. Brown TJ, Brennan MC, Li M, et al. Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol. 2016;2(11):1460–1469. doi:10.1001/jamaoncol.2016.1373. 42. Sanai N, Mirzadeh Z, Berger MS. Functional outcome after language mapping for glioma resection. N Engl J Med. 2008;358(1):18–27. doi:10.1056/NEJMoa067819. 43. Bailey P. The results of roentgen therapy on brain tumors. Am J Roentgenol Radium Ther Nucl Med. 1925;13:48–53. 44. Shapiro WR, Young DF. Treatment of malignant glioma. A controlled study of chemotherapy and irradiation. Arch Neurol. 1976;33(7):494–500. http://www.ncbi.nlm.nih.gov/pubmed/180938. 45. Walker MD, Alexander E, Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978;49(3):333–343. doi:10.3171/ jns.1978.49.3.0333. 46. Walker MD, Green SB, Byar DP, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303(23):1323–1329. doi:10.1056/ NEJM198012043032303. 47. Shapiro WR, Green SB, Burger PC, et al. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989;71(1):1–9. doi:10.3171/jns.1989.71.1.0001. 48. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980;30(9):907–911. http://www.ncbi.nlm.nih. gov/pubmed/6252514. 49. Wallner KE, Galicich JH, Krol G, et al. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 1989;16(6):1405–1409. http://www.ncbi.nlm.nih. gov/pubmed/2542195. 50. Lee SW, Fraass BA, Marsh LH, et al. Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys. 1999;43(1):79–88. http://www.ncbi.nlm.nih.gov/pubmed/9989517. 51. Pirzkall A, McKnight TR, Graves EE, et al. MR-spectroscopy guided target delineation for high-grade gliomas. Int J Radiat Oncol Biol Phys. 2001;50(4):915–928. http://www.ncbi.nlm.nih.gov/pubmed/11429219. 52. Chang EL, Akyurek S, Avalos T, et al. Evaluation of peritumoral edema in the delineation of radiotherapy clinical target volumes for glioblastoma. Int J Radiat Oncol Biol Phys. 2007;68(1):144–150. doi:10.1016/j.ijrobp.2006.12.009. 53. Kumar N, Kumar R, Sharma SC, et al. To compare the treatment outcomes of two different target volume delineation guidelines (RTOG vs MD Anderson) in glioblastoma multiforme patients: a prospective randomized study. Neuro Oncol. 2012;14:vi134–vi135. doi:10.1093/ neuonc/nos238. 54. Lee P, Eppinga W, Lagerwaard F, et al. Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis. Int J Radiat Oncol Biol Phys. 2013;86(4):609–615. doi:10.1016/j. ijrobp.2013.01.009. 55. Chen L, Guerrero-Cazares H, Ye X, et al. Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection. Int J Radiat Oncol Biol Phys. 2013;86(4):616–622. doi:10.1016/j.ijrobp.2013.02.014.

56. Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys. 1979;5(10):1725–1731. http://www.ncbi.nlm.nih.gov/pubmed/231022. 57. Chang CH, Horton J, Schoenfeld D, et al. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer. 1983;52(6):997–1007. http://www.ncbi.nlm.nih.gov/pubmed/6349785. 58. Nelson DF, Diener-West M, Horton J, et al. Combined modality approach to treatment of malignant gliomas–re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group. NCI Monogr. 1988;6:279–284. http://www.ncbi.nlm. nih.gov/pubmed/3281031. 59. Nelson DF, Curran WJ, Scott C, et al. Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma–possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: report of the Radiation Therapy Oncology Group Protocol 8302. Int J Radiat Oncol Biol Phys. 1993;25(2):193–207. http://www.ncbi.nlm.nih. gov/pubmed/8380567. 60. Scott CB, Scarantino C, Urtasun R, et al. Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. Int J Radiat Oncol Biol Phys. 1998;40(1):51–55. http://www.ncbi. nlm.nih.gov/pubmed/9422557. 61. Prados MD, Wara WM, Sneed PK, et al. Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2001;49(1):71–77. http://www.ncbi.nlm.nih.gov/ pubmed/11163499. 62. Loeffler JS, Alexander E, Shea WM, et al. Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol. 1992;10(9):1379–1385. doi:10.1200/JCO.1992.10.9.1379. 63. Sarkaria JN, Mehta MP, Loeffler JS, et al. Radiosurgery in the initial management of malignant gliomas: survival comparison with the RTOG recursive partitioning analysis. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1995;32(4):931–941. http://www.ncbi.nlm.nih. gov/pubmed/7607967. 64. Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys. 2004;60(3):853–860. doi:10.1016/j.ijrobp.2004.04.011. 65. Gutin PH, Prados MD, Phillips TL, et al. External irradiation followed by an interstitial high activity iodine-125 implant “boost” in the initial treatment of malignant gliomas: NCOG study 6G-82-2. Int J Radiat Oncol Biol Phys. 1991;21(3):601–606. http://www.ncbi.nlm.nih.gov/ pubmed/1651302. 66. Florell RC, Macdonald DR, Irish WD, et al. Selection bias, survival, and brachytherapy for glioma. J Neurosurg. 1992;76(2):179–183. doi:10.3171/ jns.1992.76.2.0179. 67. Selker RG, Shapiro WR, Burger P, et al. The Brain Tumor Cooperative Group NIH Trial 87-01: a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine. Neurosurgery. 2002;51(2):343–355, discussion 355–7. http://www.ncbi.nlm.nih.gov/ pubmed/12182772. 68. Welsh J, Sanan A, Gabayan AJ, et al. GliaSite brachytherapy boost as part of initial treatment of glioblastoma multiforme: a retrospective multi-institutional pilot study. Int J Radiat Oncol Biol Phys. 2007;68(1):159–165. doi:10.1016/j.ijrobp.2006.11.053. 69. Stieber VW, Tatter S, Mikkelsen T, et al. NABTT 2105: a phase I dose-escalation trial of GliaSite brachytherapy with conventional radiation therapy for newly diagnosed glioblastoma multiforme. J Clin Oncol. 2005;23(16_suppl):1570. doi:10.1200/jco.2005.23.16_suppl.1570.

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CHAPTER 32 70. Kleinberg L, Yoon G, Weingart JD, et al. Imaging after GliaSite brachytherapy: prognostic MRI indicators of disease control and recurrence. Int J Radiat Oncol Biol Phys. 2009;75(5):1385–1391. doi:10.1016/j.ijrobp.2008.12.074. 71. Fine HA, Dear KB, Loeffler JS, et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer. 1993;71(8):2585–2597. http://www.ncbi.nlm.nih.gov/ pubmed/8453582. 72. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet. 2002;359(9311):1011–1018. http://www.ncbi.nlm.nih.gov/ pubmed/11937180. 73. Green SB, Byar DP, Walker MD, et al. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep. 1983;67(2):121–132. http://www.ncbi.nlm.nih.gov/ pubmed/6337710. 74. Levin VA, Edwards MS, Wright DC, et al. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980;64(2–3):237–244. http:// www.ncbi.nlm.nih.gov/pubmed/7407756. 75. Prados MD, Scott C, Curran WJ, et al. Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: a retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy. J Clin Oncol. 1999;17(11):3389–3395. doi:10.1200/JCO.1999.17.11.3389. 76. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet. 1995;345(8956):1008–1012. doi:10.1016/S0140-6736(95)90755-6. 77. Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5(2):79–88. doi:10.1093/neuonc/5.2.79. 78. Westphal M, Ram Z, Riddle V, et al. Gliadel® wafer in initial surgery for malignant glioma: Long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien). 2006;148(3):269–275. doi:10.1007/ s00701-005-0707-z. 79. Kunwar S, Chang S, Westphal M, et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol. 2010;12(8):871–881. doi:10.1093/neuonc/nop054. 80. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. doi:10.1056/NEJMoa043330. 81. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466. doi:10.1016/S1470-2045(09)70025-7. 82. Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999;17(9):2762–2771. doi:10.1200/JCO.1999.17.9.2762. 83. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000;83(5):588–593. doi:10.1054/bjoc.2000.1316. 84. Gilbert MR, Friedman HS, Kuttesch JF, et al. A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy. Neuro Oncol. 2002;4(4):261– 267. http://www.ncbi.nlm.nih.gov/pubmed/12356356. 85. Combs SE, Gutwein S, Schulz-Ertner D, et al. Temozolomide combined with irradiation as postoperative treatment of primary glioblastoma multiforme. Phase I/II study. Strahlenther Onkol. 2005;181(6):372–377. doi:10.1007/s00066-005-1359-x. 86. Stupp R, Dietrich P-Y, Ostermann Kraljevic S, et al. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant

87.

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101.

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103.

High-Grade Gliomas

507.e3

temozolomide. J Clin Oncol. 2002;20(5):1375–1382. doi:10.1200/ JCO.2002.20.5.1375. Hegi ME, Diserens A-C, Gorlia T, et al. MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma. N Engl J Med. 2005;352(10):997–1003. doi:10.1056/NEJMoa043331. Rivera AL, Pelloski CE, Gilbert MR, et al. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol. 2010;12(2):116–121. doi:10.1093/neuonc/nop020. van den Bent MJ, Dubbink HJ, Sanson M, et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. J Clin Oncol. 2009;27(35):5881–5886. doi:10.1200/JCO.2009.24.1034. Preusser M, Charles Janzer R, Felsberg J, et al. Anti-O6-methylguaninemethyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain Pathol. 2008;18(4):520–532. doi:10.1111/j.1750-3639.2008.00153.x. Wick W, Platten M, Weller M. New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol. 2009;11(1):69–79. doi:10.1215/15228517-2008-078. Clarke JL, Iwamoto FM, Sul J, et al. Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol. 2009;27(23):3861–3867. doi:10.1200/JCO.2008.20.7944. Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer. 2003;88(7):1004–1011. doi:10.1038/sj.bjc.6600827. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32):4085–4091. doi:10.1200/JCO.2013.49.6968. van den Bent MJ, Erdem-Eraslan L, Idbaih A, et al. MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic Oligodendrogliomas and Oligoastrocytomas. A report from EORTC study 26951. Clin Cancer Res. 2013;19(19):5513–5522. doi:10.1158/1078-0432.CCR-13-1157. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–522. doi:10.1016/j.ccr.2010.03.017. van den Bent MJ, Gravendeel LA, Gorlia T, et al. A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. Clin Cancer Res. 2011;17(22):7148–7155. doi:10.1158/1078-0432. CCR-11-1274. Wick W, Weller M, Van Den Bent M, et al. MGMT testing - The challenges for biomarker-based glioma treatment. Nat Rev Neurol. 2014;10(7):372–385. doi:10.1038/nrneurol.2014.100. Hau P, Koch D, Hundsberger T, et al. Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology. 2007;68(9):688–690. Seiz M, Krafft U, Freyschlag CF, et al. Long-term adjuvant administration of temozolomide in patients with glioblastoma multiforme: experience of a single institution. J Cancer Res Clin Oncol. 2010;136(11):1691–1695. doi:10.1007/s00432-010-0827-6. Blumenthal DT, Gorlia T, Gilbert MR, et al. Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG. Neuro Oncol. 2017;19(8):1119–1126. doi:10.1093/neuonc/nox025. Gramatzki D, Kickingereder P, Hentschel B, et al. Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma. Neurology. 2017;88(15):1422–1430. doi:10.1212/ WNL.0000000000003809. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740–745. doi:10.1200/JCO.2008.16.3055.

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507.e4

SECTION III

Disease Sites

104. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733–4740. doi:10.1200/JCO.2008.19.8721. 105. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708. doi:10.1056/NEJMoa1308573. 106. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy– temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–722. doi:10.1056/NEJMoa1308345. 107. Taphoorn MJB, Henriksson R, Bottomley A, et al. Health-related quality of life in a randomized phase III study of bevacizumab, temozolomide, and radiotherapy in newly diagnosed glioblastoma. J Clin Oncol. 2015;33(19):2166–2175. doi:10.1200/JCO.2014.60.3217. 108. Stupp R, Hegi ME, Gorlia T, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1100–1108. doi:10.1016/S1470-2045(14)70379-1. 109. Khasraw M, Ameratunga MS, Grant R, et al. Antiangiogenic therapy for high-grade glioma. Cochrane Database Syst Rev. 2014;(9):CD008218, doi:10.1002/14651858.CD008218.pub3. 110. Lombardi G, Pambuku A, Bellu L, et al. Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2017;111:94–102. doi:10.1016/j.critrevonc.2017.01.018. 111. Nabors LB, Fink KL, Mikkelsen T, et al. Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol. 2015;17(5):708–717. doi:10.1093/neuonc/nou356. 112. Herrlinger U, Schäfer N, Steinbach JP, et al. Bevacizumab Plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized GLARIUS trial. J Clin Oncol. 2016;34(14):1611–1619. doi:10.1200/ JCO.2015.63.4691. 113. Nduom EK, Weller M, Heimberger AB. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 2015;17(suppl 7):vii9–vii14. doi:10.1093/ neuonc/nov151. 114. Jackson CM, Kochel CM, Nirschl CJ, et al. Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination. Clin Cancer Res. 2016;22(5):1161–1172. doi:10.1158/10780432.CCR-15-1516. 115. Bloch O, Crane CA, Kaur R, et al. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res. 2013;19(12):3165–3175. doi:10.1158/1078-0432.CCR-12-3314. 116. Chongsathidkiet P, Farber S, Woroniecka K, et al. Downregulation of sphingosine-1-phosphate receptor type 1 mediates T-cell sequestration in bone marrow amidst glioblastoma. J Neurosurg. 2017;126(4):A1442. 117. Wainwright DA, Chang AL, Dey M, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014;20(20):5290–5301. doi:10.1158/1078-0432.CCR-14-0514. 118. McGranahan T, Li G, Nagpal S. History and current state of immunotherapy in glioma and brain metastasis. Ther Adv Med Oncol. 2017;9(5):347–368. doi:10.1177/1758834017693750. 119. Weller M, Butowski N, Tran DD, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373–1385. doi:10.1016/S1470-2045(17)30517-X. 120. Weller M, Kaulich K, Hentschel B, et al. Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy. Int J Cancer. 2014;134(10):2437– 2447. doi:10.1002/ijc.28576. 121. Blumenthal DT, Yalon M, Vainer GW, et al. Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors. J Neurooncol. 2016;129(3):doi:10.1007/s11060-016-2190-1.

122. Reardon DA, Omuro A, Brandes AA, et al. Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro Oncol. 2017;19(suppl_3):iii21. doi:10.1093/neuonc/nox036.071. 123. Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561–2569. doi:10.1056/NEJMoa1610497. 124. Liau LM, Ashkan K, Tran DD, et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16(1):142. doi:10.1186/ s12967-018-1507-6. 125. Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018;15(7):422–442. doi:10.1038/ s41571-018-0003-5. 126. Desjardins A, Gromeier M, Herndon JE, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med. 2018;doi:10.1056/ NEJMoa1716435. NEJMoa1716435. 127. Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma a randomized clinical trial. JAMA - J Am Med Assoc. 2017;318(23):2306–2316. doi:10.1001/ jama.2017.18718. 128. Taphoorn MJB, Dirven L, Kanner AA, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma. JAMA Oncol. 2018;4(4):495–504. doi:10.1001/jamaoncol.2017.5082. 129. Lapointe L, Rivard S. Getting physicians to accept new information technology: insights from case studies. CMAJ. 2006;174(11):1573–1578. doi:10.1503/cmaj.050281. 130. Grossman R, Bukstein F, Blumenthal DT, et al. Safety of tumor treating fields and concomitant radiotherapy for newly diagnosed glioblastoma. J Clin Oncol. 2018;36(15_suppl):e14078. doi:10.1200/JCO.2018.36.15_ suppl.e14078. 131. DeAngelis LM. Anaplastic glioma: how to prognosticate outcome and choose a treatment strategy. [corrected]. J Clin Oncol. 2009;27(35):5861– 5862. doi:10.1200/JCO.2009.24.5985. 132. Wick W, Roth P, Hartmann C, et al. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016;18(11):1529– 1537. 133. Combs SE, Nagy M, Edler L, et al. Comparative evaluation of radiochemotherapy with temozolomide versus standard-of-care postoperative radiation alone in patients with WHO grade III astrocytic tumors. Radiother Oncol. 2008;88(2):177–182. doi:10.1016/j. radonc.2008.03.005. 134. Chang S, Zhang P, Cairncross JG, et al. Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of nrg oncology RTOG 9813. Neuro Oncol. 2017;19(2):252–258. doi:10.1093/neuonc/now23. 135. van den Bent MJ, Baumert B, Erridge SC, et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017;390(10103):1645–1653. doi:10.1016/ S0140-6736(17)31442-3. 136. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31(3):337–343. doi:10.1200/ JCO.2012.43.2674. 137. van den Bent MJ, Brandes AA, Taphoorn MJB, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31(3):344–350. doi:10.1200/JCO.2012.43.2229. 138. Cairncross G, Macdonald D, Ludwin S, et al. Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994;12(10):2013–2021. doi:10.1200/ JCO.1994.12.10.2013.

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CHAPTER 32 139. Cairncross JG, Wang M, Jenkins RB, et al. Benefit from procarbazine, lomustine and vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol. 2014;doi:10.1200/JCO.2013.49.3726. 140. Panageas KS, Iwamoto FM, Cloughesy TF, et al. Initial treatment patterns over time for anaplastic oligodendroglial tumors. Neuro Oncol. 2012;doi:10.1093/neuonc/nos065. 141. Ino Y, Betensky RA, Zlatescu MC, et al. Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. Clin Cancer Res. 2001;7(4):839–845. doi:10.1158/1078-0432.ccr-06-0181. 142. Douw L, Klein M, Fagel SS, et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol. 2009;8(9):810–818. doi:10.1016/S1474-4422(09)70204-2. 143. Laperriere N, Weller M, Stupp R, et al. Optimal management of elderly patients with glioblastoma. Cancer Treat Rev. 2013;39(4):350–357. doi:10.1016/j.ctrv.2012.05.008. 144. Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007;356(15):1527–1535. doi:10.1056/NEJMoa065901. 145. Roa W, Brasher PMA, Bauman G, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. 2004;22(9):1583–1588. doi:10.1200/JCO.2004.06.082. 146. Roa W, Kepka L, Kumar N, et al. International Atomic Energy Agency randomized phase III study of radiation therapy in elderly and/or frail patients with newly diagnosed glioblastoma multiforme. J Clin Oncol. 2015;33(35):4145–4150. doi:10.1200/JCO.2015.62.6606. 147. Chinot O-L, Barrie M, Frauger E, et al. Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly populations. Cancer. 2004;100(10):2208–2214. doi:10.1002/ cncr.20224. 148. Glantz M, Chamberlain M, Liu Q, et al. Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas. Cancer. 2003;97(9):2262–2266. doi:10.1002/cncr.11323. 149. Gállego Pérez-Larraya J, Ducray F, Chinot O, et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. J Clin Oncol. 2011;29(22):3050–3055. doi:10.1200/JCO.2011.34.8086. 150. Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13(7):707–715. doi:10.1016/S1470-2045(12)70164-X. 151. Malmström A, Grønberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13(9):916–926. doi:10.1016/ S1470-2045(12)70265-6. 152. Perry JR, Laperriere N, O’Callaghan CJ, et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017;376(11):1027–1037. doi:10.1056/NEJMoa1611977. 153. Hoffman WF, Levin VA, Wilson CB. Evaluation of malignant glioma patients during the postirradiation period. J Neurosurg. 1979;50(5):624– 628. doi:10.3171/jns.1979.50.5.0624. 154. de Wit MCY, de Bruin HG, Eijkenboom W, et al. Immediate postradiotherapy changes in malignant glioma can mimic tumor progression. Neurology. 2004;63(3):535–537. http://www.ncbi.nlm.nih. gov/pubmed/15304589. 155. Chamberlain MC, Glantz MJ, Chalmers L, et al. Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol. 2007;82(1):81–83. doi:10.1007/s11060-006-9241-y. 156. Gerstner ER, McNamara MB, Norden AD, et al. Effect of adding temozolomide to radiation therapy on the incidence of pseudoprogression. J Neurooncol. 2009;94(1):97–101. doi:10.1007/ s11060-009-9809-4. 157. Brandes AA, Franceschi E, Tosoni A, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 2008;26(13):2192–2197. doi:10.1200/ JCO.2007.14.8163.

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158. Taal W, Brandsma D, de Bruin HG, et al. Incidence of early pseudoprogression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer. 2008;113(2):405–410. doi:10.1002/cncr.23562. 159. Li H, Li J, Cheng G, et al. IDH mutation and MGMT promoter methylation are associated with the pseudoprogression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adjuvant temozolomide-based chemoradiotherapy. Clin Neurol Neurosurg. 2016;151:31–36. doi:10.1016/j.clineuro.2016.10.004. 160. Schlemmer HP, Bachert P, Henze M, et al. Differentiation of radiation necrosis from tumor progression using proton magnetic resonance spectroscopy. Neuroradiology. 2002;44(3):216–222. http://www.ncbi.nlm. nih.gov/pubmed/11942375. 161. Catalaa I, Henry R, Dillon WP, et al. Perfusion, diffusion and spectroscopy values in newly diagnosed cerebral gliomas. NMR Biomed. 2006;19(4):463–475. doi:10.1002/nbm.1059. 162. Gahramanov S, Raslan AM, Muldoon LL, et al. Potential for differentiation of pseudoprogression from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol vs. gadoteridol: a pilot study. Int J Radiat Oncol Biol Phys. 2011;79(2):514–523. doi:10.1016/j.ijrobp.2009.10.072. 163. Brandes AA, Tosoni A, Spagnolli F, et al. Disease progression or pseudoprogression after concomitant radiochemotherapy treatment: pitfalls in neurooncology. Neuro Oncol. 2008;10(3):361–367. doi:10.1215/15228517-2008-008. 164. Zach L, Guez D, Last D, et al. Delayed contrast extravasation MRI: a new paradigm in neuro-oncology. Neuro Oncol. 2015;17(3):doi:10.1093/ neuonc/nou230. 165. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963–1972. doi:10.1200/JCO.2009.26.3541. 166. Ellingson BM, Wen PY, Cloughesy TF. Modified criteria for radiographic response assessment in glioblastoma clinical trials. Neurother. 2017;14(2):307–320. doi:10.1007/s13311-016-0507-6. 167. Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 2015;16(15):e534–e542. doi:10.1016/ S1470-2045(15)00088-1. 168. Bloch O, Han SJ, Cha S, et al. Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article. J Neurosurg. 2012;117(6):1032–1038. doi:10.3171/2012.9.JNS12504. 169. Oppenlander ME, Wolf AB, Snyder LA, et al. An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity. J Neurosurg. 2014;120(4):846–853. doi:10.3171/2013.12. JNS13184. 170. Goldman DA, Hovinga K, Reiner AS, et al. The relationship between repeat resection and overall survival in patients with glioblastoma: a timedependent analysis. J Neurosurg. 2018;1-9:doi:10.3171/2017.6.JNS17393. 171. Chan TA, Weingart JD, Parisi M, et al. Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy. Int J Radiat Oncol Biol Phys. 2005;62(4):1133–1139. doi:10.1016/j.ijrobp.2004.12.032. 172. Gabayan AJ, Green SB, Sanan A, et al. GliaSite brachytherapy for treatment of recurrent malignant gliomas: a retrospective multiinstitutional analysis. Neurosurgery. 2006;58(4):701–709, discussion 701–9. doi:10.1227/01.NEU.0000194836.07848.69. 173. Kong D-S, Lee J-I, Park K, et al. Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer. 2008;112(9):2046–2051. doi:10.1002/cncr.23402. 174. Bokstein F, Blumenthal DT, Corn BW, et al. Stereotactic radiosurgery (SRS) in high-grade glioma: judicious selection of small target volumes improves results. J Neurooncol. 2016;126(3):551–557. doi:10.1007/ s11060-015-1997-5. 175. Ang KK, Jiang GL, Feng Y, et al. Extent and kinetics of recovery of occult spinal cord injury. Int J Radiat Oncol Biol Phys. 2001;50(4):1013–1020. http://www.ncbi.nlm.nih.gov/pubmed/11429229. 176. Hudes RS, Corn BW, Werner-Wasik M, et al. A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy

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SECTION III

Disease Sites

for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys. 1999;43(2):293–298. http://www.ncbi.nlm.nih.gov/ pubmed/10030252. 177. Voynov G, Kaufman S, Hong T, et al. Treatment of recurrent malignant gliomas with stereotactic intensity modulated radiation therapy. Am J Clin Oncol. 2002;25(6):606–611. http://www.ncbi.nlm.nih.gov/ pubmed/12478010. 178. Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2009;75(1):156–163. doi:10.1016/j. ijrobp.2008.10.043. 179. Clarke J, Neil E, Terziev R, et al. Multicenter, phase 1, dose escalation study of hypofractionated stereotactic radiation therapy with bevacizumab for recurrent glioblastoma and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 2017;99(4):797–804. doi:10.1016/j.ijrobp.2017.06.2466. 180. Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebocontrolled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys. 2011;79(5):1487– 1495. doi:10.1016/j.ijrobp.2009.12.061. 181. Vellayappan B, Kazmi F, Lim K, et al. Re-irradiation for recurrent glioblastoma multiforme (GBM): systematic review and meta-analysis. Int J Radiat Oncol. 2017;99(2):E114. doi:10.1016/j.ijrobp.2017.06.868. 182. Scoccianti S, Francolini G, Carta GA, et al. Re-irradiation as salvage treatment in recurrent glioblastoma: a comprehensive literature review to provide practical answers to frequently asked questions. Crit Rev Oncol Hematol. 2018;126:80–91. doi:10.1016/j.critrevonc.2018.03.024. 183. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507. doi:10.1056/NEJMra0708126. 184. Weller M, Tabatabai G, Kästner B, et al. MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR Trial. Clin Cancer Res. 2015;21(9):2057–2064. doi:10.1158/1078-0432. CCR-14-2737. 185. Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma–are we there yet? Neuro Oncol. 2013;15(1):4–27. doi:10.1093/neuonc/nos273. 186. Seystahl K, Wick W, Weller M. Therapeutic options in recurrent glioblastoma–An update. Crit Rev Oncol Hematol. 2016;99:389–408. doi:10.1016/j.critrevonc.2016.01.018. 187. Taal W, Oosterkamp HM, Walenkamp AME, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15(9):943–953. doi:10.1016/S1470-2045(14)70314-6. 188. Wick W, Gorlia T, Bendszus M, et al. Lomustine and Bevacizumab in Progressive Glioblastoma. N Engl J Med. 2017;377(20):1954–1963. doi:10.1056/NEJMoa1707358. 189. Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353(19):2012–2024. doi:10.1056/NEJMoa051918. 190. Blumenthal DT, Dvir A, Lossos A, et al. Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients. J Neuro Oncol. 2016;130(1):211–219. doi:10.1007/s11060-016-2237-3. 191. Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012;48(14):2192–2202. doi:10.1016/j.ejca.2012.04.011. 192. Kristensen BH, Laursen FJ, Løgager V, et al. Dosimetric and geometric evaluation of an open low-field magnetic resonance simulator for radiotherapy treatment planning of brain tumours. Radiother Oncol. 2008;87(1):100–109. doi:10.1016/j.radonc.2008.01.014. 193. Edmund JM, Nyholm T. A review of substitute CT generation for MRI-only radiation therapy. Radiat Oncol. 2017;12(1):28. doi:10.1186/ s13014-016-0747-y. 194. Bokstein F, Kovner F, Blumenthal DT, et al. A common sense approach to radiotherapy planning of glioblastoma multiforme situated in the temporal lobe. Int J Radiat Oncol Biol Phys. 2008;72(3):900–904. doi:10.1016/j.ijrobp.2008.01.053.

195. Lorentini S, Amelio D, Giri MG, et al. IMRT or 3D-CRT in glioblastoma? A dosimetric criterion for patient selection. Technol Cancer Res Treat. 2013;12(5):411–420. doi:10.7785/tcrt.2012.500341. 196. Lawrence YR, Li XA, el Naqa I, et al. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys. 2010;76(3 suppl):S20–S27. doi:10.1016/j.ijrobp.2009.02.091. 197. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21(1):109–122. http://www.ncbi.nlm.nih.gov/pubmed/2032882. 198. Payne JF, Hutchinson AK, Hubbard GB, Lambert SR. Outcomes of cataract surgery following radiation treatment for retinoblastoma. J AAPOS Off Publ Am Assoc Pediatr Ophthalmol Strabismus. 2009;13(5):454–458, e3. doi:10.1016/j.jaapos.2009.06.002. 199. Khafaga YM, Jamshed A, Allam AA, et al. Stevens-Johnson syndrome in patients on phenytoin and cranial radiotherapy. Acta Oncol. 1999;38(1):111–116. http://www.ncbi.nlm.nih.gov/pubmed/10090698. 200. Micali G, Linthicum K, Han N, West DP. Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies. Pharmacotherapy. 1999;19(2):223–227. http://www.ncbi.nlm. nih.gov/pubmed/10030773. 201. Armstrong TS, Gilbert MR. Practical strategies for management of fatigue and sleep disorders in people with brain tumors. Neuro Oncol. 2012;14(suppl 4):iv65–iv72. doi:10.1093/neuonc/nos210. 202. Lovely MP, Miaskowski C, Dodd M. Relationship between fatigue and quality of life in patients with glioblastoma multiformae. Oncol Nurs Forum. 1999;26(5):921–925. http://www.ncbi.nlm.nih.gov/ pubmed/10382191. 203. Gulliford SL, Miah AB, Brennan S, et al. Dosimetric explanations of fatigue in head and neck radiotherapy: an analysis from the PARSPORT Phase III trial. Radiother Oncol. 2012;104(2):205–212. doi:10.1016/j. radonc.2012.07.005. 204. Day J, Yust-Katz S, Cachia D, et al. Interventions for the management of fatigue in adults with a primary brain tumour. Cochrane Database Syst Rev. 2016;(4):CD011376, doi:10.1002/14651858.CD011376.pub2. 205. Lee EQ, Muzikansky A, Drappatz J, et al. A randomized, placebocontrolled pilot trial of armodafinil for fatigue in patients with gliomas undergoing radiotherapy. Neuro Oncol. 2016;18(6):849–854. doi:10.1093/ neuonc/now007. 206. Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32(34):3810–3816. doi:10.1200/JCO.2014.57.2909. 207. Hofmaier J, Kantz S, Söhn M, et al. Hippocampal sparing radiotherapy for glioblastoma patients: a planning study using volumetric modulated arc therapy. Radiat Oncol. 2016;11(1):118. doi:10.1186/ s13014-016-0695-6. 208. Thippu Jayaprakash K, Wildschut K, Jena R. Feasibility of hippocampal avoidance radiotherapy for glioblastoma. Clin Oncol (R Coll Radiol). 2017;29(11):748–752. doi:10.1016/j.clon.2017.06.010. 209. Barnett GC, West CML, Dunning AM, et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer. 2009;9(2):134–142. doi:10.1038/nrc2587. 210. Azria D, Lapierre A, Gourgou S, et al. Data-based radiation oncology: design of clinical trials in the toxicity biomarkers era. Front Oncol. 2017;7:83. doi:10.3389/fonc.2017.00083. 211. Extermann M, Aapro M, Bernabei R, et al. Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol. 2005;55(3):241–252. doi:10.1016/j. critrevonc.2005.06.003. 212. Soubeyran P, Bellera C, Goyard J, et al. Screening for vulnerability in older cancer patients: the ONCODAGE Prospective Multicenter Cohort Study. PLoS ONE. 2014;9(12):e115060. doi:10.1371/journal. pone.0115060. 213. Aquino D, Gioppo A, Finocchiaro G, et al. MRI in glioma immunotherapy: evidence, pitfalls, and perspectives. J Immunol Res. 2017;2017:5813951. doi:10.1155/2017/5813951.

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CHAPTER 32 214. Robins HI, Lassman AB, Khuntia D. Therapeutic advances in malignant glioma: current status and future prospects. Neuroimaging Clin N Am. 2009;19(4):647–656. doi:10.1016/j.nic.2009.08.015. 215. Sperduto CM, Chakravarti A, Aldape K, et al. Twenty-year survival in glioblastoma: a case report and molecular profile. Int J Radiat Oncol Biol Phys. 2009;75(4):1162–1165. doi:10.1016/j.ijrobp.2008.12.054. 216. Mayo C, Martel MK, Marks LB, et al. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys. 2010;76(3 suppl):S28–S35. doi:10.1016/j.ijrobp.2009.07.1753. 217. Mayo C, Yorke E, Merchant TE. Radiation associated brainstem injury. Int J Radiat Oncol Biol Phys. 2010;76(3 suppl):S36–S41. doi:10.1016/j. ijrobp.2009.08.078.

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218. Scoccianti S, Detti B, Gadda D, et al. Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist’s guide for delineation in everyday practice. Radiother Oncol. 2015;114(2):230–238. doi:10.1016/j.radonc.2015.01.016. 219. Bhandare N, Jackson A, Eisbruch A, et al. Radiation therapy and hearing loss. Int J Radiat Oncol. 2010;76(3):S50–S57. doi:10.1016/j. ijrobp.2009.04.096.

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33 Benign Brain Tumors: Meningiomas and Vestibular Schwannomas Michael D. Chan, C. Leland Rogers, Aadel A. Chaudhuri, John C. Flickinger, and Deepak Khuntia

MENINGIOMAS Incidence Meningiomas comprise approximately 35% of all primary intracranial neoplasms, rendering them the single most frequently reported primary intracranial tumor. Because of the significant longevity associated with this diagnosis, the estimated prevalence of 97.5 per 100,000 is significantly higher than the annual incidence of approximately 7.6 per 100,000.1 Grading Most meningiomas are benign (WHO grade I) and progress slowly, but despite this, can produce considerable morbidity from local growth, edema, or progression to higher-grade histology, resulting in more rapid growth. By current WHO standards, 20% to 30% of meningiomas are atypical (WHO grade II) and can be difficult to manage long-term and 1% to 3% are anaplastic (WHO grade III) meningiomas, which are aggressive, malignant tumors.2–4 Staging and Imaging No formal tumor staging system has been adopted. Meningiomas are optimally imaged by magnetic resonance imaging (MRI), which can be complemented, as needed, by computed tomography (CT) imaging to appraise bone involvement, hyperostosis, or intratumoral calcification. Primary Therapy The optimal primary therapy for meningiomas historically has been regarded as resection, with observation being commonly employed for small, nonprogressive tumors. Surgery produces excellent results when gross total resection is safely accomplished. Stereotactic radiosurgery (SRS) is used in selected patients, for whom the diagnosis is commonly based on

imaging, without biopsy confirmation, and it produces very high rates of local control. Fractionated external beam radiation therapy (EBRT) is sometimes used as primary therapy when surgery is not feasible, the tumor is too large for SRS or close to a critical structure, or by patient choice. Fractionated EBRT produces excellent long-term local control for large, nonresectable, or complex meningiomas. Adjuvant Therapy Stereotactic radiosurgery or EBRT is often employed postoperatively following subtotal resection of a recurrent benign meningioma, a newly diagnosed or recurrent atypical meningioma, or an anaplastic meningioma, following any extent of resection. As grade increases, local control rates with SRS diminish rather dramatically. There is less agreement on the adjuvant use of irradiation following subtotal resection of a newly diagnosed benign lesion, or following gross total resection of an atypical meningioma. In these settings, either immediate treatment or close surveillance is presently defensible. Systemic therapies have yielded very little efficacy to date, and a number of ongoing trials are continuing to test several novel cytotoxic, antiangiogenic, and immune checkpoint inhibitors. Palliation Palliation can, on occasion, be the aim of treatment for patients, including those with advanced meningiomatosis, or with refractory high-grade or multiply recurrent low-grade tumors that have failed standard treatments. A clear need exists for improved management options for such patients.

VESTIBULAR SCHWANNOMAS Incidence Vestibular schwannomas occur with an estimated incidence of 1.2 per 100,000 person-years. This is a disease primarily of adults and represents approximately 8% of brain tumors and the vast majority of tumors of the cerebellopontine angle. The exception would be patients with neurofibromatosis type 2, where pediatric presentations occur. Bilateral vestibular schwannoma is a pathognomonic feature of NF2. Biologic Characteristics Both sporadic and NF2-associated tumors commonly have biallelic inactivating mutations of the tumor suppressor gene NF2 (chromosome 22q12), which encodes the cytoskeletal protein merlin. Staging Evaluation The recommended workup includes neurologic examination with careful attention to cranial nerve function, contrast-enhanced MRI, formal audiometric testing, and other testing as clinically indicated.

Primary Therapy and Results Tumors may be managed with microsurgical resection, SRS to 12 to 13 Gy, or FSRT using either a standard approach (i.e., 45 Gy at 1.8 Gy per fraction) or a hypofractionated approach (i.e., 20 Gy at 4 Gy per fraction). Local control is more than 90% with all treatment modalities. Published reports of treatment-related toxicities, such as hearing loss, facial neuropathy, and trigeminal neuropathy or neuralgia, are generally less frequent with FSRT or expertly performed SRS in appropriately selected patients. Surveillance MRI scans performed in the first few years after definitive radiation therapy may not accurately depict a tumor’s ultimate response to treatment, because there can be variability in the size and appearance of a schwannoma during this time. There are no prospective randomized trials to guide treatment decisions, and multidisciplinary evaluation of each patient is an integral component of appropriate management.

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CHAPTER 33

Benign Brain Tumors: Meningiomas and Vestibular Schwannomas

Benign brain tumors affect the brain as often as do primary malignant brain tumors. An extremely large spectrum of benign neoplasms can be identified within the central nervous system. In this chapter, we focus on the two most common entities, meningiomas and vestibular schwannomas. Harvey Cushing first used the phrase “meningioma” to describe tumors originating predominately from the meningeal coverings of the brain and spinal cord.5 “Meningioma” does aptly describe a range of clinically comparable histologic patterns and, therefore, the name has endured. Although meningiomas are often approached as benign tumors, studies with long-term follow-up reveal that they are susceptible to infiltrate locally and to recur.4,6 This chapter considers the available data on intracranial meningiomas in a succinct fashion. For a more detailed review and lengthier bibliography, we refer you to the online version of this chapter.

Etiology and Epidemiology Based on surgical series, approximately 8000 meningiomas are diagnosed each year in the United States. Radiographic and autopsy studies suggest an even greater number of patients with clinically occult tumors.7–9 A recent epidemiologic study revealed that meningiomas are the most frequently reported primary intracranial neoplasm, constituting approximately 35% of all brain primaries.1,10,11 The likelihood of developing a meningioma is proportional to age. Pediatric meningiomas are rare, but are more likely to exhibit an aggressive clinical course.12–16 Meningiomas are most often diagnosed during the sixth to seventh decades of life.17,18 However, the age-specific incidence continues to rise thereafter, even beyond 85 years of age.10 Although there are known associations with certain genetic, environmental, and hormonal risk factors, most meningiomas arise without discernible causation. Genetic factors will be discussed in an ensuing “Biologic Characteristics/Molecular Biology” section. Radiation exposure—stemming largely from studies of atomic bomb fallout, but also from studies of cranial and scalp irradiation (tinea capitis)—is a well-described etiologic factor for meningiomas.19–23 Recent data suggest lower dose exposure, such as seen in dental x-rays, may also increase the risk of meningioma development.24 Indeed, radiation-induced meningiomas are the most commonly reported secondary neoplasm.20 A role for sex hormones in meningioma induction is supported by several findings. Meningiomas occur more frequently in females, at a ratio of 2 : 1 or 3 : 1.7,25–27 The incidence appears to increase with hormone replacement therapy, with long-acting oral contraceptives, and with obesity. Moreover, tumor size or symptoms may worsen during the luteal phase of menses or pregnancy. Despite these observations, the precise role of hormones is unclear. In both sexes, more than 70% of meningiomas express progesterone receptors, up to 40% estrogen receptors, but nearly 40% androgen receptors as well.7,28 Although clinical responses to mifepristone, an antiprogestational agent have been described, this approach proved negative in a randomized trial.28a

Prevention and Early Detection At this time, there are no known preventative interventions and no evidence in favor of screening. For patients with asymptomatic, incidentally detected meningiomas, surveillance with magnetic resonance imaging (MRI) (annually, for example), with the intent of ruling out aggressive clinical behavior, remains a judicious practice.

Biologic Characteristics/Molecular Biology Meningiomas occur more frequently in certain rare genetic conditions, such as type 2 neurofibromatosis (NF2).12,29 Mutation in the NF2 gene on chromosome 22q12 is the most common cytogenetic alteration. Nearly all NF2 meningiomas have mutations of the NF2 gene, and most

509

susceptible families have alterations of the NF2 locus.30,31 Genetic losses of chromosomes 1p, 10, and 14q have been linked with malignant progression or recurrence, but have not yet been validated as independent prognostic markers.7,30,31 Markers of tumor aggressiveness have been studied.32–34 MIB-1 expression has been correlated with time to recurrence in some series,35 but not in others.36 Tumors with NF2, AKT1, SMO, PIK3CA, and TRAF7 mutations have been found in approximately 80% of sporadic meningiomas, but none has been reliably correlated to more aggressive biologic behavior.37–39 The loss of CDKN2A (generally through locus loss on 9p) has been identified as a marker associated with progression from grade I to grade II tumors.40 Telomerase reverse transcriptase promoter (TERTp) mutations have been aligned with shorter overall survival with progressive and higher grade meningioma, with median overall survival 2.7 years with a TERTp mutation versus 10.8 years without it (p = 0.003).41 Recently, six distinct DNA methylation-based tumor classes have been identified and validated as having an increased likelihood of recurrence.42 A study by Sahm et al.42 suggested that these methylation classes more accurately identified patients with grade I tumors that were at higher risk of progression, and grade II tumor associated with a lower recurrence risk, in comparison to the traditional World Health Organization (WHO) grading system.

Pathology and Pathways of Spread The WHO published updated grading criteria in 2016.43 This system describes 3 grades and 13 histologic subtypes of meningioma (Table 33.1). Strong associations between grade, recurrence-free survival, and overall survival have been confirmed,43 but even with improved criteria disparities remain, particularly regarding the proportion of patients with grade II (atypical) histology. A recent, large analysis reported that 5% of meningiomas were atypical.10 However, Perry et al.28 found that over 20% were WHO grade II. Willis et al.44 re-graded patients using WHO 2007 guidelines, and reported that 20.4% were atypical. Another analysis found that, whereas 4.4% of meningiomas were categorized as atypical from 1994 to 1999, this steadily increased to 32.7% to 35.5% since 2004 (Fig. 33.1).3 The WHO grade is a dominant prognostic factor.28,45,46 Compared with a grade I meningioma, a grade II tumor carries a 7- to 8-fold increased recurrence risk at 3 to 5 years.47 Grade III meningiomas are even more aggressive, with a 5-year overall survival of 32% to 64%.7,13,27,48–52 In addition to grade considerable differences in meningioma outcomes are seen by site of origin. Tumors at the base of skull tend to be more favorable with respect to outcomes despite being less readily resectable owing to location. These differences are also reflected in molecular profile,53 progression risk,54 tumor grade, and even the likelihood of transformation to a higher grade.55 Meningiomas tend to spread along the dura and, when located at the skull base, may spread through skull foramina. Peritumoral vasogenic edema can develop as a result of invasive tumor growth into surrounding brain, but more commonly is not a manifestation of brain invasion, rather of vascular compromise or a result of vasoactive substrates.

Clinical Manifestations/Patient Evaluation/Staging Most data regarding the diagnosis and treatment of meningiomas are based on surgical series. As such, an inherent bias exists toward symptomatic tumors. Symptoms depend largely on the location of the lesion, but can be influenced considerably by the presence of edema. Skull base meningiomas can present with cranial nerve palsies or neuropathies.56 Sphenoid wing meningiomas may present with seizures.57 With the increasing use of contrast-enhanced computed tomography (CT) and MRI for head trauma, headaches, and so forth, the number

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510

SECTION III

TABLE 33.1

Disease Sites

The 2016 World Health Organization (WHO) Criteria for Meningioma Grading

Grade I (Benign)

Grade II (Atypical)

Grade III (Anaplastic/Malignant)

Any major variant other than clear cell, chordoid, papillary, or rhabdoid Does not fulfill criteria for grades II or III

Frequent mitoses (≥4 per 10 hpf) or Three or more of the following: Sheeting architecture Hypercellularity (focal or diffuse) Prominent nucleoli Small cells with high nuclear cytoplasmic ratio Foci of spontaneous necrosis or Additional subtypes/features Chordoid meningioma Clear cell meningioma Brain invasion

Excessive mitotic index (>20 per 10 hpf) or Frank anaplasia defined as focal or diffuse loss of meningothelial differentiation resembling: Sarcoma Carcinoma Or melanoma or Additional subtypes/features Papillary meningioma Rhabdoid meningioma

hpf, High powered field. Modified from Perry A, Louis DN, Scheithauer BW, et al. Meningeal tumours. In Louis DN, Ohgaki H, Wiestler OD, et al., eds. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2007. Modified with the kind assistance of Arie Perry. Atypical Meningiomas as a Percentage of Total Meningioma Diagnoses 50% 45% 40%

p = 0.001 (1994–99 vs 2006)

*

35%

*

*

Primary Therapy

30% 25%

*

20%

Benign Histology (WHO Grade I) 35.5% 32.7%

35%

2005

2006

15% 10%

4.4%

5% 0%

1994 –99

2000

2001

2002

2003

from treatment-related imaging findings.70 Current limitations of biologic imaging include lack of specificity of compounds (specifically, octreotidelabelled compounds when tumors are located around the sella) and lack of prospective data. Despite these limitations, based on recent data, especially for skull-base locations, Gallium tetraxentan octreotate (Ga-DOTATATE) positron emission tomography (PET) imaging has been accepted as a standard in Europe, especially to aid radiotherapy treatment planning.

2004

Year Fig. 33.1 Line graph depicting atypical meningiomas as a percentage of total meningiomas over time. Data points represent total percentage of WHO grade II meningiomas diagnosed in each calendar year (bars represent 95% confidence interval).3

of incidentally discovered meningiomas has risen. Incidentally discovered meningiomas are often smaller and may show little growth over time.58–60 Although the clinical behavior of incidental meningiomas is not uniformly predictable, younger age and larger size at detection portend an increased risk of progression.58 Contrast-enhanced MRI is the imaging modality of choice for meningiomas. Tumors at the skull base may also be imaged with CT to evaluate hyperostosis, bony invasion, or involvement of skull base foramina. Additionally CT may identify calcifications, a finding predictive of more indolent growth.7,11 MRI is generally superior for visualization of the contrast-enhanced lesion,61–64 and MRI T2 signal changes may presage more aggressive behavior.60,65 Biologic imaging has been evaluated as an imaging modality for meningioma and, although still considered experimental, may ultimately prove useful in determination of grade,66,67 in tumor delineation for radiation treatment planning,68,69 and for differentiation of recurrence

Surgery. Surgery is a mainstay in the management of meningioma. It provides tissue for histologic typing and grading; in the majority of series the extent of resection correlates with rates of tumor recurrence.6,71,72 In 1957 Simpson6 reported a series of 265 patients treated surgically, giving rise to the standard system used to grade the extent of resection. The Simpson grade of resection, and the associated crude recurrence rates are summarized in Table 33.2. Modern series employing current surgical and imaging techniques have validated this association.18,27,73,74 Surgery remains an appropriate therapy for many patients with meningioma. Convexity meningiomas are often managed with resection because these can typically be completely resected without significant morbidity. However, even with convexity tumors, those surrounding or invading major draining veins or venous sinuses can pose considerable difficulty. Tumors involving the skull base are more challenging, but may also be managed surgically. As is the case with meningiomas of the cavernous sinus and other select skull base sites, close proximity to critical neurovascular structures renders radical resection potentially morbid. Optic nerve sheath meningiomas intricately involve the nerve’s vasculature, and resection, which commonly leads to vision loss, is rarely advised. However, primary radiation therapy has a favorable track record. The major risk factors for postsurgical recurrence include tumor grade,48 extent of resection,6 prior recurrence,75 and presence of pertumoral edema.76 Postoperative radiotherapy. Adjuvant radiotherapy is not recommended following gross total resection of a newly diagnosed grade I meningioma. Radiotherapy has often been used after subtotal resection, although considering the absence of randomized trials, differences in clinical practice are to be expected. Many patients are observed after subtotal resection.77–79 A multitude of retrospective series have reported that radiotherapy improves local control after subtotal resection. Fig. 33.2 illustrates progression-free survival (PFS) outcomes from 70 series with

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CHAPTER 33

Benign Brain Tumors: Meningiomas and Vestibular Schwannomas

Simpson’s Definitions of “Five Distinct Grades of Operation,” With Respective Recurrence Riska

Progression-Free Survival by Treatment Era Subtotal Resection ! Postoperative EBRT

TABLE 33.2

Grade

Definition of Resection Extent

Recurrence

I

Macroscopically complete removal of tumor, with excision of its dural attachments and any abnormal bone

9%

II

Macroscopically complete removal of tumor, with coagulation of its dural attachments

19%

III

Macroscopically complete removal of tumor, without resection or coagulation of dural attachments or of extradural extensions (e.g., invaded sinus or hyperostotic bone)

29%

IV

Partial removal, leaving tumor in situ

44%

V

Simple decompression or biopsy

N/A

70 Retrospective studies, n= 13,793 5–10 year PFS, ~ Grade I Progression-free survival 100% GTR STR STR+EBRT 1° EBRT SRS

40% 20% 0% 1980 1985 1990 1995 2000 2005 2010 2015 Year Totals:

n mean f/u 13,793 10-276 mo

GTR STR STR+RT 74-98% 38-64% 68-100%

98%: Tx after 1980* (n ! 77)

0.8 77%: Tx before 1980* (n ! 40)

0.4 0.2

*1980: “when CT or MRI was used for planning therapy.”

0.0

Recurrences were identified “in a purely clinical sense to imply the reappearance of symptoms.” Dr. Simpson calculated recurrence risk in a crude fashion, often excluding patients who had surgery within the prior 5 years. N/A, Not applicable. Modified from Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiat. 1957;20:22–39.

60%

1.0

0.6

a

80%

511

SRS 1˚ EBRT 46-100% 86-100%

Fig. 33.2 Scatterplot comparing 5-year progression-free survival following gross-total resection (GTR) alone, subtotal resection (STR) alone, STR plus external beam radiation therapy (STR+EBRT), primary EBRT and stereotactic radiosurgery (SRS) for patients with meningioma. The x-axis is the year of publication.

long-term results following gross total resection alone, subtotal resection alone, subtotal resection with EBRT, primary radiotherapy, and SRS.7,80 Goldsmith et al.48 reported a series of 140 patients who received radiotherapy following subtotal resection, and identified a dose-response. Benign, subtotally resected tumors had significantly improved PFS (93% vs. 65% at 10 years) when a dose greater than 52 Gy was delivered. Moreover, they found significantly improved outcome with CT or MRI-based treatment planning (Fig. 33.3).48 Other studies have exhibited superior cause-specific and possibly even overall survival with radiotherapy after subtotal resection.74,75,81

Recurrent Meningioma Recurrent meningiomas of any WHO grade display a considerably higher rate of recurrence than newly diagnosed tumors.27,74,75,82 In this setting,

0 5 10 15 20 Fig. 33.3 Progression-free survival of patients with meningioma treated with external beam radiotherapy (EBRT) based on treatment era. Treatment planning techniques changed after 1980 with the advent of computed tomography (CT) and magnetic resonance imaging (MRI). Local control has likely improved secondary to better targeting of the tumor.48

postoperative radiotherapy decreases the rate of tumor progression.75,82 In a series by Taylor et al.75, the local control benefit of postoperative radiotherapy at first recurrence (88% vs. 30% at 5 years) translated into an overall survival benefit (90% vs. 45% at 5 years). Miralbel et al.82 reported 78% PFS at 8 years for recurrent tumors treated with surgery and postoperative radiotherapy after first recurrence versus 11% for patients treated with surgery alone. In the Radiation Therapy Oncology Group (RTOG) 0539 protocol, recurrent meningiomas were classified into the intermediate risk cohort. Of note, there was no statistical difference in outcomes between grade II and recurrent grade I tumors at the first report of RTOG 0539, underscoring the worse prognosis of even grade I recurrent tumors.83 Ultimately multiply recurrent meningiomas of any grade behave very aggressively, and progression rates become similar, irrespective of grade. In a Response Assessment in Neuro-Oncology (RANO) review of 555 patients who in large measure were surgery and radiation refractory, the results of medical therapies for meningioma were reported. The weighted average 6-month progression-free survival rate (PFS6) was 29% for the WHO grade I group, similar to a PFS6 of 26% for the WHO grades II and III, further underscoring the biologic aggressiveness of recurrent tumors.84 Definitive external beam radiation therapy. Early reports of primary radiotherapy revealed inferior local control rates on the order of 47%, compared with resection.85 However, these reports included patients treated in the 1960s and 1970s, prior to the advent of modern imaging and treatment planning paradigms, possibly resulting in significant geographic miss. Many recent series using conformal techniques have corroborated excellent results from definitive radiotherapy with local control in excess of 90% at 5 to 10 years.80,86–92 Total doses have ranged from 45 Gy80 to 57.6 Gy,93 typically in 1.8 to 2.0 Gy per fraction. The higher cumulative doses were predominately for higher-grade, large, or recurrent meningiomas. For most patients, doses in the range of 50 Gy to 54 Gy with standard fractionation have produced excellent results with current imaging-based planning and treatment. Fig. 33.4 depicts two examples of tumors appropriate for definitive external beam radiotherapy. Recently, fractionated stereotactic (FSRT) series have been reported with excellent local control and superior functional outcomes in such regions as the cavernous sinus; however, these results are not directly comparable, because the largest tumors are typically not treated with FSRT (Fig. 33.5).80

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512

SECTION III

Disease Sites

A

B

C

D

Fig. 33.4 Examples of meningioma cases for which fractionated external beam radiotherapy (EBRT) would be indicated. (A) An axial slice of a T1-weighted magnetic resonance image (MRI) of a patient with an optic nerve sheath meningioma encasing the optic chiasm. This patient was treated with fractionated EBRT and exhibited stable useful vision at last follow-up 3 years after therapy. (B) An axial slice of a spoiled gradient recall acquisition MRI sequence of a patient with type II neurofibromatosis. This patient developed multiple meningiomas including a parietal menigioma that was resected, two right sphenoid wing meningiomas that were treated with radiosurgery, and a left sphenoid wing meningioma that required fractionated radiotherapy at time of progression. (C) and (D) Show the EBRT isodoses for these cases. The optic nerve sheath meningioma was prescribed a dose of 52.2 Gy in 1.8 Gy fractions. The sphenoid wing meningioma, which exhibited more rapid progression on serial imaging, was treated to 54 Gy in 1.8 Gy fractions. The lesions remained controlled at 3 and 2 years, respectively.

Optic Nerve Sheath Meningioma Optic nerve sheath meningiomas represent only 1% to 2% of total tumors,94–98 but pose considerable clinical challenges owing to their intimate association with the optic nerve and its vasculature. Historically, treatments included resection or observation, both leaving patients with poor visual outcomes. On this account, fractionated EBRT is increasingly utilized. Turbin et al.99 reported 64 patients treated with either surgery alone, surgery plus radiotherapy, radiotherapy alone, or observation. They found that radiotherapy alone resulted in excellent tumor control and was the only modality not leading to worsening of visual acuity.99 Other series have confirmed excellent outcomes, with stabilization or improvement in visual acuity in up to 90%, with local control exceeding 90%.97,100–105 Doses of 40 Gy to 54 Gy with fractions of 1.6 Gy to 1.8 Gy have been

standard, and have produced results more favorable than observation, surgery alone, or surgery plus irradiation.7,99,100,106 Stereotactic radiosurgery. Over the past two decades, SRS has become an acceptable and frequently utilized modality and it is generally considered suitable for meningiomas less than 3 cm in maximum diameter, with well-defined margins (a crucial selection factor, because SRS, unlike EBRT or FSRT, utilizes no clinical target volume/planning target volume [CTV/PTV] margins), with little or no surrounding edema, and at sufficient distance from critical normal tissues to permit appropriate dose restrictions.73,107 Long-term local control has exceeded 85% in the majority of studies.17,108–117 Table 33.3 compares the outcomes for SRS to those of definitive EBRT; this is not a direct comparison, but a compilation of retrospective series reported in the literature and therefore inherently biased in terms of patient selection. Radiosurgery also appears to have equivalent local control outcomes to surgery for

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CHAPTER 33

Benign Brain Tumors: Meningiomas and Vestibular Schwannomas

513

Cavernous Sinus Meningiomas: EBRT Alone vs Surgery + EBRT SFRT Alone

Microsurgery + SFRT

Optic nerve (visual acuity)

Exophthalmos V

(facial neuralgia)

OM

(oculomotor)

Pain

(e.g., headaches)

0

20

40

60

% change

0

20

40

60

80

% change

No improvement Healed Improved No change Fig. 33.5 Comparison of toxicity profiles of stereotactic fractionated radiotherapy (SFRT) alone versus combined microsurgery and SFRT.

Comparative Analysis of Results With SRS and EBRT by Grade of Meningioma in Multiple Retrospective Seriesa

TABLE 33.3

Number (n)

Mean or Median Follow-Up (mo)

5-Year PFS (%)

5-Year OS (%)

Gr I—SRS

2281

19–103

75–100

82–100

—EBRT

Grade/ Treatment

3588

21–108

79–100

74–97

Gr II—SRS

119

27–48

26–72

40–83

—EBRT

345

32–66

20–68

28–91

39

32–48

0–72

0–59

123

34–59

9–52

28–47

Gr III—SRS —EBRT a

Five-year progression-free survival (PFS) and overall survival (OS) are compared for all series combined. EBRT, External beam radiotherapy; mo, months; SRS, stereotactic radiosurgery.

smaller meningiomas. Pollock et al.73 found that PFS after radiosurgery was equivalent to Simpson grade 1 resection, and superior to Simpson grade 2 or 3 to 4 resection. A recent series by Kano et al.118 demonstrates no benefit of prior microsurgery for patients with cavernous sinus meningiomas. The University of Pittsburgh’s initial publication of the long-term outcomes following SRS described the utilization of a median marginal dose of 16 Gy.107 The rate of new neurologic toxicity was 5%. Since this report it has become evident that lower single doses may be a sufficient. In the University of Pittsburgh’s recent update of 972 patients, the median marginal dose was 14 Gy. Other reports have shown good local control with doses of 12 Gy.112,119 Fig. 33.6 illustrates the potential dosimetric advantages of lower marginal doses. Tumor volume is also associated with the success or failure of SRS. DiBiase et al.120 reported 5-year disease-free survival of 91.9% for patients with tumors 10 cc or smaller versus 68% for larger tumors. Kondziolka et al.107 similarly cited a decreased control rate with larger tumors.107

Hypofractionated stereotactic radiotherapy. The use of hypofractionated stereotactic radiotherapy (FSRT) for meningiomas has increased with the increased availability of technology to deliver stereotactic radiotherapy. Recent data suggest that for larger volume tumors (>4.9 cc), the use of hypofractionation may decrease the likelihood of posttreatment edema as compared with single fraction radiosurgery.121 As such, larger tumors may be more safely treated with hypofractionated radiotherapy. In contrast, Conti et al.122 reported outcomes of 229 patients with 245 meningiomas treated with single or multifraction radiosurgery; they identified that tumor volume, tumor grade, brain/tumor interface, and lesion location influenced posttreatment edema (PTE), whereas hypofractionation did not provide sufficient prevention of PTE. Moreover, no patient with a skull-base meningioma developed symptomatic PTE.122 Additional potential indications for hypofractionation include tumors with greater proximity to the optic apparatus, as well as reirradiation.123 Several series have now been reported for FSRT showing equivalent local control to SRS and conventionally fractionated EBRT.121,124–129 The most commonly reported fractionation scheme for treatment of benign meningioma has been 25 Gy in five fractions.126 In practice, certain patterns are emerging. SRS is employed for small volume (generally ≤ 3 cm or < 4 cc) well-defined tumors, either definitively or postoperatively, FSRT is used for slightly larger tumors (generally 3 cm to 5 cm, or smaller than 12 to 15 cc), whereas EBRT is used for larger tumors, tumors with poorly defined margins, tumors with parenchymal invasion, multifocal relapses, high-grade tumors, and tumors with significant edema.

Incidentally Detected Meningioma With the increasing use of MRI in general medical decision-making, the number of incidentally discovered meningiomas has risen. Most patients with incidental meningiomas can undergo a period of serial imaging follow-up and defer definitive therapy until tumor progression is identified. Several series have documented the natural history of incidental meningiomas.65 Most of these tumors are likely to represent grade I meningiomas because they are more common and more likely to have been asymptomatic. Risk factors for tumor progression include younger patients, larger tumors at the time of discovery, non–skull-base location, and noncalcified tumors.11,65

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514

SECTION III

Disease Sites

Fig. 33.6 Comparison of dose profiles of cavernous sinus meningioma using standard 14 Gy (left) marginal dose versus 12 Gy (right). Note the proximity of the 8 Gy isodose line (green) to the optic structures (red contours) with each prescription dose, given otherwise identical plans.

Higher Risk Patients (WHO Grades II/III)

Role of Radiotherapy in Atypical Meningiomas

Atypical Histology (WHO Grade II)

100

Percent recurrence

Considerable controversy exists regarding the proper treatment paradigms for grade II meningiomas.3,130 These tumors carry considerably higher recurrence risk.7,17,52,74,131–133 Although grade II tumors are often treated with combined surgery and postoperative irradiation, this has not been universally adopted, particularly following gross total resection (GTR).49,134–139 Several centers have reported the rates of adjuvant radiation therapy following GTR, varying from 7% to 30%.136,139–143 After an incomplete resection, postoperative radiotherapy is typically, although not uniformly, recommended. Several of the series cited immediately above also reported the rates of postoperative RT following subtotal resection.136,139,141–143 The range was broad, from 13%143 to 74%.141 When employed, RT may be either SRS or EBRT. Relatively higher doses, as compared with those to grade I tumors, may be advisable. One study demonstrated improved local control with doses exceeding 53 Gy.48 A recent analysis of combined photon and proton therapy for atypical and anaplastic meningiomas found improved cause-specific and overall survival with a total dose exceeding 60 CGE.144 The role of early adjuvant EBRT in patients with atypical meningioma was recently described in a retrospective cohort study, with 51 patients in the early adjuvant EBRT group and 30 patients in the salvage EBRT group. Six of 51 (12%) patients in the early adjuvant EBRT group recurred/progressed compared with 34 of 35 (97%) patients in the observation group. Of these 34 patients, 30 received salvage EBRT, mostly after reexcision. Of these 30 (40%), 12 patients recurred/progressed again after salvage EBRT, compared with 6 of 51 (12%) patients after early adjuvant RT (p = 0.003). After EBRT 5-year PFS was significantly better for early adjuvant EBRT compared with salvage EBRT (69% vs. 28%, log-rank p < 0.001); reexcision followed by salvage EBRT may not be as effective as early adjuvant EBRT.145 Radiosurgery has been used for atypical tumors.13,52,109,146–148 Hakim et al.,109 using a median marginal dose of 15 Gy, achieved 4-year local control of 83%. However, caution is to be recommended. Although control of disease within the radiosurgical volume has been acceptable, marginal failures remain problematic.147,148 Two recent series have suggested that the PFS benefit of adjuvant radiotherapy for resected atypical meningioma may not extend to those treated with SRS.135,136 The series from the Barrow Neurologic Institute did however suggest a trend for improved PFS over observation in the subset with subtotally resected tumors.135 Radiosurgery may therefore best be reserved for less aggressive, smaller meningiomas. Aghi et al.140 reported a 5-year recurrence rate of 41% following gross total, Simpson grade I resection of 108 atypical meningiomas

No radiotherapy Radiotherapy

80 60 40 20 0

0

3

6

9

12

Years

Fig. 33.7 Recurrence rates of atypical meningiomas after complete resection based on whether the patient received postoperative radiotherapy.

(Fig. 33.7). Recurrences led to numerous reoperations and to worse survival. Eight of these patients received postoperative EBRT, to a mean dose of 60.2 Gy to the resection bed with a 1 cm margin. Among this small cohort there were no further recurrences.140 In the RTOG Phase II trial (RTOG-0539), patients with atypical histology were assigned postoperative radiotherapy, 54 Gy in 30 fractions following gross total resection, and 60 Gy in 30 fractions following subtotal resection; long-term outcomes are pending. In the current BN-003 trial, patients with gross totally resected WHO grade II meningioma are treated with intensity-modulated radiation (IMRT), 59.4 Gy in 33 fractions.

Malignant Histology (WHO Grade III) Five-year recurrence rates in two large surgical series ranged from 72% to 78%.50,133 Overall survival at 5 years ranged from 32% to 64%.149 Failure of local tumor control is often a cause of death from these tumors.49,51,150,151 Patients with WHO grade III tumors are frequently treated with postoperative radiotherapy. A recent series from the Cleveland Clinic reported 13 patients over a 23 year period, 3 of whom received postoperative irradiation. They suggested that postoperative radiotherapy improved survival over surgery alone.149 In another publication by Dziuk et al.,151 19 of 38 patients received initial postoperative radiation therapy and experienced significant improvement in 5-year disease-free survival of 80% versus 15% (p = 0.002).151 As with grade II tumors, there appears

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CHAPTER 33

Benign Brain Tumors: Meningiomas and Vestibular Schwannomas

to be a dose-response with grade III meningiomas.51,144,152,153 DeVries et al.152 found an improvement in local control and survival with greater than 60 Gy. Similarly, Boskos et al.144 reported improved overall survival with doses exceeding 60 Gy and a trend toward further improvement beyond 65 Gy. Nevertheless, caution must be used with aggressive dose escalation. One report of accelerated hyperfractionation revealed a 55% rate of grade 3 to 5 toxicities. Within current cooperative group trials, RTOG-0539 employed 60 Gy in 30 fractions for patients with malignant (WHO grade III). The EORTC (European Organisation for Research and Treatment of Cancer) 22042-26042 protocol uses similar dose and fractionation following Simpson grades 1 to 3 resection, but adds 10 Gy in a five-fraction boost after Simpson grade 4 or 5 surgery.

Radiation-Induced Meningioma Reports have suggested that radiation-induced meningiomas are more likely to be clinically aggressive and multifocal.20,22,154 Multifocal tumors have been reported to be between 4.6% and 29% of radiation-induced meningiomas.20,22 Moreover, the identification of atypical or malignant histology may be modestly more frequent, from 24% to 38%.155 The latency between radiation exposure and the development of a secondary meningioma ranges from 2 to 63 years, although exposure to radiotherapy at a young age,155 larger radiation fields, and higher doses156 tend to predict for a shorter latency. Radiation-induced meningiomas have often already been treated with radiation therapy, often close to tolerance doses for brain, limiting the role of additional fractionated EBRT. The management of such tumors centers around resection, if possible. Aggressive resection in the setting of previously irradiated tissue, however, poses the risk of wound breakdown and cerebrospinal fluid leak. Full-dose reirradiation has been reported in cases of recurrent meningioma and conceivably can be accomplished in the radiation-induced variant given the longer latency between treatment courses.150,157–159 SRS and FSRT have also been reported.160,161 Kondziolka et al.160 described a series of 19 patients with radiation-induced meningioma treated with radiosurgery and reported a control rate of 75% with acceptable toxicity. The advantage of the stereotactic approaches is that they can potentially deliver a curative dose of radiation while sparing the increased cumulative integral dose delivered by conventional external beam radiotherapy. The disadvantage of a focal approach, however, is the high out-of-field failure rate caused by the prior field cancerization.161

Neurofibromatosis-Related Meningioma Meningiomas occur in 45% to 58% of patients with type 2 neurofibromatosis29 The presence of meningiomas correlates to a 2.5-fold increased relative risk of death in patients with NF2.162 Natural history studies of NF2-related meningiomas suggest a salutatory/episodic growth pattern interspersed by long periods of quiescence.163 Goutagny et al.164 reported a series of NF2-related meningiomas in which the likelihood of atypical or malignant histology was found to be 29% and 6%, respectively. A concern with the use of radiotherapy for NF2-related tumors in general is the possibility of malignant degeneration. However, a recent series by Liu et al.165 evaluating the role of SRS in the treatment of NFrelated meningiomas did not report any cases of malignant degeneration among 93 tumors treated in 12 patients with NF2. Local control in that series was 92% at 5 years. SRS represents a potentially useful treatment modality given the often numerous meningiomas present in a patient with NF2, the high local control rate, and the limited toxicity. Systemic therapy. Systemic agents have not had a significant impact on the general management of meningioma to date. Several classes of agents have been evaluated, including hormonal therapy, chemotherapy, immune modulators, and targeted agents.166–168 Hydroxyurea has been used for several years, but radiographic responses are uncommon and rates of progression for atypical and malignant histology have remained high.169

515

Because a majority of meningiomas express progesterone receptors, a randomized trial of the antiprogestin, mifepristone versus placebo was conducted. Mifepristone resulted in increased toxicity, but no improvement in response.170 Several recent trials employing novel receptor-tyrosine kinase targeted agents have been disappointing as well.171,172 The RANO group published a summary of 47 studies of patients with surgery and radiation refractory meningioma treated with a variety of systemic agents.84 The only outcome extractable across these studies was PFS 6. In this high-risk group with progressive, multiply recurrent meningioma, the weighted average PF 6 was less than 30% for WHO grade I or WHO II/III tumors, documenting a critical need for new approaches to patients who have anaplastic or multiply recurrent tumors, have failed multiple local therapies, or have diffuse and progressive meningiomatosis. These remain challenges for future investigation.

Irradiation Techniques and Tolerance Several methods of target delineation have been described, and there is controversy concerning the optimal method to account for microscopic spread along dura, bone, and into the brain. With external beam irradiation, margins as large as 2 cm beyond the gross tumor volume (GTV) have been described using modern imaging.74 However, margins as small as 1 mm to 2 mm in fractionated stereotactic radiotherapy series and 0 mm for SRS, have produced good long-term outcome (although the follow-up in most SRS series is shorter than in the fractionated radiotherapy series, and patients selected for radiosurgery are inherently different, customarily with smaller, lower grade, and frequently skull base tumors, each of which portends improved prognosis).86,87 Such tight margins may not be safe for meningiomas beyond grade I. Recent reports of radiosurgery for atypical meningioma have found that increased conformality predicted for a higher rate of locoregional failure.146,173 In contemporary trials, a CTV margin of 1-2 cm for higher grade meningiomas has often been used. In the current NRG Oncology BN-003 study, target margins are tighter. The GTV is expanded 5 mm to create the CTV, and the CTV margin may be reduced to 3 mm around natural barriers to tumor growth, such as uninvolved skull or falx. For margins abutting uninvolved brain parenchyma, the CTV is defined as the GTV with no expansion unless there is brain invasion, in which setting the CTV remains GTV plus 5 mm.

Proton Therapy Whereas no randomized trials of photon versus proton therapy for meningioma have been conducted, several of these patients have tumors in critical locations, in close proximity to adjacent radiosensitive structures, and generally have considerable longevity in their favor. Further, given that one of the organs-at-risk is rather peculiar to the disease itself (i.e., the meninges), which is susceptible to neoplastic transformation following radiation exposure, several dosimetric comparison studies have been conducted and for large tumors, typically treated with EBRT, intensity-modulated proton therapy would likely produce dosimetric benefit; therefore, its utilization needs to be considered on a case-by-case basis, with appropriate cross-technology comparisons.

Dural Tail The dural tail is a thickening of the enhancement extending from the meningioma as seen on contrast-enhanced MRI or CT. Targeting of the dural tail within the CTV is a subject of controversy. The dural tail was initially thought to result from direct tumor invasion into surrounding dura, although surgical series have found that the dural tail is composed almost entirely of hypervascular dura; it is typically an imaging finding, not routinely visualized at surgery.7,174–177 The dural tail is not included in the Simpson resection grading scale, and the results of surgery alone have largely been obtained without specific

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attention to it. Furthermore, radiosurgical series have generally not targeted the dural tail.7,17,107,110 Inclusion of the dural tail within the radiation treatment volume can significantly increase the volume of the intended target. In the completed RTOG 0539 trial and the present NRG BN-003 protocol, the dural tail was not specifically targeted.

Hyperostosis Inclusion of hyperostotic bone within the CTV is also worthy of discussion. A Simpson grade 1 resection includes gross total resection of tumor, its dural attachments and any abnormal bone.6 Biopsy series have demonstrated a significant rate of bone involvement by meningioma in cases of hyperostosis,178 which is associated with a higher rate of recurrence.179,180 It is justifiable to target hyperostotic bone within the treatment volume when this can be accomplished safely. However, this question needs to be addressed more thoroughly. Donald Simpson, in his august publication of outcome by resection grade, noted that in a prior era, hyperostosis with meningioma was identified in 36% of his patients.6 He found that recurrence from invaded bone was uncommon and felt its importance may be overrated. Further investigation will be required to establish unequivocally the need for complete resection of hyperostotic bone or inclusion of it in the adjuvant radiation therapy fields. In our era many more patients are diagnosed earlier with smaller tumors for whom hyperostosis can typically be identified much more readily with better imaging.

Toxicities of EBRT The toxicities associated with external beam radiotherapy are commonly related to the location. Many patients experience fatigue, and some have alopecia. Late toxicities include cataract formation, cranial nerve palsy or neuropathy, and panhypopituitarism can occur.181,182 Rarely, patients experience symptomatic radionecrosis and may require long-term steroid therapy or surgical intervention.48 Debus et al.86 reported a series of 189 patients who received radiotherapy with modern fractionation schedules, treatment planning, and delivery techniques. The rate of grade III toxicities was 2.2%, even less in patients with no preexisting deficit. Cognitive decline remains a possible late effect, although this is controversial in the setting of partial brain irradiation and smaller treatment volumes.183 A recent randomized trial of low-grade brain tumors treated with partial brain irradiation, either simple 3D techniques, or more sophisticated FSRT techniques with smaller PTV margins found categorical cognitive benefit from the more refined technique in children and young adults.184 Like most other sequelae, cognitive toxicity also has site-specific, dose-volume relationships.82,92,185 Temporal lobe dose predicts for cognitive decline,186,187 and large treatment volumes are more likely to lead to symptomatic decline.188 The likelihood of radiationinduced cognitive loss rises over time after brain radiotherapy. Cavernous sinus meningiomas, located just medial to the hippocampus and sphenoid wing meningiomas, lateral to the hippocampus, may carry a higher risk of cognitive decline.189 These patients may also be at greater risk of late endocrine deficiencies.

Toxicities of SRS The nature of the toxicities of SRS also depends on tumor size and location; most toxicities are related to damage to nerves or to radiation-induced edema. Sensory nerves, such as the optic nerve, are more susceptible to injury than motor nerves. Fraction sizes of 10 Gy or less to the anterior visual pathway carry a 1% to 2% rate of optic neuropathy, but rates rise quickly at doses higher than 10 Gy.17 A recent report from Japan suggests that point doses higher than 10 Gy may be acceptable when necessary.190 Edema is a considerably more common complication with single fraction radiosurgery than with standard fractionation.7,101,119,191–195 Several risk factors have been identified for radiosurgery-induced edema,

including higher marginal dose, tumor diameter greater than 4 cm, presence of pretreatment edema, and periventricular or parasagittal location.a A recent series found that parasagittal meningiomas had a greater than four-fold increased risk of peritumoral edema after radiosurgery.198 Response assessment. No official response assessment criteria are available to date. The RANO group has formed a subcommittee to develop recommendations for standardized response assessment criteria for systemic therapies for meningioma.199 Ultimately, the goal will be to have these as standardized response assessment criteria for cooperative group clinical trials. Because meningiomas are commonly slow growing tumors, they are also commonly slow to respond to radiotherapy and, in most cases, will leave a residual imaging abnormality after treatment. With single fraction SRS, the University of Pittsburgh reported that within the first four years, only 58% of tumors had decreased in size, but that by 10 years, 88% of tumors had decreased.200 The University of Heidelberg reported a series of meningiomas treated with fractionated stereotactic radiotherapy in which 70% of patients experienced no change in tumor volume with a median follow-up of 5.7 years.93 Grade II tumors have a greater rate of both in-field and marginal failure and this failure pattern is important in assessing a response for grade II tumors after either fractionated radiotherapy or radiosurgery.148

Treatment Algorithm/Controversies/Clinical Trials A treatment algorithm is presented in Fig. 33.8. Corresponding dose and treatment volume guidelines are contained in Table 33.4. These depict a literature-based approach defined by risk strata. However, many controversies persist. There is substantial debate concerning (1) which patients to observe, (2) who to treat with primary fractionated radiotherapy or radiosurgery rather than surgery, and (3) the selection of patients for postoperative radiotherapy. Gross total resection of a benign (WHO grade I) meningioma is considered definitive, but there is less agreement following subtotal resection of a WHO grade I, or following gross total resection of a grade II meningioma. Subtotally resected grade II meningiomas are frequently managed with irradiation and all grade III meningiomas demand aggressive treatment, irrespective of resection extent. Despite aggressive management, however, current approaches are insufficient for many patients at high risk. New systemic and biologic treatments are needed.

Contemporary Trials Two prospective cooperative group trials evaluating the role of radiotherapy in the management of meningioma have recently completed accrual. The EORTC completed enrollment on a Phase II trial (22042-26042) aimed at evaluating PFS in patients with grade II and III meningioma and await preliminary results. This study stratified tumors based on degree of resection and histology. Patients with Simpson grade 1 to 3 resection received standard postoperative radiotherapy (60 Gy in 30 fractions), whereas those with lesser resection received an additional boost (10 Gy in 5 fractions). The RTOG 0539 trial adopted a risk stratification approach to the postoperative management of meningiomas. Patients at low risk, including gross totally or subtotally resected WHO grade I tumors, we observed. Those at intermediate-risk, including recurrent WHO grade I and gross totally resected WHO grade II tumors, received postoperative radiotherapy (54 Gy in 30 fractions). Patients at high risk with WHO grade III tumors or subtotally resected or recurrent WHO grade II tumors, received 60 Gy in 30 fractions. Initial results of the patients at intermediate risk, which were recently published, demonstrated a PFS of 93.8%.83 a

References 7, 65, 107, 119, 192, 196, 197.

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CHAPTER 33

Benign Brain Tumors: Meningiomas and Vestibular Schwannomas

Incidental

Grade I

Short interval Follow-up imaging

Growth or symptoms

No growth or symptoms

Treatment (surgery, SRS, EBRT)

Continued observation

GTR

Observation

Grade II

STR

GTR

Adjuvant EBRT, SRS, or observation

Consider risk stratification

517

Grade III

STR

Maximal safe resection ! postoperative radiotherapy

Adjuvant EBRT or SRS

High risk (brain Low risk invasion, high mitotic index)

Adjuvant EBRT or SRS

Adjuvant EBRT, SRS, or observation Fig. 33.8 Treatment Algorithm for Meningiomas Based on Grade and Operative Status. EBRT, External beam radiation therapy; GTR, gross-total resection; SRS, stereotactic radiosurgery; STR, subtotal resection.

TABLE 33.4

Meningioma Radiotherapy/Radiosurgery Dose Selection Suggestions

Modality

Dose

GTV

CTV

Grade I

EBRT

50.4–54 Gya

Fractions 28–30

Enhancing tumor on postoperative MRI

Same as GTV

Grade II

EBRT

54–55.8 Gy

30–31

Enhancing tumor with tumor bed on postoperative MRI

1-cm expansion on CTV

Grade III

EBRT

59.4–63 Gy

33–35

Enhancing tumor with tumor bed on postoperative MRI

2-cm expansion on CTV (reduce to 1 cm at 54 Gy)

Grade I

SRSb

12–14 Gy

1

Enhancing tumor

Same as GTV

Grade II

SRS

14–18 Gy

1

Enhancing tumor

Same as GTV

Grade III

SRS

>14 Gy

1

Enhancing tumor

Same as GTV

a

Good outcomes have been obtained with 45 Gy for optic nerve sheath meningiomas. SRS, for present purposes assumes single fraction radiosurgery. Good results have been reported with fractionated stereotactic treatments as well, for instance 5 Gy × 5.272 CTV, Clinical target volume; EBRT, external beam radiation therapy; GTV, gross tumor volume; MRI, magnetic resonance imaging; postop, postoperatively; SRS, stereotactic radiosurgery. b

The current generation of prospective studies for meningioma include the NRG BN-003 and the ROAM (Radiation vs. Observation of Atypical Meningioma) Phase III trials. Both of these studies randomize completely resected atypical meningioma to adjuvant radiation versus observation, and assess modern quality of life and neurocognitive metrics. Vestibular schwannoma, previously erroneously referred to as acoustic neuroma, is a benign neoplasm originating from the epineural schwann cells of the vestibular portion of the eighth cranial nerve. Most cases are unilateral and sporadic, although bilateral vestibular schwannoma is pathognomonic for type 2 neurofibromatosis (NF2). Although these tumors are rarely fatal, symptoms, such as hearing loss, tinnitus, imbalance, and cranial nerve deficits, can significantly impair the quality of life. Management options include observation, resection, SRS, or fractionated stereotactic radiation therapy.

Etiology and Epidemiology The incidence of vestibular schwannoma is increasing, and has recently been estimated at 1.2 per 100,000 population per year.201 More widespread use of intracranial imaging with CT and MRI has contributed to the increased incidence, because vestibular schwannomas are identified on MRI in 0.2% of asymptomatic patients.8 Roughly 85% to 90% of cerebellopontine angle tumors are vestibular schwannomas. Some cases can be

attributed to genetic syndromes, such as NF2, which pathognomonically presents with bilateral vestibular schwannomas. Over 90% of cases, however, are sporadic and unilateral. Risk factors for the development of sporadic vestibular schwannomas are poorly understood at present, with limited and highly controversial studies suggesting that risk may be increased with cell phone usage,202 occupational exposure to loud noise, and dental x-rays.203 The median age of patients at diagnosis is 50 years; however, patients with NF2 typically manifest symptoms by age 20 to 30 years. One report suggested that in those with a 20 or more years of occupational exposure to loud noise, there is a 10-fold increase in the risk of developing vestibular schwannoma.204

Biologic Characteristics Biallelic inactivating mutations of the tumor suppressor gene NF2, located on chromosome 22q12, are commonly found in both sporadic and NF2-associated vestibular schwannomas.205 NF2 encodes the cytoskeletal protein merlin, which functions in embryonic development, cell adherence, maintenance of cell membrane stability, and cell proliferation. Merlin has been hypothesized to suppress tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1, an E3 ubiquitin ligase.206 Merlin interacts with a wide variety of cell receptors and signaling pathways, such as EGFR, ERBB2, CD44, Rac, Ras/raf, and Wnt, providing opportunities

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for investigation of targeted therapies for vestibular schwannoma.207 Vestibular schwannoma samples have also been shown to express higher levels of phosphorylated ErB3 expression relative to healthy controls, suggesting increased signaling along this pathway may contribute to tumorigenesis.208 CXCR4 mRNA levels were also elevated in vestibular schwannoma surgical samples compared with healthy vestibular nerves, suggesting a role in pathogenesis.209 Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR)-1 have been shown to be expressed at high levels in vestibular schwannoma.210 Loss of heterozygosity of chromosome 22q has also been implicated in the tumorigenesis of vestibular schwannoma, likely owing to loss of the genes SMARCB1, LZTR1, and NF2 (all of which are harbored on chromosome 22q).211

Pathology and Pathways of Spread Vestibular schwannomas are histologically similar to schwannomas arising from other cranial and peripheral nerves. Their histologic appearance is characterized by alternating zones of dense and sparse cellularity, known as Antoni A and B areas (Fig. 33.9). Most vestibular schwannomas arise from the superior and inferior branches of the vestibular portion of the eighth cranial nerve, within

A

the internal auditory canal. It is rare for these tumors to originate along the cochlear nerve. Over time, progressive tumor growth may fill the internal auditory canal and extend into the cerebellopontine angle, causing compression of the brainstem and other nearby cranial nerves, most commonly the trigeminal and facial nerves. The natural history of vestibular schwannoma is typically characterized by gradually progressive growth with gradual sensorineural hearing loss and potentially other cranial nerve deficits. A subset of patients can present with sudden hearing loss, presumed to be related to a vascular, possibly venous, nerve infarct, and hence generally irreversible. Less than 5% of tumors may regress slightly with surveillance.212 The average growth rate has been estimated at 1 mm to 2 mm per year for sporadic lesions212,213 and 3 mm per year for patients with NF2-associated lesions.214 Tumor size and growth rate do not consistently correlate with hearing loss, however. Cystic schwannoma is a well-recognized tumor subtype that tends to behave more aggressively, invading and splaying adjacent cranial nerves. It is rare for malignant degeneration to occur.

Clinical Manifestations, Patient Evaluation, and Staging Vestibular schwannoma is increasingly detected as an incidental finding on MRI or CT performed for other reasons. MRI is the imaging method of choice for visualizing vestibular schwannomas, which typically appear as contrast-enhancing lesions originating within the internal auditory canal on T1-weighted MRI images (Fig. 33.10A, B). The extent of the tumor may be described using the Koos grading system (Table 33.5). Symptoms associated with vestibular schwannoma are related to the tumor’s size and location with respect to nearby critical structures. When tumors are symptomatic, patients may complain of hearing loss (95% objective, 66% subjective), tinnitus (63%), imbalance or vertigo (61%), facial numbness or pain (17%), facial paresis or taste disturbance (6%), other cranial nerve deficits, or cerebellar dysfunction.215 Involvement of the cochlear nerve is primarily responsible for hearing loss and tinnitus. Involvement of the vestibular nerve results in unsteadiness. Facial numbness is primarily caused by the trigeminal nerve being affected. In the rare instance of taste disturbance or facial paresthesias, facial nerve involvement is the culprit. Sensorineural hearing loss classically affects high frequencies preferentially and may therefore be mistaken for noise- or age-related hearing loss. An example of a typical patient’s audiogram is shown in Fig. 33.11, along with the two mainstream classification systems for audiogram findings specific to patients with vestibular schwannoma, namely the Gardner-Robertson216 and American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS)217 methods (Table 33.6). As a rule, patients whose speech discrimination score is 50% or less than 50 dB or more may not benefit from an approach focused on the preservation of hearing.218 Each case must be considered individually, however, particularly in patients with bilateral vestibular schwannomas or other causes of contralateral hearing compromise. Facial nerve function is characterized clinically by the HouseBrackmann grading scale (Table 33.6). When clinically indicated, additional studies may be performed, such as facial nerve electromyography, caloric testing, or electronystagmography (Table 33.7).

Primary Therapy B Fig. 33.9 Histopathology of Vestibular Schwannoma. Tumors are well-circumscribed with areas of hyper- and hypocellularity (Antoni A and B areas) and contain thick-walled vessels. (A) Depicts hypercellularity (Antoni A areas). (B) Depicts hypocellularity (Antoni B area) adjacent to a hypotrophic vessel. (Courtesy of Michael Castro, MD.)

Because vestibular schwannoma is rarely a life-threatening diagnosis, the primary goals of therapy are local control and preservation of function. Options include surveillance, resection, SRS, and FSRT. No true randomized, controlled trials have been published about patients with vestibular schwannoma, and interpretation of a singleinstitution series is limited by differences in factors, such as patient selection, treatment techniques, and methods of assessing and reporting tumor control, and treatment or tumor-related neurologic deficits. For

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CHAPTER 33

Benign Brain Tumors: Meningiomas and Vestibular Schwannomas

A

B

C

D

519

Fig. 33.10 T1-weighted, contrast-enhanced magnetic resonance imaging (MRI) images from a 39-year-old woman with a right-sided vestibular schwannoma. She was treated with fractionated stereotactic radiotherapy (FSRT) to 50.4 Gy at 1.8 Gy/fraction. Shown are representative pretreatment axial (A) and coronal (B) images, posttreatment axial (C), and coronal (D) images obtained 19 months after completing FSRT. Increased central necrosis is demonstrated in the posttreatment images.

Koos Staging System for Vestibular Schwannoma

TABLE 33.5 Stage I

Small intracanalicular tumor

Stage II

Small intracanalicular tumor with extension into cerebellopontine angle

Stage III

Larger tumor occupying cerebellopontine cistern without brainstem displacement

Stage IV

Extremely large tumor with marked displacement of brainstem and cranial nerves

Adapted from Koos W. [Microsurgery as a condition for progress in the treatment of acoustic nerve neurinoma]. Wien Med Wochenschr. 1977;127(8):246–249.273

example, local control may be determined radiographically as a lack of tumor growth, or absence of clinical signs of progressive tumor growth, or absence of need for further intervention. The natural history of vestibular schwannoma following radiation therapy may be characterized by a transient increase in size,63 often with a necrotic-appearing center (see Fig. 33.10C,D), followed by stability or regression. This type of

MRI finding may confound the results of some published SRS series, particularly in early years, before this phenomenon was recognized. Hearing deficits are also analyzed in multiple different fashions, including subjectively (typically by querying patients about their ability to use the telephone with the affected ear) or using objective audiometric data. Facial function is typically scored using the House-Brackmann system (see Table 33.6), but investigators differ in their method of defining “significant” facial and other cranial nerve toxicity. Outcomes may also be reported as crude or actuarial rates, adding to the heterogeneity of published case series. Currently, treatment modality is chosen based on physician familiarity, bias and choice, patient characteristics (age, symptoms, location and size of lesions), the availability of different technologies, and, of course, patient choice as well. Analysis of the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2009 revealed that 49.04% of patients underwent surgery alone, 23.55% radiotherapy alone, 1.98% both surgery and radiotherapy, and 24.16% were observed.201 Observation was the most common management strategy for patients age 10 years or younger and those 81 years or older, whereas surgery was most common for patients age 11 to 70 years. Patients undergoing surgery had significantly larger tumors than those receiving only radiotherapy (2 cm vs. 1.5 cm, p 1 year) after combined-modality therapy in ATC has been so rare as to provoke reports of single cases,182 subsequent series support the benefit of combined-modality approaches. Swaak-Kragten et al.183 conducted a study of 30 patients with ATC treated with an adjuvant approach combining surgery, EBRT, and single-agent chemotherapy with doxorubicin administered concurrently with EBRT and continued after EBRT completion; they reported an encouraging improvement in 1-year survival from 9% (historical controls) to 23% (new patient cohort). Haigh et al.184 reported a 75% 2-year survival in 8 patients undergoing complete surgical resection and adjuvant EBRT and chemotherapy. Tan et al.185 reported an estimated 5-year survival of 60% for 5 patients who underwent complete resection. Four patients had received postoperative EBRT, 3 with post-EBRT doxorubicin-based chemotherapy. Pudney et al.186 reported a median OS of 13 months for 5 patients with stage IVB ATC treated with either EBRT concurrent with doxorubicin or induction docetaxel, doxorubicin, and cyclophosphamide. Three patients developed progression of local disease, and 1 developed distant metastases. Higashiyama et al.187 reported a 12-month survival rate of 44% in 9 patients with stage IVB ATC treated with induction paclitaxel. This survival rate compared favorably with a historical control group of 50 patients treated without induction paclitaxel; their 12-month survival was just 5.9%. A retrospective review of 10 consecutive patients with stage IVA and IVB ATC from the Mayo Clinic who were treated with aggressive combined modality therapy (surgery if feasible, early initiation of docetaxel and doxorubicin, with the addition of concurrent EBRT followed by adjuvant chemotherapy as tolerated) had an unexpectedly long median OS of 60 months, compared with a 5- to 6-month median OS among an analogous historical group of patients.178 A current study is evaluating such aggressive combined modality therapy in a randomized Phase II clinical trial (NSC737754) using surgery when possible, concurrent IMRT, and paclitaxel with or without pazopanib.188 The optimal EBRT fractionation schedule has not yet been determined. Of patients treated with a moderate dose (57.6 Gy) slightly accelerated radiotherapy, given twice daily 3 days per week, combined with concurrent weekly doxorubicin, 70% required a 1-week interruption in treatment because of pharyngoesophagitis and tracheitis.179 Moderatedose (60.8 Gy) accelerated fractionation even without concurrent chemotherapy may be too toxic, with a median OS of just 10 weeks.189 Low-dose (40 Gy) hyperfractionated accelerated radiotherapy with sequential but not concurrent chemotherapy (doxorubicin) seems to be well tolerated with 1-year and 3-year OS of 50% and 35%, respectively.181

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Disease Sites

Moderate-dose (60 Gy) hyperfractionated accelerated radiotherapy without concurrent chemotherapy seems to be well tolerated with a median OS of 13.6 months and 1-year and 5-year OS of 66.7% and 0, respectively.190 However, others have reported less than 10% 1-year survival with hyperfractionated accelerated radiotherapy to a median dose of 57 Gy in patients with nonmetastatic disease.191 In an active clinical trial, IMRT is being used with conventional daily fractionation to a total dose of 66 Gy in 33 fractions of 2 Gy each 5 days per week over a 6.5 week period of time.188 In a report of the Surveillance, Epidemiology and End Results database from the National Cancer Institute, the only factors predicting for lower cause-specific mortality were age younger than 60 years, intrathyroidal tumor, and combined use of surgery and EBRT.192 However, the overall cause-specific mortality rate was 80.7% at 1 year. An extension of the Mayo Clinic experience has been completed recently.104 The major findings were median OS and 1-year survival for the later cohort were 9 months (95% CI, 4 to 22 months) and 42% versus 3 months and 10% for the earlier cohort. Median OS was 21 months compared with 3.9 months in the pooled MMT (multimodal therapy) versus PI (palliative intention) groups for the later cohort [HR, 0.32; p = 0.0006)] Among only patients in the later cohort who had stage IVB disease, median OS was 22.4 versus 4 months (HR, 0.12; 95%; CI, 0.03 to 0.44; p = 0.0001), with 68% versus 0% alive at 1 year (MMT vs. PI). Among patients with stage IVC cancer, OS did not differ by therapy. Overall with these data it appears that MMT conveys longer survival in ATC among patients with stage IVA/B disease. The use of multimodality therapy, including surgery, EBRT, and chemotherapy, is appropriate and offers the best chance for long-term survival, but more active systemic agents need to be found to improve survival significantly.

IRRADIATION TECHNIQUES AND TOLERANCE EBRT Treatment Volumes and Doses Treatment of the thyroid bed or gland and the regional lymph nodes is challenging because of the contour of the body in this anatomic area; the potential extension of disease to the upper mediastinum; involvement of lymph nodes in the central and lateral neck and mediastinum; and the close proximity of the lungs, spinal cord, esophagus, larynx, pharyngeal constrictors, and brachial plexus. Historically, several approaches have been reported for the initial extended fields, including a single anterior electron field,126 an anterior field with a posterior supplemental field for the mediastinum, and lateral fields.132 For optimal treatment in an adjuvant setting or for locoregionally advanced or recurrent disease treated with curative intent, the clinical target volume should include the thyroid bed (including gross disease if present), lymph nodes of the central and lateral neck (typically bilateral levels II through VI, consider adding level VII when level II is involved or in the case of bulky adenopathy), and upper mediastinum. When treating for palliation, it is reasonable to consider treating only the gross tumor volume plus margin. Treatment planning should be image based (CT simulation) and incorporate CT, 18F-fluorodeoxyglucose (18F-FDG) fused PET/CT, and MRI. At the Mayo Clinic, we have chosen to use IMRT or intensitymodulated volumetric modulated arc therapy (VMAT) in the treatment of these patients, which allows us to administer a more conformal high dose (60 Gy to 70 Gy) quickly with improved homogeneity to the thyroid bed or gross disease and high-risk areas (lymph nodes and tracheoesophageal groove), while lowering the dose to normal organs at risk, including the salivary glands, epiglottis, false vocal cords, true vocal cords, arytenoids, central and posterior aspects of the pharyngeal

constrictors and esophagus, brachial plexus, and spinal cord. The use of IMRT and VMAT has allowed for more elegant treatment of this disease site compared with conventional two-dimensional and three-dimensional treatment planning (Fig. 44.6). IMRT improves the minimum and mean dose to the planning tumor volume and significantly reduces the dose to the spinal cord.140,141,193,194 This is true for treatment of the thyroid tumor bed and locoregional nodal sites. The radiation dose used in the postoperative setting for microscopic residual disease should be 60 Gy in 6 weeks. However, some centers have suggested 40 Gy given over 3 to 3.5 weeks is adequate.123 For known gross residual disease, dose escalation to 66 Gy to 70 Gy is reasonable. One retrospective study from the United Kingdom suggested a possible dose-response effect at greater than 50 Gy for patients treated with curative intent.122 The use of higher doses without added morbidity may be feasible with IMRT, VMAT, and IMPT. Although no definitive evidence indicates a dose-response relationship between radiation dose and local control probability, there is some suggestion that higher doses are associated with lower local recurrence rates.132,195

Treatment Tolerance With the increasing availability of IMRT, VMAT, and IMPT, dose escalation may be more readily achievable in the primary setting without increasing toxicity while lowering toxicity in the adjuvant setting.139–141 Ideal planning target volumes and dose remain inadequately characterized, however. Early experiences with IMRT seem to suggest that escalation of dose to subclinical sites of possible involvement (nodal regions outside the thyroid bed to 54 Gy), the margin-negative thyroid bed (60 Gy to 63 Gy), margin-positive regions (66 Gy), and gross disease (70 Gy) is technically feasible without increasing toxicity.140,141 One treatment is given each day, 5 days a week, 1.8 Gy to 2.0 Gy per treatment. Acute radiation reactions include dermatitis, laryngitis, pharyngitis, tracheitis, and esophagitis. Late sequelae are uncommon but may include laryngeal edema, cartilage necrosis, esophageal stenosis, myelitis, brachial plexopathy, and pulmonary fibrosis.

TREATMENT ALGORITHM, CONCLUSIONS, AND FUTURE POSSIBILITIES Treatment Algorithm The initial approach to a potentially malignant thyroid mass is to perform FNA biopsy. This technique permits the identification of patients with definite cancer or for whom there is a high degree of suspicion for malignancy. At initial operation (i.e., open biopsy, thyroid lobectomy, and near-total or total thyroidectomy), the surgeon can assess tumor size, determine the presence or absence of gross local invasion or regional lymph nodal metastasis, and define the postoperative status (i.e., presence or absence of gross residual disease). The surgical pathologist can identify the degree of tumor differentiation (i.e., histologic grade); the tumor histologic type; and, if requested, the DNA ploidy. Typically, DTC is treated by near-total or total thyroidectomy unless the primary tumor is 1 cm or less in diameter. A lobectomy can be considered in DTC if tumor size is >1 cm and < 4 cm without ETE and without clinical evidence of any lymph node metastases (cN0). MTC is treated by total thyroidectomy. ATC is treated by total thyroidectomy if an R0 or R1 resection can be achieved, whereas lymphoma probably requires only an open biopsy to verify the diagnosis; however, if an R0 or R1 resection can be attained in ATC, it should be pursued. Postoperatively, all patients undergoing more than a lobectomy require thyroid hormone therapy, but only patients with DTC should receive TSH-suppressive doses of thyroxine. Knowledge of patient age, cell type, pTNM stage, and postoperative status permits classification of patients into risk groups, which may

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CHAPTER 44

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A

B Fig. 44.6 (A) Three-dimensional treatment planning isodose curves for a patient with locally recurrent and progressive papillary thyroid carcinoma, deemed nonresectable. Treatment uses anteroposterior fields followed by oblique fields to the left neck for a total dose of 70 Gy. (B) Intensity-modulated radiotherapy (IMRT) treatment plan for a patient with resected recurrent Hürthle cell carcinoma. Treatment uses nine IMRT fields delivering 60 Gy to central lower neck and 54 Gy to lateral upper neck and mediastinum.

influence the selection of subsequent postoperative adjuvant therapy. The treatment of patients with different tumor histologies is outlined in the following paragraphs and summarized as four steps in the accompanying treatment algorithm (Table 44.6).

Papillary Thyroid Carcinoma, Follicular Thyroid Carcinoma, and Hürthle Cell Carcinoma Patients with FCDC with documented distant metastases (e.g., lung, bone) at presentation undergo RAI scanning 6 to 8 weeks postoperatively and are treated with 131I therapy; the dose depends on the extent of metastases and avidity for RAI. Serum thyroglobulin levels are obtained before RAI therapy; they are closely monitored to gauge progress in terms of tumor control. Patients with nonresectable or resected but gross residual FCDC are typically given the opportunity for a whole-body scan and possible RAI

therapy. If a whole-body scan reveals no significant uptake after therapy, a course of EBRT can be considered. Patients 45 years of age or older with locally invasive disease usually are given RAI therapy. Some authorities consider the addition of EBRT, especially if serum thyroglobulin levels continue to be elevated despite apparently adequate treatment with RAI. The role of remnant ablation in patients with intrathyroidal or node-positive PTC remains controversial, although currently it is not routinely recommended in low-risk DTC. Use of the AGES, AMES, or MACIS prognostic classifications may permit a more selective use of RAI. Generally, most patients with FTC or HCC undergo postoperative whole-body scans and are considered candidates for RRA. This may be an overaggressive position because the prognosis is excellent for minimally invasive FTC after surgery alone, and HCC usually does not avidly uptake RAI.

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SECTION III

TABLE 44.6

Disease Sites

Treatment Algorithm

Step I: Initial Neck Exploration/Thyroid Resection FCDC: usually near-total or total thyroidectomy; for low-risk patients lobectomy, and for very-low risk PTC consider "active surveillance" MTC: total thyroidectomy ATC: when FNA nondiagnostic, open biopsy; for localized disease total thyroidectomy; aim for R0 or R1 resection, avoid debulking Lymphoma: FNA or open biopsy Lymph nodes: removal of central compartment nodes in FCDC and MTC; modified radical neck dissection for involved lateral nodes Step II: Thyroid Hormone Therapy Replacement doses for MTC, ATC, lymphoma TSH-suppressive doses for FCDC except microcarcinoma Step III: Outcome Prediction by Risk-Group Classification Gauged according to age, stage, histologic type, and cancer type-specific scoring systems (e.g., AMES, MACIS) Step IV: Patient Selection for RAI Therapy, EBRT, Chemotherapy, or Combinations, Targeted Therapies FCDC: RAI therapy indicated for distant spread, nonresectable or residual neck tumor, possibly invasive disease in PTC, and most cases of FTC or HCC; EBRT for local or metastatic tumor nonresponsive to RAI therapy; targeted therapy for RAIR-TC symptomatic or rapidly progressive; almost no role for chemotherapy in differentiated FCDC MTC: residual or recurrent neck disease considered for EBRT; targeted therapy for advanced MTC symptomatic or rapidly progressive; chemotherapy considered for palliation only ATC: postbiopsy or thyroidectomy EBRT and concurrent chemotherapy; targeted therapy Lymphoma: CHOP chemotherapy plus EBRT AMES, Age, metastasis, extent, and size; ATC, anaplastic thyroid cancer; CHOP, cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), prednisone; EBRT, external beam radiotherapy; FNA, fine-needle aspiration, FCDC, follicular cell–derived cancer; FTC, follicular thyroid carcinoma; HCC, Hürthle cell carcinoma; MACIS, metastasis, age, completeness of resection, invasion, and size; MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma; RAI, radioactive iodine; RAIR-DTC, radioiodine-refractory differentiated thyroid cancer; TSH, thyroid-stimulating hormone.

Medullary Thyroid Carcinoma Because MTC may be bilateral and multicentric and because nodal metastases are common at presentation, most authorities recommend an initial surgical approach of total thyroidectomy, central compartment node removal, and possible modified radical neck dissection if the lateral neck is involved with disease. There is no role for TSH-suppressive or RAI therapy in this condition. Recurrent disease in the neck or mediastinum is typically treated by repeat surgical exploration. EBRT may have a role in local control if disease becomes nonresectable, and it can be usefully employed in the treatment of osseous metastases, especially when vertebral deposits threaten the spinal cord. Combination chemotherapy has been used in stage IV MTC, as has subcutaneous octreotide therapy. These treatments have not been shown to improve CSS in disseminated, symptomatic MTC. Oral targeted therapy with multikinase inhibitors are now FDA approved for progressive and metastatic MTC. Selective RET inhibitors are on clinical trials (NCT03037385, NCT03157128).

Anaplastic Thyroid Cancer Usually only ATC diagnosis requires FNA; when nondiagnostic an open biopsy is performed. Extensive initial resection should be considered if it can be achieved without significant morbidity, aiming for an R0 or R1 resection. Debulking surgery should be avoided. Most patients with ATC are given EBRT postoperatively, and many are given the option of concurrent chemotherapy during EBRT. Unresectable stage IVB disease should be managed with EBRT plus chemotherapy in patients who desire aggressive multimodal treatment in an effort to improve overall survival. No generally approved efficacious chemotherapeutic program is available to patients with ATC. Recently a combination oral targeted therapy has been FDA approved for ATC (dabrafenib plus trametinib) based on limited data.

Primary Thyroid Lymphoma In contrast to the outlook for ATC, much greater optimism is expressed in managing primary thyroid lymphomas. A gradual shift has occurred from subtotal thyroidectomy to open biopsy and FNA biopsy in diagnosing this condition. Recognition of the probably systemic nature of the disease led initially to an acceptance of the role of EBRT to the involved thyroid gland and regional nodes. More definitive data point to the use of combined-modality therapy in the management of this disease, typically combining R-CHOP chemotherapy with EBRT.

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CHAPTER 44 50. Hu MI, Ying AK, Jimenez C. Update on medullary thyroid cancer. Endocrinol Metab Clin North Am. 2014;43:423–442. 53. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2:1023–1029. 63. Grani G, Lamartina L, Durante C, et al. Follicular thyroid cancer and Hurthle cell carcinoma: challenges in diagnosis, treatment, and clinical management. Lancet Diabetes Endocrinol. 2018;6:500–514. 75. Tuttle RM, Haugen B, Perrier ND. Updated American Joint Committee on Cancer/tumor-node-metastasis staging system for differentiated and anaplastic thyroid cancer (eighth edition): what changed and why? Thyroid. 2017;27:751–756. 88. Iniguez-Ariza N, Kaggal Suneetha, Hay ID. Role of Radioactive Iodine for Remnant Ablation in Patients with Papillary Thyroid Cancer. In: Mancino LTK AT, ed. Managment of Differentiated Thyroid Cancer. Switzerland: Springer; 2017:205–222. 91. Hay ID, Johnson TR, Kaggal S, et al. Papillary thyroid carcinoma (PTC) in children and adults: comparison of initial presentation and long-term postoperative outcome in 4432 patients consecutively treated at the Mayo Clinic during eight decades (1936-2015). World J Surg. 2018;42: 329–342.

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104. Prasongsook N, Kumar A, Chintakuntlawar AV, et al. Survival in response to multimodal therapy in anaplastic thyroid cancer. J Clin Endocrinol Metab. 2017;102:4506–4514. 148. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384: 319–328. 149. Cabanillas M, Terris DJ, Sabra M. Information for Clinicians: approach to the patient with progressive radioactive iodine refractory thyroid cancer- When to use systemic therapy. Thyroid. 2017. 150. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621–630. 151. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–141. 152. Elisei R, Schlumberger MJ, Muller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639–3646. 178. Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience using aggressive multimodal therapy. Thyroid. 2011;21:25–30.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 44

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SECTION III

Disease Sites

47. Skinner MA, Moley JA, Dilley WG, et al. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med. 2005;353:1105–1113. 48. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–690. 49. Landa I, Ibrahimpasic T, Boucai L, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest. 2016;126:1052–1066. 50. Hu MI, Ying AK, Jimenez C. Update on medullary thyroid cancer. Endocrinol Metab Clin North Am. 2014;43:423–442. 51. Raue F, Frank-Raue K. Update on multiple endocrine neoplasia type 2: focus on medullary thyroid carcinoma. J Endocr Soc. 2018;2:933–943. 52. WHO. Classification of Tumours of Endocrine Organs. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2017. 53. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2:1023–1029. 54. Volante M, Bussolati G, Papotti M. The story of poorly differentiated thyroid carcinoma: from Langhans’ description to the Turin proposal via Juan Rosai. Semin Diagn Pathol. 2016;33:277–283. 55. Volante M, Collini P, Nikiforov YE, et al. Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach. Am J Surg Pathol. 2007;31:1256–1264. 56. Hughes DT, Haymart MR, Miller BS, et al. The most commonly occurring papillary thyroid cancer in the United States is now a microcarcinoma in a patient older than 45 years. Thyroid. 2011;21:231–236. 57. McConahey WM, Hay ID, Woolner LB, et al. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc. 1986;61:978–996. 58. Hay ID, Gonzalez-Losada T, Reinalda MS, et al. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. World J Surg. 2010;34:1192–1202. 59. Hay ID. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am. 1990;19:545–576. 60. Dinneen SF, Valimaki MJ, Bergstralh EJ, et al. Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades. J Clin Endocrinol Metab. 1995;80:2041–2045. 61. Brennan MD, Bergstralh EJ, van Heerden JA, McConahey WM. Follicular thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc. 1991;66:11–22. 62. Englum BR, Pura J, Reed SD, et al. A bedside risk calculator to preoperatively distinguish follicular thyroid carcinoma from follicular variant of papillary thyroid carcinoma. World J Surg. 2015;39:2928–2934. 63. Grani G, Lamartina L, Durante C, et al. Follicular thyroid cancer and Hurthle cell carcinoma: challenges in diagnosis, treatment, and clinical management. Lancet Diabetes Endocrinol. 2018;6:500–514. 64. Kushchayeva Y, Duh QY, Kebebew E, et al. Comparison of clinical characteristics at diagnosis and during follow-up in 118 patients with Hurthle cell or follicular thyroid cancer. Am J Surg. 2008;195:457–462. 65. Alfalah H, Cranshaw I, Jany T, et al. Risk factors for lateral cervical lymph node involvement in follicular thyroid carcinoma. World J Surg. 2008;32:2623–2626. 66. Grebe SK, Hay ID. Thyroid cancer nodal metastases: biologic significance and therapeutic considerations. Surg Oncol Clin N Am. 1996;5:43–63. 67. Podda M, Saba A, Porru F, et al. Follicular thyroid carcinoma: differences in clinical relevance between minimally invasive and widely invasive tumors. World J Surg Oncol. 2015;13:193. 68. Kim HJ, Sung JY, Oh YL, et al. Association of vascular invasion with increased mortality in patients with minimally invasive follicular thyroid carcinoma but not widely invasive follicular thyroid carcinoma. Head Neck. 2014;36:1695–1700. 69. Sugino K, Ito K, Nagahama M, et al. Prognosis and prognostic factors for distant metastases and tumor mortality in follicular thyroid carcinoma. Thyroid. 2011;21:751–757.

70. McIver B, Hay ID, Giuffrida DF, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery. 2001;130:1028–1034. 71. Frank-Raue K, Buhr H, Dralle H, et al. Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. Eur J Endocrinol. 2006;155:229–236. 72. Grebe SK, Hay ID. The role of surgery in the management of differentiated thyroid cancer. J Endocrinol Invest. 1997;20:32–35. 73. Mack LA, Pasieka JL. An evidence-based approach to the treatment of thyroid lymphoma. World J Surg. 2007;31:978–986. 74. AJCC. Cancer Staging Manual. 8th ed. Chicago, IL, USA: Springer International Publishing; 2017. 75. Tuttle RM, Haugen B, Perrier ND. Updated American Joint Committee on Cancer/tumor-node-metastasis staging system for differentiated and anaplastic thyroid cancer (eighth edition): what changed and why? Thyroid. 2017;27:751–756. 76. Kim M, Kim WG, Oh HS, et al. Comparison of the seventh and eighth editions of the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis staging system for differentiated thyroid cancer. Thyroid. 2017;27:1149–1155. 77. Lamartina L, Grani G, Arvat E, et al. 8th edition of the AJCC/TNM staging system of thyroid cancer: what to expect (ITCO#2). Endocr Relat Cancer. 2018;25:L7–L11. 78. Nixon IJ, Wang LY, Migliacci JC, et al. An international multiInstitutional validation of age 55 years as a cutoff for risk stratification in the AJCC/UICC staging system for well-differentiated thyroid cancer. Thyroid. 2016;26:373–380. 79. Hay ID, McConahey WM, Goellner JR. Managing patients with papillary thyroid carcinoma: insights gained from the Mayo Clinic’s experience of treating 2,512 consecutive patients during 1940 through 2000. Trans Am Clin Climatol Assoc. 2002;113:241–260. 80. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns]. Cancer. 1998;83:2638–2648. 81. Larsen PR, Davis TF, Hay ID. The thyroid gland. In: Wilson JDFD, Kronenberg HM, et al, eds. Williams Textbook of Endocrinology. Philadelphia: WB Saunders; 1998:389–515. 82. Grant CS, Hay ID, Gough IR, et al. Local recurrence in papillary thyroid carcinoma: is extent of surgical resection important? Surgery. 1988;104:954–962. 83. Hay ID, Bergstralh EJ, Goellner JR, et al. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery. 1993;114:1050–1057, discussion 7–8. 84. Hay ID, Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery. 1987;102:1088–1095. 85. Shah JP, Loree TR, Dharker D, et al. Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg. 1992;164:658–661. 86. Simpson WJ, McKinney SE, Carruthers JS, et al. Papillary and follicular thyroid cancer. Prognostic factors in 1,578 patients. Am J Med. 1987;83:479–488. 87. Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973-1991. Cancer. 1997;79:564–573. 88. Iniguez-Ariza N, Kaggal Suneetha, Hay ID. Role of Radioactive Iodine for Remnant Ablation in Patients with Papillary Thyroid Cancer. In: Mancino LTK AT, ed. Managment of Differentiated Thyroid Cancer. Switzerland: Springer; 2017:205–222. 89. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery. 1988;104:947–953. 90. DeGroot LJ, Kaplan EL, Straus FH, Shukla MS. Does the method of management of papillary thyroid carcinoma make a difference in outcome? World J Surg. 1994;18:123–130. 91. Hay ID, Johnson TR, Kaggal S, et al. Papillary thyroid carcinoma (PTC) in children and adults: comparison of initial presentation and long-term

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CHAPTER 44 postoperative outcome in 4432 patients consecutively treated at the Mayo Clinic during eight decades (1936-2015). World J Surg. 2018;42:329–342. 92. Grebe SK, Hay ID. Follicular thyroid cancer. Endocrinol Metab Clin North Am. 1995;24:761–801. 93. van Heerden JA, Hay ID, Goellner JR, et al. Follicular thyroid carcinoma with capsular invasion alone: a nonthreatening malignancy. Surgery. 1992;112:1130–1136, discussion 6–8. 94. Mueller-Gaertner HW, Brzac HT, Rehpenning W. Prognostic indices for tumor relapse and tumor mortality in follicular thyroid carcinoma. Cancer. 1991;67:1903–1911. 95. Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery. 1995;118:1131–1136, discussion 6–8. 96. Loree TR. Therapeutic implications of prognostic factors in differentiated carcinoma of the thyroid gland. Semin Surg Oncol. 1995;11:246–255. 97. D’Avanzo A, Ituarte P, Treseler P, et al. Prognostic scoring systems in patients with follicular thyroid cancer: a comparison of different staging systems in predicting the patient outcome. Thyroid. 2004;14:453–458. 98. Davis NL, Bugis SP, McGregor GI, Germann E. An evaluation of prognostic scoring systems in patients with follicular thyroid cancer. Am J Surg. 1995;170:476–480. 99. Brierley J, Tsang R, Simpson WJ, et al. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid. 1996;6:305–310. 100. Gharib H, McConahey WM, Tiegs RD, et al. Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970. Mayo Clin Proc. 1992;67:934–940. 101. Pyke CM, Hay ID, Goellner JR, et al. Prognostic significance of calcitonin immunoreactivity, amyloid staining, and flow cytometric DNA measurements in medullary thyroid carcinoma. Surgery. 1991;110:964–970, discussion 70–1. 102. de Groot JW, Plukker JT, Wolffenbuttel BH, et al. Determinants of life expectancy in medullary thyroid cancer: age does not matter. Clin Endocrinol (Oxf). 2006;65:729–736. 103. Venkatesh YS, Ordonez NG, Schultz PN, et al. Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer. 1990;66:321–330. 104. Prasongsook N, Kumar A, Chintakuntlawar AV, et al. Survival in response to multimodal therapy in anaplastic thyroid cancer. J Clin Endocrinol Metab. 2017;102:4506–4514. 105. Bilimoria KY, Bentrem DJ, Ko CY, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg. 2007;246:375–381, discussion 81–4. 106. Famakinwa OM, Roman SA, Wang TS, Sosa JA. ATA practice guidelines for the treatment of differentiated thyroid cancer: were they followed in the United States? Am J Surg. 2010;199:189–198. 107. Panigrahi B, Roman SA, Sosa JA. Medullary thyroid cancer: are practice patterns in the United States discordant from American Thyroid Association guidelines? Ann Surg Oncol. 2010;17:1490–1498. 108. Ballantyne AJ. Resections of the upper aerodigestive tract for locally invasive thyroid cancer. Am J Surg. 1994;168:636–639. 109. Friedman M, Danielzadeh JA, Caldarelli DD. Treatment of patients with carcinoma of the thyroid invading the airway. Arch Otolaryngol Head Neck Surg. 1994;120:1377–1381. 110. Grant CS, Hay D. Local recurrence of papillary thyroid carcinoma after unilateral or bilateral thyroidectomy. Wien Klin Wochenschr. 1988;100:342–346. 111. Hay ID, Grant CS, Bergstralh EJ, et al. Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery. 1998;124:958–964, discussion 64–6. 112. Mazzaferri EL. A vision for the surgical management of papillary thyroid carcinoma: extensive lymph node compartmental dissections and selective use of radioiodine. J Clin Endocrinol Metab. 2009;94:1086–1088. 113. Mazzaferri EL, Doherty GM, Steward DL. The pros and cons of prophylactic central compartment lymph node dissection for papillary thyroid carcinoma. Thyroid. 2009;19:683–689.

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114. Noguchi S, Murakami N, Yamashita H, et al. Papillary thyroid carcinoma: modified radical neck dissection improves prognosis. Arch Surg. 1998;133:276–280. 115. Sanders LE, Cady B. Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg. 1998;133:419–425. 116. Sawka AM, Thephamongkhol K, Brouwers M, et al. Clinical review 170: a systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab. 2004;89:3668–3676. 117. Hay ID. Selective use of radioactive iodine in the postoperative management of patients with papillary and follicular thyroid carcinoma. J Surg Oncol. 2006;94:692–700. 118. Sacks W, Fung CH, Chang JT, et al. The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: a systematic analysis of the peer-reviewed literature from 1966 to April 2008. Thyroid. 2010;20:1235–1245. 119. Sawka AM, Brierley JD, Tsang RW, et al. An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer. Endocrinol Metab Clin North Am. 2008;37:457–480, x. 120. Lamartina L, Durante C, Filetti S, Cooper DS. Low-risk differentiated thyroid cancer and radioiodine remnant ablation: a systematic review of the literature. J Clin Endocrinol Metab. 2015;100:1748–1761. 121. Simpson WJ, Panzarella T, Carruthers JS, et al. Papillary and follicular thyroid cancer: impact of treatment in 1578 patients. Int J Radiat Oncol Biol Phys. 1988;14:1063–1075. 122. Ford D, Giridharan S, McConkey C, et al. External beam radiotherapy in the management of differentiated thyroid cancer. Clin Oncol (R Coll Radiol). 2003;15:337–341. 123. Simpson WJ, Carruthers JS. The role of external radiation in the management of papillary and follicular thyroid cancer. Am J Surg. 1978;136:457–460. 124. Wartofsky L. Highlights of the American Thyroid Association Guidelines for patients with thyroid nodules or differentiated thyroid carcinoma: the 2009 revision. Thyroid. 2009;19:1139–1143. 125. Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid cancer. Impact of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4). Cancer. 1996;77:172–180. 126. Tsang RW, Brierley JD, Simpson WJ, et al. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer. 1998;82:375–388. 127. Brierley J, Tsang R, Panzarella T, Bana N. Prognostic factors and the effect of treatment with radioactive iodine and external beam radiation on patients with differentiated thyroid cancer seen at a single institution over 40 years. Clin Endocrinol (Oxf). 2005;63:418–427. 128. Wilson PC, Millar BM, Brierley JD. The management of advanced thyroid cancer. Clin Oncol (R Coll Radiol). 2004;16:561–568. 129. Hu A, Clark J, Payne RJ, et al. Extrathyroidal extension in welldifferentiated thyroid cancer: macroscopic vs microscopic as a predictor of outcome. Arch Otolaryngol Head Neck Surg. 2007;133:644–649. 130. Benker G, Olbricht T, Reinwein D, et al. Survival rates in patients with differentiated thyroid carcinoma. Influence of postoperative external radiotherapy. Cancer. 1990;65:1517–1520. 131. O’Connell ME, A’Hern RP, Harmer CL. Results of external beam radiotherapy in differentiated thyroid carcinoma: a retrospective study from the Royal Marsden Hospital. Eur J Cancer. 1994;30A:733–739. 132. Tubiana M, Haddad E, Schlumberger M, et al. External radiotherapy in thyroid cancers. Cancer. 1985;55:2062–2071. 133. Terezakis SA, Lee KS, Ghossein RA, et al. Role of external beam radiotherapy in patients with advanced or recurrent nonanaplastic thyroid cancer: memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys. 2009;73:795–801. 134. Besic N, Hocevar M, Zgajnar J, Petric R. Pilko G. Aggressiveness of therapy and prognosis of patients with Hurthle cell papillary thyroid carcinoma. Thyroid. 2006;16:67–72. 135. Foote RL, Brown PD, Garces YI, et al. Is there a role for radiation therapy in the management of Hurthle cell carcinoma? Int J Radiat Oncol Biol Phys. 2003;56:1067–1072.

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Disease Sites

136. Schwartz DL, Rana V, Shaw S, et al. Postoperative radiotherapy for advanced medullary thyroid cancer–local disease control in the modern era. Head Neck. 2008;30:883–888. 137. Biermann M, Pixberg MK, Schuck A, et al. Multicenter study differentiated thyroid carcinoma (MSDS). Diminished acceptance of adjuvant external beam radiotherapy. Nuklearmedizin. 2003;42:244–250. 138. Schuck A, Biermann M, Pixberg MK, et al. Acute toxicity of adjuvant radiotherapy in locally advanced differentiated thyroid carcinoma. First results of the multicenter study differentiated thyroid carcinoma (MSDS). Strahlenther Onkol. 2003;179:832–839. 139. Ask A, Bjork-Eriksson T, Zackrisson B, et al. The potential of proton beam radiation therapy in head and neck cancer. Acta Oncol. 2005;44: 876–880. 140. Rosenbluth BD, Serrano V, Happersett L, et al. Intensity-modulated radiation therapy for the treatment of nonanaplastic thyroid cancer. Int J Radiat Oncol Biol Phys. 2005;63:1419–1426. 141. Schwartz DL, Lobo MJ, Ang KK, et al. Postoperative external beam radiotherapy for differentiated thyroid cancer: outcomes and morbidity with conformal treatment. Int J Radiat Oncol Biol Phys. 2009;74: 1083–1091. 142. Kim JH, Kim MS, Yoo SY, et al. Stereotactic body radiotherapy for refractory cervical lymph node recurrence of nonanaplastic thyroid cancer. Otolaryngol Head Neck Surg. 2010;142:338–343. 143. Berdelou A, Lamartina L, Klain M, et al. Treatment of refractory thyroid cancer. Endocr Relat Cancer. 2018;25:R209–R223. 144. Sherman SI. Cytotoxic chemotherapy for differentiated thyroid carcinoma. Clin Oncol (R Coll Radiol). 2010;22:464–468. 145. Crouzeix G, Michels JJ, Sevin E, et al. Unusual short-term complete response to two regimens of cytotoxic chemotherapy in a patient with poorly differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2012;97:3046–3050. 146. Spano JP, Vano Y, Vignot S, et al. GEMOX regimen in the treatment of metastatic differentiated refractory thyroid carcinoma. Med Oncol. 2012;29:1421–1428. 147. Shimaoka K, Schoenfeld DA, DeWys WD, et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer. 1985;56:2155–2160. 148. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384: 319–328. 149. Cabanillas M, Terris DJ, Sabra M. Information for Clinicians: approach to the patient with progressive radioactive iodine refractory thyroid cancer- When to use systemic therapy. Thyroid. 2017. 150. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621–630. 151. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–141. 152. Elisei R, Schlumberger MJ, Muller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639–3646. 153. Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11:962–972. 154. Bible KC, Suman VJ, Molina JR, et al. A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H. J Clin Endocrinol Metab. 2014;99:1687–1693. 155. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36:7–13. 156. Schutz FA, Je Y, Richards CJ, Choueiri TK. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol. 2012;30:871–877. 157. Bible KC. Individualization of therapies for patients with advanced differentiated thyroid cancers. J Clin Endocrinol Metab. 2012;97:3092– 3093.

158. Sharma A, Jasim S, Reading CC, et al. Clinical presentation and diagnostic challenges of thyroid lymphoma: a cohort study. Thyroid. 2016;26:1061–1067. 159. Derringer GA, Thompson LD, Frommelt RA, et al. Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases. Am J Surg Pathol. 2000;24:623–639. 160. Thieblemont C, Mayer A, Dumontet C, et al. Primary thyroid lymphoma is a heterogeneous disease. J Clin Endocrinol Metab. 2002;87:105–111. 161. Campbell BA, Voss N, Woods R, et al. Long-term outcomes for patients with limited stage follicular lymphoma: involved regional radiotherapy versus involved node radiotherapy. Cancer. 2010;116:3797–3806. 162. Hoskin PJ, Diez P, Williams M, et al. Participants of the Lymphoma Radiotherapy G. Recommendations for the use of radiotherapy in nodal lymphoma. Clin Oncol (R Coll Radiol). 2013;25:49–58. 163. Hoskin PJ, Kirkwood AA, Popova B, et al. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol. 2014;15:457–463. 164. Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol. 2011;100:86–92. 165. Campbell BA, Connors JM, Gascoyne RD, et al. Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy: involved-field versus involved-node radiotherapy. Cancer. 2012;118:4156–4165. 166. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol. 2004;22:3032–3038. 167. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med. 1998;339:21–26. 168. Yu JI, Nam H, Ahn YC, et al. Involved-lesion radiation therapy after chemotherapy in limited-stage head-and-neck diffuse large B cell lymphoma. Int J Radiat Oncol Biol Phys. 2010;78:507–512. 169. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–242. 170. Mounier N, Briere J, Gisselbrecht C, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2–associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood. 2003;101:4279–4284. 171. Goutsouliak V, Hay JH. Anaplastic thyroid cancer in British Columbia 1985-1999: a population-based study. Clin Oncol (R Coll Radiol). 2005;17:75–78. 172. Schlumberger M, Parmentier C, Delisle MJ, et al. Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer. 1991;67:564–566. 173. Sugino K, Ito K, Mimura T, et al. The important role of operations in the management of anaplastic thyroid carcinoma. Surgery. 2002;131: 245–248. 174. Tallroth E, Wallin G, Lundell G, et al. Multimodality treatment in anaplastic giant cell thyroid carcinoma. Cancer. 1987;60:1428–1431. 175. Tennvall J, Lundell G, Wahlberg P, et al. Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery. Br J Cancer. 2002;86:1848–1853. 176. Besic N, Auersperg M, Us-Krasovec M, et al. Effect of primary treatment on survival in anaplastic thyroid carcinoma. Eur J Surg Oncol. 2001;27: 260–264. 177. Levendag PC, De Porre PM, van Putten WL. Anaplastic carcinoma of the thyroid gland treated by radiation therapy. Int J Radiat Oncol Biol Phys. 1993;26:125–128. 178. Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience using aggressive multimodal therapy. Thyroid. 2011;21:25–30. 179. Kim JH, Leeper RD. Treatment of anaplastic giant and spindle cell carcinoma of the thyroid gland with combination Adriamycin and radiation therapy. A new approach. Cancer. 1983;52:954–957. 180. Simpson WJ. Anaplastic thyroid carcinoma: a new approach. Can J Surg. 1980;23:25–27.

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CHAPTER 44 181. De Crevoisier R, Baudin E, Bachelot A, et al. Combined treatment of anaplastic thyroid carcinoma with surgery, chemotherapy, and hyperfractionated accelerated external radiotherapy. Int J Radiat Oncol Biol Phys. 2004;60:1137–1143. 182. Haddad R, Mahadevan A, Posner MR, Sullivan C. Long term survival with adjuvant carboplatin, paclitaxel, and radiation therapy in anaplastic thyroid cancer. Am J Clin Oncol. 2005;28:104. 183. Swaak-Kragten AT, de Wilt JH, Schmitz PI, et al. Multimodality treatment for anaplastic thyroid carcinoma–treatment outcome in 75 patients. Radiother Oncol. 2009;92:100–104. 184. Haigh PI, Ituarte PH, Wu HS, et al. Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer. 2001;91:2335–2342. 185. Tan RK, Finley RK 3rd, Driscoll D, et al. Anaplastic carcinoma of the thyroid: a 24-year experience. Head Neck. 1995;17:41–47, discussion 7–8. 186. Pudney D, Lau H, Ruether JD, Falck V. Clinical experience of the multimodality management of anaplastic thyroid cancer and literature review. Thyroid. 2007;17:1243–1250. 187. Higashiyama T, Ito Y, Hirokawa M, et al. Induction chemotherapy with weekly paclitaxel administration for anaplastic thyroid carcinoma. Thyroid. 2010;20:7–14. 188. Randomized A, Phase II. Study of Concurrent Intensity Modulated Radiation Therapy (IMRT), Paclitaxel and Pazopanib (NSC 737754)/ Placebo, for the Treatment of Anaplastic Thyroid Cancer. (Accessed September 20, 2018, 2018, at https://clinicaltrials.gov/.).

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189. Mitchell G, Huddart R, Harmer C. Phase II evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol. 1999;50:33–38. 190. Wang Y, Tsang R, Asa S, et al. Clinical outcome of anaplastic thyroid carcinoma treated with radiotherapy of once- and twice-daily fractionation regimens. Cancer. 2006;107:1786–1792. 191. Dandekar P, Harmer C, Barbachano Y, et al. Hyperfractionated Accelerated Radiotherapy (HART) for anaplastic thyroid carcinoma: toxicity and survival analysis. Int J Radiat Oncol Biol Phys. 2009;74: 518–521. 192. Kebebew E, Greenspan FS, Clark OH, et al. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer. 2005;103:1330–1335. 193. Nutting CM, Convery DJ, Cosgrove VP, et al. Improvements in target coverage and reduced spinal cord irradiation using intensity-modulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland. Radiother Oncol. 2001;60:173–180. 194. Posner MD, Quivey JM, Akazawa PF, et al. Dose optimization for the treatment of anaplastic thyroid carcinoma: a comparison of treatment planning techniques. Int J Radiat Oncol Biol Phys. 2000;48:475–483. 195. Meadows KM, Amdur RJ, Morris CG, et al. External beam radiotherapy for differentiated thyroid cancer. Am J Otolaryngol. 2006;27:24–28. 196. Ebihara S, Saikawa M. Survey and analysis of thyroid carcinoma by the Japanese society of thyroid surgery. Thyroidology Clin Exp. 1998;10:89–95.

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45 Unknown Head and Neck Primary Site William M. Mendenhall, Anthony A. Mancuso, and Peter T. Dziegielewski

KEY POINTS Incidence Carcinoma of an unknown primary tumor (CUP) in the head and neck describes a patient with cervical node metastases without a physically or radiologically identifiable primary tumor site. Approximately 3% of patients with head and neck squamous cell carcinomas have a CUP. Biologic Characteristics Biologic characteristics are similar to head and neck mucosal squamous cell carcinomas with known primary sites. Most CUPs are thought to be of tonsillar fossa or tongue base origin and behave similarly. Staging Evaluation Evaluation begins with a history and complete head and neck physical examination, including palpation of the tonsils and base of tongue. This is followed by in-office flexible laryngoscopy. Imaging studies should be ordered next and include computed tomography (CT) of the neck and chest with contrast or positron emission tomography (PET)-CT with a diagnostic neck CT with contrast. A problem with PET-CT is that there is a 30% false–positive rate in the oropharynx, the most likely site of the primary tumor. After imaging, a trip to the operating room (OR) is necessary to perform panendoscopy, tonsillectomies, and base of tongue biopsies or lingual tonsillectomy. Directed nasopharyngeal and hypopharyngeal biopsies are not typically necessary unless there is a suspicion of cancer at these sites.1

Primary Therapy and Results Treatment philosophies are either surgery-based or radiotherapy (RT)-based. Surgery-based approaches include panendoscopy, direct biopsies to suspicious sites, palatine and lingual tonsillectomies as well as neck dissection(s). This is followed by RT or chemoradiation therapy (CRT).2 RT-based treatments involve treating the affected neck with or without elective treatment of the contralateral neck as well as wide-field RT to the oropharynx plus or minus nasopharynx.3 Because the tongue base has a high likelihood of harboring the primary tumor site and exhibits lymphatic drainage to both sides of the neck, both sides of the neck are usually irradiated. Adjuvant Therapy Concomitant cisplatin chemotherapy is administered for N2 and N3 neck disease and for close and positive margins or extracapsular extension following an initial neck dissection. Locally Advanced Disease Radiotherapy is administered to the oropharynx, nasopharynx, and both sides of the neck with concomitant chemotherapy followed by evaluation for a neck dissection. Palliation Moderate-dose RT (30 Gy/10 fractions or 20 Gy/2 fractions with a 1-week interfraction interval) is administered to the involved neck.

In 25% to 50% of patients with squamous cell carcinoma metastatic to the cervical lymph nodes, the primary lesion cannot be found, even after an extensive evaluation. Patients with metastatic adenopathy in the upper neck have a good prognosis when treated aggressively, compared with those with metastatic lymph nodes in the level IV nodes or supraclavicular fossa.4 The latter group is more likely to have a primary lesion located below the clavicles, and the probability of cure is remote. Most patients have either squamous cell carcinoma or poorly differentiated carcinoma. Patients with adenocarcinoma almost always have a primary lesion below the clavicles; however, if the nodes are located in the upper neck, a salivary gland, thyroid, or parathyroid primary tumor cannot be excluded. This chapter addresses the treatment of patients presenting with squamous cell or poorly differentiated carcinoma in the upper or middle neck. Squamous cell carcinoma presenting in a parotid area lymph node is almost always metastatic from a cutaneous primary site and will not be addressed.5

of tongue should be palpated with a gloved finger, despite patient discomfort and gagging. The oropharynx may be sprayed with lidocaine to help the patient tolerate the examination. Flexible laryngoscopy will provide visualization of the nasopharynx and larynx/hypopharynx. A fine-needle aspirate (FNA) biopsy of the lymph node should be performed under ultrasound guidance; multiple samples should be taken and sent for cytology, p16/human papilloma virus (HPV) testing, and Epstein-Barr virus testing.6–13 Epstein-Barr virus detection is useful for finding a nasopharyngeal primary tumor in geographic areas where this malignancy is prevalent.11 Most occult primary cancers in the United States will be of oropharyngeal origin.13 Imaging is the next step and should include CT of the neck and chest with contrast or a PET-CT with a diagnostic CT neck with contrast.14,15 The recommended diagnostic algorithm is depicted in Box 45.1.16 If the primary site cannot be identified on imaging, the patient is taken to the OR for panendoscopy and directed biopsies. All necessary imaging should be completed prior to proceeding to the OR to avoid false–positive results on PET or CT. Proper imaging allows the surgeon to achieve optimal visualization of the upper aerodigestive tract mucosa and obtain a biopsy of any suspicious areas. Palatine tonsillectomy and lingual tonsillectomy are performed simultaneously either by trans-oral

DIAGNOSTIC EVALUATION A complete head and neck examination with thorough evaluation of the oropharynx and nasopharynx is performed. The tonsils and base

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CHAPTER 45

BOX 45.1

TABLE 45.1

General History Physical examination Careful examination of the neck and supraclavicular regions Examination of oral cavity, pharynx, and larynx (indirect laryngoscopy with a flexible endoscope)

Laboratory Studies Complete blood cell count Blood chemistry profile

Patient Group

FDG-PET Negativea

FDG-PET Positivea

PEØ/RadØ

3/4

No data

PE+ or Rad+

8/12

3/5

Total

11/16 (68.8%)

3/5 (60%)

a

Number of primary sites detected/number of patients. FDG-PET, fludeoxyglucose-positron emission tomography; PEØ, physical examination negative; PE+, physical examination suspicious, not definitely positive; RadØ, radiologic examination negative; Rad+, radiologic examination (CT or MR) suspicious, not definitely positive. From Cianchetti M, Mancuso AA, Amdur R, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009;119(12):2348–2354.

Direct Endoscopy and Directed Biopsies Nasopharynx, both tonsils, base of tongue, both pyriform sinuses, and any suspicious or abnormal mucosal areas Ipsilateral tonsillectomy Fine-needle aspirate or core-needle biopsy of the cervical node

Detection of a Primary Site Versus Patient Group

TABLE 45.2 Patient Group

From Mendenhall WM, Parsons JT, Mancuso AA, et al. Head and neck: management of the neck. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology, 3d ed. Philadelphia: JB Lippincott; 1998:1135–1156 (Table 44.20, p 1152).

Biopsy-Proven Primary Site/No. Pts (%)

PEØ/RadØ

21/72 (29.2%)

PEØ/Rad+

51/82 (62.2%)

PE+/RadØ

15/25 (60.0%)

PE+/Rad+ Total

robotic surgery (TORS), trans-oral laser microsurgery (TLM), or transoral endoscopic assisted mucosectomy.2,17 Both tonsils must be addressed, because about 5% of patients will have a contralateral synchronous tonsil cancer.18, 19 Two meta-analyses have shown that the sensitivity and specificity of PET-CT in identifying the primary site of a CUP are 88% to 97% and 68% to 75%, respectively.20,21 In approximately 25% of cases fludeoxyglucose (FDG)-PET was the only means of detecting a primary site.21 This was certainly the case in a series at the University of Florida (Table 45.1).13 Historically, primary head and neck cancers were found in 126 of 236 patients (53%) in the University of Florida series (Tables 45.2 and 45.3).13 The most common primary sites were tonsillar fossa (59 patients, 45%) and base of tongue (58 patients, 44%).13 The reason for the decreased likelihood of detecting cancers in other sites may be that they are found on physical examination with fiberoptic endoscopy and on radiographic evaluation.10,22,23 In contrast, it is still difficult to discern a small primary cancer hidden in the lymphoid tissue of the tonsillar fossa or tongue base. Utilizing a TORS, TLM, or an endoscopic approach offers many advantages. The cameras utilized provide up-close high magnification views of the tonsils, glossotonsillar sulcus, and base of tongue. Tumors can be identified and potentially resected during the same session. A systematic review of the TORS for CUP has recently shown that 72% to 90% of unknown primaries can be identified using this approach.2 Graboyes et al.24 found that 89% of primary lesions could be identified using TLM. PET-CT combined with a TLM approach has proven to identify a CUP in 93% of patients with half of the primary cancers being found in the ipsilateral tonsil.25 The greatest advantage in identifying a primary site is when the lesion is in the tongue base. Using TORS, TLM, or endoscopic-assisted lingual tonsillectomy may identify the primary cancer in 50% to 75% of cases.17,26

761

Detection of the Primary Site by FDG-PET or FDG-PET/CT

Diagnostic Algorithm

Radiographic Studies Chest roentgenogram Computed tomography or magnetic resonance imaging (MRI) scans of head and neck (special attention to nasopharynx, pharynx, and larynx)

Unknown Head and Neck Primary Site

39/57 (68.4%) 126/236 (53.4%)

PEØ, Physical examination negative; PE+, physical examination suspicious, not definitely positive; RadØ, radiologic examination negative; Rad+, radiologic examination (CT or MR) suspicious, not definitely positive. From Cianchetti M, Mancuso AA, Amdur R, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009;119(12):2348–2354.

Detection of the Primary Site on Tonsillectomy

TABLE 45.3

Patient Group PEØ/RADØa

No. of Patients With Pathologically Proven Site in Tonsillar Fossa/ No. of Patients Having Tonsillectomy 9/22 (41.1%)

PE+ and/or RAD+a

26/57 (45.6%)

Total

35/79 (44.3%)

Radiographic evaluation = computed tomography (CT) or magnetic resonance imaging (MRI) with or without fludeoxyglucose-singlephoton emission computed tomography (FDG-SPECT) or fludeoxyglucose-positron emission tomography (FDG-PET) or FDG-PET/CT. PEØ, Physical examination negative; PE+, physical examination suspicious, not definitely positive; RadØ, radiologic examination negative; Rad+, radiologic examination (CT or MR) suspicious, not definitely positive. From Cianchetti M, Mancuso AA, Amdur R, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009;119(12):2348–2354. a

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762

SECTION III

Disease Sites

With improvements in surgical access to the oropharynx, CUP can likely have its primary site identified. It is recommended that patients undergo a complete radiologic and surgical (TORS, TLM, or endoscopyassisted) work-up of a CUP.3

PRIMARY THERAPY AND RESULTS Identifying the Primary Cancer Site When identified, most CUPs are found in the oropharynx.27–29 Outside of endemic areas, the likelihood of the primary site being in the nasopharynx or hypopharynx is low.1 The majority (~75%) of the cancer found in the oropharynx will be p16/HPV-positive and will behave similarly to known tonsil and base of tongue cancers; thus, treatment strategies are similar.30 Identifying the primary site is important for several reasons. First, it may allow for complete resection of the lesion, which may obviate the need for RT or it could allow for a lower adjuvant dose of RT.2 Second, it could avoid the need for high-dose RT to the entire oropharynx, which is known to cause grade 3 dysphagia in 50% of patients.31 By identifying the primary site, RT fields may be narrowed with potentially lower doses, thereby decreasing long-term morbidity. Patients with tonsillar cancers may require treatment of the ipsilateral neck, which will significantly reduce acute and long-term toxicity. Lastly, identification of the primary site may result in a modest improvement in the likelihood of a cure.32,33

TREATMENT TECHNIQUES AND ALGORITHM If treated surgically, a transoral procedure, such as TORS, is typically invoked. If the primary site is not identified, surgery is limited to a palatine and lingual tonsillectomy with or without a neck dissection. If the primary site is identified, it can be resected and a neck dissection can be performed at the same setting. For tonsil cancers, the resection usually consists of a radical tonsillectomy; for base of tongue lesions, a hemi-base glossectomy is performed. Because most primary lesions, are of oropharyngeal origin, elective neck dissection focuses on levels II–IV.2 The final pathology will then dictate adjuvant RT/CRT plans. The most common indications for adjuvant therapy are close/positive margins, perineural invasion, and extracapsular extension.2,34,35 Other options range from treatment of the involved neck alone with a neck dissection or RT to irradiation of the suspected primary site and both sides of the neck followed by evaluation for a planned neck dissection.36–38 Although treatment of the potential mucosal primary site and contralateral neck appears to reduce the risk of a local-regional recurrence, the impact on survival is modest at best. Therefore, patients with a single positive node without extracapsular extension may be treated with a neck dissection alone and followed closely, provided that the neck was not violated with an open procedure prior to surgery.39–41 If RT is indicated to treat the involved neck, we usually irradiate the nasopharynx and oropharynx as well as both sides of the neck (Fig. 45.1A).4 Although it may be tempting to irradiate the involved neck alone or combined with RT to the ipsilateral mucosal sites deemed to be at risk, the base of tongue is a midline structure that probably harbors the undetected primary site as often as the tonsillar fossa, so it has been our policy to treat the entire oropharynx.42 Failure to do so is likely associated with an increased risk of a local-regional recurrence, and further RT would be complicated by the initial treatment.43 It is not necessary to irradiate the oral cavity unless the patient has submandibular (level I) adenopathy, in which case we either do a neck dissection and observe the patient or irradiate the oral cavity and oropharynx. We no longer irradiate the larynx and hypopharynx as the likelihood of a primary tumor in these sites is low and the morbidity is significant.42

It could be argued that the nasopharynx should also be eliminated from the primary treatment volumes; however, the incidence of positive retropharyngeal nodes is relatively high in patients presenting with advanced neck disease44 so that the volumes must include the skull base (jugular foramen and retropharyngeal nodes) and at least part of the nasopharynx. It is our belief that a modest increase in the size of the treatment volumes to irradiate the nasopharynx adequately does not significantly increase morbidity. Patients are treated with parallel-opposed fields at 1.8 Gy per fraction to a midline dose of 64.8 Gy with reduction off the spinal cord at 45-Gy tumor dose (see Fig. 45.1B).45 The lower neck is treated through a separate en face anterior field. Treatment is administered with cobalt-60, 4-MV x-rays, or 6-MV x-rays. Dosimetry is obtained at the level of the central axis (which usually corresponds to the oropharynx) and the nasopharynx. The dose to the nasopharynx is usually 3 to 5 Gy lower than the central axis. Currently, most radiation oncologists obtain a multilevel 3-dimensional dosimetric analysis to evaluate the dose delivered to the clinical target volume, planning target volume, and organs at risk. Patients with ipsilateral nodes may be treated with intensitymodulated radiotherapy (IMRT) to reduce the dose to the contralateral parotid (≤ 26 Gy mean dose) and reduce the likelihood of long-term xerostomia. Patients with bilateral-positive nodes may be treated with parallel-opposed fields to reduce the risk of a marginal miss.46 Patients with advanced, fixed adenopathy undergo a boost to the involved part of the neck using anteroposterior wedged beams to a total dose in the range of 70 to 75 Gy. Concomitant chemotherapy should be considered for patients with N2 and N3 neck disease. Our preference is to use weekly cisplatin (30 mg/m2) or cisplatin 100 mg/m2 every 3 weeks for 2 cycles.47 Treatment of the neck depends on the extent and location of the adenopathy. Patients with N1 and early N2b neck disease located in the high-dose fields may be treated with irradiation alone if the nodes have resolved completely.48–50 Similarly, if the patient has undergone an excisional biopsy of a single positive node, the neck may be treated with radiation alone with a 95% likelihood of control of neck disease.51 Patients undergo a CT of the neck one month after RT or a PET-CT three months after completing RT, and the decision whether to proceed with neck dissection depends on the likelihood that a viable tumor remains in the neck.52–56 The criteria employed for determining whether a neck dissection should be performed are outlined in Table 45.4.52,54 Because the likelihood of a cure is low if a regional recurrence develops in a clinically positive neck after treatment with RT or CRT alone, we usually proceed with a modified neck dissection if the risk of residual disease exceeds 5%.57 In practice, patients with N2 to N3 neck disease and those with gross disease after an open neck biopsy often undergo a planned neck dissection after RT.50,58 The treatment algorithm is depicted in Fig. 45.2.

RESULTS Historically, most CUPs were likely p16/HPV-negative oropharyngeal tumors. As the prevalence of p16/HPV-positive mediated oropharyngeal cancers has increased, the outcomes of CUP have tended to parallel those of known oropharyngeal cancers. Thus, treatment regimens, and their controversies, have begun to mimic those for oropharyngeal cancers.29,59 The current National Comprehensive Cancer Network guidelines for head and neck CUP recommend that patients with a head and neck CUP of squamous cell histology be divided into two groups: (1) N1 disease and (2) N2 or greater disease. Those with N1 CUP are recommended to undergo a primary surgical approach with an upfront neck dissection. The reasoning is that many of these patients may avoid RT

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CHAPTER 45

Unknown Head and Neck Primary Site

763

TSD

A

B Fig. 45.1 (A) Radiation Treatment Technique for Carcinoma From an Unknown Primary Site. Superiorly, the portal treats the nasopharynx and the jugular (level II) and spinal accessory (level V) lymph nodes to the base of skull. The posterior border is behind the spinous process of C2. The inferior border is at the thyroid notch. Anteroinferiorly, the skin and subcutaneous tissues of the submentum are shielded, except in the case of advanced neck disease. The anterior tongue margin is set to obtain a 2-cm margin on the base of tongue and tonsillar fossa, as well as the nasopharynx. One portal reduction is shown (reduce off spinal cord). (B) Fields for Bilateral Lower Neck Radiotherapy. The larynx shield should be carefully designed. Because the internal jugular vein lymph nodes (level III) lie adjacent to the posterolateral margin of the thyroid cartilage, the shield cannot cover the entire thyroid cartilage without producing a low-dose area in these nodes. A common error in the treatment of the lower neck is to extend the low neck portal laterally out to the shoulders, encompassing lateral supraclavicular lymph nodes that are at negligible risk while partially shielding the high-risk midjugular lymph nodes with a large rectangular laryngeal block. The inferior extent of the shield is at the cricoid cartilage or first or second tracheal ring; the shield must be tapered because the nodes tend to lie closer to the midline as the lower neck is approached. Lateral borders of the low neck portals are designed to cover only the lymph nodes in the root of the neck when the risk of low-neck disease on that side is small (i.e., stage N0 or N1 disease). With clinically positive lymph nodes in the lower neck or if major disease is present in the upper neck, the lateral border of the low-neck field is widened on that side to cover the entire supraclavicular region out to the junction of the trapezius muscle with the clavicle. TSD, target-to-skin distance. (A, From Mendenhall WM, Mancuso AA, Amdur RJ, et al. Squamous cell carcinoma metastatic to the neck from an unknown head and neck primary site. Am J Otolaryngol. 2001;22(4):261–267. B, From Million RR, Cassisi NJ, Mancuso AA, et al. Management of the neck for squamous cell carcinoma. In Million RR, Cassisi NJ, eds. Management of Head and Neck Cancer: A Multidisciplinary Approach. 2nd ed. Philadelphia: JB Lippincott Company; 1994:75–142.)

or be eligible for a lower dose of RT and avoid concurrent chemotherapy. Patients with more extensive neck disease are less likely to avoid higher doses of RT or CRT; thus, neck dissection is saved as a salvage procedure if needed. These guidelines are based on the best available evidence, which is not clear-cut for CUP. Most data are historical and heterogeneous owing to the rarity of the disease. Some centers report increased survival with primary surgery, whereas others show similar results with primary RT. Thus, the question: How can treatment be optimized to avoid unnecessary procedures while optimizing outcomes? Until multiinstitutional prospective studies are conducted, each multidisciplinary team will need to formulate its own protocols. Here we present the current survival outcomes based on treatment philosophies. An increased number of surgical studies are showing promising survival with a primary surgery and adjuvant RT approach. Control rates are high, and long-term toxicities are decreasing with lower doses of adjuvant RT.

Graboyes et al.24 published data on 65 patients with CUP treated with a TLM and neck dissection approach. All patients underwent palatine and lingual tonsillectomy or wide local excision of an oropharyngeal primary tumor if found at the time of surgery. The 5-year overall survival (OS) and disease-specific survival rates were 98% and 97%, respectively. In patients whose primary site was not found in the specimens, the 5-year OS rate was 100%. Of these patients, 26% did not receive adjuvant RT. At Dalhousie University, a similar approach yielded a 93% detection rate of a primary cancer with 5-year OS and 3-year disease-specific survival rates of 80% with a 100% control rate.25 In 2017, Patel et al.60 performed a multi-institutional review of CUP of the head and neck treated with a primary surgical approach and found that a reduction in RT volume could be achieved in 46% of patients who were found to have primary tonsillar or glossotonsillar sulcus tumors. When the primary tumor was found, treating the contralateral neck was avoided in 30% of patients.

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764

SECTION III

Disease Sites

Predictive Value of Postradiotherapy CT Findings at 4 Weeks in the Hemi-Neck Correlated to Neck Dissection Pathology (N = 193 Hemi-Necks)

TABLE 45.4

NPV Finding

No./Total No.

%

85/118

72

24/75

32

Any lymph node >1.5 cm Any focally abnormal lymph node

PPV

a

No./Total No.

%

49/57

86

49/136

36

75/98

77

34/95

36

Any lymph node enhancement

111/147

76

21/46

46

Any lymph node with calcification

Any lymph node with focal lucency

102/144

71

15/49

31

Two or more focally abnormal lymph nodesa

90/113

80

34/80

43

Any lymph node >1.5 cm and any focally abnormal lymph node

32/34

94

55/159

35

Focally abnormal lymph node = grades 3 to 4 focal lucency, focal enhancement, or focal calcification. CT, computed tomography; NPV, negative predictive value; PPV, positive predictive value. From Liauw SL, Mancuso AA, Amdur RJ, et al. Postradiotherapy neck dissection for lymph node-positive head and neck cancer: the use of computed tomography to manage the neck. J Clin Oncol. 2006;24:1421–1427.

a

Two or more nodes clinically positive

One node clinically positive

Neck dissection

One node pathologically positive, no ECE

Two or more nodes pathologically positive or ECE

Follow

Postoperative RT

Early N2 disease

Advanced N2–N3

RT

RT and concomitant chemotherapy

CT 1 month after RT

Risk of residual disease !5%

Risk of residual disease "5%

Follow

Neck dissection

Fig. 45.2 Treatment algorithm. CT, Computed tomography; ECE, extracapsular extension; RT, radiotherapy.

A population-based cohort study in Sweden examining head and neck CUP found that p16-positive versus p16-negative tumors had a 5-year OS rate of 88% versus 61%. The 5-year OS rate for patients treated with surgery plus RT or CRT were 81% and 88%, respectively.61 Lou et al.62 presented 133 cases of head and neck CUP and found that local-regional failure in those treated with primary neck dissection was 13.5% versus 38% for those treated with primary neck RT. Their study demonstrates the continued importance of neck dissection in CUP treatment.62 A recent German study also concluded that optimal survival was achieved with neck dissection and adjuvant RT.63 Additionally, a study from India found that a neck dissection plus 50 Gy RT yielded very favorable outcomes with a 50-month median survival of 74%. The favorable response to a lower dose of RT likely reflects the p16-positive nature of most cases.64 Other primary RT regimens are also showing high control rates with lower toxicity, given the adoption of intensity-modulated RT (IMRT) and volumetric modulated arc RT. Increasingly, more centers are tailoring CUP treatment based on identifying a likely primary target owing to more precise staging.

The incidence of subsequent mucosal primary lesions was compared by Erkal et al.65 for patients with a known primary site and a series of 126 patients treated for an unknown primary site at the University of Florida. The incidence for both groups was similar at 5 years, suggesting either that mucosal irradiation significantly reduced the risk of primary site failure or that patients with unknown primary sites have a much lower risk of a second primary head and neck cancer developing subsequently (Fig. 45.3).65 The 5-year absolute and cause-specific survival rates for the 126 patients with a CUP site were 47% and 67%, respectively. The 5-year outcomes stratified by N category are shown in Fig. 45.4.65 Reddy and Marks43 reported 52 patients treated to the neck alone (16 patients) or to the neck and potential head and neck primary sites (36 patients). Failure in the head and neck mucosa occurred in 44% of those who underwent treatment to the neck alone, compared with 8% in those who underwent irradiation of the head and neck mucosa (p = 0.0005). The 5-year survival rates were similar for the two treatment groups. Grau et al.66 reported 273 patients treated with curative intent at five cancer centers in Denmark between 1975 and 1995 with surgery alone (23 patients), RT to the ipsilateral neck alone or combined with

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CHAPTER 45

Rates of recurrence or second primary (%)

p = 0.81 Unknown site: rate of mucosal recurrence (n = 126) 13% Known site: rate of second primary (n = 1112) 9%

60 40 20

COMPLICATIONS

0 0

1

2

3

4

The main complications of RT for patients treated for an unknown head and neck primary tumor are xerostomia and dysphagia. IMRT may be used to reduce the dose to the contralateral parotid gland so long as the patient does not have bilateral clinically positive neck nodes. It is difficult to limit the dose to the parotid if there are positive nodes in the same side of the neck without risking underdosing the adenopathy and increasing the risk of a marginal miss.46 The risk of bone exposure, radiation myelitis, or radiation-induced malignancy is low. The complications of neck irradiation include fibrosis and lymphedema of the larynx and submentum. The latter complications may be minimized by sparing an anterior strip of skin when designing the parallel-opposed lateral portals used to encompass the suspected primary site. This will also reduce the risk of desquamation, particularly in

5

Time (yr) Fig. 45.3 The rate of developing carcinomas in head and neck mucosal sites for patients treated for carcinomas with an unknown head and neck mucosal site compared with the rate for developing metachronous carcinomas in head and neck mucosal sites for patients treated for carcinomas with a known head and neck mucosal site. (From Erkal HS, Mendenhall WM, Amdur RJ, et al. Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head-and-neck mucosal site treated with radiation therapy alone or in combination with neck dissection. Int J Radiat Oncol Biol Phys. 2001;50(1):55–63.)

100 Incidence of systemic failure (%)

Initial nodal control (%)

100 80 60 40

N1 (n = 13) 100% N2A (n = 33) 100% N2B (n = 31) 81% N2C (n = 7) 80% N3 (n = 42) 46%

20 0

0

1

2

A

p = 0.0001

3

4

p = 0.07

40 20

0

1

2

3

4

5

Time (yr) 100

Cause-specific survival (%)

Absolute survival (%)

60

B

Time (yr)

80 60 40 N1 (n = 13) 62% N2A (n = 31) 64% N2B (n = 28) 45% N2C (n = 7) 38% N3 (n = 40) 32%

20 0

N1 (n = 13) 0% N2A (n = 31) 7% N2B (n = 28) 14% N2C (n = 7) 14% N3 (n = 40) 26%

80

0

5

100

C

765

surgery (26 patients), and RT to the neck and head and neck mucosa alone or combined with surgery (224 patients). The ipsilateral oropharynx unintentionally received some irradiation in patients treated to the ipsilateral neck alone, depending on the treatment technique.66 The 5-year rates of freedom from failure in the head and neck mucosa were as follows: surgery alone, 45%; RT with or without surgery to the ipsilateral neck, 77%; and RT to the head and neck mucosa with or without surgery 87%. Failure in the oropharynx, particularly the base of tongue, was the most common location of mucosal site failure.

100 80

Unknown Head and Neck Primary Site

0

1

2

p = 0.0006

3 Time (yr)

4

80 60 40 20 0

5

D

N1 (n = 13) 100% N2A (n = 31) 88% N2B (n = 28) 75% N2C (n = 7) 46% N3 (n = 40) 39% 0

1

2

p = 0.0001

3

4

Time (yr)

Fig. 45.4 Disease and survival outcomes according to N category after initial treatment. (A) Nodal control rates. (B) Systemic failure (distant metastases). (C) Absolute survival. (D) Cause-specific survival. (From Erkal HS, Mendenhall WM, Amdur RJ, et al. Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head-and-neck mucosal site treated with radiation therapy alone or in combination with neck dissection. Int J Radiat Oncol Biol Phys. 2001;50(1):55–63 [Figure 3.6, pp 58–60].)

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5

766

SECTION III

Disease Sites

patients who receive concomitant chemotherapy. A 10-mm wide midline block in the en face low-neck field may diminish the likelihood of postirradiation edema and stricture of the hypopharynx/cervical esophagus. The probability of complications is directly related to radiation dose and volume. Complications of a transoral resection of the oropharynx include hemorrhage, dysphagia, lingual nerve or hypoglossal nerve injury, velopharyngeal insufficiency, and dysphonia. Neck dissection complications include hematoma, seroma, lymphedema, wound infection, wound dehiscence, chyle fistula, damage to cranial nerves VII, X, XI, and XII, carotid exposure, and carotid rupture. The incidence of complications after neck dissection is higher when the operation follows a course of RT. The incidence of postoperative complications in a series of 143 patients treated with RT to the primary lesion and neck followed by unilateral neck dissection was 23%.50 Seventeen patients (12%) required a second operation and four patients (3%) experienced fatal complications.50 The incidence of complications was higher for maximum subcutaneous doses exceeding 60 Gy. Taylor et al.67 updated the University of Florida experience with an analysis of the incidence of moderate (2+) and severe (3+) wound complications in a series of 205 patients who underwent a planned unilateral neck dissection after radiation therapy. RT was given once daily in 123 patients, twice daily in 80 patients, and with both techniques in the remaining 2 patients. The incidence of wound complications tended to increase with total dose and dose per fraction.

15.

17.

18. 20.

21.

24.

25.

26.

CONCLUSIONS

27.

The diagnostic evaluation of patients with squamous cell CUP of the head and neck includes a complete head and neck examination with flexible laryngoscopy, FNA of the neck node, CT from the skull base to the clavicles or PET-CT, panendoscopy, and transoral palatine and lingual tonsillectomies. The primary site will be detected in approximately 50% to 75% of patients and will be located in the oropharynx in more than 80% of patients. The treatment of these patients is controversial. Treatment can be primarily surgical with postoperative RT directed to the discovered primary site and appropriate neck(s) or RT-based. Given that most CUPs will end up being HPV-mediated cancers of the tonsillar fossa or tongue base, long-term survival is likely over 90%.

28.

Acknowledgments The authors thank the research support staff of the Department of Radiation Oncology at the University of Florida in Gainesville, Florida, for their efforts preparing the manuscript for publication.

29.

30.

31.

34.

35.

CRITICAL REFERENCES 1. Tanzler ED, Amdur RJ, Morris CG, et al. Challenging the need for random directed biopsies of the nasopharynx, pyriform sinus, and contralateral tonsil in the workup of unknown primary squamous cell carcinoma of the head and neck. Head Neck. 2016;38:578–581. 3. Dharmawardana N, Campbell JM, Carney AS, Boase S. Effectiveness of primary surgery versus primary radiotherapy on unknown primary head and neck squamous cell carcinoma: a systematic review protocol. JBI Database System Rev Implement Rep. 2018;16:308–315. 5. Hinerman RW, Indelicato DJ, Amdur RJ, et al. Cutaneous squamous cell carcinoma metastatic to parotid-area lymph nodes. Laryngoscope. 2008;118:1989–1996. 11. Macdonald MR, Freeman JL, Hui MF, et al. Role of Epstein-Barr virus in fine-needle aspirates of metastatic neck nodes in the diagnosis of nasopharyngeal carcinoma. Head Neck. 1995;17:487–493. 12. Begum S, Gillison ML, Nicol TL, Westra WH. Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin

39.

42.

55.

61.

in patients with metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13:1186–1191. Johansen J, Buus S, Loft A, et al. Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study. Head Neck. 2008;30:471–478. Wallis S, O’Toole L, Karsai L, Jose J. Transoral endoscopic base of tongue mucosectomy for investigation of unknown primary cancers of head and neck. Clin Otolaryngol. 2018. Dziegielewski PT, Boyce BJ, Old M, et al. Transoral robotic surgery for tonsillar cancer: addressing the contralateral tonsil. Head Neck. 2017;39:2224–2231. Zhu L, Wang N. 18F-fluorodeoxyglucose positron emission tomographycomputed tomography as a diagnostic tool in patients with cervical nodal metastases of unknown primary site: a meta-analysis. Surg Oncol. 2013;22:190–194. Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer. 2004;101:2641–2649. Graboyes EM, Sinha P, Thorstad WL, et al. Management of human papillomavirus-related unknown primaries of the head and neck with a transoral surgical approach. Head Neck. 2015;37:1603–1611. Kuta V, Williams B, Rigby M, et al. Management of head and neck primary unknown squamous cell carcinoma using combined positron emission tomography-computed tomography and transoral laser microsurgery. Laryngoscope. 2017. Fu TS, Foreman A, Goldstein DP, de Almeida JR. The role of transoral robotic surgery, transoral laser microsurgery, and lingual tonsillectomy in the identification of head and neck squamous cell carcinoma of unknown primary origin: a systematic review. J Otolaryngol Head Neck Surg. 2016;45:28. Szyszko TA, Cook GJR. PET/CT and PET/MRI in head and neck malignancy. Clin Radiol. 2018;73:60–69. Liu X, Li D, Li N, Zhu X. Optimization of radiotherapy for neck carcinoma metastasis from unknown primary sites: a meta-analysis. Oncotarget. 2016;7:78736–78746. Hu KS, Mourad WF, Gamez ME, et al. Five-year outcomes of an oropharynx-directed treatment approach for unknown primary of the head and neck. Oral Oncol. 2017;70:14–22. Keller LM, Galloway TJ, Holdbrook T, et al. p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary. Head Neck. 2014;36:1677–1684. Madani I, Vakaet L, Bonte K, et al. Intensity-modulated radiotherapy for cervical lymph node metastases from unknown primary cancer. Int J Radiat Oncol Biol Phys. 2008;71:1158–1166. Chen AM, Meshman J, Hsu S, et al. Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin. Head Neck. 2018;40:227–232. Geltzeiler M, Doerfler S, Turner M, et al. Transoral robotic surgery for management of cervical unknown primary squamous cell carcinoma: updates on efficacy, surgical technique and margin status. Oral Oncol. 2017;66:9–13. Olsen KD, Caruso M, Foote RL, et al. Primary head and neck cancer. Histopathologic predictors of recurrence after neck dissection in patients with lymph node involvement. Arch Otolaryngol Head Neck Surg. 1994;120:1370–1374. Barker CA, Morris CG, Mendenhall WM. Larynx-sparing radiotherapy for squamous cell carcinoma from an unknown head and neck primary site. Am J Clin Oncol. 2005;28:445–448. Hitchcock KE, Amdur RJ, Mendenhall WM, et al. Lessons from a standardized program using PET-CT to avoid neck dissection after primary radiotherapy for N2 squamous cell carcinoma of the oropharynx. Oral Oncol. 2015;51:870–874. Axelsson L, Nyman J, Haugen-Cange H, et al. Prognostic factors for head and neck cancer of unknown primary including the impact of human papilloma virus infection. J Otolaryngol Head Neck Surg. 2017;46:45.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 45

REFERENCES 1. Tanzler ED, Amdur RJ, Morris CG, et al. Challenging the need for random directed biopsies of the nasopharynx, pyriform sinus, and contralateral tonsil in the workup of unknown primary squamous cell carcinoma of the head and neck. Head Neck. 2016;38:578–581. 2. Kang SY, Dziegielewski PT, Old MO, Ozer E. Transoral robotic surgery for carcinoma of unknown primary in the head and neck. J Surg Oncol. 2015;112:697–701. 3. Dharmawardana N, Campbell JM, Carney AS, Boase S. Effectiveness of primary surgery versus primary radiotherapy on unknown primary head and neck squamous cell carcinoma: a systematic review protocol. JBI Database System Rev Implement Rep. 2018;16:308–315. 4. Mendenhall WM, Mancuso AA, Amdur RJ, et al. Squamous cell carcinoma metastatic to the neck from an unknown head and neck primary site. Am J Otolaryngol. 2001;22:261–267. 5. Hinerman RW, Indelicato DJ, Amdur RJ, et al. Cutaneous squamous cell carcinoma metastatic to parotid-area lymph nodes. Laryngoscope. 2008;118:1989–1996. 6. McGuirt WF, McCabe BF. Significance of node biopsy before definitive treatment of cervical metastatic carcinoma. Laryngoscope. 1978;88:594–597. 7. Parsons JT, Million RR, Cassisi NJ. The influence of excisional or incisional biopsy of metastatic neck nodes on the management of head and neck cancer. Int J Radiat Oncol Biol Phys. 1985;11:1447–1454. 8. Ellis ER, Mendenhall WM, Rao PV, et al. Incisional or excisional neck-node biopsy before definitive radiotherapy, alone or followed by neck dissection. Head Neck. 1991;13:177–183. 9. Robbins KT, Cole R, Marvel J, et al. The violated neck: cervical node biopsy prior to definitive treatment. Otolaryngol Head Neck Surg. 1986;94:605–610. 10. Martin H, Morfit HM. Cervical lymph node metastasis as the first symptom of cancer. Surg Gynecol Obstet. 1944;78:133–159. 11. Macdonald MR, Freeman JL, Hui MF, et al. Role of Epstein-Barr virus in fine-needle aspirates of metastatic neck nodes in the diagnosis of nasopharyngeal carcinoma. Head Neck. 1995;17:487–493. 12. Begum S, Gillison ML, Nicol TL, Westra WH. Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13:1186–1191. 13. Cianchetti M, Mancuso AA, Amdur RJ, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009;119:2348–2354. 14. Mukherji SK, Drane WE, Mancuso AA, et al. Occult primary tumors of the head and neck: detection with 2-[F-18] fluoro-2-deoxy-D-glucose SPECT. Radiology. 1996;199:761–766. 15. Johansen J, Buus S, Loft A, et al. Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study. Head Neck. 2008;30:471–478. 16. Mendenhall WM, Parsons JT, Mancuso AA, et al. Head and neck: management of the neck. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. Philadelphia: Lippincott-Raven; 1998:1135–1156. 17. Wallis S, O’Toole L, Karsai L, Jose J. Transoral endoscopic base of tongue mucosectomy for investigation of unknown primary cancers of head and neck. Clin Otolaryngol. 2018. 18. Dziegielewski PT, Boyce BJ, Old M, et al. Transoral robotic surgery for tonsillar cancer: addressing the contralateral tonsil. Head Neck. 2017;39:2224–2231. 19. Durmus K, Rangarajan SV, Old MO, et al. Transoral robotic approach to carcinoma of unknown primary. Head Neck. 2014;36:848–852. 20. Zhu L, Wang N. 18F-fluorodeoxyglucose positron emission tomographycomputed tomography as a diagnostic tool in patients with cervical nodal metastases of unknown primary site: a meta-analysis. Surg Oncol. 2013;22:190–194. 21. Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer. 2004;101:2641–2649.

Unknown Head and Neck Primary Site

766.e1

22. Fletcher GH, Jesse RH, Healey JE, Thomas GW. Oropharynx. In: MacComb WS, Fletcher GH, eds. Cancer of the Head and Neck. Baltimore: Williams & Wilkins; 1967:179–212. 23. Jones AS, Cook JA, Phillips DE, Roland NR. Squamous carcinoma presenting as an enlarged cervical lymph node. Cancer. 1993;72:1756–1761. 24. Graboyes EM, Sinha P, Thorstad WL, et al. Management of human papillomavirus-related unknown primaries of the head and neck with a transoral surgical approach. Head Neck. 2015;37:1603–1611. 25. Kuta V, Williams B, Rigby M, et al. Management of head and neck primary unknown squamous cell carcinoma using combined positron emission tomography-computed tomography and transoral laser microsurgery. Laryngoscope. 2017. 26. Fu TS, Foreman A, Goldstein DP, de Almeida JR. The role of transoral robotic surgery, transoral laser microsurgery, and lingual tonsillectomy in the identification of head and neck squamous cell carcinoma of unknown primary origin: a systematic review. J Otolaryngol Head Neck Surg. 2016;45:28. 27. Szyszko TA, Cook GJR. PET/CT and PET/MRI in head and neck malignancy. Clin Radiol. 2018;73:60–69. 28. Liu X, Li D, Li N, Zhu X. Optimization of radiotherapy for neck carcinoma metastasis from unknown primary sites: a meta-analysis. Oncotarget. 2016;7:78736–78746. 29. Hu KS, Mourad WF, Gamez ME, et al. Five-year outcomes of an oropharynx-directed treatment approach for unknown primary of the head and neck. Oral Oncol. 2017;70:14–22. 30. Keller LM, Galloway TJ, Holdbrook T, et al. p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary. Head Neck. 2014;36:1677–1684. 31. Madani I, Vakaet L, Bonte K, et al. Intensity-modulated radiotherapy for cervical lymph node metastases from unknown primary cancer. Int J Radiat Oncol Biol Phys. 2008;71:1158–1166. 32. Haas I, Hoffmann TK, Engers R, Ganzer U. Diagnostic strategies in cervical carcinoma of an unknown primary (CUP). Eur Arch Otorhinolaryngol. 2002;259:325–333. 33. Koivunen P, Laranne J, Virtaniemi J, et al. Cervical metastasis of unknown origin: a series of 72 patients. Acta Otolaryngol. 2002;122:569–574. 34. Chen AM, Meshman J, Hsu S, et al. Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin. Head Neck. 2018;40:227–232. 35. Geltzeiler M, Doerfler S, Turner M, et al. Transoral robotic surgery for management of cervical unknown primary squamous cell carcinoma: updates on efficacy, surgical technique and margin status. Oral Oncol. 2017;66:9–13. 36. Coster JR, Foote RL, Olsen KD, et al. Cervical nodal metastasis of squamous cell carcinoma of unknown origin: indications for withholding radiation therapy. Int J Radiat Oncol Biol Phys. 1992;23:743–749. 37. Weir L, Keane T, Cummings B, et al. Radiation treatment of cervical lymph node metastases from an unknown primary: an analysis of outcome by treatment volume and other prognostic factors. Radiother Oncol. 1995;35:206–211. 38. Mendenhall WM. Unknown primary squamous cell carcinoma of the head and neck. Curr Cancer Ther Rev. 2005;1:167–748. 39. Olsen KD, Caruso M, Foote RL, et al. Primary head and neck cancer. Histopathologic predictors of recurrence after neck dissection in patients with lymph node involvement. Arch Otolaryngol Head Neck Surg. 1994;120:1370–1374. 40. Huang DT, Johnson CR, Schmidt-Ullrich R, Grimes M. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study. Int J Radiat Oncol Biol Phys. 1992;23:737–742. 41. Mendenhall WM, Amdur RJ, Hinerman RW, et al. Postoperative radiation therapy for squamous cell carcinoma of the head and neck. Am J Clin Otolaryngol. 2003;24:41–50. 42. Barker CA, Morris CG, Mendenhall WM. Larynx-sparing radiotherapy for squamous cell carcinoma from an unknown head and neck primary site. Am J Clin Oncol. 2005;28:445–448.

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766.e2

SECTION III

Disease Sites

43. Reddy SP, Marks JE. Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: results of bilateral neck plus mucosal irradiation vs. ipsilateral neck irradiation. Int J Radiat Oncol Biol Phys. 1997;37:797–802. 44. McLaughlin MP, Mendenhall WM, Mancuso AA, et al. Retropharyngeal adenopathy as a predictor of outcome in squamous cell carcinoma of the head and neck. Head Neck. 1995;17:190–198. 45. Million RR, Cassisi NJ, Mancuso AA, et al. Management of the neck for squamous cell carcinoma. In: Million RR, Cassisi NJ, eds. Management of Head and Neck Cancer. Philadelphia: J.B. Lippincott Company; 1994:75–142. 46. Mendenhall WM, Mancuso AA. Radiotherapy for head and neck cancer–is the “next level” down? Int J Radiat Oncol Biol Phys. 2009;73:645–646. 47. Mendenhall WM, Riggs CE, Amdur RJ, et al. Altered fractionation and/or adjuvant chemotherapy in definitive irradiation of squamous cell carcinoma of the head and neck. Laryngoscope. 2003;113:546–551. 48. Peters LJ, Weber RS, Morrison WH, et al. Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy. Head Neck. 1996;18:552–559. 49. Johnson CR, Silverman LN, Clay LB, Schmidt-Ullrich R. Radiotherapeutic management of bulky cervical lymphadenopathy in squamous cell carcinoma of the head and neck: is postradiotherapy neck dissection necessary? Radiat Oncol Investig. 1998;6:52–57. 50. Mendenhall WM, Million RR, Cassisi NJ. Squamous cell carcinoma of the head and neck treated with radiation therapy: the role of neck dissection for clinically positive neck nodes. Int J Radiat Oncol Biol Phys. 1986;12:733–740. 51. Mack Y, Parsons JT, Mendenhall WM, et al. Squamous cell carcinoma of the head and neck: management after excisional biopsy of a solitary metastatic neck node. Int J Radiat Oncol Biol Phys. 1993;25:619–622. 52. Ojiri H, Mancuso AA, Mendenhall WM, Stringer SP. Lymph nodes of patients with regional metastases from head and neck squamous cell carcinoma as a predictor of pathologic outcome: size changes at CT before and after radiation therapy. AJNR Am J Neuroradiol. 2002;23:1627–1631. 53. Yeung AR, Liauw SL, Amdur RJ, et al. Lymph node-positive head and neck cancer treated with definitive radiotherapy: can treatment response determine the extent of neck dissection? Cancer. 2008;112:1076–1082. 54. Liauw SL, Mancuso AA, Amdur RJ, et al. Postradiotherapy neck dissection for lymph node-positive head and neck cancer: the use of computed tomography to manage the neck. J Clin Oncol. 2006;24:1421–1427.

55. Hitchcock KE, Amdur RJ, Mendenhall WM, et al. Lessons from a standardized program using PET-CT to avoid neck dissection after primary radiotherapy for N2 squamous cell carcinoma of the oropharynx. Oral Oncol. 2015;51:870–874. 56. Goenka A, Morris LG, Rao SS, et al. Long-term regional control in the observed neck following definitive chemoradiation for node-positive oropharyngeal squamous cell cancer. Int J Cancer. 2013;133:1214–1221. 57. Mendenhall WM, Villaret DB, Amdur RJ, et al. Planned neck dissection after definitive radiotherapy for squamous cell carcinoma of the head and neck. Head Neck. 2002;24:1012–1018. 58. Brizel DM, Prosnitz RG, Hunter S, et al. Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004;58:1418–1423. 59. Zhou MJ, van Zante A, Lazar AA, et al. Squamous cell carcinoma of unknown primary of the head and neck: favorable prognostic factors comparable to those in oropharyngeal cancer. Head Neck. 2017. 60. Patel SA, Parvathaneni A, Parvathaneni U, et al. Post-operative therapy following transoral robotic surgery for unknown primary cancers of the head and neck. Oral Oncol. 2017;72:150–156. 61. Axelsson L, Nyman J, Haugen-Cange H, et al. Prognostic factors for head and neck cancer of unknown primary including the impact of human papilloma virus infection. J Otolaryngol Head Neck Surg. 2017;46:45. 62. Lou J, Wang S, Wang K, et al. Squamous cell carcinoma of cervical lymph nodes from an unknown primary site: the impact of neck dissection. J Cancer Res Ther. 2015;11(suppl 2):C161–C167. 63. Al Kadah B, Papaspyrou G, Linxweiler M, et al. Cancer of unknown primary (CUP) of the head and neck: retrospective analysis of 81 patients. Eur Arch Otorhinolaryngol. 2017;274:2557–2566. 64. Krishnatreya M, Sharma J, Kataki A, Kalita M. Survival in carcinoma of unknown primary to neck nodes treated with neck dissection and radiotherapy. Ann Med Health Sci Res. 2014;4:S165–S166. 65. Erkal HS, Mendenhall WM, Amdur RJ, et al. Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head-and-neck mucosal site treated with radiation therapy alone or in combination with neck dissection. Int J Radiat Oncol Biol Phys. 2001;50:55–63. 66. Grau C, Johansen LV, Jakobsen J, et al. Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology. Radiother Oncol. 2000;55:121–129. 67. Taylor JM, Mendenhall WM, Parsons JT, Lavey RS. The influence of dose and time on wound complications following post-radiation neck dissection. Int J Radiat Oncol Biol Phys. 1992;23:41–46.

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46 Management of the Neck Vincent Grégoire, Thierry Duprez, Benoît Lengelé, and Marc Hamoir

Assessment and treatment of regional lymph nodes in the neck are of utmost importance in the treatment of patients with head and neck squamous cell carcinoma (HNSCC). The philosophy of treatment of the neck has evolved over the past several decades. Radiation oncologists and head and neck surgeons have progressively realized that extensive treatments are associated with more morbidity, but not always with a better oncologic outcome than less extensive procedures. Today, a comprehensive approach to the treatment of the neck needs to be multidisciplinary, taking into account the patient’s quality of life without jeopardizing cure and survival. A better understanding of the patterns of lymph node metastasis promoted the use not only of selective dissection but also of selective irradiation in selected patients. Concepts are still evolving; for example, the need and extent of post-concomitant chemoradiation neck node dissection continues to be evaluated. In this chapter, the discussion will be limited to management of the neck for oral cavity, oropharyngeal, hypopharyngeal, and laryngeal squamous cell carcinoma.

ANATOMY OF THE LYMPHATIC SYSTEM OF THE NECK The head and neck region has a rich network of lymphatic vessels draining from the base of the skull through the jugular nodes, spinal accessory nodes, and transverse cervical nodes to the venous jugulosubclavian confluence or the thoracic duct on the left side and the lymphatic duct on the right side.1,2 A comprehensive anatomic description of this network was made by Rouvière more than 50 years ago.1 The whole lymphatic system of the neck is contained in the celluloadipose tissue delineated by the aponeurosis enveloping the muscles, vessels, and nerves (Fig. 46.1). The lymphatic drainage is mainly ipsilateral, but structures such as the soft palate, tonsils, base of the tongue, posterior pharyngeal wall, and especially the nasopharynx have bilateral drainage. On the other hand, sites such as the true vocal cord, paranasal sinuses, and middle ear have few or no lymphatic vessels at all. The nomenclature of head and neck lymph nodes has been complicated by various confusing synonyms that are still in use in major textbooks and articles. Several expert bodies have proposed the adoption of systematic classifications aimed at standardizing the terminology. Following the description by Rouvière, the TNM (primary tumor, regional nodes, metastases) atlas proposed a terminology that divides the head and neck lymph nodes into 12 groups.3 In parallel to this classification, the Committee for Head and Neck Surgery and Oncology of the American Academy for Otolaryngology–Head and Neck Surgery has been working on a classification (the so-called Robbins classification), dividing the neck into six levels, including eight node groups.4 This classification is based on the description of a level system that has been used for a long time by the Head and Neck Service at the Memorial Sloan-Kettering Cancer Center

(MSKCC).5 Because one of the objectives in developing the Robbins classification was to create a standardized system of terminology for neck dissection procedures, only the lymph node groups routinely removed during neck dissection were considered. The terminology proposed by Robbins was recommended by the International Union Against Cancer (UICC).6 Recently a task force composed of worldwide opinion leaders in the field of head and neck radiation oncology reviewed and updated the previously published guidelines on nodal level delineation, and came up with a proposal corresponding more closely with the TNM atlas (Table 46.1).7 The major advantage of this new proposal (the so-called modified from Robbins classification) over the TNM terminology is the definition of the boundaries of the node levels. The delineation of these boundaries is based on anatomic structures such as major blood vessels, muscles, nerves, bones, and cartilage that are easily identifiable on computed tomography (CT) or magnetic resonance (MR) axial imaging sections. The anatomic boundaries are oriented to a patient lying in a supine position with the neck in a neutral position. Level Ia is a unique median region that contains the submental nodes. The lymph nodes are located in a triangular region limited anteriorly by the platysma muscle, posteriorly by the mylohyoid muscles, cranially by the symphysis of the mandible, caudally by the hyoid bone, and laterally by the anterior belly of the digastric muscle. The medial limit of level Ia is virtual because the region continues into the contralateral level Ia. Nodes in level Ia drain the skin of the chin, mid lower lip, tip of the tongue, and anterior floor of the mouth. Level Ia is at greatest risk for harboring metastases from cancer arising from the floor of the mouth, anterior oral tongue, anterior mandibular alveolar ridge, and lower lip. Level Ib contains the submandibular nodes located in the space between the inner side of the mandible laterally and the digastric muscle medially, from the symphysis menti anteriorly to the submandibular gland posteriorly. The submandibular nodes receive efferent lymphatics from the submental lymph nodes, lower nasal cavity, hard and soft palate, maxillary and mandibular alveolar ridges, cheek, upper and lower lips, and most of the anterior tongue. Nodes in level Ib are at risk for developing metastases from cancers of the oral cavity, anterior nasal cavity, soft tissue structures of the mid-face, and submandibular gland. Level II contains the upper jugular lymph nodes located around the upper one-third of the internal jugular vein (IJV) and upper spinal accessory nerve. It extends from the insertion of the posterior belly of the digastric muscle to the mastoid cranially to the carotid bifurcation (a surgical landmark) or the caudal border of the body of the hyoid bone (a clinical landmark) caudally. Level II can be further subdivided into level IIa and IIb by the posterior edge of the internal jugular vein. Level II receives efferent lymphatics from the face, parotid gland, and submandibular, submental, and retropharyngeal nodes. Level II also directly receives the collecting lymphatics from the nasal cavity, pharynx,

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768

SECTION III

Disease Sites

VIII (pA) VIII (siP) Xa (Mt) IX (M) Xb IX (B) IX (F) Xa (sA)

Ia (sMT)

SEJ VIa (AJ)

A

Xa (Mt) Xb VIIa

Xa (sA) II (Kütner)

VIII (diP)

II

VIII (sP)

SAN

Ia (sMT)

V

Ib (sMB) III

VIb (iH)

III (Poirier)

VIb (pL) VIb (pT)

V

VIb (R)

TCA IVa IVb Vc Fig. 46.1 Superficial (A) and deep (B) lymphatic node groups of the head and neck. AJ, anterior jugular; B, buccal; diP, deep intraparotid; F, facial; iH, infrahyoid; M, malar; Mt, mastoid; pA, preauricular; pL, prelaryngeal; pT, pretracheal; R, recurrent or paratracheal; sA, subauricular; SAN, spinal accessory nerve; SEJ, superficial external jugular; siP, superficial intraparotid; sMb, submandibular; sMt, submental; sP, subparotid; TCA, transverse cervical artery.

B

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CHAPTER 46

Comparison Between the TNM Atlas for Lymph Nodes in the Neck and the Guidelines of the Lymph Node Levels Modified From Robbins.

TABLE 46.1

TNM ATLAS TERMINOLOGY

ROBBINS – MODIFIED NODE LEVELS

Group No.

Terminology

Level

Terminology

1

Submental nodes

Ia

Submental group

2

Submandibular nodes

Ib

Submandibular group

3

Cranial jugular nodes

II

Upper jugular group

4

Middle jugular nodes

III

Middle jugular group

5

Caudal jugular nodes

IVa IVb

Lower jugular group Medial supraclavicular group

6

Dorsal cervical nodes along

V Va

Posterior triangle group Upper posterior triangle nodes

Spinal accessory nerve

Vb

Lower posterior triangle nodes

7

Supraclavicular nodes

Vc

Lateral supraclavicular group

8

Prelaryngeal and paratracheal nodes

VI VIa VIb

Anterior compartment group: Anterior jugular nodes Prelaryngeal, pretracheal, and paratracheal nodes

9

Retropharyngeal nodes

VII VIIa VIIb

Prevertebral compartment group: Retropharyngeal nodes Retro-styloid nodes

10

Parotid nodes

VIII

Parotid group

11

Buccal nodes

IX

Bucco-facial group

12

Retroauricular and occipital nodes

X Xa Xb

Posterior skull group: Retroauricular and subauricular nodes Occipital nodes

No., number

larynx, external auditory canal, middle ear, and sublingual and submandibular glands. The nodes in level II are therefore at greatest risk for harboring metastases from cancers arising from the nasal cavity, oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, and major salivary glands. Level IIb is more likely associated with primary tumors arising in the oropharynx or nasopharynx and is less frequently involved in tumors of the oral cavity, larynx, or hypopharynx. Level III contains the middle jugular lymph nodes located around the middle third of the IJV. It is the caudal extension of level II. It is limited cranially by the caudal border of the body of the hyoid bone and caudally by a plane in which the omohyoid muscle crosses the IJV (a surgical landmark) or by the caudal border of the cricoid cartilage (a clinical landmark). Level III contains a highly variable number of lymph nodes and receives efferent lymphatics from levels II and V and some efferent lymphatics from the retropharyngeal, pretracheal, and recurrent laryngeal nodes. It collects the lymphatics from the base of the tongue, tonsils, larynx, hypopharynx, and thyroid gland. Nodes in level III are at greatest risk for harboring metastases from cancers of the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. Level IVa contains the lower jugular lymph nodes located around the inferior third of the IJV from the caudal limit of level III to a limit set arbitrarily 2 cm cranial to the sternoclavicular joint, caudally. Level IVa receives efferent lymphatics primarily from levels III and V; some

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efferent lymphatics from the retropharyngeal, pretracheal, and recurrent laryngeal nodes; and collecting lymphatics from the hypopharynx, larynx, and thyroid gland. Level IVa nodes are at high risk for harboring metastases from cancers of the hypopharynx, larynx, thyroid, and cervical esophagus. Rarely metastases from the anterior oral cavity may manifest in this location with minimal or no proximal nodal disease. Level IVb contains the medial supraclavicular lymph nodes located in the continuation of level IVa down to the cranial edge of the sternal manubrium. Level IVb receives efferent lymphatics primarily from levels IVa and Vc, some efferent lymphatics from the pretracheal, and recurrent laryngeal nodes, and collecting lymphatics from the hypopharynx, esophagus, larynx, trachea, and thyroid gland. Level IVb nodes are at high risk for harboring metastases from cancers of the hypopharynx, subglottic larynx, trachea, thyroid, and cervical esophagus. Levels Va and Vb include the lymph nodes of the posterior triangle group. This group includes the lymph nodes located along the lower part of the spinal accessory nerve and the transverse cervical vessels. It extends from a plane crossing the cranial edge of the body of the hyoid bone to a plane crossing the cervical transverse vessels caudally. The distinction between the upper posterior triangle (level Va) and the lower posterior triangle (level Vb) allows lymph node involvement of the upper two-thirds of the spinal accessory nerve chain to be differentiated from that of the transverse cervical vessel chain.8,9 A horizontal plane defined by the caudal edge of the cricoid cartilage separates these two compartments. The demarcation between the posterior end of level IIb and the uppermost part of level Va has still not been clearly defined. From an anatomic point of view, the uppermost part of level Va includes lymph nodes belonging to the occipital region (see level Xb).10 Thus, it was proposed to use the hyoid bone as a radiological landmark to define the cranial limit of level Va. Levels Va and Vb receive efferent lymphatics from the occipital and postauricular nodes and from the occipital and parietal scalp; skin of the lateral and posterior neck and shoulder, nasopharynx, oropharynx (tonsils and base of the tongue); and the thyroid gland. Level Vb lymph nodes are at high risk for harboring metastases from cancers of the nasopharynx, oropharynx, and thyroid gland. Nodes in level Va are more often associated with primary cancers of the nasopharynx, oropharynx, or cutaneous structures of the posterior scalp, whereas those in level Vb are more commonly associated with tumors arising in the thyroid gland. Level Vc contains the lateral supraclavicular nodes located in the continuation of the posterior triangle nodes (levels Va and Vb) from the cervical transverse vessels down to a limit set arbitrarily 2 cm cranial to the sternal manubrium (i.e., a similar limit than the caudal border of level IVa). It corresponds partly to the area known as the “the supraclavicular fossa” also called the triangle of Ho, which was clinically defined in the mid-seventies before the era of CT for the neck staging of nasopharyngeal carcinoma.11 Level Vc receives efferent lymphatics from the posterior triangle nodes (levels Va and Vb) and is more commonly associated with nasopharyngeal tumors. Level VI lymph nodes contain the anterior compartment nodes including superficially, the anterior jugular nodes (level VIa), and in the deep previsceral space, the prelaryngeal, pretracheal, and paratracheal (recurrent laryngeal nerve) nodes (level VIb). Level VIa is contained between the anterior edges of the sternocleidomastoid muscles. It is limited cranially by the caudal limit of level Ib, caudally by the cranial edge of the sternal manubrium, anteriorly by the platysma, and posteriorly by the anterior surface of the infrahyoid muscles. These nodes mostly drain the integuments of the lower face and anterior neck. Consequently, their treatment should be addressed only in lower lip tumors and in advanced gingivomandibular carcinomas invading the soft tissues of the chin. Consequently, for all other primary tumor locations, it is proposed to set the cranial limit of level VIa at the caudal edge of the

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Disease Sites

body of the thyroid cartilage. Level VIb is contained between the two common carotid arteries. Its most cranial part is composed of two to three inconstant infrahyoid nodes, which rest on the thyrohyoid membrane and drain the anterior floor of mouth, tip of the tongue, and lower lip. Level VIb is limited caudally by the cranial edge of the sternal manubrium. Level VIb receives efferent lymphatics from the anterior floor of mouth, the tip of the tongue, the lower lip, the thyroid gland, the glottic and subglottic larynx, the hypopharynx, and the cervical esophagus. These nodes are at high risk for harboring metastases from cancers of the lower lip, the oral cavity (floor of mouth and tip of the tongue), the thyroid gland, the glottic and subglottic larynx, the apex of the piriform sinus, and the cervical esophagus. Level VIIa contains the retropharyngeal nodes, which lie within the retropharyngeal space, extending cranially from the upper edge of the first cervical vertebrae to the cranial edge of the body of the hyoid bone caudally. Typically, retropharyngeal nodes are divided into a medial and a lateral group. The lateral group lies medial to the internal carotid artery and lateral to a line parallel to the lateral edge of the longus capiti muscle. The medial group is an inconsistent group of one to two lymph nodes intercalated in or near the midline. The retropharyngeal node receives efferent lymphatics from the mucosa of the nasopharynx, the Eustachian tube, and the soft palate. These nodes are at risk of harboring metastases from cancers of the nasopharynx, the posterior pharyngeal wall, and the oropharynx (mainly the tonsillar fossa and the soft palate). Level VIIb contains the retrostyloid nodes, which are the cranial continuation of the level II nodes. They are located in the fatty space around the jugulocarotid vessels up to the base of skull (jugular foramen). Retrostyloid nodes receive efferent lymphatics from the nasopharyngeal mucosa, and are at risk of harboring metastases from cancers of the nasopharynx, and from any other head and neck tumor with massive infiltration of upper level II nodes through retrograde lymph flow. Level VIII contains the parotid node group, which includes the subcutaneous preauricular nodes, the superficial and deep intraparotid nodes, and the subparotid nodes. These nodes extend from the zygomatic arch and the external auditory canal down to the mandible. The parotid group nodes receive efferent lymphatic from the frontal and temporal skin, the eyelids, the conjunctiva, the auricle, the external acoustic meatus, the tympanum, the nasal cavities, the root of the nose, the nasopharynx, and the Eustachian tube. They are at risk of harboring metastasis from cancers of these regions, but especially from tumors of the frontal and temporal skin, the orbit, the external auditory canal, the nasal cavities, and the parotid gland. Level IX contains the malar and buccofacial node group, which includes inconsistent superficial lymph nodes around the facial vessels on the external surface of the buccinator muscle. The buccofacial nodes receive efferent vessels from the nose, the eyelids, and the cheek. They are at risk of harboring metastases from cancers of the skin of the face, the nose, the maxillary sinus (infiltrating the soft tissue of the cheek), and the buccal mucosa. Level Xa contains the retroauricular (also called mastoid) and subauricular nodes, which includes superficial nodes lying on the mastoid process from the cranial edge of the external auditory canal cranially to the tip of the mastoid caudally. The retroauricular nodes receive efferent vessels from the posterior surface of the auricle, the external auditory canal, and the adjacent scalp. They are at risk of harboring metastases mainly from skin cancers of the retroauricular area. Level Xb contains the occipital lymph nodes, which are the cranial and superficial continuation of the level Va nodes up to the cranial protuberance. Level Xb nodes receive efferent vessels from the posterior part of the hair-bearing scalp and are at risk of metastases from skin cancers of the occipital area.

IMAGING OF THE NECK The armamentarium available for the imaging workup of the metastatic cervical lymph nodes includes CT, MRI, ultrasonography, and positron emission tomography (PET).12 Nodal imaging is mandatory in a pretreatment workup because clinical assessment of the nodal status in patients with a thick and/or small neck has a low sensitivity and because deeply located nodes remain inaccessible at palpation in all patients.13 CT and MRI are standard cross-sectional imaging modalities through which anatomic “slices” of the entire neck depict the contours and internal structure of the nodes (Figs. 46.2 and 46.3). MRI may have an advantage over CT scanning because of the higher spontaneous tissue contrast accurately depicting and delineating fatty and nonfatty tissues. The multiplanar capability of MRI has been an advantage of this technique since its introduction into clinical use in the early 1980s. However, the multirow detector technology and the spiral acquisition modality of newer-generation CT systems have boosted the multiplanar reformatting capabilities of CT scans, which now equal those of MR images. The major criteria for nodal malignancy using CT and/or MRI include the size of the nodes (a short axis >10 mm) and the presence of a central necrosis (hypodensity on CT images; hypointensity on T1-weighted MR images and hyperintensity on T2-weighted MR images). Central necrosis is well highlighted by intravenous contrast agent perfusion, which enhances nodal areas with arterial blood supply on both CT and MR images. However, the two techniques share common weaknesses: the inability to detect micrometastatic deposits within normal-sized nodes (false–negative results) and the risk for inappropriate classification of malignancy in nodes that are enlarged by benign reactive changes (false–positive results). Thus far, neither MRI nor CT can provide perfect diagnostic accuracy for a nodal metastatic workup. It has been shown in a large series of patients that the two techniques have an almost similar and unsatisfactory performance.14 Ultrasonography has long been regarded as a low-cost, widely available, and innocuous alternative to CT/MRI, with the additional advantages of color Doppler flow–encoded vascular architecture depiction and fine-needle aspiration guidance. However, time demands and operator skill requirements are limiting factors, as well as the unresolved technical difficulties of fusing two-dimensional ultrasound data and three-dimensional CT/MRI data for radiotherapy planning. Ultrasound is also less efficient than CT and MRI at detecting nodal necrosis,15 and deeply located nodes may be poorly accessible to the technique. Research is underway to improve the diagnostic accuracy of MRI, including experimental lymphophilic contrast agents, magnetization transfer imaging, free water diffusion-weighted imaging (DWI), magnetic resonance spectroscopy, and bolus tracking perfusion-weighted imaging.16–18 Currently, only the DWI MR technique has made a definite breakthrough in clinical routine by yielding fast-to-acquire and easy-to-process accurate quantitative data that significantly add to pretherapeutic nodal staging attempts,19–21 early prediction of therapeutic response,22 and posttreatment early detection of residual/ recurrent tumor.23 Many think that molecular imaging probes targeting either specific membrane antigens or metabolic pathways of tumor cells could be the definitive contributors to perfect diagnostic accuracy in nodal metastatic workup, in which case MRI and PET should appear breaking through synergistic modalities using the PET-MR hybrid systems. PET using fluorodeoxyglucose (FDG) as a tracer has become the most available technique for “metabolic imaging” by enhancing foci of increased glucose uptake. However, PET alone provides only restricted diagnostic accuracy. The limitations of PET can be offset by coregistering the information on anatomic CT or MR images24 (Fig. 46.4). Integrated PET/CT combines the poor anatomic localization

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was only marginally superior to that of CT or MRI. This study calls into question the routine value of FDG-PET for nodal staging.26 In addition to research on dedicated tissue-specific MR contrast agents, research is underway on PET radiopharmaceutical tracers that would allow the assessment of hypoxia, angiogenesis, apoptosis, and receptor status. These studies make up the second main field of research in oncology imaging.27 Using anatomic imaging studies to detect tumor recurrences in previously treated primary sites is unsatisfactory because extensive unspecific posttherapeutic changes may mask small foci of neoplastic recurrence.28 On the other hand, very promising data have been reported with the use of FDG-PET in this setting.29 Similar concepts apply to nodal metastases, and it may be possible that molecular and metabolic imaging methods will also become standard in nodal relapse detection. The key imaging concept for the radiation oncologist’s dayto-day practice is the capability of superimposing PET/MRI metabolic/ molecular mapping onto CT/MRI anatomic images to improve the delineation of the irradiation target.30 PET-CT and PET-MRI fusions are the founding paradigms that have now emerged into the clinical routine31 (see Figs. 46.3 and 46.4).

A

STAGING OF NECK NODE METASTASES

B

The eighth edition (2017) of the UICC’s/AJCC’s TNM classification of malignant tumor staging for neck node metastasis is presented in Table 46.2.32 For oropharyngeal, the new classification distinguishes between p16-negative (HPV negative) and p16-positive (HPV positive) tumors. This classification does not apply to nasopharyngeal, thyroid, or skin cancers. The classification for nodal staging applies whether the modality used for neck assessment is a clinical examination or imaging. The routine use of CT or MRI and—in expert hands—ultrasound is recommended especially for assessing nodes not clinically identifiable (e.g., retropharyngeal, intraparotid, or superior mediastinal nodes) or for patients for whom clinical palpation of the neck is less sensitive (e.g., those who have a thick or small neck).33 Last, it should be emphasized that the Nx classification applies only when the neck has not been assessed or could not be assessed.

Fig. 46.2 Computed tomography nodal display in a patient with left oropharyngeal squamous cell carcinoma (SCC). (A) Native contrastenhanced slice in the axial transverse plane using multislice multirow detector (MSMD) spiral acquisition technique. Hypodense fatty (F) environment allows clear delineation of the neck structures. Left oropharyngeal SCC (PT) is present. Abnormal nodes are seen within the left level II region, with anterior adenomegaly (long axis of 26 mm is shown as dotted line; short transverse axis of 18 mm is shown between the double-ended arrow), and a posterior, normal-sized node showing necrotic hypodensity (thick arrow). Normal-sized contralateral nodes are indicated (thin arrows). Observe the isodensity of the submandibular glands (ball-arrowhead) and of the muscles (double ball-arrowhead). Jugular veins (J) and carotid arteries (C) are strongly opacified at this early second phase of biphasic iodinated contrast agent perfusion. Notice the lamination of the left internal jugular vein by adenomegaly. (B) Reformatted image in the coronal plane from the same three-dimensional data set shows the primary tumor (PT), left metastatic adenopathy, and contralateral, normal-sized nodes (ball-arrowhead). Observe the irregularities of the inferior aspect of the enlarged node, suggesting extranodal spread (thin arrow) and hypodense foci corresponding to necrotic areas within adenomegaly (thick arrow). (Courtesy E. Coche, MD, PhD.)

of PET with the accurate morphologic data provided by CT. The results of a recent large, prospective study showed that FDG-PET significantly improved the staging of HNSCC because of its detection of metastatic or additional disease.25 However, a recent meta-analysis totaling 1236 patients demonstrated that the accuracy of FDG-PET

INCIDENCE AND DISTRIBUTION OF NECK NODE METASTASES Clinical and Radiologic Assessment The metastatic spread of head and neck tumors into the cervical lymph nodes is rather consistent and follows predictable pathways, at least in the neck that has not been violated by previous surgery or radiotherapy. In Table 46.3, the frequency of metastatic lymph nodes is expressed as a percentage in patients who are node-positive.34,35 The frequency of neck node metastases and the distribution of clinically involved nodes depend to a major extent on the primary tumor site. Typically, hypopharyngeal tumors have the highest propensity for nodal involvement, which occurs in 70% of cases. Cranial and anterior tumors (e.g., oral cavity tumors) mainly drain into levels I, II, and III, whereas more caudally located tumors (e.g., laryngeal tumors) mainly drain into levels II and III and, to a lesser extent, levels IV and V. Contralateral nodes are rarely involved except for midline tumors or tumors in sites where bilateral lymphatic drainage has been reported, such as the soft palate, base of the tongue, and pharyngeal wall. Even in these tumors, the incidence of contralateral involvement is much lower. In base of the tongue tumors with clinically positive nodes, the rate is 31% in the contralateral level II nodes compared with 73% in the ipsilateral level II nodes (data not shown). Node distribution follows the same pattern in the contralateral neck as in the ipsilateral neck. Except for nasopharyngeal tumors, involvement of ipsilateral level V

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SECTION III

Disease Sites

A

B

C

D Fig. 46.3 Magnetic Resonance Nodal Display in a Patient With Right Oropharyngeal Squamous Cell Carcinoma (SCC). (A) Transverse, unenhanced, T1-weighted spin-echo (SE) image showing a right level II hypointense necrotic adenopathy (arrow) with a normal contralateral node in level II (ball-arrowhead). (B) Transverse, T2-weighted fast spin-echo (FSE) image with fat suppression option in a similar slice location discloses strong hyperintensity of the necrotic node owing to fluid-like content (arrow) compared with the normal contralateral node, which displays the usual intermediate to high signal intensity (ball-arrowhead). Observe the almost similar signal intensity of the normal node and of the parotid and submandibular glands (thin arrows). (C) Transverse, contrast-enhanced, T1-weighted SE image with fat suppression option in a similar slice location as in (A) and (B) shows only peripheral ring-like enhancement of the margin of the necrotic adenomegaly (arrow). The normal contralateral node enhances slightly and homogeneously (ballarrowhead). (D) Coronal-view, precontrast, T1-weighted MRI shows a primary tumor (PT) and hypointense necrotic adenopathy (arrow).

nodes is rather rare, occurring in less than 1% of oral cavity tumors, in less than 10% of oropharyngeal and laryngeal tumors, and in about 15% of hypopharyngeal tumors. It almost never occurs in contralateral level V nodes. Metastatic lymph node involvement in the neck depends on the size of the primary tumor, increasing with the T category. In the series reported by Bataini et al.34 44% of patients with a T1 tumor had clinical

lymph node involvement; this increased to 70% for patients with T4 lesions. There are, however, no data suggesting that the relative distribution of involved neck levels varies with the T category. Retropharyngeal lymph nodes represent a special entity because they are usually not clinically detectable. The incidence of retropharyngeal lymph node involvement can be estimated only from series in which CT or MRI of the retropharynx has been systematically performed as

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A

B

C

D

Management of the Neck

773

Fig. 46.4 CT-MRI-PET Image Fusion. (A) Postcontrast, reformatted CT image in the coronal plane shows bilateral, mildly enlarged metastatic nodes in the carotid-jugular chains. Tumoral involvement of the nodes remains speculative because of the borderline short-axis diameter and absence of obvious necrotic changes. (B) Superimposition of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) data on a CT image demonstrates increased glucose uptake within the nodes. (C) Postcontrast, T1-weighted, axial transverse MRI from three-dimensional gradient-echo acquisition using spoiled gradients (SPGR) shows bilateral anterior, horseshoe-sized oropharyngeal tumor and metastatic left-sided nodes in level II. (D) Superimposition of FDG-PET data on an MRI demonstrates increased glucose uptake within the primary tumor and metastatic nodes. (Courtesy M. Lonneux, MD, PhD.)

part of the diagnostic procedure. Retropharyngeal node involvement occurs in primary tumors arising from (or invading) the mucosa of the occipital and cervical somites, such as the nasopharynx, pharyngeal wall, and soft palate (Table 46.4). The incidence of retropharyngeal lymph node involvement is higher in patients in whom involvement of other neck node levels has also been documented.36–38 However, in patients with clinical stage N0 nasopharyngeal tumors and, to a lesser extent, in patients with pharyngeal wall tumors, the incidence of

retropharyngeal node involvement is still significant—between 16% and 40%. Also, as already described for the other lymph node levels, involvement depends on the T category and is typically lower for T1 tumors.

Pathologic Lymph Node Metastases The distribution of pathologic lymph node metastasis in patients with primary tumors of the oral cavity, oropharynx, hypopharynx, and larynx

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SECTION III

Disease Sites

can be derived from retrospective series in which a systematic radical neck node dissection was proposed as part of the initial treatment procedures.39–42 Retrospective series are essentially biased regarding patient and treatment selection, but these series from the Head and Neck Department at MSKCC are the largest and most consistent data ever published on that matter. The results of these retrospective studies

Union for International Cancer Control (UICC)/American Joint Committee on Cancer Staging (AJCC) Classification for Neck Node Metastasis (8th ed.) for Patients With Oral Cavity, Oropharyngeal, Hypopharyngeal, and Laryngeal Tumors

TABLE 46.2

Stage

Definition for Oral Cavity, Hypopharyngeal, Laryngeal, and p16-Negative Oropharyngeal Tumors

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral node, ≤ 3 cm in greatest dimension

N2a

Metastasis in a single ipsilateral node, > 3 cm but ≤ 6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral nodes, ≤ 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral nodes, ≤ 6 cm in greatest dimension

N3a

Metastasis in a lymph node > 6 cm in greatest dimension without extracapsular spread

N3b

Metastasis in single or multiple node(s) with extracapsular spread

Stage

Definition for p16 positive oropharyngeal tumors

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Unilateral metastasis ≤ 6 cm in greatest dimension

N2

Metastasis in contralateral nodes ≤ 6 cm in greatest dimension

N3

Metastasis in a lymph node > 6 cm in greatest dimension

From Brierley JD, Gospodarowicz MK, Wittekind CH. TNM Classification of Malignant Tumours, 8th ed. Hoboken, NJ: Wiley-Blackwell; 2017.).

are shown in Tables 46.5 and 46.6. The data are presented in terms of the number of neck dissections with positive lymph nodes divided by the total number of neck dissection procedures and expressed as a percentage. Most patients (> 99% for patients with N0 tumors and 95% for patients with N+ tumors) had unilateral treatment only, and no distinction between the ipsilateral and contralateral neck was made. Overall, metastatic disease was detected in 33% of the prophylactic neck dissections and in 82% of the therapeutic neck dissections. In these series, the overall sensitivity and specificity of the clinical examination reached 85% and 62%, respectively. As already observed with the pattern of clinical metastatic lymph nodes, the distribution of pathologically confirmed metastatic lymph nodes depended on the primary tumor site. Typically, in patients with clinical stage N0 oral cavity tumors, metastatic lymph nodes were observed in levels I to III, and in patients with clinical stage N0 oropharyngeal, hypopharyngeal, and laryngeal tumors, in levels II to IV. This pattern of node distribution is similar to that determined from the clinical palpation of the neck. It should be noted that the T-category distribution was different in the various groups. Of patients with laryngeal tumors, 54% (42 of 79) had stage T3 to T4 tumors (mainly, supraglottic lesions) compared with 27% of patients with oral cavity tumors (52 of 192), 25% of patients with hypopharyngeal tumors (6 of 24), and 17% of patients with oropharyngeal tumors (8 of 47). Such a difference in T category presumably explains the high incidence of microscopic node metastases in the group with laryngeal tumors. The pattern of metastatic node distribution in patients who underwent therapeutic neck dissection was similar to that observed in patients with N0 tumors, with the difference that significant pathologic infiltration of an additional nodal level was typically observed—level IV for oral cavity tumors and levels I and V for oropharyngeal, hypopharyngeal and, to a lesser extent, laryngeal tumors. Overall, this observation illustrates the gradual infiltration of node levels in the neck. This concept is well illustrated by the prevalence of metastases in level V. In the MSKCC series,43 the prevalence of pathologic infiltration in level V was quite low, averaging 3% in 1277 neck dissections in patients with oral cavity, oropharyngeal, hypopharyngeal, and laryngeal tumors. The prevalence peaked at 11% for hypopharyngeal tumors with pathologically positive nodes (see Table 46.6). A thorough analysis of level V infiltration showed that for all tumor sites pooled together, infiltration of level V without metastases in levels I to IV was observed in only one patient (0.2%). This patient had a hypopharyngeal tumor. Infiltration in level V remained below 1% when a single pathologically confirmed positive node was also observed in levels I to III, but reached 16% when a single

Distribution of Clinical Metastatic Neck Nodes From Oral Cavity and Pharyngolaryngeal Squamous Cell Carcinomas

TABLE 46.3

Patients With N+ Disease

Tumor Site

DISTRIBUTIONa OF METASTATIC LYMPH NODES PER LEVEL (PERCENTAGE OF NODE-POSITIVE PATIENTS) I

II

III

IV

Oral cavity (n = 787)

36%

42/3.5

79/8

18/3

5/1

Oropharynx (n = 1479)

64%

13/2

81/24

23/5

9/2.5

Hypopharynx (n = 847)

70%

2/0

80/13

51/4

Supraglottic larynx (n = 428)

55%

2/0

71/21

48/10

V

Otherb

1/0

1.4/0.3

13/3

2/1

20/3

24/2

3/1

18/7

15/4

2/0

a

Ipsilateral/contralateral nodes. Parotid, buccal nodes. Modified from Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer. 1972;29:1446–1449; Bataini JP, Bernier J, Asselain B, et al. Primary radiotherapy of squamous cell carcinoma of the oropharynx and pharyngolarynx. Tentative multivariate modelling system to predict the radiocurability of neck nodes. Int J Radiat Oncol Biol Phys. 1988;14:635–642. b

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Management of the Neck

Incidence of Retropharyngeal Lymph Nodes in Oral Cavity and Pharyngolaryngeal Primary Tumors

TABLE 46.4

INCIDENCE OF RETROPHARYNGEAL LYMPH NODES (PERCENTAGE OF TOTAL NO. PATIENTS) N0 Neck Diseasea

N+ Neck Diseaseb

Primary Site Oropharynx Pharyngeal wall Soft palate Tonsillar fossa Base of tongue Hypopharynx (piriform sinus, postcricoid area) Supraglottic larynx Nasopharynx

Overall 18/93 (19%) 7/53 (13%) 16/176 (9%) 5/121 (4%) 7/136 (5%) 4/196 (2%) 14/19 (74%)

6/37 (16%) 1/21 (5%) 2/56 (4%) 0/31 (0%) 0/55 (0%) 0/87 (0%) 2/5 (40%)

12/56 (21%) 6/32 (19%) 14/120 (12%) 5/90 (6%) 7/81 (9%) 4/109 (4%) 12/14 (86%)

Chua et al.37

Nasopharynx

106/364 (29%)

21/134 (16%)

85/230 (37%)

Chong et al.38

Nasopharynx

Not stated

Not stated

59/91 (65%)

Authors McLaughlin et al.36

a

Clinically negative nodes in levels I to V. Clinically positive nodes in levels I to V.

b

Incidence of Pathologic Lymph Node Metastasis in Squamous Cell Carcinomas of the Oral Cavity

TABLE 46.5

DISTRIBUTION OF METASTATIC LYMPH NODES PER LEVEL (PERCENTAGE OF NECK DISSECTION PROCEDURES) THERAPEUTIC RND (IMMEDIATE OR SUBSEQUENT)a

PROPHYLACTIC RNDa Tumor Site

No. RNDs

I

II

III

IV

V

No. RNDs

I

II

III

IV

V

Tongue

58

14%

19%

16%

3%

0%

129

32%

50%

40%

20%

0%

Floor of mouth

57

16%

12%

7%

2%

0%

115

53%

34%

32%

12%

7%

Gum

52

27%

21%

6%

4%

2%

52

54%

46%

19%

17%

4%

Retromolar trigone

16

19%

12%

6%

6%

0%

10

50%

60%

40%

20%

0%

9

44%

11%

0%

0%

0%

17

82%

41%

65%

65%

0%

192

20%

17%

9%

3%

1%

323

46%

44%

32%

16%

3%

Cheek Total a

Prophylactic RND: 192 patients/procedures; Therapeutic RND: 308 pts, 323 procedures. RND, radical neck dissection. Modified from Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990;160:405–409.

pathologically confirmed positive node was also observed in level IV. When more than one level was infiltrated, the probability of level V involvement progressively increased, reaching 40% when levels I to IV were all involved. The pattern of involvement of level I is also a good illustration of the concept of gradual node infiltration. In the MSKCC series, pathologic involvement of level I was found in only 2% of patients with clinical N0 oropharyngeal tumors and was not observed in patients with clinical N0 hypopharyngeal tumors (see Table 46.6). On the other hand, in patients with clinically positive nodes, metastases in level I were reported in 15% and 10% of patients with oropharyngeal and hypopharyngeal tumors, respectively.

Incidence of Skip Metastases in the Neck Skip metastases are metastases that do not progress in an orderly manner from one level to the next (e.g., from level I to level II). Depending on their frequency, skip metastases in patients with clinical stage N0 tumors may have a profound implication for the therapeutic management of the neck. In the series from the MSKCC,42 8 of 343 patients with clinical

stage N0 tumors (2.5%) developed skip metastases. Seven of these patients had oral cavity tumors that metastasized in level IV or V only. One patient had a laryngeal tumor. These low figures are in good agreement with a rate of neck failure outside the dissected levels of 3% (2 of 64 lesions) observed in patients with pathologic N0 lesions treated at the same institution by supraomohyoid neck dissection.44 Most of these patients had tumors of the oral cavity. None of them received postoperative radiation therapy because they were all free of metastases. Byers et al.45 carefully evaluated the frequency of skip metastases in 270 patients primarily treated by surgery at the MDACC from 1970 to 1990 for squamous cell carcinoma of the oral tongue. Of these patients, 12 had metastases in level III only, 9 had metastases in level IV only, and 2 had metastases in level IIb (i.e., nodes that are far enough posterior to the internal jugular vein). In addition, in 90 of the patients who had pathologic stage N0 tumors after selective neck dissection of levels I to III and who did not receive postoperative radiation therapy, 9 subsequently developed recurrence in level IV. Altogether (in levels IIb, III, and IV), the frequency of skip metastases reached 12% (32 of 270

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776

SECTION III

Disease Sites

Incidence of Pathologic Lymph Node Metastasis in Squamous Cell Carcinomas of the Oropharynx, Hypopharynx, and Larynx

TABLE 46.6

DISTRIBUTION OF METASTATIC LYMPH NODES PER LEVEL (PERCENTAGE OF NECK DISSECTION PROCEDURES) PROPHYLACTIC RNDa

THERAPEUTIC RNDb

No. RNDs

I

II

III

IV

V

No. RNDs

I

II

III

IV

V

Oropharynx Base of tongue + vallecula

21

0%

19%

14%

9%

5%

58

10%

72%

41%

21%

9%

Tonsillar fossa

27

4%

30%

22%

7%

0%

107

17%

70%

42%

31%

9%

Total Oropharynx

48

2%

25%

19%

8%

2%

165

15%

71%

42%

27%

9%

Tumor Site c

Hypopharynxc Piriform sinus

13

0%

15%

8%

0%

0%

79

6%

72%

72%

47%

8%

Pharyngeal wall

11

0%

9%

18%

0%

0%

25

20%

84%

72%

40%

20%

Total Hypopharynx

24

0%

12%

12%

0%

0%

104

10%

75%

72%

45%

11%

Larynxd Supraglottic larynx

65

6%

18%

18%

9%

2%

138

6%

62%

55%

32%

5%

Glottic larynx

14

0%

21%

29%

7%

7%

45

9%

42%

71%

24%

2%

Total Larynx

79

5%

19%

20%

9%

3%

183

7%

57%

59%

30%

4%

a

Prophylactic RND: Oropharynx 47 pts, 48 procedures; Hypopharynx 24 pts/procedures; Larynx 78 pts, 79 procedures. Therapeutic RND: Oropharynx 157 pts, 165 procedures; Hypopharynx 102 pts, 104 procedures; Larynx 169 pts, 183 procedures. c Modified from Candela FC, Kothari K, Shah JP. Patterns of cervical node metastases from squamous carcinoma of the oropharynx and hypopharynx. Head Neck. 1990;12:197–203. d Modified from Candela FC, Shah J, Jaques DP, et al. Patterns of cervical node metastases from squamous carcinoma of the larynx. Arch Otolaryngol Head Neck Surg. 116:432–435. RND, radical neck dissection; Pts, patients. b

lesions). If one excludes the skip metastases in level IIb and III, the frequency reached only 7% (18 of 270 lesions).

Incidence and Pattern of Node Distribution in the Contralateral Neck Very few data are available on the pattern of pathologic node distribution in the contralateral neck. Bilateral neck dissection was performed only when the surgeon thought there was a high risk of contralateral node involvement (e.g., with tumors of the oral cavity or oropharynx reaching the midline or extending beyond it, or with hypopharyngeal and supraglottic tumors). Obviously, in such cases bilateral radical neck dissection was never performed, so an accurate estimate of the pattern of node involvement in levels I to V of the contralateral neck is not possible. Furthermore, in almost every study, data on both sides of the neck were pooled for presentation. Kowalski et al.46 presented data on 90 patients who underwent bilateral supraomohyoid neck dissection and in whom the pattern of node distribution in each side of the neck was reported separately. Most of these patients had squamous cell carcinoma of the lip or oral cavity. In the ipsilateral neck, pathologic infiltration in levels I, II, and III reached 20%, 15%, and 15%, respectively. In the contralateral neck corresponding values reached 13%, 11%, and 0%, respectively. These figures are in good agreement with data on clinical node distribution showing that both sides of the neck exhibited a similar pattern of node distribution, but with a lower incidence in the contralateral neck. Foote et al.47 reported the rate of contralateral neck failure in a limited series of 46 patients with clinical stage N0 base of the tongue tumors treated by some form of glossectomy and ipsilateral neck dissection. None of these patients received postoperative radiation therapy. Ten patients (22%) had contralateral neck recurrence; the most common sites were levels II, III, and IV. It appears that in two of these patients,

recurrence was also observed at the primary site. The development of delayed contralateral neck metastases was not related to the clinical or pathologic extent of the base of the tongue tumor. O’Sullivan et al.48 reported a retrospective series of 228 patients with tonsillar carcinoma who were treated for the primary tumor and in the ipsilateral neck only with radiation therapy. The vast majority of these patients had T1 to T2 and N0 to N1 disease. Contralateral recurrence in the neck was observed in only eight patients (2%), including five patients with local recurrence as well. No neck failures occurred in the 133 patients with N0 neck classification. Although not significant because of the small number of events, involvement of a midline structure (i.e., soft palate and base of the tongue) appeared to be a prognostic factor for contralateral neck recurrence. A recent reevaluation of such finding was performed on 102 subsequent patients treated unilaterally by radiotherapy from 1999 to 2014, and confirmed the value on unilateral treatment in those selected patients.49 Similar results were reported in a series of 101 node-negative tonsil carcinoma (mainly, stage T1 to T3) cases treated unilaterally.50 Only two neck recurrences were observed in the contralateral neck.

RECOMMENDATIONS FOR SELECTION OF TARGET VOLUMES IN THE NECK Metastatic lymph node involvement of primary squamous cell carcinoma of the oral cavity, pharynx, and larynx typically follows a predictive pattern. Data on clinical and pathologic neck node distribution as well as on neck recurrence after selective dissection procedures support the concept that not all neck node levels should be treated as part of the initial management strategy of head and neck primaries of squamous cell origin.51,52 However, the data on which such a concept is based have come from retrospective series and so may include possible biases (e.g.,

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CHAPTER 46

Management of the Neck

777

Recommendations for Selection of Clinical Target Volume in the Neck for Oral Cavity and Oropharyngeal Tumors

TABLE 46.7

LEVELS TO BE INCLUDED IN CTV

Nodal Category (AJCC/UICC 8th ed.)

Ipsilateral Neck

Contralateral Neck

Oral Cavity N0-1 (in level I, II, or III)

I, II,a III, + IVab

I, II,a III, + IVab

N2a-b

I, II, III, IVae, Va,bc,d

I, II,a III, + IVa for anterior tongue tumor

N2c

According to N category on each side of the neck

According to N category on each side of the neck

N3

I, II, III, IVae, Va,b ± adjacent structures according to clinical and radiologic datad

I, II,a III, + IVa for anterior tongue tumor

Oropharyngeal p16-Negativef N0-1 (in level II, III, or IV) (Ib)g, II, III, IVae, + VIIa for posterior pharyngeal wall tumor

II, III, IVa, + VIIa for posterior pharyngeal wall tumor

N2a-b

Ib, II, III, IVae, Va,b, + VIIad

II, III, IVa, + VIIa for posterior pharyngeal wall tumor

N2c

According to N category on each side of the neck

According to N category on each side of the neck

N3

Ib, II, III, IVa, Va,b, + VIIa ± adjacent structures according to clinical and radiologic datad

II, III, IVa, + VIIa for posterior pharyngeal wall tumor

a

Level IIb could be omitted. For anterior tongue tumor and any tumor with extension to the oropharynx (e.g., anterior tonsillar pillar, tonsillar fossae, base of tongue); for N1 tumor with involvement of level III. c Level V could be omitted if only levels I to III are involved. d Level VIIb should be included in case of bulky infiltration of the upper part of level II. e Level IVb should be included in case of infiltration of level IVa. f For p16-positive tumor, no data suggest that the selection of the neck node levels should be different than for the p16-negative tumors, but owing to the new TNM classification, it is recommended to consider the number, the location, and the laterality of the positive nodes to select the levels to be treated. g Any tumor with extension to the oral cavity (e.g., retromolar trigone, mobile tongue, inferior gum, oral side of anterior tonsillar pillar). AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; CTV, clinical target volume; RP, retropharyngeal nodes. b

in patient selection, use of a series from the preimaging area, and so on) that could limit their validity. Tables 46.7 and 46.8 present recommendations for the selection of clinical target volumes in the neck for oral cavity and pharyngolaryngeal squamous cell carcinomas. These guidelines can be applied whether the treatment modality is surgery or radiotherapy. A complete discussion on choosing between these two modalities is beyond the scope of this chapter, but factors to consider include the neck classification, the treatment option for the primary tumor, HPV and EBV status, the performance status of the patient, and the institutional policy agreed on by a multidisciplinary head and neck tumor board. Selective treatment of the neck is appropriate for patients with clinical N0 HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx.44,52,53 Typically, level Ia to III nodes should be treated for oral cavity tumors, and level II to IVa nodes should be treated for oropharyngeal, hypopharyngeal, and laryngeal tumors. Robbins8 suggested that elective treatment of level IIb nodes is probably not necessary for patients with clinical N0 primary tumors of the oral cavity, larynx, or hypopharynx. Byers et al.45 suggested that level IV nodes be included in the treatment of the mobile tongue because of the high incidence (10%) of skip metastases. Retropharyngeal nodes should be treated in tumors of the posterior pharyngeal wall. For subglottic tumors, tumors with subglottic or transglottic extension, or hypopharyngeal tumors with esophageal extension, level VI nodes should also be included in the treatment volume. As proposed by Byers,53 similar guidelines could be recommended for patients who have N1 tumors without radiologic evidence of extracapsular infiltration. For hypopharyngeal tumors however, owing to their high lymphophilicity, comprehensive treatment of level Ib to V may be advisable. When an involved lymph node is located at a boundary

of a level that has not been selected for the target volume, it is recommended to extend the selection to include the adjacent level.54 Typically, this applies only for oropharyngeal tumors with a single lymph node involved in level II at the boundary with level Ib or for an oral cavity tumor with an N1 node in level III at the boundary with level IV. For patients with multiple nodes (N2b), the available data suggest that adequate treatment should include nodes in levels Ib (Ia for oral cavity) to V. Level Ib nodes could, however, be omitted for laryngeal tumors, and level V nodes omitted for oral cavity tumors with neck involvement limited to levels I to III. Prophylactic treatment of the retropharyngeal nodes should be systematically performed for oropharyngeal and hypopharyngeal tumors. Patients with N0 disease should have level VIb nodes treated for subglottic tumors, tumors with subglottic or transglottic extension, or hypopharyngeal tumors with esophageal extension. It has been proposed that patients with nodes in the upper neck (i.e., upper level II nodes) have the upper limit of the target volume extended to include the retrostyloid nodes (level VIIa).54 Similarly, the supraclavicular nodes (level IVb) should be included in the target volume in cases of lower neck involvement (i.e., level IVa or Vb nodes).54 No data are available on the distribution of pathologic metastatic neck nodes in patients presenting with a single ipsilateral large node (N2a or N3) or with bilateral or contralateral nodes (N2c). For patients with a single large node—in the absence of data—it appears safe not to recommend selective treatment. For N3 disease, the type of treatment of the neck is also likely to be dictated by the local extension of the node into the adjacent structures (e.g., paraspinal muscles, parotid gland, blood vessels). For N2c tumors, one proposal is to consider each side of the neck separately, such as selective treatment on both sides for a small single node on each side, selective treatment for a small single node on one side, and more extensive treatment on the other side in

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778

SECTION III

Disease Sites

Recommendations for Selection of Clinical Target Volume in the Neck for Hypopharyngeal and Laryngeal Tumors (T1N0 Glottic Tumors Excluded)

TABLE 46.8

Nodal Category (AJCC/UICC 8th ed.)

LEVELS TO BE INCLUDED IN THE CTV Ipsilateral Neck

Contralateral Neck

IIa, III, IVa, + VIIa for posterior pharyngeal wall tumor + VI for apex of piriform sinus or esophageal extension

IIa, III, IVa, + VIIa for posterior pharyngeal wall tumor + VI for esophageal extension

N1, N2a-b

Ib, II, III, IVab, Va,b, + VIIa + VI for piriform sinus or esophageal extensionc

II,a III, IVa, + VIIa for posterior pharyngeal wall tumor + VI for esophageal extension

N2c

According to N category on each side of the neck

According to N category on each side of the neck

N3

Ib, II, III, IVab, Va,b, + VIIa + VI for piriform sinus or esophageal extension± adjacent structures according to clinical and radiologic datab

II,a III, IVa, + VIIa for posterior pharyngeal wall tumor + VI for esophageal extension

Laryngeal N0-1 (in level II, III, or IV)

IIa, III, IVab, + VI for transglottic or subglottic extension

IIa, III, IVa, + VI for transglottic or subglottic extension

N2a-b

II, III, IVab, Va,b, + VI for transglottic or subglottic extensionc

IIa, III, IVa, + VI for transglottic or subglottic extension

N2c

According to N category on each side of the neck

According to N category on each side of the neck

N3

Ib, II, III, IVab, Va,b, + VI for transglottic or subglottic extension± adjacent structures according to clinical and radiologic datac

IIa, III, IVa, + VI for transglottic or subglottic extension

Hypopharyngeal N0

a

Level IIb could be omitted. Level IVb should be included in case of infiltration of level IVa. c Level VIIb should be included in case of bulky infiltration of the upper part of level II. AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; CTV, clinical target volume; RP, retropharyngeal (nodes). b

the case of multiple nodes. In patients with p16-positive oropharyngeal squamous cell carcinoma, no data suggest that the selection of the neck node levels should differ from that for the p16-negative tumors. Owing the new TNM classification, it is recommended to consider the number, the location, and the laterality of the positive nodes to select the levels to be treated. Prophylactic treatment of the contralateral neck for N0 disease lacks consensus and is likely to be based on clinical judgment rather than on strong scientific evidence. Typically, patients with midline tumors or tumors originating from or extending to a site that has bilateral lymphatic drainage (e.g., the base of the tongue, vallecula, posterior pharyngeal wall) are thought to benefit from bilateral neck treatment, whereas well-lateralized tumors (e.g., the lateral border of the tongue, retromolar trigone, tonsillar fossa) can be spared contralateral treatment. It has also been reported that the risk of contralateral neck metastases increased with involvement of the ipsilateral neck in patients with tumors of the pharynx and larynx.55 Putting all these data together, it would seem advisable to restrict treatment to the ipsilateral neck for tumors of the lower gum (not approaching the midline), lateral floor of the mouth, lateral border of the mobile tongue, upper gum, cheek, retromolar trigone, tonsillar fossa (without extension to the base of the tongue, soft palate, or posterior pillar), and lateral wall of the piriform sinus. In other situations in which prophylactic contralateral neck treatment is recommended, selection of the node levels to be treated should follow rules similar to those for the ipsilateral neck. In principle, a similar approach should apply for the definition of the node levels to be irradiated postoperatively. However, if the selection criteria for postoperative radiotherapy are capsular rupture, a metastatic node over 3 cm in diameter, or more than one metastatic node, then irradiation of levels I to V will typically be performed. As for primary irradiation, the retrostyloid space and supraclavicular fossae should be included in the target volume, depending on the location of the metastatic

nodes.54 For laryngeal tumors, level I nodes could be omitted. For oral cavity tumors with metastatic nodes located in level I and/or II only, postoperative irradiation of level V could be omitted. Retropharyngeal (level VIIb) and paratracheal (level VIb) nodes should be treated as mentioned earlier.

NECK NODE DISSECTION PROCEDURES AND SENTINEL NODE BIOPSY In 1991, based on the definition of the neck level, the Committee for Head and Neck Surgery and Oncology of the American Academy for Otolaryngology–Head and Neck Surgery made several recommendations for neck dissection terminology. The main objective was to develop standardized terminology limited to the use of a few defined procedures in which the lymphatic and nonlymphatic structures removed were unambiguously described. Such recommendations had to correlate with the biology of neck metastases and meet the standards of oncologic principles. The goal of each type of neck dissection is to remove the lymphatic structures (nodes and vessels) that are poorly individualized in the fatty tissue of the neck. When it is oncologically sound, some or all nonlymphatic structures of the neck, such as the internal jugular vein, spinal accessory nerve, sternocleidomastoid muscles, and submandibular glands, may be preserved. Since the 1991 classification, revisions have been proposed; the current neck dissection terminology and definitions8,9,56–58 are summarized in Table 46.9. Radical neck dissection (RND), previously considered to be the standard basic procedure, is defined as the resection of lymph node levels I to V, including removal of the sternocleidomastoid muscles, internal jugular vein, and spinal accessory nerve. Modified RND refers to the removal of all lymph nodes routinely resected by RND, but sparing one or more nonlymphatic structures (i.e., spinal accessory nerve, internal jugular vein, sternocleidomastoid

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CHAPTER 46

Classification of Neck Dissection: Definitions and Terminology

TABLE 46.9

Type of Neck Dissection

Lymph Node Levels Resected

Nonlymphatic Structures Removed

Radical neck dissection

I, II, III, IV, V

SCM, IJV, SAN

Modified radical neck dissection

I, II, III, IV, V

Preservation of one or more of the following: SCM, IJV, SAN

Selective neck dissection

Preservation of one or more of the following: I, II, III, IV, V. Parentheses are used to denote levels or sublevels removed: SND (I-IV)

None

Extended neck dissection

Resection of one or more or additional lymph node group not routinely removed by radical neck dissection (e.g., parapharyngeal, paratracheal nodes)

Resection of one or more nonlymphatic structures not routinely removed by radical neck dissection (e.g., carotid artery, hypoglossal nerve, overlying skin)

IJV, internal jugular vein; SAN, spinal accessory nerve; SCM, sternocleidomastoid muscle. Modified from Robbins KT. Classification of neck dissection. Current concepts and future considerations. Otolaryngol Clin North Am. 1998;31:639–656.

Management of the Neck

muscles) usually removed during RND (Fig. 46.5). Medina59 subclassified modified RND into three types: type I preserves the spinal accessory nerve only; type II preserves the spinal accessory nerve and sternocleidomastoid muscles; and type III preserves the spinal accessory nerve, sternocleidomastoid muscles, and internal jugular vein. Type III is also called by European authors “functional neck dissection,” as first described by Suarez60 and popularized by Bocca and associates.61,62 However, in their classic description, the submandibular gland was not removed. Selective neck dissection (SND) is dissection with preservation of one or more lymph node levels routinely resected in RND (Fig. 46.6). To avoid confusion in terminology for the different subtypes of SND, the 2002 revision of the node dissection classification excluded “named” node dissections (e.g., supraomohyoid node dissection, posterolateral node dissection) and proposed that the term selective neck dissection (SND) be followed in parentheses by the node levels or sublevels removed, for example, SND(I to III).56 Super-selective neck dissection (SSND) is a SND limited to the dissection of two or fewer contiguous neck levels. The feasibility of SSND for residual lymph node disease after chemoradiation was first reported by Robbins et al.63 Extended RND is defined by the removal of one or more additional lymph node groups (e.g., parapharyngeal or paratracheal lymph nodes) or nonlymphatic structures (e.g., carotid artery, paraspinal muscles, vagus nerve), or both, nonroutinely resected during a radical neck dissection. Any additional structures removed should be identified in parentheses. A method recently introduced in HNSCC for detecting occult micrometastases in the neck is lymphoscintigraphy associated with sentinel lymph node biopsy (SLNB). The concept is based on identification of the primary echelon of lymphatic drainage followed by the harvest of the sentinel lymph node within this basin only, assuming that if the sentinel lymph node is negative, there is no need for a comprehensive neck dissection. The technique was initially proposed

I

I II

II SAN, SCM, and IJV removed

III

SAN preserved

Va

Va

Vb

III

Vb

IV

A

IV

RND

779

B

MRND type I

Fig. 46.5 Lymph node levels and nonlymphatic structures removed in radical neck dissection (A) and modified radical neck dissection type I (B). In radical neck dissection for levels I to V, the spinal accessory nerve (SAN), sternocleidomastoid muscle (SCM), and internal jugular vein (IJV) are resected. In a modified radical neck dissection type I for levels I to V, the sternocleidomastoid muscle and internal jugular vein are resected. The spinal accessory nerve is preserved.

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780

SECTION III

Disease Sites

I II

III

Va

Vb

SND I-III

III

Va

Vb

IV

A

I

II

B

IV

SND II-IV

Fig. 46.6 Examples of selective neck dissection (SND). In SND I to III or supraomohyoid neck dissection (A), only levels I, II, and III are removed. In SND II to IV or lateral neck dissection (B), only levels II, III, and IV are removed.

for the detection of lymph node invasion in cutaneous melanoma, and thereafter in various sites.64–66 SLNB of cervical lymph nodes was introduced as a minimally invasive diagnostic procedure, able to predict more accurately the nodal status in patients who were node-negative with oral and selected oropharyngeal squamous cell carcinoma.67 Additional discussion on this topic can be found in the online chapter. Sentinel lymph node biopsy has been shown to improve staging of clinical N0 (cN0) tumors in patients with early squamous cell carcinoma of the oral cavity and oropharynx by identifying micrometastases.69,70 Several centers have now adopted SLNB alone as a staging tool for early clinical N0, oral, and selected oropharyngeal squamous cell carcinomas.69 In experienced teams, it is now acknowledged that SLNB is a reliable diagnostic procedure for staging the cN0 neck and identifying patients with occult nodal metastatic disease.70,71 A recent meta-analysis including 21 prospective studies and 847 patients showed a pooled estimate of sensitivity of 93% and the negative predictive value (NPV) ranged from 80% to 100%. The rate of detection of occult metastases ranged from 14% to 60% (median: 34%). The vast majority of the patients had early oral squamous cell carcinomas.72 Moreover, it was recently reported in a study including a limited number of patients, that SLNB was associated with significantly less postoperative morbidity as compared with elective neck dissection.73 Because sentinel lymph nodes are worked up thoroughly, a high number of occult metastases are revealed. Occult metastases are, by definition, clinical stage N0 neck metastases detected by histologic testing. They are further divided into macrometastases (> 2 mm in largest dimension), micrometastases (< 2 mm in greatest dimension), and isolated tumor cells.74–76 Isolated tumor cells are recognized as a separate entity, and are single tumor cells or small clusters of tumor cells not more than 0.2 mm in greatest dimension. Such cells are typically detected after immunohistochemical or molecular biologic testing only, and they do not show evidence of metastatic activity (e.g., proliferation or stromal reaction) or penetration of vascular or lymphatic sinus walls.75 The debate continues whether patients with micrometastases or isolated tumor cells in sentinel lymph nodes have a risk similar to that for

patients with metastases in the neck who have clinically invaded lymph nodes. There is evidence supporting further treatment to the neck in patients with micrometastases in sentinel lymph nodes.76 Regarding isolated tumor cells only, a watchful waiting policy could be warranted, although there is a low risk for metastases in nonsentinel lymph nodes. Larger series are required to establish the importance/significance of micrometastases and isolated tumor cells and to define an acceptable level of incorrectly down-staged isolated tumor cell disease in patients who have other metastases in the neck. Additional discussion on this topic can be found in the online chapter.

NECK NODE DELINEATION AND IRRADIATION TECHNIQUES Delineation of the Clinical Target Volume Several authors have proposed recommendations for the delineation of the neck node levels.58,77–80 Detailed comparison of these guidelines revealed a few important discrepancies, preventing uniform target volume delineation in the neck among radiation oncologists. A critical review of the two proposals was undertaken in the early 2000s in collaboration with representatives of the major European and North American clinical cooperative groups to generate an international set of guidelines for the delineation of the neck node levels in a node-negative neck.81 The correspondence between these guidelines and neck dissection procedures was further validated.82 In the late 2000s, a few amendments were proposed to take into account the specific situation of a node-positive and postoperative neck.54,83 Most recently, in 2013, a task force composed of opinion leaders in the field of head and neck radiation oncology from European, Asian, Australian/New Zealand, and North American clinical research organizations (DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG) was formed to review and update the previously published guidelines on nodal level delineation.7 The updated 2014 consensus guidelines for neck node delineation are presented in Table 46.10 and Fig. 46.7. The volumes delineated in Fig. 46.7 correspond to the clinical target volume (CTV) and do not

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CHAPTER 46

Management of the Neck

The sentinel lymph node can be identified by peritumoral injection of a radioactive tracer. The tracer mimics lymph spread and accumulates in the first-echelon node. With the help of lymphoscintigraphy and a gamma probe, the sentinel lymph node is localized and selectively excised. Histologic evaluation of the sentinel lymph node allows for pathologic staging of the neck. Additionally, lymphoscintigraphy and SLNB provide information on the presence of atypical basins or lymphatic flow that is not predictable and would typically not be addressed by a selective node dissection.68 In conclusion, with a high detection rate and a high sensitivity, SLNB seems clearly an accurate and safe diagnostic modality to detect occult lymph node metastases in early oral cavity SCC clinically N0. The conclusions of the meta-analysis gathering many studies with a small number of patients need to be validated by large multicenter studies with long-term follow-up. Also, prospective studies are needed to determine whether the implementation of SLNB alone would reduce patient morbidity but still be as effective as SND. In particular, the effect of SLNB on at least one-third of patients with a positive SLNB remains an issue because the pathologic status of the SLN is only known a few days after the surgical procedure. Those patients require two surgical interventions instead of one to complete the neck dissection.71 Some of those patients could have some delay before starting postoperative radiotherapy, when indicated. Futhermore, the morbidity in those patients should be compared with the morbidity in a group of patients who underwent SND electively. Development of rapid analysis of the SLN using molecular biology techniques could solve this issue.

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780.e1

CHAPTER 46

TABLE 46.10

Management of the Neck

781

Consensus Boundaries, Node Levels I to X BOUNDARIES

Level

Cranial

Caudal

Anterior

Posterior

Lateral

Medial

Ia, submental

Mylo-hyoid m.

Platysma m. (caudal edge of ant belly digastric m.)

Symphysis menti

Body of hyoid bone/ mylo-hyoid m.

Medial edge of ant. belly, digastric m.

n.a.

Ib, submandibular

Cranial edge, submandibular gland; ant, mylo-hyoid m.

Plane through caudal edge hyoid bone and mandible; alternatively caudal edge submandibular gland (most caudal); platysma m.

Symphysis menti

Post edge submandibular gland (caudal)/post belly digastric m. (cranial)

Medial aspect mandible (inner side) down to caudal edge; platysma m. (caudal); medial pterygoid m. (posterior)

Lat edge of ant belly of digastric m. (caudally); post belly of digastric m. (cranially)

II, upper jugular

caudal edge lateral process of C1

caudal edge body of hyoid bone

post. edge submandibular gland/post edge of post belly of digastric m.

post edge sternocleidomastoid m.

deep (medial) surface of sternocleidomastoid m./platysma m./ parotid gland/ posterior belly of digastric m.

medial edge of internal carotid artery; scalenius m.

III, middle jugular

caudal edge body of hyoid bone

caudal edge cricoid cartilage

Ant edge sternocleidomastoid m.; post third thyro-hyoid m.

post edge sternocleidomastoid m.

deep (medial) surface sternocleidomastoid m.

medial edge common carotid artery; scalenius m.

IVa, lower jugular

caudal edge cricoid cartilage

2 cm cranial to sternal manubrium

ant edge of sternocleidomastoid m. (cranial); body of sternocleidomastoid m. (caudal)

post edge sternocleidomastoid m. (cranial); scalenius mm. (caudal)

deep (medial) surface of sternocleidomastoid m. (cranial); lat edge sternocleidomastoid m. (caudal)

Med. edge common carotid art; lat edge thyroid gland; scalenius m. (cranial); medial edge sternocleidomastoid m. (caudal)

IVb, medial supraclavicular

caudal border of level IVa (2 cm cranial to sternal manubrium)

cranial edge of sternal manubrium

deep surface sternocleidomastoid m.; deep aspect of clavicle

ant edge scalenius m. (cranial); lung apex, brachiocephalic vein, brachiocephalic trunc (R side), common carotid and subclavian arteries on the L side (caudal)

lateral edge of scalenius m.

lateral border of level VI (pre-tracheal component); medial edge common carotid artery

Va-b, posterior trianglea

Cranial edge of body of hyoid bone

Plane just below transverse cervical vessels

Post edge sterocleidomastroid m.

Ant border trapezius m.

Platysma m.; skin

Levator scapulae m.; scalenius m. (caudal)

Vc, lateral supraclavicular

Plane just below transv cervical vessels (caudal border level V)

2 cm cranial to sternal manubrium (caudal border level IVa)

Skin

Ant border trapezius m. (cranial); ±1 cm ant to serratus ant m. (caudal)

Trapezius m. (cranial); clavicle (caudal)

Scalenius m.; lat edge sternocleidomastoid m., lat edge level IVa

VIa, ant jugular

Caudal edge hyoid bone or submandibular gland (most caudal)

Cranial edge sternal manubrium

Skin; platysma m.

Ant aspect infrahyoid (strap) m.

Ant edge both sternocleidomastoid m.

n.a.

Continued

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782

SECTION III

TABLE 46.10

Disease Sites

Consensus Boundaries, Node Levels I to X—cont’d BOUNDARIES

Level

Cranial

Caudal

Anterior

Posterior

Lateral

Medial

VIb, pre-laryngeal, pre-tracheal, para-tracheal, rec. laryngeal nerve

Caudal edge thyroid cartilage

Cranial edge sternal manubrium

Post aspect infrahyoid (strap) m.

Ant aspect larynx, thyroid gland and trachea (prelaryngeal and pre-tracheal LN; pre-vertebral m. (R); esophagus (L)

Common carotid artery, both sides

Lat aspect trachea and esophagus (caudally)

VIIa, retropharyngeal

Upper edge C1 body; hard palate

Cranial edge body of hyoid bone

Post edge sup or middle pharyngeal constrictor m.

Longus capitis m., longus colli m.

Medial edge int carotid artery

Line parallel to lat edge of longus capiti m.

VIIb, retro-styloid

Base of skull (jugular foramen)

Caudal edge lat process of C1 (upper limit, level II)

Post edge prestyloid parapharyngeal space

C1 vertebral body, base of skull

Styloid process; deep parotid gland

Medial edge int carotid artery

VIII, parotid node

Zygomatic arch, ext auditory canal

Angle of mandible

Post edge mandibular ramus & masseter m. (lat); medial pterygoid m. (med)

Ant edge sternocleidomastroid m. (lat); post belly digastric m. (med)

SMAS layer sub-cutaneous tissue

Styloid process and styloid m.

IX, bucco-facial

Caudal edge of orbit

Caudal edge mandible

SMAS layer subcutaneous tissue

Ant edge masseter m. and corpus adiposum buccae (Bichat’s fat pad)

SMAS layer sub-cutaneous tissue

Buccinator m.

Xa, retro-auricular nodes

Cranial edge ext auditory canal

Tip of mastoid

Ant edge mastoid (caudal) Post edge ext auditory canal (cranial)

Ant border occipital LN, post edge sternocleidomastroi m.

Sub-cutaneous tissue

Splenius capitis m. (caudal); temporal bone (cranial)

Xb, occipital nodes

Ext occipital protuberance

Cranial border level V

Post edge sternocleidomastoid m.

Ant (lat) edge trapezius m.

Subcutaneous tissue

Splenius capitis m.

a

Surgically, level V is subdivided in two groups of upper (Va) and lower (Vb) nodes according to their respective relationships with the cricoid cartilage. Ant, anterior; art, artery; ext, external; int, internal; L, left; lat, lateral; LN, lymph nodes; m., muscle; med, medial; post, posterior; R, right; sup, superior; transv, transverse.

include margins for organ motion or setup inaccuracy. The boundaries are based on a patient lying supine with the head in a “neutral” position. The terms cranial and caudal refer to structures closer to the cephalic and pedal ends, respectively. The terms anterior and posterior were chosen to be less confusing than the terms ventral and dorsal, respectively. It is beyond the scope of this chapter to discuss in depth these recommendations. The reader is referred to the original publication.7 A few specific issues, however, merit attention. The proposal for the node level delineation is valid irrespective of the nodal status of the patient (i.e. node-negative or node-positive). However, the translation from the node levels to CTV delineation may need some adjustments as a function of the nodal status setting. In the patient who is node-negative and in those with a single small lymph node or with several small lymph nodes not abutting one of the surrounding structures (e.g., muscle, salivary gland), the CTV will be defined by the association of one or several of the node levels. For larger lymph nodes abutting or infiltrating one of the surrounding structures (e.g., sternocleidomastoid muscle, the paraspinal muscles or the parotid gland), CTV delineation may need to take account of macroscopic and microscopic tumor infiltration outside of the node. Based on experts’ opinion, an isotropic expansion by 10 mm to 20 mm

into these structures from the visible edge of the node (i.e., the nodal gross tumor volume) appears reasonable, excluding bone and airway.83 Last, the proposal for the node level delineation still holds for the postoperative situation, at least from a conceptual point of view.

Irradiation Techniques With the use of intensity-modulated radiotherapy (IMRT), there is no longer a standard recipe for setting up field sizes and borders according to bony landmarks. Instead, the irradiation technique should be selected and adapted so that the entire planning target volume receives the prescribed dose within the adopted dose-volume constraints and in full consideration of the International Commission on Radiation Units and Measurements recommendations.84 The dose prescription depends on various factors, such as prophylactic versus therapeutic irradiation, or the use of combined-modality treatment, planned neck node dissection, and postoperative irradiation, and so on, which are beyond the scope of this chapter for comprehensive review. For primary radiotherapy, a typical prophylactic dose of about 50 Gy, 54 Gy, or 56 Gy in 2 Gy, 1.8 Gy, or 1.6 Gy per fraction is given over 5 to 7 weeks, and a therapeutic dose of about 70 Gy in 2 Gy per fraction is given over 7 weeks. In 2018, irradiations are typically

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CHAPTER 46

33

IX

32 11 47 12 13 32 14 2 48 31 27 4

VIIa VIIb

VIII

Ia 12 13 18 3 27 5 2 4 14 15 22 16 21

Ib VIIa

VIII Xa 35

A

III V

25 39 40 29 1 4 15 16 5 22

38

20

Vc

IVa

28 34 1

Ib

4 II

5 14 16 15 22 23 21 20 37

V

20 36

B VIa

D

II Xb

Xb

17 19

11

IX

30

783

Management of the Neck

VIb VIa 6 26 1 4 16 22 44

C IVb

5 24

VIb VIa

26 1 16 4 10 9

22 4124

23

E

42 46 45 23 20

F

43 46 45 20 23 44 8 7 Fig. 46.7 Head and neck CT sections performed on a 32-year-old volunteer immobilized with a head-neckshoulder thermoplatic mask. The head was set in a “neutral” position. Iodinated contrast medium (60 mL) (Omnipaque 350, HealthCare, Diegem, BE) was injected intravenously at a rate of 1 mL/s, then after a 3-min gap, another 50 mL were injected at a rate of 1.5 mL/s. The examination was performed on a Toshiba (Toshiba Aquilon LB, Toshiba Medical System Corporation, Japan) helicoidal CT (300 mAs and 120 keV) using a slice thickness of 2.0 mm, an interval reconstruction of 2.0 mm, and a helicoidal pitch of 11. CT sections were reconstructed using a 512 × 512 matrix. Sections were taken at the level of the top edge of the 1st cervical vertebra (A), the bottom edge of the 2nd cervical vertebra (B), mid 4th cervical vertebra (C), the bottom edge of the 6th cervical vertebra (D), mid 1st thoracic vertebra (E), and top edge of the 2nd thoracic vertebra (F). Each node level corresponds to node groups and thus does not include any security margin for organ motion, patient motion, or setup inaccuracy. 1, common carotid artery; 2, internal carotid artery; 3, external carotid artery; 4, internal jugular vein; 5, external jugular vein; 6, anterior jugular vein; 7, right brachiocephalic trunc; 8, right brachiocephalic vein; 9, left subclavian artery; 10, left subclavian vein; 11, facial vessels; 12, masseter m.; 13, pterygoid m.; 14, longus capitis m.; 15, longus colli m.; 16, sternocleidomastoid m.; 17, digastric (ant. belly) m.; 18, digastric (post. belly) m.; 19, platysma m. 20, trapezius m.; 21, splenius capitis m.; 22, scalenius m.; 23, levator scapulae m.; 24, serratus anterior m.; 25, thyrohyoid m.; 26, sternohyoid m.; 27, parotid gland; 28, submandibular gland; 29, thyroid gland; 30, mastoid; 31, styloid process; 32, mandible; 33, maxilla; 34, hyoid bone; 35, odontoid process; 36, 2nd cervical vertebra; 37, 4th cervical vertebra; 38, 6th cervical vertebra; 39, thyroid cartilage; 40, cricoid cartilage; 41, clavicle; 42, 1st thoracic vertebra; 43, 2nd thoracic vertebra; 44, rib; 45, lung apex; 46, esophagus; 47, Bichat’s fat pad; 48, prestyloid parapharyngeal space.

performed using a simultaneous integrated boost approach with therapeutic dose of 70 Gy (35 Gy × 2 Gy per fraction over 7 weeks) and an elective dose of 54.25 Gy (35 Gy × 1.55 Gy per fraction over 7 weeks). For postoperative irradiation, depending on the risk factors, doses usually range from 60 Gy to 66 Gy in 2-Gy fractions over 6 to 6.5 weeks.

CONTROL OF THE N0 NECK Guidelines generally recommend performing prophylactic treatment of the neck in patients with primary HNSCC clinically staged at N0 but having a probability of 20% or more of occult lymph node metastases.85 Elective neck dissection and elective neck irradiation are equally

effective in preventing disease occurrence in the cN0 neck. The choice between these two procedures generally depends on the treatment modality chosen for the primary tumor and many other factors. However, the basic rule that should govern the choice between surgery and radiotherapy (RT) is to favor a single-modality treatment if possible, avoiding overtreatment. For example, supraglottic laryngectomy with selective neck node dissection is just as effective as primary radiation therapy of the larynx and neck for treating a T1 or T2N0 supraglottic laryngeal tumor. For such a disease stage, the need for postoperative radiotherapy is quite low. Conversely, for a T3N0 supraglottic laryngeal tumor, a conservative treatment approach with primary radiotherapy or concomitant chemoradiation should be favored because of the

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784

SECTION III

Disease Sites

Risk of occult metastasis Yes

No Watchful policy

Neck treatment Surgery for primary

Selective neck dissection

RT/CH for primary

Selective neck irradiation

pN0

pN!

FU

pN1 no ECS

"pN1 and/or ECS

FU

Postoperative RT/RT-CH

cavity, the Brazilian Head and Neck Cancer Study Group was unable to show any difference either in 5-year actuarial overall survival (OS) or in the rate of neck failure.86 Postoperative irradiation was delivered in cases with a positive margin of the primary tumor and/or positive lymph nodes. This study is biased, however, by the fact that patients included in the SND group and found to have a positive lymph node (on frozen section) during the neck dissection were offered a modified RND. With these limitations in mind, in some of these studies the level of the neck recurrence was reported, allowing an estimate of the failure rate in the neck inside and outside the dissected levels (Table 46.11). In most of these studies, neck recurrence was reported only in patients in whom the primary tumor had been controlled, excluding neck recurrence as a result of reseeding from the recurrent primary tumor. After SND(I to III) or SND(II to IV), the rate of neck failure in nondissected levels was low, typically below 10%. Consequently, SND can be considered the optimal procedure for surgically managing N0 neck disease in patients with a high risk of occult lymph node metastasis.

Neck Control After Radiotherapy Fig. 46.8 Treatment algorithm for clinically negative neck (N0) disease. ECS, extracapsular spread; FU, follow-up; RT, radiotherapy; RT-CH, concomitant chemoradiation.

necessity of postlaryngectomy RT and the nonsuperiority of the surgical approach (Fig. 46.8).

Neck Control After Neck Node Dissection Selective neck dissection has become more widely used despite some concerns that it may not be as effective as a more comprehensive form of neck dissection, such as a modified radical neck dissection. Anticipating the conclusions that could be drawn from the MSKCC data with regard to the extent of the neck dissection, several groups have been performing SND since the 1950s.44,46,53,86–96 Such selective neck procedures were initially proposed for patients who were clinically node-negative and later extended to those who were clinically node-positive. These studies are biased because the patients treated by a selective procedure were probably highly selected with regard to the tumor site, tumor stage, and nodal status. In addition, in most of these patients, postoperative RT was usually performed in the presence of high-risk features for primary tumor or neck recurrence, such as close or positive resection margins, multiple node involvement, large node infiltration, or extracapsular spread. It is likely that the irradiated field encompassed the node levels that were not dissected but that could be at risk for microscopic infiltration. Originally, SND was typically considered a method for accurately staging neck disease, but not one that could affect regional control and survival rates. A retrospective review of 359 patients with stage T1 to T2 N0 squamous cell carcinoma of the oral cavity and oropharynx treated at the University of Pittsburgh showed significant improvement in regional control, disease-free survival, and regional recurrence-free survival rates for the group of patients who underwent SND along with primary tumor excision as compared with another group of patients who underwent excision of the primary tumor only.89 The patients who underwent SND were three times more likely to receive postoperative RT, most likely because of identification of adverse prognostic factors in the pathologic specimen. In a prospective randomized trial comparing modified RND and SND (I to III) (supraomohyoid nodes) for patients who were clinically node-negative with T2 to T4 tumors of the oral

Table 46.12 presents the percentage of neck recurrences in large retrospective series of pharyngolaryngeal squamous cell carcinomas treated with conventional fractionated RT.97–99 Some of the patients reported in these series were treated in the late 1950s, so the data must be interpreted with caution because of the likelihood of large uncertainties about the absolute dose calculation and dose distribution. Altogether, the neck control rates reached more than 92% after radiotherapy. After salvage surgery, the ultimate neck control rate reached a range of 94% to 100%. As expected, because of the high probability of regional control obtained with standard fractionation regimens, altered fractionation regimens or combined chemoradiation regimens did not improve the neck control rates.100,101 All of these studies were performed using two-dimensional irradiation techniques, that is, with target volumes extending typically from the base of the skull to the clavicles. With the introduction of 3D-CRT, IMRT, and selective neck irradiation, one important issue is the potential risk of geographic miss outside of the irradiated volumes. Eisbruch et al.102 reported a series of 135 patients treated bilaterally from 1994 to 2002 with 3D-chemoradiation therapy (CRT) or IMRT for primary tumors located mainly in the oropharynx (n = 80) and without node metastasis in the contralateral neck. Of these, 73 patients received postoperative RT, but none had neck node dissection on the contralateral neck. In the contralateral neck, the CTV typically included the level II to IV and retropharyngeal nodes. For the contralateral level II nodes, the upper limit was set at the junction between the posterior belly of the digastric muscle and the jugular vein. The median prophylactic dose was 50.4 Gy or 50 Gy in fractions of 1.8 Gy or 2 Gy. With a median follow-up of 30 months (range, 6 to 105 months), 15 patients had a regional recurrence (of these, 6 also had a primary tumor recurrence), 11 on the ipsilateral side and 4 on the contralateral side. Only 1 of the 15 patients presented a retropharyngeal node recurrence marginal to the CTV. Using a similar treatment philosophy, Bussels et al.103 did not report any recurrence on the ipsilateral side of the neck with N0 disease treated with parotid-sparing 3D-CRT in a series of 72 patients with oral cavity and pharyngolaryngeal squamous cell carcinoma. Chao et al.104 also looked at the pattern of recurrence in a series of 126 patients treated postoperatively (n = 74) or primarily (n = 52) for HNSCC by IMRT from 1997 to 2000. In this series, the lower neck (below the thyroid notch) was treated with a “traditional” anterior field. With a median follow-up of 26 months, 17 recurrences (13%) were observed. Six of these patients had recurrence outside of the target volumes, of which only one was in the lower neck of a patient with N0 disease.

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CHAPTER 46

785

Management of the Neck

TABLE 46.11 Neck Failure After Selective Neck Dissection for Squamous Cell Carcinomas of the Oral Cavity, Oropharynx, Hypopharynx, and Larynx NECK FAILURE (PERCENTAGE OF PATIENTS WITH PRIMARY TUMOR CONTROLLED)

Author

Year

Site

Clinical Category (AJCC 1980)

Byers87

1988

Oral cavity, oropharynx, hypopharynx, larynx

T1-4 N0

I, I-III, II-IV, I-V

45/299 (15%)a

31/299 (10%)

51

Byers

1985

Oral cavity, oropharynx

T1-4 N0-3

I-III

21/234 (9%)

16/234 (7%)

5/234 (2%)

Byers88

1999

Oral cavity, oropharynx, hypopharynx, larynx

T1-4 N0-1-2b

I, I-III, I-IV, II-IV

37/517 (7%)

26/517 (5%)

11/517 (2%)

19/284 (6.5%)

13/284 (4.5%)

6/284 (2%)

3/64 (4.5%)

3/64 (4.5%)d

Dissected Levels

Total

Dissected Levels

Nondissected Levels 14/299 (5%)b

Byers88

1999

Oral cavity, oropharynx

T1-4 N0-1-2b

I-III, I-IV

Brazilian86 HNCSG

1998

Oral cavity

T2-4 N0

I-IIIc

Duvvuri89

2004

Oral cavity, oropharynx

T1-2 N0

I-III

1997

Oral cavity + oropharynx Hypopharynx + larynx

T1-4 N0-3 T1-4 N0-3

I-III/I-IV II-IV

Pitman94

1997

Oral cavity, orohypopharynx, larynx

T1-4 N0

I-III/I-IV II-IV

Spiro44

1988

Oral cavity, oropharynx, larynx

T1-4 N0-1

I-III

95

1996

Oral cavity, oropharynx (98%)

T1-4 N0-1-2a-2b

I-III

2009

Oral cavity, oropharynx, hypopharynx, larynx

T1-4 N0-3

I-III/I-IV II-IV/II-V

Pellitteri

Spiro

93

Schmitz96

6/64 (9%) 17/180 (9.5%)

12/180 (6.5%)e

5/180 (3%)

7/42 (17%) 1/25 (4%)

2/42 (5%) 1/25 (4%)

5/42 (12%)f 0/25 (0%)

5/142 (3.5%)

5/142 (3.5%)

0/142 (0%)

12/107 (11%)

5/107 (4.5%)

7/107 (6.5%)

16/296 (5.5%)

8/296 (2.7%)

8/296 (2.7%)

6/210 (2.9%)g

4/210 (1.9%)

2/210 (0.9%)

1/39 (2.6%)h

0/39 (0%)

1/39 (2.6%)

a

Patients treated by surgery alone. Six of these patients had failure on the contralateral nondissected neck. c Part of a randomized study comparing radical modified versus supraomohyoid neck dissection. d One of these patients had failure on the contralateral nondissected neck. e Including one neck failure of unknown location. f Three of these patients had failure on the contralateral nondissected neck. g One of these patients had failure on the contralateral nondissected neck. Another patient presented with late neck recurrence, and a second primary tumor occurred 11 months later. h One of these patients had failure on the contralateral nondissected neck. AJCC, American Joint Committee on Cancer; HNCSG, Head and Neck Cancer Study Group. b

TABLE 46.12

Authors Bernier and Bataini

97

Neck Failure After Primary Radiotherapy for Node-Negative Patients

Years

Primary Tumor Site

Control of Neck After Radiotherapy

After Salvage Surgery

No. Patients

Dose/Overall Treatment Time 45–55 Gy/4.5–5.5 wk

93%

Not stated

57–72 Gy/6–9 wka

92% at 10 yr

94% at 10 yr

50 Gy/5 wk

96.7%

100%

1958-1974

Oropharynx, hypopharynx, larynx

611

Johansen99

1963-1991

Oropharynx, hypopharynx, larynx

1324

Alpert98

1971-1998

Supraglottic larynx

98

a

Including 28% of patients with a split course.

CONTROL OF THE N1 TO N3 NECK Neck Control After Surgery Alone The surgical management of N1 neck tumors is more controversial (Fig. 46.9). Traditionally, a comprehensive neck dissection (RND and modified RND) has been the surgical standard for patients presenting with neck disease. Andersen et al.105 reported that the rates of regional recurrences in the dissected neck following RND or modified RND type I for N1 or N2 disease were similar. Selective procedures have, however, gained popularity. In the retrospective study by Byers et al.,88 including 517 SND procedures mainly for patients with N0 or N1 neck disease, 50 patients had pathologic N1 disease. Of these patients, 36 received postoperative radiotherapy for the presence of risk factors

associated either with the primary tumor or the nodal site and only 1 (3%) presented with a regional recurrence. In patients who did not receive irradiation despite the presence of risk factors, 5 of 14 (36%) had neck failure. In a large retrospective review of 296 selective node dissections in levels I to III, Spiro et al.95 reported a rate of regional failure of 6.5% in patients staged with a pathologically positive neck disease. Most patients with pathologically invaded lymph nodes had postoperative radiotherapy. Recently, Schmitz et al.96 reported a regional failure rate of 8% in neck disease of pathologic N1 without better regional control in the necks treated with postoperative irradiation, suggesting that postoperative irradiation is not justified in pathologic N1 neck disease without extracapsular spread. With the inherent limitation of retrospective studies, it appears that SND for patients

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786

SECTION III

Disease Sites

cN!

N1

"N1

Surgery for primary

RT/RT-CH for primary

Surgery for primary

RT/RT-CH for primary

SND MRND

Selective RT/RT-CH

MRND RND/ERND

Comprehensive RT/RT-CH

pN!

Neck dissection for residual disease or node "3 cm

pN0

pN!

FU

pN1 no ECS

"pN1 or ECS

pN1 no ECS

"pN1 or ECS

FU

Postoperative RT/RT-CH

FU

Postoperative RT/RT-CH

Fig. 46.9 Treatment algorithm for clinically positive neck disease. ECS, extracapsular spread; ERND, extended radical neck dissection; FU, follow-up; MRND, modified radical neck dissection; RND, radical neck dissection; RT, radiotherapy; RT-CH, concomitant chemoradiation; SND, selective neck dissection.

with limited neck disease is a safe procedure, providing that postoperative irradiation is given in the presence of risk factors for regional relapse. Despite the use of aggressive single and combined treatment protocols, patients with locally advanced metastatic neck disease still have a poor prognosis because of the high risk of regional failure and distant metastases.106,107 However, the concept of using a less than radical procedure has gained acceptance even for advanced regional disease. Khafif et al.108 reported the results of 118 patients with N2 to N3 disease treated with RND or modified RND and were unable to find any difference in OS between the two groups. The recurrence rate in the modified RND group increased significantly in comparison with the group of patients treated with standard RND (52% vs. 33%), but some modified RND procedures were not really comprehensive. In a study comparing RND and modified RND (type I) in 212 patients with N2 and N3 lesions, the MSKCC group reported an overall 5-year neck control rate of 86% and a 5-year actuarial survival rate of 61%.105 No difference was found between the two groups. Adjuvant postoperative RT enhances regional control but does not seem to improve survival rates significantly.109 Investigators of the Royal Prince Alfred Hospital in Sydney, Australia, reported the outcome of 181 patients who had 233 neck dissections for N2 to N3 disease (163 extended RND, RND, or modified RND and 70 SND).110 Postoperative RT to the neck was given in 82% of the patients. At 5 years, control of disease in the treated neck was achieved in 86%. Adjuvant RT significantly improved neck control rates (p = 0.004), but did not alter survival rates. The utility of extended RND depends on whether acceptable control rates are attainable without prohibitive morbidity. Shaha111 described the results in 40 patients with N2 to N3 tumors treated by extended RND combined with postoperative RT. The regional control rate reached 70% at 2 years, with one perioperative death. The morbidity of extended RND depends on the additional structure or structures removed. If a common carotid artery is removed, the perioperative mortality rate ranges from 6% to 58%.112,113 However, when the structures sacrificed

are of no major neurovascular significance (e.g., parotid gland lymph nodes, paraspinal muscles), the additional morbidity is minimal.

Neck Control After Primary Radiotherapy The lower probability of regional control of the positive neck with RT has been documented by several retrospective series performed in the pre-HPV era.97,99,114 In an old series from the Institut Curie in Paris,97 1646 patients with squamous cell carcinoma of the oropharynx and pharyngolarynx had a 3-year regional control probability of 98%, 90%, 88%, and 71% for N0, N1, N2, and N3 lesions (AJCC 1976 classification), respectively. The nodal size was an even more discriminating factor, with nodal failure rates of 6%, 14%, and 39% for nodes below 3 cm, between 4 and 7 cm, and more than 7 cm, respectively.114 In this series, 75% of the neck nodes were treated by a form of two-dimensional concomitant boost approach with total doses in the range of 70 Gy to 85 Gy in 5 to 6 weeks. In the series of 458 patients who were node-positive with squamous cell carcinoma of the larynx and pharynx treated at Aarhus University Hospital from 1963 to 1991, the 5-year neck node control rate reached 68%, 68%, and 56% for N1, N2, and N3 lesions (UICC 1982 stage), respectively.99 A key issue in the management of positive neck disease by RT is whether these results can be improved by hyperfractionated or accelerated regimens, or concomitant chemoradiation. In randomized studies comparing a standard fractionated regimen with an altered fractionated regimen, no improvement was observed between the two arms115–117 (Table 46.13). In the European Organization for Research and Treatment of Cancer (EORTC) 22791 study, only patients with N0 or N1 neck disease were included and, because of the very good control of neck disease in the standard arm, it was not surprising that the hyperfractionated regimen did not bring any benefit.115 In the Danish Head and Neck Cancer Group (DAHANCA) 6 and 7 trials, no significant regional improvement was observed with the accelerated regimen in the patients who were node positive.116 Similarly, despite a benefit in OS, the Toronto trial did not observe any increase in the control of neck disease with

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CHAPTER 46

TABLE 46.13

Management of the Neck

787

Probability of Neck Node Control After Altered Fractionated Regimens CONTROL OF NECK

Author

Primary Tumor Site

Stage

Treatment Schedule

Standard Arm

Experimental Arm

Horiot115 EORTC 22791 (n = 325)

Oropharynx

T2-3NO-1MO

Standard: 70 Gy/35 f/7 wk Experimental: 80.5 Gy/70 f/7 wk

N0: 93% at 5 yr N1: 90% at 5 yr

N0: 93% at 5 yr N1: 90% at 5 yr

Overgaard116 DAHANCA 6 and 7 (n = 1476)

Oral cavity, pharynx, supraglottic larynx

Stage I-IV

Standard: 62-68 Gy/6-7 wk Experimental: 62-68 Gy/5-6 wk

N−: 68% N+: 44%

N−: 77%ab N+: 52%ac

Cummings117 (n = 331)

Oropharynx, hypopharynx, larynx

Stage III-IV

Standard: 51 Gy/20 f/4 wk Experimental: 58 Gy/40 f/4 wk

All stages: 71% at 5 yr

All stages: 68%d at 5 yr

a

Locoregional control. Odds ratio (95% CI): 0.65 (0.50–0.85). c Odds ratio (95% CI): 0.72 (0.49–1.05). d p = 0.80. DAHANCA, Danish Head and Neck Cancer Group; EORTC, European Organization for Research and Treatment of Cancer; f, fraction. b

TABLE 46.14

Probability of Neck Node Control After Concomitant Chemoradiation CONTROL OF NECK

Authors Calais

119

Primary Tumor Site

(n = 222)

Lavertu120 (n = 100)

Stage

Treatment Schedule

Standard Arm

Experimental Arm

Oropharynx

Stage III-IV

a

Standard: 70 Gy/7 wk Experimental: 70 Gy/7 wk + carboplatin and 5-FU × 3

All stages: 69%

All stages: 81%

Oral cavity, pharynx, larynx

Stage III-IVb

Standard: 65–72 Gy/7 wk Experimental: 65-72 Gy/7 wk + cisplatin and 5-FU × 2

N1: 6/10 (60%) N2–N3: 13/27 (48%)

N1: 8/8 (100%) N2–N3: 17/26 (65%)

a

75% of patients were node positive. 71% of patients were node positive. 5-FU, 5-fluorouracil. b

an accelerated hyperfractionated regimen.117 Such limited effect of altered fractionation regimens on nodal control was confirmed in the updated Meta-analysis of Radiotherapy in Carcinomas of Head and Neck (MARCH), which pooled 33 randomized studies, totaling 10,524 patients, and only observed a 1.4% improvement compared with standard fractionation RT (p = 0.06).118 The difference was however much larger with the use of hyperfractionnated radiotherapy reaching 4.1% at 5 years (HR 0.88, 95% CI 0.79–0.98; p = 0.017). Contrary to results achieved with altered fractionation regimens, concomitant chemoradiation regimens appear to have an impact on the control of disease in the neck119,120 (Table 46.14). In the study by Calais et al.,119 all neck stages were analyzed together. However, because 75% of the patients were node positive, it is very unlikely that the 12% improvement rate resulted only from a beneficial effect in the patients with N0 lesions. In the study by Lavertu et al.,120 which included fewer patients, the improvement in node control was observed for all positive neck categories. Finally, the use of concomitant cetuximab and RT also improved control of the node-positive neck (1998 AJCC staging) over RT alone, standard fractionation or altered fractionation, in the randomized study of Bonner et al.121 No benefit was observed in the patients who were node negative; however, these results need to be interpreted with caution because the study was not powered for subgroup analysis.

Neck Control in Human Papillomavirus–Positive Patients Retrospective analyses have shown that patients who are HPV positive have a better outcome after RT or concomitant CRT compared with those who are HPV negative.122 This effect was especially true in

nonsmoking patients who were HPV positive. It appears that the beneficial effect of HPV infection does not only result from a lower recurrence rate at the primary tumor site; it also results from a lower recurrence rate at the neck level.123 Because this later study reported on postoperative RT, it is still unclear whether this positive effect results from an increased radiosensitivity of HPV-infected SCC cells or from a better general prognosis for patients who were f HPV positive, irrespective of the treatment modality. All the above data suggest that patients with HPV-positive SCC may benefit from a different, probably less intensive treatment approach compared with those who are HPV negative. Studies are on the way to validate this new paradigm, but in the meantime, treatments should be applied irrespective of the HPV status.

Indications for Postoperative Irradiation or Chemoradiation The benefit of postoperative RT in HNSCC progressively emerged in the 1970s and 1980s as a standard of care for patients at high risk of locoregional relapse after surgery.124–127 Prognostic indicators for locoregional relapse after surgery include the primary disease site, surgical margins at the primary site, presence of perineural invasion, number of metastatic lymph nodes, and presence of extracapsular rupture.128,129 Based on the clustering of these pathologic factors, the MDACC proposed to stratify patients into three risk categories, conditioning the need for postoperative RT130 (Table 46.15). In the absence of any risk factor, the need for postoperative RT could not be shown. Patients with extracapsular rupture or a combination of two or more risk factors were identified as being at high risk of locoregional relapse; for these patients a randomized study showed the benefit of a radiation dose of 63 Gy (in 35 fractions) as compared with 57.6 Gy (in 32 fractions).131 For patients

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with only one risk factor other than extracapsular rupture, a dose of 57.6 Gy was shown to be optimal. A subsequent study from the same group further validated the use of these categories of risk factors and also documented the time between surgery and the start of postoperative RT and the total treatment time (from surgery to the end of RT) as additional risk factors.132 In this study, it was also shown that patients with a high risk of relapse benefited from accelerated treatment (63 Gy in 5 weeks vs. 63 Gy in 7 weeks) in terms of both locoregional control and survival. With the need to further improve locoregional control rates after surgery and postoperative RT, a few trials combining postoperative concomitant chemotherapy and RT were reported in the 1990s.133,134 Although the results favored the combined approach, these studies did not really influence the pattern of care of patients primarily treated with surgery. The European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) conducted similarly designed studies aimed at assessing the benefit of postoperative RT (60 Gy to 66 Gy) combined with cisplatin (100 mg/ m2) given on days 1, 22, and 43 for patients with a variety of risk factors that were slightly different between the two trials.135,136 In the EORTC study, a highly statistically significant benefit in favor of the combined treatment was observed for both locoregional control and OS (Table 46.16). In the RTOG study, the benefit in locoregional control probability did not translate into a statistically significant difference in survival rates. Combined-modality treatment did not decrease the incidence of distant metastasis in either of these studies. In both studies, the concomitant use of chemotherapy significantly enhanced the acute local

TABLE 46.15 Prognostic Factors for Locoregional Relapse After Surgery Moderate Risk Positive margin at the primary (R1) or close margin (< 5 mm) Primary tumor in the oral cavity Perineural invasion Two or more invaded lymph nodes Two or more invaded node levels Invaded node(s) >3 cm in diameter More than 6 weeks between surgery and start of radiotherapy

High Risk Extracapsular spread (ECS) A combination of two or more of the moderate risk factors

From Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys. 1993;26:3–11.

TABLE 46.16

toxicity of radiotherapy and only half the patients could actually receive the full treatment as planned. A meta-analysis of these two studies demonstrated a statistically significant benefit of combined chemoradiation, but only in patients who had positive surgical margins and/or extracapsular spread, that is, patients with the highest risk of relapse after surgery.137 For the other patients, radiotherapy alone can still be considered as a standard of care.

Indications for Postradiotherapy Neck Node Dissection Advances in chemoradiation for advanced head and neck carcinoma have shown that organ preservation is feasible without compromising disease-free survival and OS.138,139 This strategy has led to controversial issues concerning the role of node dissection after RT or chemoradiation for patients with N2 to N3 disease at initial diagnosis. A residual neck mass may be present in as many as 30% to 60% of patients after completion of chemoradiation. For these patients, irrespective of the neck category, there was a consensus in the literature favoring an immediate neck node dissection because of the very low probability of achieving neck control with salvage surgery when recurrence develops.140 Whether a neck dissection should be proposed for all patients with N2 to N3 disease at diagnosis or only for those without a complete response has been a matter of debate for a long time.141–151 That neck dissection could be avoided following complete nodal response to irradiation is a consequence of a better response assessment using imaging,152 and improved regional control with chemoradiation119,138,153,154 and with hyperfractionated or accelerated radiotherapy.155,156 Currently many arguments support the position that systematic planned neck dissection is no longer justified in patients without clinically residual disease in the neck,157 and many institutions have switched to neck dissection for residual disease in the neck only.141,148,151,158 Improvement in assessing the neck status with imaging has contributed enormously to this change in paradigm. Additional discussion on this topic can be found in the online chapter. The use of fluorodeoxyglucose (FDG) PET scan has also progressively gained interest in this setting. A meta-analysis of 51 studies including 2335 patients assessing the diagnostic performance of FDG-PET with or without CT proved to have a high accuracy for detecting residual disease.168 The weighted mean (95% CI) pooled sensitivity, specificity, PPV, and NPV of posttreatment FDG PET(CT) for the neck evaluation were 72.7% (66.6% to 78.2%), 87.6% (85.7% to 89.3%), 52.1% (46.6% to 57.6%), and 94.5% (93.1% to 95.7%), respectively. Scans done 12 or more weeks after completion of definitive therapy had moderately higher diagnostic accuracy on meta-regression analysis using time as a covariate than scan done earlier after completion of RT-CH. Because the NPV remains exceptionally high, a negative posttreatment FDG-PET

Efficacy of Concomitant Chemotherapy and Postoperative Radiotherapy LOCOREGIONAL CONTROL RATE

Authors

OVERALL SURVIVAL RATE

Site

Regimen

Radiotherapy

Chemoradiation

Radiotherapy

Chemoradiation

(n = 334)

Oral cavity, oropharynx, hypopharynx, larynx

66 Gy (6.5 wk) vs. 66 Gy (6.5 wk) + cisplatin (100 mg/m2) on days 1, 22, 43

69% at 5 yr

82% at 5 yr p = 0.007 (Gray’s test).

40% at 5 yr

53% at 5 yr p = 0.02 (log-rank)

Cooper136 (n = 416)

Oral cavity, oropharynx, hypopharynx, larynx

60–66 Gy (6-6.5 wk) vs. 60–66 Gy (6–6.5 wk) + cisplatin (100 mg/m2) on days 1, 22, 43

72% at 2 yr

82% at 2 yr p = 0.01 (Gray’s test)

56% at 2 yr

64% at 2 yr p = 0.19 (log-rank)

135

Bernier

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CHAPTER 46 is highly suggestive of absence of viable disease and suggests that neck dissection can be safely deferred in patients with a negative metabolic evaluation. This strategy was recently confirmed in a large United Kingdom randomized trial (UK PET NECK trial) including 562 patients with advanced nodal disease. Mehanna et al.169 demonstrated noninferiority between PET-CT surveillance with neck dissection performed only in incomplete or equivocal response and planned neck dissections in patients with N2 to N3 disease.169 Over the trial 2-year follow-up period, overall survival was similar among patients in the PET-CT surveillance arm compared with those who underwent planned neck dissection (84.9% vs. 81.5%, respectively). In addition, mainly as a result of fewer neck dissections (54 vs. 221), PET-CT-guided surveillance, as compared with neck dissection, resulted in a 2-year cost saving of £1,492 (≈$2000 US or €1700) per person. There was also a small difference in global health status scores on the EORTC QLQ-C30 questionnaire in favor of the surveillance group at 6 months after randomization. This difference narrowed at 12 months and disappeared by 24 months. The results of a lifetime cost-effectiveness analysis of PET-CT–guided management from a United Kingdom secondary care perspective were recently reported, which indicated that the use of PET-CT–guided management for patients with advanced head and neck cancer after primary CRT reduces lifetime costs and improves patient health outcomes.170 Together with these studies, well-defined qualitative interpretation criteria have been proposed and prospectively validated for post (C) RT FDG-PET assessment of the primary tumor and the neck.171 The Hopkins 5-point qualitative therapy response interpretation criteria for head and neck PET-CT showed excellent NPV and predicted OS and progression-free survival in patients with HNSCC. To summarize, balancing the benefit with the increased morbidity of post chemoadiation surgery, current evidence suggests that neck node dissection be restricted to those patients with a noncomplete response after organ-preservation protocol. In this situation, growing evidence supports the approach of using SND even in patients with initial advanced nodal disease and with clinically persistent disease, with less than 5% of subsequent neck failure.172–176 It has been recently demonstrated that SSND was a reliable surgical option for patients with residual disease confined to a single neck level.177 In all studies reporting on post concomitant chemoradiation selective neck dissection, the rate of major postoperative complications was less than 10% and comparable to the rate of complications observed after primary surgery.145,173,178–180 Despite the absence of a prospective study comparing SND and SSND with comprehensive node dissection after organ preservation protocols, one would intuitively expect less fibrosis, shoulder dysfunction, and neck deformity in patients who underwent limited surgery.

LATE COMPLICATIONS AFTER NECK TREATMENT Complications of Neck Node Dissection In addition to the medical complications inherent in any surgical procedure, neck dissection may potentially be associated with some specific perioperative complications and late complications or sequelae. The description of perioperative complications is beyond the scope of this chapter. Readers interested in such topics will find detailed information in a textbook dedicated to head and neck surgery.181 Recognized complications after neck dissection include numbness and/or burning of the neck and ear; neck pain; shoulder discomfort; neck tightness; lower lip weakness; decreased range of motion of the head, neck, and shoulder; lymph edema; cramping and spasms of the neck musculature; and cosmetic disfigurement. In 2001, Shah et al.182 proposed a neck dissection specific quality-of-life questionnaire used

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789

in a series of patients who had undergone neck dissection as part of their treatment. Some of these patients had been previously treated by chemotherapy (25%) or RT (50%). Neck tightness and shoulder discomfort had the greatest effect on quality of life. Advanced tumor stage, often requiring more radical surgery and use of chemotherapy or RT, was associated with a worse quality of life after neck dissection. Overall, the quality of life after neck dissection tends to improve with time.182 The most noticeable sequela induced by spinal accessory nerve resection is the decreased ability to abduct the shoulder above 90 degrees. However, any type of neck dissection may result in impairment of shoulder function.183 Studies reported that preservation of the spinal accessory nerve in modified RND and SND was associated with a better quality of life and fewer shoulder disorders in both the short and long term.182 Using the University of Washington quality-of-life questionnaire, the Liverpool group reported that little morbidity associated with shoulder dysfunction was observed in patients following a unilateral level I to III or I to IV neck dissection in comparison with patients undergoing primary surgery without neck dissection.184 However, unilateral neck dissection extending to level V and bilateral SND (I to III or I to IV) were associated with statistically significantly worse shoulder dysfunction. Adjuvant RT seemed to have a detrimental effect on shoulder dysfunction, whether or not the patient had had a unilateral SND. In another series, assessment of patients who underwent neck dissection with or without RT at least 1 year previously revealed that neck pain was present in one-third of patients, shoulder pain in 37%, and loss of sensation in 65% (related to the number of dissected levels and to RT).185 A prospective study on objective assessment after treatment concluded that adjuvant RT had no effect on shoulder joint function and that shoulder disability was inevitable in all types of neck dissections, whether or not the spinal accessory nerve was spared. However, shoulder function was better after SND and modified RND than after RND, although electromyographic findings were similar after either RND or modified RND and SND.186 The benefit of postoperative physical therapy has been stressed, and it should be started in the early postoperative period after all types of neck dissections.187

Complications of Neck Irradiation Late complications after head and neck irradiation are discussed in the disease-specific chapters. In the following section, only specific complications arising in the soft tissues of the neck will be reviewed. They mainly concern subcutaneous fibrosis, thyroid dysfunction, and carotid artery stenosis. Typically, late complication probability depends on the total dose, dose per fraction, time interval between fractions, volume of normal tissue receiving a high dose, and use of concomitant chemotherapy and/or a biologic modifier. The probability of grade 3 to 4 (RTOG late morbidity scale) subcutaneous fibrosis in the neck is rather low after standard RT. From randomized studies performed in the 1990s, it can be estimated at around 3%.119,156,188,189 After accelerated or hyperfractionated treatments, no increase in grade 3 to 4 subcutaneous toxicity was observed, providing that enough time was allowed between fractions.156 In an EORTC trial with only a 4-hour interfraction time, a 50% risk of fibrosis was documented at 5 years after treatment.190 After concomitant chemoradiation, randomized trials reported a substantial increase in late skin morbidity, reaching figures of around 10%.119 Clinically indolent hypothyroidism in patients with lower neck irradiation has been reported at rates of up to 24%.191,192 Most patients usually develop hypothyroidism within 1 year after treatment. Postoperative RT, especially after laryngeal surgery, including partial thyroidectomy, has been shown to be a risk factor. Yearly thyroid function testing (i.e., thyroid-stimulating-hormone level) is advised in the follow-up of patients with irradiation to the neck.

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CHAPTER 46

Management of the Neck

Investigators from the University of Florida reported a negative predictive value (NPV) of CT scan of 94% to 97% for the detection of residual or recurrent neck metastasis, providing that very strict criteria were used.159–161 In a large Canadian study (n = 363), an NPV of 100% was reported for CT scan using a regression of the initial diameter equal or more than 80% at 6 to 8 weeks after concomitant chemoradiation.162 In a previously reported study, the same group has showed that CT assessment of patients with N3 nodes was not adequate.163 Also, in the studies mentioned above, the specificity (thus the positive predictive value) of CT scan was found to be very low, around 28%. In this framework, could MRI outperform CT examinations? A meta-analysis showed that CT and MRI were equivalent for the detection of pretreatment lymph-node metastases in HNSCC.164 Diffusion-weighted MRI was recently reported as a better tool than conventional MRI for initial regional staging and for assessment of treatment response early after the end of chemoradiation.165,166 The value of MRI in selecting patients for post-RT neck dissection was recently assessed in a Danish series of 100 patients with oropharynx SCC.167 Neck response was evaluated two months after the completion of RT or CRT. MRIs were classified as either negative if no evidence of residual neck disease was noted by the radiologist or as positive if suspicion was noted. In the 60 patients with suspicion for residual neck disease who underwent neck dissection, only 7 had histologic evidence of residual disease. Sensitivity, specificity, positive predictive value (PPV), NPV, and overall accuracy of MRI were 69%, 41%, 15%, 90%, and 45%, respectively. The high rate of false–positive evaluations illustrates the low specificity and PPV of post-RT MRI.

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789.e1

790

SECTION III

Disease Sites

Carotid artery stenosis after neck irradiation has been reported by several authors, but very few studies have investigated the incidence, disease patterns, and risk factors including tobacco use, hypertension, hyperlipidemia, diabetes, and so forth. Matched control Doppler ultrasound examinations have reported significant carotid stenosis in 30% to 50% of patients with previous irradiation to the neck.193 Compared with the general population, a relative risk of stroke of 5.6 has been reported in patients with previous irradiation to the neck.194 This relative risk was further increased for patients older than 60 years and with follow-up longer than 10 years. Increased attention to the clinical signs of carotid stenosis together with proper management of the other risk factors (e.g., diabetes, hypertension, hypercholesterolemia, smoking, obesity) should contribute to a decreased incidence of stroke and neurologic sequelae in this patient population. All of the published data on late complications are from the era before IMRT was available. With the use of modern RT techniques (IMRT), a major reduction in late complications is anticipated, mainly through a reduction in the volume of normal tissue irradiated at a high dose and a reduction of the “uncontrolled” hot spot within or outside of the planning target volume. More fatigue, headache, and nausea and vomiting have also been reported with IMRT, likely owing to irradiation of the posterior fossa.195 However, the introduction of IMRT has raised the controversial concern of an increased risk of radiation-induced secondary neoplasms because a larger volume of normal tissue might be irradiated at a lower dose in comparison with standard twodimensional techniques. Also, depending on the radiation technic used, the delivery of a specified dose to the isocenter from modulated fields may require a longer beam time compared with the same dose delivered to a nonmodulated field. The IMRT treatment plan then results in an increase in the number of monitor units by a factor of 2 to 3, thus increasing the dose outside the boundary of the primary collimator caused by leakage and scattered radiation.196 As a consequence, the total body dose received may be substantially increased. It is estimated that an additional 0.5% of surviving patients will develop a secondary malignancy as a result of an increased volume of normal tissue receiving a small radiation dose. This number needs to be added to the 0.25% of surviving patients who subsequently develop a radiation-induced malignancy. In all, it is estimated that about 0.75% of surviving patients may develop a secondary malignancy as a result of the switch to IMRT, which is approximately twofold greater than the incidence observed after more conventional RT.197 The progressive introduction of volumetric modulated arc therapy (VMAT), which requires lower monitor units, provides superior organs-at-risk sparing, and is associated with less scattered dose, and is likely to reduce this slight excess risk of radiationinduced malignancy.198 Whatever the contribution of IMRT in the induction of secondary cancers may be, bear in mind that even if IMRT increases the probability of locoregional control and the potential for increased cause-specific survival, this group of patients experiences comorbidities and an increased risk for a second primary tumor associated with their lifestyle. This may decrease the relative importance of radiation-induced secondary malignancies.

MANAGEMENT OF RECURRENT NECK DISEASE Whether treated by RT, surgery, chemotherapy, or a combination of all three, the prognosis of patients with recurrence of disease in the neck remains abysmal. Recurrent neck disease is invariably associated with unfavorable prognostic factors. Extranodal extension is almost always reported and multiple lymph node levels are frequently involved.199 Neck disease recurrences are often not resectable because of involvement of the wall of the common carotid artery or the internal carotid artery, the paraspinal muscles, and the cranial nerves. Even when salvage surgery

is attempted, the inability to achieve a complete resection with clear margins is generally the rule. Few studies have specifically addressed the problem of recurrent neck disease following curative treatment in HNSCC. Godden et al.199 retrospectively reviewed the charts of 35 patients with recurrent neck disease after either primary surgery (80% of patients; 50% had postoperative RT and 18 had neck dissection) or primary RT. Recurrence in the neck was managed by neck dissection in 25 patients of whom 18 had postoperative RT. Ten patients (29%) were considered inoperable. Nine of the 18 patients with an initial neck dissection had a recurrence in previously dissected level II. This high rate of level II recurrence stresses the necessity of adequate training for surgeons performing neck dissection procedures. In this series, ultimate control of neck disease was obtained in only 5 of the 35 patients and 4-year OS did not exceed 20%. The likelihood of successful salvage treatment in patients with neck disease recurrence after primary RT is very low. Bernier et al.97 reviewed 116 patients with isolated nodal failure after RT alone for oropharyngeal, hypopharyngeal, and laryngeal carcinoma. Fourteen patients had salvage neck dissection and 18 were reirradiated. In only one patient (1%) was the salvage neck dissection successful. In 1999, the University of Florida reviewed the medical records of 51 patients who experienced recurrent disease in the neck only.200 Of the 18 patients (35%) who underwent salvage treatment (chemotherapy alone in 4 patients, chemotherapy and neck dissection in 1 patient, neck dissection alone in 11 patients, and neck dissection with postoperative RT in 2 patients), all had subsequent relapse of disease (locally, regionally, or distantly). Control of the neck at 5 years was only 9% for the patients who underwent salvage treatment, which was similar to the rate of neck control for the whole population. For the whole group of patients, absolute and cause-specific survival rates reached 10% at 5 years for both endpoints. However, at 3 years, patients who received salvage treatment had absolute and cause-specific survival rates of 44%. In comparison, none of the 33 remaining patients was alive at 3 years. More recently, in a series of 540 patients, investigators from two institutions in the Netherlands reviewed the effectiveness of salvage neck dissection for regional pathologic lymphadenopathy after chemoradiation.201 Patients with neck dissection for residual (persistent lymph node metastases diagnosed within 3 months after treatment) and recurrent regional disease (recurrent lymph node metastases diagnosed at least 3 months after treatment) were included. In 68 patients was the metastases considered as nonresectable. Salvage neck dissection was performed in 61 patients, 45 for regional residual disease and 16 for recurrent regional disease. In the group of patients who had salvage neck dissection, the 5-year regional control and OS rates were 79% and 36%, respectively. Patients with recurrent disease had a better outcome than patients with residual disease. The 5-year regional control was 77% for residual disease and 86% for recurrent disease, but the difference was not statistically significant. In multivariate analysis, recurrent disease and negative surgical margins were shown as significant independent predictors for a better OS. Of note, only 8 of 16 patients who had salvage neck dissection for recurrent disease had histologically positive tumor in the specimen. These results confirm that salvage neck dissection may benefit selected patients with limited recurrence in the neck. In 2010, the Institut Gustave Roussy reported a series of 93 patients who had recurrence after chemoradiation.202 Salvage surgery was performed in 40% of these patients; in this group 2-year OS was 43.4%. Univariate analysis demonstrated that initial stage IV disease and concurrent local and regional failure were significant prognostic factors for poor OS. In the group of patients without initial stage IV disease who had either an isolated regional or tumor recurrence, the 2-year OS reached 83%, whereas it was 0 in the group of patients with initial stage IV disease and concurrent local and regional failure. These results

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CHAPTER 46 confirm that salvage surgery should be proposed only to selected patients with isolated resectable treatment failure in the neck. Few institutions have evaluated salvage treatment with aggressive combined modality approaches that include low-dose reirradiation (preoperative or postoperative with or without concurrent chemoradiation) combined with an attempt at gross resection plus intraoperative radiotherapy with either electrons or high-dose-rate brachytherapy.203 Although the series involve small numbers of patients, early results suggest potential improvements in both locoregional control and survival rates compared with those of standard salvage approaches, and further evaluation is warranted. In summary, most of the patients with regional recurrence are unable to undergo salvage treatment; when salvage treatment with standard approaches (surgical resection, external beam radiation therapy) is attempted, control of neck disease remains poor. Salvage neck dissection alone should be restricted to patients with limited recurrence of disease in the neck.

CRITICAL REFERENCES 1. Rouvière H. Anatomie Humaine Descriptive Et Topographique. 6th ed. Paris: Masson et Cie; 1948:226–230. 4. Robbins KT, Medina JE, Wolfe GT, et al. Standardizing neck dissection terminology. Official report of the Academy’s Committee for Head and Neck Surgery and Oncology. Arch Otolaryngol Head Neck Surg. 1991;117:601–605. 7. Grégoire V, Ang K, Budach W, et al. Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines. Radiother Oncol. 2014;110(1):172–181. 26. Kyzas PA, Evangelou E, Denaxa-Kyza D, et al. 18 F-Fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis. J Natl Cancer Inst. 2008;100:712–720. 39. Candela FC, Kothari K, Shah JP. Patterns of cervical node metastases from squamous carcinoma of the oropharynx and hypopharynx. Head Neck. 1990;12:197–203. 40. Candela FC, Shah J, Jaques DP, et al. Patterns of cervical node metastases from squamous carcinoma of the larynx. Arch Otolaryngol Head Neck Surg. 1990;116:432–435. 41. Shah JP, Candela FC, Poddar AK. The patterns of cervical lymph node metastases from squamous carcinoma of the oral cavity. Cancer. 1990;66:109–113. 52. Clayman GL, Frank DK. Selective neck dissection of anatomically appropriate levels is as efficacious as modified radical neck dissection for elective treatment of the clinically negative neck in patients with squamous cell carcinoma of the upper respiratory and digestive tracts. Arch Otolaryngol Head Neck Surg. 1998;124:348–352. 72. Govers TM, Hannink G, Merkx MA, et al. Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a diagnostic meta-analysis. Oral Oncol. 2013;49:726–732. 77. Gregoire V, Coche E, Cosnard G, et al. Selection and delineation of lymph node target volumes in head and neck conformal radiotherapy:

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proposal for standardizing terminology and procedure based on the surgical experience. Radiother Oncol. 2000;56:135–150. 84. ICRU report 83: prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy (IMRT). J ICRU. 2010;10:1. 97. Bernier J, Bataini JP. Regional outcome in oropharyngeal and pharyngolaryngeal cancer treated with high dose per fraction radiotherapy: analysis of neck disease response in 1646 cases. Radiother Oncol. 1986;6:87–103. 98. Alpert TE, Morbidini-Gaffney S, Chung CT, et al. Radiotherapy for the clinically negative neck in supraglottic laryngeal cancer. Cancer J. 2004;10:335–338. 99. Johansen LV, Grau C, Overgaard J. Nodal control and surgical salvage after primary radiotherapy in 1782 patients with laryngeal and pharyngeal carcinoma. Acta Oncol. 2004;43:486–494. 115. Horiot JC, Le Fur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol. 1992;25:231–241. 116. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet. 2003;362:933–940. 119. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999;91:2081–2086. 132. Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;51:571–578. 135. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945–1952. 136. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350:1937–1944. 156. Beitler JJ, Zhang Q, Fu KK, et al. Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys. 2014;89(1):13–20. 157. Mehanna H, Wong WL, McConkey CC, et al; PET-NECK Trial Management Group. PET-CT surveillance versus neck dissection in advanced head and neck cancer. N Engl J Med. 2016;374(15):1444–1454. 182. Shah S, Har-El G, Rosenfeld RM. Short-term and long-term quality of life after neck dissection. Head Neck. 2001;23:954–961. 195. Nutting CM, Morden JP, Harrington KJ, et al; PARSPORT trial management group. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2011;12(2):127–136. 201. van der Putten L, van den Broek GB, de Bree R, et al. Effectiveness of salvage selective and modified radical neck dissection for regional pathologic lymphadenopathy after chemoradiation. Head Neck. 2009;31:593–603.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 46

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Disease Sites

45. Byers RM, Weber RS, Andrews T, et al. Frequency and therapeutic implications of “skip metastases” in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997;19:14–19. 46. Kowalski LP, Magrin J, Waksman G, et al. Supraomohyoid neck dissection in the treatment of head and neck tumors. Survival results in 212 cases. Arch Otolaryngol Head Neck Surg. 1993;119:958–963. 47. Foote RL, Olsen KD, Davis DL, et al. Base of tongue carcinoma. Patterns of failure and predictors of recurrence after surgery alone. Head Neck. 1993;15:300–307. 48. O’Sullivan B, Warde P, Grice B, et al. The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys. 2001;51:332–343. 49. Huang SH, Waldron J, Bratman SV, et al. Re-evaluation of ipsilateral radiation for T1-T2N0-N2b tonsil carcinoma at the Princess Margaret Hospital in the human papillomavirus era, 25 years later. Int J Radiat Oncol Biol Phys. 2017;98(1):159–169. 50. Jackson SM, Hay JH, Flores AD, et al. Cancer of the tonsil. The results of ipsilateral radiation treatment. Radiother Oncol. 1999;51:123–128. 51. Byers RM. Neck dissection: concepts, controversies, and technique. Semin Surg Oncol. 1991;7:9–13. 52. Clayman GL, Frank DK. Selective neck dissection of anatomically appropriate levels is as efficacious as modified radical neck dissection for elective treatment of the clinically negative neck in patients with squamous cell carcinoma of the upper respiratory and digestive tracts. Arch Otolaryngol Head Neck Surg. 1998;124:348–352. 53. Byers RM. Modified neck dissection. A study of 967 cases from 1970 to 1980. Am J Surg. 1985;150:414–421. 54. Grégoire V, Hamoir M, Levendag P, et al. Proposal for the delineation of the nodal CTV in the node-positive and the postoperative neck. Radiother Oncol. 2006;79:15–20. 55. Marks JE, Devineni VR, Harvey J, et al. The risk of contralateral lymphatic metastases for cancers of the larynx and pharynx. Am J Otolaryngol. 1992;13:34–39. 56. Robbins KT, Clayman G, Levine PA, et al. Neck dissection classification update. Revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology–Head and Neck Surgery. Arch Otolaryngol Head Neck Surg. 2002;128:751–758. 57. Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg. 2008;134:536–538. 58. Som PM, Curtin HD, Mancuso AA. An imaging-based classification for the cervical nodes designed as an adjunct to recent clinically based nodal classifications. Arch Otolaryngol Head Neck Surg. 1999;125:388–396. 59. Medina JE. A rational classification of neck dissections. Otolaryngol Head Neck Surg. 1989;100:169–176. 60. Suarez O. El problema de las metastasis linfaticas y alejadas del cancer de laringe e hipofaringe. Rev Otorinolaringol. 1963;23:83–89. 61. Bocca E, Pignataro O. A conservation technique in radical neck dissection. Ann Otol Rhinol Laryngol. 1967;76:975–987. 62. Bocca E, Pignataro O, Sasaki CT. Functional neck dissection. A description of operative technique. Arch Otolaryngol Head Neck Surg. 1980;106:524–527. 63. Robbins KT, Doweck I, Samant S, Vieira F. Effectiveness of superselective and selective neck dissection for advanced nodal metastases after chemoradiation. Arch Otolaryngol Head Neck Surg. 2005;131:965–969. 64. Morton DL, Wen DR, Wong JH, et al. Technical details of intra-operative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392–399. 65. Pan D, Narayan D, Ariyan S. Merkel cell carcinoma. Five case reports using sentinel lymph node biopsy and a review of 110 new cases. Plast Reconstr Surg. 2002;110:1259–1265. 66. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349:546–553. 67. Shoaib T, Soutar DS, MacDonald DG, et al. The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck. Cancer. 2001;91:2077–2083.

68. Pitman KT, Johnson JT, Brown ML, et al. Sentinel lymph node biopsy in head and neck squamous cell carcinoma. Laryngoscope. 2002;112:2101–2113. 69. Ross GL, Soutar DS, MacDonald DG, et al. Improved staging of cervical metastasis in clinically negative patients with head and neck squamous cell carcinoma. Ann Surg Oncol. 2004;11:213–218. 70. Stoekli SJ, Pfalz M, Steinert H, et al. Histopathological features of occult metastasis detected by sentinel lymph node biopsy in oral and oropharyngeal squamous cell carcinoma. Laryngoscope. 2002;112:111–115. 71. Civantos FJ, Zitsch RP, Schuller DE, et al. Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. J Clin Oncol. 2010;28:1395–1400. 72. Govers TM, Hannink G, Merkx MA, et al. Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a diagnostic meta-analysis. Oral Oncol. 2013;49:726–732. 73. Murer K, Huber GF, Haile SR, Stoeckli SJ. Comparison of morbidity between sentinel node biopsy and elective neck dissection for treatment of the n0 neck in patients with oral squamous cell carcinoma. Head Neck. 2011;33:1260–1264. 74. Hermanek P, Hutter RVP, Sobin LH, Wittekind C. Classification of isolated tumor cells and micrometastasis. Cancer. 1999;86:2668–2673. 75. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours. International Union Against Cancer (UICC). ed 6. New York: Wiley-Liss; 2002:10–13. 76. Atula T, Hunter KD, Cooper LA, et al. Micrometastases and isolated tumour cells in sentinel lymph nodes in oral and oropharyngeal squamous cell carcinoma. Eur J Surg Oncol. 2009;35:532–538. 77. Gregoire V, Coche E, Cosnard G, et al. Selection and delineation of lymph node target volumes in head and neck conformal radiotherapy. Proposal for standardizing terminology and procedure based on the surgical experience. Radiother Oncol. 2000;56:135–150. 78. Nowak PJ, Wijers OB, Lagerwaard FJ, et al. A three-dimensional CT-based target definition for elective irradiation of the neck. Int J Radiat Oncol Biol Phys. 1999;45:33–39. 79. Wijers OB, Levendag PC, Tan T, et al. A simplified CT-based definition of the lymph node levels in the node negative neck. Radiother Oncol. 1999;52:35–42. 80. Martinez-Monge R, Fernandes PS, Gupta N, et al. Cross-sectional nodal atlas. A tool for the definition of clinical target volumes in threedimensional radiation therapy planning. Radiology. 1999;211:815–828. 81. Grégoire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck. DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines. Radiother Oncol. 2003;69:227–236. 82. Levendag P, Grégoire V, Hamoir M, et al. Intraoperative validation of CT-based lymph nodal levels, sublevels IIA and IIB. Is it of clinical relevance in selective radiation therapy? Int J Radiat Oncol Biol Phys. 2005;62:690–699. 83. Apisarnthanarax S, Elliott D, El Naggar AK, et al. Determining optimal clinical target volume margins in head and neck cancer based on microscopic extracapsular extension of metastatic neck nodes. Int J Radiat Oncol Biol Phys. 2006;64:678–683. 84. ICRU report 83: prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy (IMRT). J ICRU. 2010;10:1. 85. Weiss MH, Harrison LB, Isaacs RS. Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg. 1994;120:699–702. 86. Brazilian Head and Neck Cancer Study Group. Results of a prospective trial on elective modified radical classical versus supraomohyoid neck dissection in the management of oral squamous carcinoma. Am J Surg. 1998;176:422–427. 87. Byers RM, Wolf PF, Ballantyne AJ. Rationale for elective modified neck dissection. Head Neck Surg. 1988;10:160–167. 88. Byers RM, Clayman GL, McGill D, et al. Selective neck dissections for squamous carcinoma of the upper aerodigestive tract. Patterns of regional failure. Head Neck. 1999;21:499–505.

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CHAPTER 46 89. Duvvuri U, Simental AA Jr, DAngelo G, et al. Elective neck dissection and survival in patients with squamous cell carcinoma of the oral cavity and oropharynx. Laryngoscope. 2004;114:2228–2234. 90. Jesse RH, Ballantyne AJ, Larson D. Radical or modified neck dissection. A therapeutic dilemma. Am J Surg. 1978;136:516–519. 91. Lingeman RE, Helmus C, Stephens R, et al. Neck dissection. Radical or conservative. Ann Otol Rhinol Laryngol. 1977;86:737–744. 92. Medina JE, Byers RM. Supraomohyoid neck dissection. Rationale, indications, and surgical technique. Head Neck. 1989;11:111–122. 93. Pellitteri PK, Robbins KT, Neuman T. Expanded application of selective neck dissection with regard to nodal status. Head Neck. 1997;19: 260–265. 94. Pitman KT, Johnson JT, Myers EN. Effectiveness of selective neck dissection for management of the clinically negative neck. Arch Otolaryngol Head Neck Surg. 1997;123:917–922. 95. Spiro RH, Morgan GJ, Strong EW, et al. Supraomohyoid neck dissection. Am J Surg. 1996;172:650–653. 96. Schmitz S, Machiels JP, Weynand B, et al. Results of selective neck dissection in the primary management of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2009;266:437–443. 97. Bernier J, Bataini JP. Regional outcome in oropharyngeal and pharyngolaryngeal cancer treated with high dose per fraction radiotherapy. Analysis of neck disease response in 1646 cases. Radiother Oncol. 1986;6:87–103. 98. Alpert TE, Morbidini-Gaffney S, Chung CT, et al. Radiotherapy for the clinically negative neck in supraglottic laryngeal cancer. Cancer J. 2004;10:335–338. 99. Johansen LV, Grau C, Overgaard J. Nodal control and surgical salvage after primary radiotherapy in 1782 patients with laryngeal and pharyngeal carcinoma. Acta Oncol. 2004;43:486–494. 100. Nakfoor BM, Spiro IJ, Wang CC, et al. Results of accelerated radiotherapy for supraglottic carcinoma. A Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary experience. Head Neck. 1998;20:379–384. 101. Dische S, Saunders M, Barrett A, et al. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol. 1997;44:123–136. 102. Eisbruch A, Marsh LH, Dawson LA, et al. Recurrences near base of skull after IMRT for head-and-neck cancer. Implications for target delineation in high neck and for parotid gland sparing. Int J Radiat Oncol Biol Phys. 2004;59:28–42. 103. Bussels B, Maes A, Hermans R, et al. Recurrences after conformal parotid-sparing radiotherapy for head and neck cancer. Radiother Oncol. 2004;72:119–127. 104. Chao KS, Ozyigit G, Tran BN, et al. Patterns of failure in patients receiving definitive and postoperative IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2003;55:312–321. 105. Andersen PE, Shah JP, Cambronero E, et al. The role of comprehensive neck dissection with preservation of the spinal accessory nerve in the clinically positive neck. Am J Surg. 1994;168:499–502. 106. Merino OR, Lindberg RD, Fletcher GH. An analysis of distant metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer. 1977;40:145–151. 107. Carew JF, Singh B, Shah JP. Cervical lymph nodes. In: Shah JP, Johnson NW, Batsakis JG, Dunitz M, eds. Oral Cancer. New York: Thieme; 2003:215–249. 108. Khafif RA, Gelbfish GA, Asase DK, et al. Modified radical neck dissection in cancer of the mouth, pharynx, and larynx. Head Neck. 1990;12:476–482. 109. Shah JP. Cervical lymph node metastases—diagnostic, therapeutic, and prognostic implications. Oncology (Williston Park). 1990;4:61–69. 110. Clark J, Li W, Smith G, et al. Outcome of treatment for advanced cervical metastatic squamous cell carcinoma. Head Neck. 2005;27:87–94. 111. Shaha AR. Extended neck dissection. J Surg Oncol. 1990;45:229–233. 112. Brennan JA, Jafek BW. Elective carotid artery resection for advanced squamous cell carcinoma of the neck. Laryngoscope. 1994;104:259–263. 113. Maves MD, Bruns MD, Keenan MJ. Carotid artery resection for head and neck cancer. Ann Otol Rhinol Laryngol. 1992;101:778–781.

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114. Bataini JP, Bernier J, Asselain B, et al. Primary radiotherapy of squamous cell carcinoma of the oropharynx and pharyngolarynx. Tentative multivariate modelling system to predict the radiocurability of neck nodes. Int J Radiat Oncol Biol Phys. 1988;14:635–642. 115. Horiot JC, Le Fur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma. Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol. 1992;25:231–241. 116. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck. DAHANCA 6 and 7 randomised controlled trial. Lancet. 2003;362:933–940. 117. Cummings B, OSullivan B, Keane T, et al. 5-Year results of 4 week/twice daily radiation schedule. The Toronto Trial. [Abstract.]. Radiother Oncol. 2000;56:S8. 118. Lacas B, Bourhis J, Overgaard J, et al; MARCH Collaborative Group. Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis. Lancet Oncol. 2017;18(9):1221–1237. 119. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999;91:2081–2086. 120. Lavertu P, Bonafede JP, Adelstein DJ, et al. Comparison of surgical complications after organ-preservation therapy in patients with stage III or IV squamous cell head and neck cancer. Arch Otolaryngol Head Neck Surg. 1998;124:401–406. 121. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–578. 122. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. 123. Klozar J, Koslabova E, Kratochvil V, et al. Nodal status is not a prognostic factor in patients with HPV-positive oral/oropharyngeal tumors. J Surg Oncol. 2013;107(6):625–633. 124. Nisi KW, Foote RL, Bonner JA, et al. Adjuvant radiotherapy for squamous cell carcinoma of the tongue base. Improved local-regional disease control compared with surgery alone. Int J Radiat Oncol Biol Phys. 1998;41:371–377. 125. Lundahl RE, Foote RL, Bonner JA, et al. Combined neck dissection and postoperative radiation therapy in the management of the high-risk neck. A matched-pair analysis. Int J Radiat Oncol Biol Phys. 1998;40:529–534. 126. Vikram B, Strong EW, Shah JP, et al. Failure in the neck following multimodality treatment for advanced head and neck cancer. Head Neck Surg. 1984;6:724–729. 127. Dixit S, Vyas RK, Toparani RB, et al. Surgery versus surgery and postoperative radiotherapy in squamous cell carcinoma of the buccal mucosa. A comparative study. Ann Surg Oncol. 1998;5:502–510. 128. Amdur RJ, Parsons JT, Mendenhall WM, et al. Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications. Int J Radiat Oncol Biol Phys. 1989;16:25–36. 129. Parsons JT, Mendenhall WM, Stringer SP, et al. An analysis of factors influencing the outcome of postoperative irradiation for squamous cell carcinoma of the oral cavity. Int J Radiat Oncol Biol Phys. 1997;39:137–148. 130. Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer. First report of a prospective randomized trial. Int J Radiat Oncol Biol Phys. 1993;26:3–11. 131. Rosenthal DI, Mohamed ASR, Garden AS, et al. Final report of a prospective randomized trial to evaluate the dose-response relationship for postoperative radiation therapy and pathologic risk groups in patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 2017;98(5):1002–1011. 132. Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;51:571–578.

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791.e4

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Disease Sites

133. Haffty BG, Son YH, Sasaki CT, et al. Mitomycin C as an adjunct to postoperative radiation therapy in squamous cell carcinoma of the head and neck. Results from two randomized clinical trials. Int J Radiat Oncol Biol Phys. 1993;27:241–250. 134. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma. Final report of a randomized trial. Int J Radiat Oncol Biol Phys. 1996;36:999–1004. 135. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945–1952. 136. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350:1937–1944. 137. Bernier J, Cooper J, Pajak T, et al. Defining risk levels in locally advanced head and neck cancers. A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck. 2005;27:843–850. 138. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091–2098. 139. Lefebvre JL, Lartigau E. Preservation of form and function during management of cancer of the larynx and hypopharynx. World J Surg. 2003;27:811–816. 140. Mendenhall WM, Villaret DB, Amdur RJ, et al. Planned neck dissection after definitive radiotherapy for squamous cell carcinoma of the head and neck. Head Neck. 2002;24:1012–1018. 141. Narayan K, Crane CH, Kleid S, et al. Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy. For some or for all? Head Neck. 1999;21:606–613. 142. Stenson KM, Haraf DJ, Pelzer H, et al. The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy. The feasibility of selective neck dissection. Arch Otolaryngol Head Neck Surg. 2000;126:950–956. 143. Clayman GL, Johnson CJ 2nd, Morrison W, et al. The role of neck dissection after chemoradiotherapy for oropharyngeal cancer with advanced nodal disease. Arch Otolaryngol Head Neck Surg. 2001;127:135–139. 144. McHam SA, Adelstein DJ, Rybicki LA, et al. Who merits a neck dissection after definitive chemoradiotherapy for N2-N3 squamous cell head and neck cancer? Head Neck. 2003;25:791–798. 145. Brizel DM, Prosnitz RG, Hunter S, et al. Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004;58:1418–1423. 146. Argiris A, Stenson KM, Brockstein BE, et al. Neck dissection in the combined-modality therapy of patients with locoregionally advanced head and neck cancer. Head Neck. 2004;26:447–455. 147. Goguen LA, Posner MR, Tishler RB, et al. Examining the need for neck dissection in the era of chemoradiation therapy for advanced head and neck cancer. Arch Otolaryngol Head Neck Surg. 2006;132:526–531. 148. Forest VI, Nguyen-Tan PF, Tabet JC, et al. Role of neck dissection following concurrent chemoradiation for advanced head and neck carcinoma. Head Neck. 2006;28:1099–1105. 149. Vedrine PO, Thariat J, Hitier M, et al. Need for neck dissection after chemoradiotherapy? A study of the French GETTEC Group. Laryngoscope. 2008;118:1775–1780. 150. Lango MN, Andrews GA, Ahmad S, et al. Postradiotherapy neck dissection for head and neck squamous cell carcinoma: pattern of pathologic residual carcinoma and prognosis. Head Neck. 2009;31:328–837. 151. Corry J, Peters L, Fisher R, et al. N2-N3 neck nodal control without planned neck dissection for clinical/radiologic complete respondersresults of Trans Tasman Radiation Oncology Group Study 98.02. Head Neck. 2008;30:737–742. 152. Peters LJ, Weber RS, Morrison WH, et al. Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy. Head Neck. 1996;18:552–559.

153. Adelstein DJ, Saxton JP, Lavertu P, et al. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck. 1997;19:567–575. 154. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med. 1998;338:1798–1804. 155. Parsons JT, Mendenhall WM, Cassisi NJ, et al. Neck dissection after twice-a-day radiotherapy: morbidity and recurrence rates. Head Neck. 1989;11:400–404. 156. Beitler JJ, Zhang Q, Fu KK, et al. Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys. 2014;89(1):13–20. 157. Hamoir M, Ferlito A, Schmitz S, et al. The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease. Oral Oncol. 2012;48:203–210. 158. Lambrecht M, Dirix P, Van den Bogaert W, Nuyts S. Incidence of isolated regional recurrence after definitive (chemo-) radiotherapy for head and neck squamous cell carcinoma. Radiother Oncol. 2009;93:498–502. 159. Liauw SL, Mancuso AA, Amdur RJ, et al. Postradiotherapy neck dissection for lymph node-positive head and neck cancer: the use of computed tomography to manage the neck. J Clin Oncol. 2006;24:1421–1427. 160. Ojiri H, Mendenhall WM, Stringer SP, et al. Post-RT CT results as a predictive model for the necessity of planned post-RT neck dissection in patients with cervical metastatic disease from squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2002;52:420–428. 161. Yeung AR, Liauw SL, Amdur RJ, et al. Lymph node-positive head and neck cancer treated with definitive radiotherapy: can treatment response determine the extent of neck dissection? Cancer. 2008;112:1076–1082. 162. Clavel S, Charron MP, Bélair M, et al. The role of computed tomography in the management of the neck after chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2012;82:567–573. 163. Igidbashian L, Fortin B, Guertin L, et al. Outcome with neck dissection after chemoradiation for N3 head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2010;77:414–420. 164. de Bondt RB, Nelemans PJ, Hofman PA, et al. Detection of lymph node metastases in head and neck cancer: a meta-analysis comparing US, USgFNAC, CT and MR imaging. Eur J Radiol. 2007;64:266–272. 165. Vandecaveye V, De Keyzer F, Vander Poorten V, et al. Head and neck squamous cell carcinoma: value of diffusion-weighted MR imaging for nodal staging. Radiology. 2009;251:134–146. 166. Vandecaveye V, Dirix P, De Keyzer F, et al. Diffusion-weighted magnetic resonance imaging early after chemoradiotherapy to monitor treatment response in head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2012;82:1098–1107. 167. Lilja-Fischer JK, Jensen K, Eskildsen HW, et al. Response evaluation of the neck in oropharyngeal cancer: value of magnetic resonance imaging and influence of p16 in selecting patients for post-radiotherapy neck dissection. Acta Oncol. 2015;54(9):1599–1606. 168. Gupta T, Master Z, Kannan S, et al. Diagnostic performance of post-treatment FDG PET or FDG PET/CT imaging in head and neck cancer: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2011;38(11):2083–2095. 169. Mehanna H, Wong WL, McConkey CC, et al; PET-NECK Trial Management Group. PET-CT surveillance versus neck dissection in advanced head and neck cancer. N Engl J Med. 2016;374(15):1444–1454. 170. Smith AF, Hall PS, Hulme CT, et al. Cost-effectiveness analysis of PET-CT-guided management for locally advanced head and neck cancer. Eur J Cancer. 2017;85:6–14. 171. Marcus C, Ciarallo A, Tahari AK, et al. Head and neck PET/CT: therapy response interpretation criteria (Hopkins Criteria)-inter-reader reliability, accuracy, and survival outcomes. J Nucl Med. 2014;55(9):1411–1416. 172. Robbins KT, Doweck I, Samant S, Viera F. Effectiveness of superselective and selective neck dissection for advanced nodal metastases after chemoradiation. Arch Otolaryngol Head Neck Surg. 2005;131:965–969.

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CHAPTER 46 173. Stenson KM, Huo D, Blair E, et al. Planned post-chemoradiation neck dissection. Significance of radiation dose. Laryngoscope. 2006;116(1):33–36. 174. Doweck I, Robbins KT, Mendenhall WM, et al. Neck-level-specific nodal metastases in oropharyngeal cancer. Is there any role for selective neck dissection after definitive radiotherapy? Head Neck. 2003;25:960–967. 175. Mukhija V, Gupta S, Jacobson AS, et al. Selective neck dissection following adjuvant therapy for advanced head and neck cancer. Head Neck. 2009;31:183–188. 176. Dhiwakar M, Robbins KT, Vieira F, et al. Selective neck dissection as an early salvage intervention for clinically persistent nodal disease following chemoradiation. Head Neck. 2012;34:188–193. 177. Robbins KT, Dhiwakar M, Vieira F, et al. Efficacy of super-selective neck dissection following chemoradiation for advanced head and neck cancer. Oral Oncol. 2012;48:1185–1189. 178. Stenson KM, Haraf DJ, Pelzer H, et al. The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy. The feasibility of selective neck dissection. Arch Otolaryngol Head Neck Surg. 2000;126(8):950–956. Review. 179. Proctor E, Robbins KT, Viera F, et al. Postoperative complications after chemoradiation for advanced head and neck cancer. Head Neck. 2004;26:272–277. 180. Hillel AT, Fakhry C, Pai SI, et al. Selective versus comprehensive neck dissection after chemoradiation for advanced oropharyngeal squamous cell carcinoma. Otolaryngol Head Neck Surg. 2009;141:737–742. 181. Medina JE, Houck JR, O’Malley BB. Management of cervical lymph nodes in squamous cell carcinoma. In: Harrison LB, Sessions RB, Ki Hong W, eds. Head and Neck Cancer: A Multi-Disciplinary Approach. Philadelphia: Lippincott-Raven; 1998:353–378. 182. Shah S, Har-El G, Rosenfeld RM. Short-term and long-term quality of life after neck dissection. Head Neck. 2001;23:954–961. 183. Leipzig B, Suen JY, English JL, et al. Functional evaluation of the spinal accessory nerve after neck dissection. Am J Surg. 1983;146:526–530. 184. Laverick S, Lowe D, Brown JS, et al. The impact of neck dissection on health-related quality of life. Arch Otolaryngol Head Neck Surg. 2004;130:149–154. 185. van Wilgen CP, Dijkstra PU, van der Laan BF, et al. Morbidity of the neck after head and neck cancer therapy. Head Neck. 2004;26:785–791. 186. Erisen L, Basel B, Irdesel J, et al. Shoulder function after accessory nerve-sparing neck dissections. Head Neck. 2004;26:967–971. 187. Blessing R, Mann W, Beck C. How important is preservation of the accessory nerve in neck dissection? Laryngol Rhinol Otol (Stuttg). 1986;65:403–405. 188. Lee DJ, Cosmatos D, Marcial VA, et al. Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. Int J Radiat Oncol Biol Phys. 1995;32:567–576.

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189. Trotti A. Toxicity in head and neck cancer. A review of trends and issues. Int J Radiat Oncol Biol Phys. 2000;47:1–12. 190. Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers. Results of the EORTC 22851 randomized trial. Radiother Oncol. 1997;44:111–121. 191. Kumpulainen EJ, Hirvikoski PP, Virtaniemi JA, et al. Hypothyroidism after radiotherapy for laryngeal cancer. Radiother Oncol. 2000;57:97–101. 192. Sinard RJ, Tobin EJ, Mazzaferri EL, et al. Hypothyroidism after treatment for nonthyroid head and neck cancer. Arch Otolaryngol Head Neck Surg. 2000;126:652–657. 193. Abayomi OJ. Neck irradiation, carotid injury and its consequences. Oral Oncol. 2004;40:872–878. 194. Dorresteijn LD, Kappelle AC, Boogerd W, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol. 2002;20:282–288. 195. Nutting CM, Morden JP, Harrington KJ, et al; PARSPORT trial management group. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2011;12(2):127–136. 196. Williams BC, Hounsella R. X-ray linkage considerations for IMRT. Br J Radiol. 2001;74:98–102. 197. Hall EJ, Wuu CS. Radiation-induced second cancers. The impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys. 2003;56:83–88. 198. Sakthivel V, Mani GK, Mani S, Boopathy R. Radiation-induced second cancer risk from external beam photon radiotherapy for head and neck cancer: impact on in-field and out-of-field organs. Asian Pac J Cancer Prev. 2017;18(7):1897–1903. 199. Godden DR, Ribeiro NF, Hassanein K, et al. Recurrent neck disease in oral cancer. J Oral Maxillofac Surg. 2002;60:748–753. 200. Mabanta SR, Mendenhall WM, Stringer SP, et al. Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes. Head Neck. 1999;21:591–594. 201. van der Putten L, van den Broek GB, de Bree R, et al. Effectiveness of salvage selective and modified radical neck dissection for regional pathologic lymphadenopathy after chemoradiation. Head Neck. 2009;31:593–603. 202. Tan HK, Giger R, Auperin A, et al. Salvage surgery after concomitant chemoradiation in head and neck squamous cell carcinomas stratification for postsalvage survival. Head Neck. 2010;32:139–147. 203. Foote RL, Garrett P, Rate W, et al. IORT for head and neck cancer. In: Gunderson LL, Willett CG, Harrison LB, Calvo FA, eds. Intra-Operative Irradiation: Techniques and Results. Totowa, NJ: Humana Press; 1999:471–497.

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47 Cutaneous Carcinoma Michael J. Veness and Julie Howle

KEY POINTS Incidence Cutaneous basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are the most frequent cancers worldwide. Caucasian populations residing in locations with high level exposure to ultraviolet (UV) radiation, such as Australia and New Zealand and the Southern United States, have a particularly high lifetime risk for developing skin cancer. Biologic Characteristics The natural history of skin cancers varies widely with the histologic type, ranging from tumors with an indolent course and a high cure rate of 90% to 95% (e.g., BCC, low-risk SCC) to aggressive tumors with high (30% to 50%) mortality rates (e.g., Merkel cell carcinoma [MCC]). Staging Evaluation After biopsy confirmation, patients should be staged with history and physical examination and, when indicated, blood chemistry, chest radiographs, contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)/CT scans. Sentinel lymph node biopsy (SLNB) is indicated in select patients with MCC and investigational in those patients at high risk of SCC. Primary Treatment Surgery is the primary treatment for most skin cancers. Nonsurgical treatment, such as radiotherapy (RT), may be preferable for treating select BCCs and SCCs, particularly on and around the midface (e.g., nose, lower eyelids), lips, and ears because it may lead to better functional and cosmetic results than surgery. Topical and locally destructive treatments may also be effective in cases of superficial (1 mm to 2 mm) skin cancer.

Adjuvant Treatment In patients with BCCs and SCCs, the indications for postoperative (or adjuvant) RT include the presence of close or positive surgical margins, perineural invasion (PNI), invasion of bone or cartilage, and extensive skeletal muscle infiltration. Most patients with MCC should be considered for wide-field adjuvant RT. Patients with a high incidence of occult nodal spread (and not undergoing an SLNB) may benefit from elective nodal treatment, often wide-field RT that may also encompass the primary site (e.g., select high-risk SCC, most MCC). No effective systemic adjuvant therapy is currently available for nonmelanoma skin cancers (NMSCs). The addition of concurrent chemotherapy with RT in select high-risk cases may be considered, but is not supported by high-level evidence. The emergence of targeted immunomodualtors (PD 1 inhibitors), especially in metastatic MCC, has been associated with improved outcome in responding patients. Locally Advanced Disease and Palliation Surgery with adjuvant RT is the standard treatment for locally advanced and operable tumors. In certain patients, definitive RT (often hypofractionated) can still offer an excellent possibility of achieving local control (80% to 95%) in patients with locally advanced carcinomas who are either medically unable to undergo surgery or whose tumor is technically nonresectable. In unwell patients unsuitable for an extended course of definitive RT, a short course (one to four fractions) of RT can reduce symptoms for most patients with advanced inoperable cancer or with metastatic masses (e.g., pain, discharge, bleeding).

Cutaneous BCC and SCC, the most common malignancies in the world, occur at epidemic rates in high UV-exposed countries such as Australia, New Zealand, and the Southern United States.1 Collectively, these two carcinomas account for most (95%) patients with NMSC and are far more common than malignant melanomas, which account for only 5% of all skin malignancies. BCC is the most common type of NMSC, with an incidence of more than twice that of SCC. Other NMSCs that are infrequently encountered include MCC, also known as primary cutaneous neuroendocrine carcinoma, a rare small-cell carcinoma originally described by Toker in 1972,2 adnexal carcinomas such as sebaceous gland carcinomas accounting for less than 1% of all skin cancers,3 and eccrine carcinomas accounting for less than 0.01% of malignancies of the skin. NMSCs may be disfiguring and associated with local morbidity, and excluding MCC, are rarely lethal.

of UV light.4 Other less-common etiologic factors include exposure to chemical carcinogens (e.g., arsenic, tar, anthracene, and crude paraffin oil), chronic irritation or inflammation, and ionizing radiation. The incidence and aggressiveness of SCC and MCC (both immunogenic carcinomas) are markedly increased in individuals with compromised immune function, including patients with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia,5 and organ transplant recipients with iatrogenic immunosuppression.6 In contrast, the incidence of BCC is not markedly increased, and the outcome is similar as for patients who are immunocompetent. Some genetic syndromes are also associated with a much higher risk of developing skin carcinoma. Individuals with xeroderma pigmentosum are susceptible (up to 10,000 fold increase) to developing BCC and SCC at a young age because of defective repair of UV lightinduced DNA damage.7 These patients usually die in their early 20s from disseminated SCC or multiple myeloma. The basal cell nevus syndrome (or Gorlin’s syndrome) is a rare genetic form of BCC inherited through an autosomal-dominant gene usually associated with numerous (sometimes hundreds) BCCs developing in early adulthood both in

ETIOLOGY AND EPIDEMIOLOGY Sun exposure is the main etiologic factor for NMSC, particularly in Caucasians, whose skin is susceptible to the chronic carcinogenic effect

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CHAPTER 47

Cutaneous Carcinoma

793

sun-exposed and nonexposed areas. Of note, 85% carry the PTCH1 gene mutation.8 Individuals with epidermodysplasia verruciformis tend to develop nodules of SCC within large verrucous plaques in the third and fourth decades of life.

PREVENTION Unprotected sun exposure, especially during the summer, is the main determinant for the subsequent development of skin cancer. Children and adolescents should be especially educated in regard to sun protection. The damage of excessive UV exposure is irreversible; despite this, adults can still reduce their risk by avoiding further excessive UV exposure. Preventive measures to reduce skin cancer include avoidance of sunlight exposure—particularly limiting time spent outdoors between 10 AM and 3 PM—and wearing protective physical barriers, such as hats and clothing. If sun exposure cannot be limited because of occupational, cultural, or other factors, the use of sunscreens that are either opaque or that block UVA and UVB radiation is recommended. The use of tanning booths is also a factor in the risk of developing skin cancer, and guidelines regarding their appropriate use should be followed. Sparse high-level evidence does indicate that the regular application of topical sunscreen protection in the general population reduces the development of new skin cancers, compared with discretionary application; however, this should not preclude a recommendation of taking sensible precautions and using sunscreens when appropriate.9

CLINICAL MANIFESTATIONS, PATHOBIOLOGY, AND PATHWAYS OF SPREAD Basal Cell Carcinoma Clinical Presentation and Pathology Basal cell carcinoma constitutes approximately 80% of all NMSC and is the most common malignancy worldwide. Most BCCs arise on the sun-exposed head and neck (80% to 85%); lesions occur less frequently on the trunk or extremities. Lesions may manifest as an asymptomatic nodule, a pruritic plaque, or a bleeding ulcer that characteristically waxes and wanes.10,11 Many (up to 40% to 50%) patients treated for BCC develop at least one or more further BCC within 5 years.12 Careful evaluation of sun-exposed skin should therefore be part of any followup examination. There are numerous variants of BCC, each of which has distinctive clinical and histologic features and natural history. The characteristics of commonly occurring types are briefly summarized. Nodular BCC, colloquially referred to as rodent ulcer, is the most frequently observed variant; it accounts for approximately 50% of all lesions (Fig. 47.1). It arises as a distinct papule that may develop central umbilication, progressing to central ulceration. The margins of this lesion appear pearly (pale and translucent) and contain enlarged capillaries (telangiectasia). Histologic features include the presence of large islands of monomorphous basaloid cells, varying in size and shape, embedded in a fibroblastic stroma in the dermis. The basaloid cells have large, oval hyperchromatic nuclei, scant cytoplasm, and no intercellular bridges. The peripheral cell layer of the aggregate frequently shows palisading, whereas central cells are less organized. Nodular BCC may show a varying degree of pigmentation (blue, brown, or black), depending on the number of melanocytes present in the lesion, and may be difficult to differentiate clinically from MM.13 Superficial BCC manifests as red, scaly macules with indistinct margins, usually located on the trunk. It enlarges into a crusted, erythematous patch without induration that may be difficult to

Fig. 47.1 A 65-year-old woman with a 1-cm nodular tip of nose basal cell carcinoma. These lesions are slow growing and often located on the midface. The cosmetic outcome of excision and reconstruction is often suboptimal with radiotherapy (RT), an excellent treatment option. Note the black line delineating the RT field, typically 1 cm beyond gross tumor (broken line).

differentiate clinically from solar keratosis, psoriasis, SCC in situ, or extramammary Paget’s disease. Histologic examination shows multiple foci of buds of neoplastic cells with peripheral palisading originating from the undersurface of the epidermis.10 Morpheic (sclerosing) BCCs appear as single flat, indurated, ill-defined macules. The lesions generally have a smooth, shiny surface that becomes depressed as it grows into a plaque. It is characterized histologically by the presence of small groups and narrow strands of basaloid cells embedded in a dense, fibrous connective tissue; there is little peripheral palisading. Morpheic BCC have a propensity to recur if not appropriately treated, and PNI is often reported to be present.14 Infiltrative BCC has an opaque yellowish appearance and blends subtly with the surrounding skin.14 Histologically, the lesion is characterized by poorly circumscribed spiky cell aggregates in the superficial portion and the main bulk, consisting of strands of neoplastic cells infiltrating the reticular dermis and subcutis.

Biology and Pattern of Spread The biologic behavior of BCC varies with the histologic type. A superficial BCC may remain stable for a long time or enlarge gradually over many years to become a nodulo-ulcerative variant. Nodular BCC grow slowly over many years by peripheral and deep invasion, particularly along embryonal fusion planes. Morpheic and infiltrative BCCs are more aggressive variants that may infiltrate deeper structures. The finding of PNI in BCC is uncommon (2% to 3% of patients), and generally occurs in the setting of recurrent disease or in morpheic histology. Compared with PNI in SCC, patients have a relatively favorable prognosis, although the treatment is similar.15 Lesions located around the orbit with PNI present may gain access to the orbit via the first or second division of the trigeminal nerve. High-risk BCC occur in the midface, or so-called H zone (Fig. 47.2), which includes the periauricular region, glabella, medial canthus, nose, nasolabial region, and columella, and contains embryonal fusion planes. BCC may also be large (>10 mm) and/or recurrent and many will benefit from adjuvant RT.16 The depth of invasion of tumors in this region is

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794

SECTION III

Disease Sites

frequently underestimated, often leading to inadequate excision, especially deep, and a higher rate of local recurrence without further treatment. Histologic examination often reveals extensive infiltration of deeper structures by small nests of undifferentiated basal cells. This type of lesion may invade the orbit, nose, and maxilla, resulting in significant deformity (Fig. 47.3). It should be readily recognized and treated promptly, often necessitating extensive surgery with or without adjuvant RT. The BCC rarely spreads to the regional lymph nodes or distant organs with an overall incidence of metastasis less than 0.01%.17 Most metastases occur in the regional lymph nodes with distant spread usually preceded by regional metastasis. Regional disease typically develops in association with large, ulcerated lesions in the head and neck that have recurred despite treatment.

Squamous Cell Carcinoma

Clinical Presentation and Pathology Squamous cell carcinoma arises from epidermal keratinocytes and, most commonly, develops from skin exhibiting solar (or UV) damage. Actinic

Medial canthus

(or solar) keratosis (AK) is generally a precursor or premalignant lesion, and at least 50% to 60% of all invasive SCCs arise from AK. Although quality data are lacking, only a very small minority (1 cm is associated with 50% mortality rate), vascular and lymphatic invasion, poor sebaceous differentiation, highly infiltrative growth pattern, and intraepithelial carcinomatous changes in the overlying epithelia.33 Biology and pattern of spread. Sebaceous carcinoma behaves more aggressively than SCC, with a propensity for nodal and hematogenous spread.34 Patients developing nodal metastases require regional surgery and adjuvant RT. Many will develop distant relapse, which is incurable, with most series documenting a 20% to 30% cause-specific mortality.33

Eccrine Carcinoma Clinical presentation and pathology. Sweat gland (eccrine, apocrine, apoeccrine) carcinomas are exceedingly rare, arise most frequently in

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CHAPTER 47 the skin of the head and neck or the extremities, and manifest as painless papules or nodules that grow slowly. This type of neoplasm is usually diagnosed in individuals 50 to 70 years of age. Histologically, eccrine or sweat gland carcinomas may resemble carcinomas of the breast, bronchus, and kidney and are difficult to differentiate from cutaneous metastases. Many histologic variants are reported, which include ductal eccrine carcinoma, mucinous eccrine carcinoma, porocarcinoma, syringoid eccrine carcinoma, clear cell carcinoma, and microcystic adnexal carcinoma (MAC).35 Biology and pattern of spread. Eccrine carcinoma has a more aggressive behavior than BCC and SCC. In a series of 14 patients who underwent surgical excision with negative excision margins, 11 developed at least one local recurrence, and 5 relapsed at regional nodes or distant sites. One patient died of uncontrolled local relapse, and four died of distant metastasis 2 months to 10 years after diagnosis.35 Apocrine carcinoma arises most commonly from apocrine glands of the axilla, but it can originate from apocrine glands of the vulva and eyelids and from ceruminal glands of the external auditory canal. It manifests clinically as a red-purple single or multinodular, firm or cystic dermal, mass in elderly individuals. The natural history of apocrine carcinoma is not well documented, but nodal and distant metastases have been reported.36,37

Microcystic Adnexal Carcinoma Clinical presentation and pathology. Microcystic adnexas carcinoma is a rare locally aggressive carcinoma that belongs to the spectrum of adnexal carcinomas and most often arises on the midface.38 It usually grows slowly over years and often is deeply invasive when diagnosed. It arises equally in males and females and tends to occur in adults 55 to 60 years old and occasionally in children. Histologically, the tumor is composed of keratin horn cysts, nests, or cords of basaloid cells that are usually more prominent in the superficial dermis. Tumor strands and cystically dilated tubules are arranged in solid islands and embedded in deeper desmoplastic stroma. The cells usually show no atypia or mitoses, and the differential diagnosis may include trichoadenoma, syringoma, desmoplastic trichoepithelioma, or morpheaform BCC.39 Biology and pattern of spread. Patients with MAC often present with advanced and deeply invasive lesions after years of slow growth and misdiagnosis. Perineural invasion is reported to be present in many cases, particularly in the recurrent setting. Lymph node metastases rarely occur. MAC tends to be a locally recurrent tumor with morbidity related to local invasion and destruction.

PATIENT EVALUATION AND STAGING Most patients with NMSC present with an asymptomatic skin lesion, and often have a history of other NMSCs. Symptoms suggestive of PNI, such as pain, tingling, and hypesthesia, should be specifically sought from the patient. Up to 60% of patients with PNI may be clinically asymptomatic (microscopic PNI), and a crawling sensation on the skin termed formication is suggestive for sensory nerve involvement.40 The most common primary sites associated with PNI are the frontozygomatic (supraorbital nerve) and infraorbital (infraorbital nerve) regions. Patients occasionally present with cranial nerve palsy as the first sign of PNI. Facial nerve involvement is often preceded by muscle fasciculations followed by progressive hemifacial paralysis. Patients may be misdiagnosed with Bell’s palsy and any patient with a past history of skin cancer should also have PNI considered as a possibility.41 Clinical evaluation of patients with NMSC should consist of inspection and palpation of the involved area and the draining lymph nodes.

Cutaneous Carcinoma

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Fig. 47.8 Axial computed tomography scan showing metastatic cancer in the left parotid gland. There is concentric nodal enlargement, contrast enhancement of the rim, and central necrosis, all features consistent with a metastatic node from squamous cell carcinoma.

Imaging studies (chest radiography, CT, or MRI) generally are not required in most patients with NMSC, but should be obtained as indicated (e.g., clinically suspicious lymph nodes). Lymph node metastasis and bone involvement are best assessed with contrast-enhanced CT scan acquired with soft tissue and bone windows (Fig. 47.8). Targeted 3T MRI, with and without contrast enhancement and fat suppression, should be obtained for all patients in whom PNI is suspected, with the findings of an enlarged or abnormally enhancing nerve raising the possibility of PNI. Relevant clinical information and the suspicion of PNI should be communicated to the radiologist.42 Patients may require biopsy of a suspected (usually enlarged) nerve to confirm the diagnosis.43 PET-CT is rarely indicated to stage patients with NMSC.

Staging of Basal and Squamous Cell Carcinoma Staging systems have been criticized for lacking clinical and prognostic relevance, especially for patients with SCC. The current American Joint Committee on Cancer (AJCC) TNM (primary tumor, regional nodes, metastases) staging system has recently been updated and improved, allowing clinicians to better identify the patients with a high-risk SCC.44 The AJCC 8th edition incorporates several changes to the T classification for tumors of the head and neck. Tumors are classified as T1 if less than 2 cm, T2 if 2 cm or greater and less than 4 cm, T3 if 4 cm or greater and/or PNI (> 0.1 mm) and/or deep invasion (beyond fat or Breslow > 6 mm) and/or minor bone erosion. T4 is further subdivided into T4a if gross cortical/bone marrow invasion is present or in T4b if skull base invasion/skull foramen invasion. An alternative staging system based on an analysis of 1818 clinically node-negative SCC (n = 974 patients) is the Brigham and Women’s Hospital system (BWH). In this study one point was given for the presence of each independent variable: size ≥ 2 cm, poor differentiation, PNI (≥ 0.1 mm calibre), or invasion beyond adipose tissue, to divide tumors into 4 T stages: T1 (0 high-risk factors), T2a (1 high-risk factor), T2b (2-3 high-risk factors) and T3 (all 4 risk factors). The majority of tumors (95%) were categorized as T1/T2a, with only a small minority (1% to 3%) developing nodal metastases. Patients with a T2b/T3 SCC (6% in total) experienced the majority of nodal metastases and cancer deaths. The BWH system was compared with the AJCC/UICC systems and demonstrated greater homogeneity, distinctiveness, and sequentially higher risk of recurrence or death with each alternative T stage.45

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Despite recent improvements in the staging system for a primary SCC, the AJCC 8th edition has been criticized for its lack of prognostication between nodal stages despite the incorporation of the presence of extracapsular spread. It has been suggested that staging systems for cutaneous SCC would benefit by the development of a specific system not based along the lines of the mucosal SCC head and neck staging system.46,47 Staging of Merkel cell carcinoma. Numerous staging systems have been utilized in the past; however the AJCC 8th edition staging system is evidence-based and prognostic. For the first time, it separates into clinically and pathologically staged groups. Any patient with a clinically or pathologically confirmed nodal metastases will be considered as stage III, with subcategories in the pathologic group. Four clinical stages of MCC are recognized in the new AJCC staging system, based on features at time of presentation: stage 0 (in situ Merkel cell carcinoma); stage I (localized disease, primary lesion ≤ 2 cm); stage II (localized disease, primary lesion > 2 cm); stage III (nodal spread); stage IV (metastatic disease beyond the local nodes.48 Patients presenting with a clinically or radiologically detected, pathologically confirmed nodal MCC metastasis (pN1b) without a primary lesion (i.e., unknown primary), are now staged in the better prognostic group 3a rather than 3b, as in the previous AJCC staging system.

Primary Tumor

Fig. 47.9 A 71-year-old man with a squamous cell carcinoma occupying the medial third of his left lower eyelid. Because of the potential functioning implications of wide excision he was treated successfully with definitive radiotherapy (RT). Note the RT field delineated in solid black line and the internal eye shield to protect his globe.

The general strategy for managing most early NMSC is similar for either BCC or SCC. Various surgical and medical approaches are available, including curettage and electrodesiccation, Mohs’s micrographic surgery, cryotherapy, surgical resection, and definitive RT. Numerous topical (e.g., 5FU, imiquimod) and intralesional (e.g., methotrexate, interferon) options as well as other modalities (e.g., photodynamic therapy) are also available, often with ill-defined criteria for using them. Additionally, the evidence to support topical or intralesional treatment is predominantly low level with long-term follow-up (up to 5 years) lacking and therefore clinicians need to consider various issues prior to any recommendation. Such treatments are essentially limited to select superficial NMSC and premalignant conditions (e.g., AK).49 With correct case selection the various surgical and medical approaches are similarly effective in curing most NMSC. The choice of treatment for individual patients is determined by factors such as the site and size of a lesion, anticipated functional and cosmetic results, treatment time and cost, patient age, occupation, and general condition. Carcinomas in the H zone or embryonic fusion planes may have extensive local spread, so treatment that ensures wide marginal (especially deep) coverage should be selected. Overall, surgery is preferred for most patients. Simple procedures can yield high local control rates for patients with small lesions. Younger patients who have years of future exposure to sunlight are often better treated by surgery than by RT, although in certain cases RT may still be considered a better option. In numerous settings, especially in the setting of a close or positive margin or the presence of PNI, postoperative RT may be beneficial to reduce the risk of local recurrence. Other factors such as high-grade histology, invasion of bone and cartilage, and extensive skeletal muscle infiltration may also contribute to a decision to recommend adjuvant RT. Local RT is an effective option when excision is incomplete and re-excision is not considered possible. In a study of 315 patients with primary cutaneous SCC of the head and neck undergoing wide local excision, patients undergoing surgery followed by adjuvant RT (n = 52) had a 92% reduced risk of recurrence (hazard ratio, 0.08; 95% CI, 0.0 to 0.26; p < 0.001) compared with those treated with surgery alone.50

Contrary to some perception most NMSC (BCC and SCC) are very responsive to RT, with MCC considered exquisitely radioresponsive. Primary (or definitive) RT is often recommended for lesions on and around the nose, lower eyelids, medial canthus, and ears, where it may yield better functional and cosmetic results than surgery51 (Fig. 47.9). Extensive lesions of the cheek, lip, and oral commissures that would require full-thickness resection may also be better irradiated. RT avoids the need for an operation and the surgical morbidity, scarring, and requirement for reconstruction, and it has the benefit of being able to treat both wide thickness (5 mm to 30+ mm) and deep margins, tissue that would otherwise require excision (with or without reconstruction). This particular advantage may result in improved cosmesis in situations in which a flap or graft is required. RT is particularly useful in areas of the midface, such as the periorbital region (especially the medial canthus), lower eyelid, nose (particularly the ala and tip), nasolabial fold, lip, and chin, where excision and reconstruction could have a greater impact on form and function. Elderly patients with comorbid conditions are also often better approached with RT (often hypofractionated). The lower lip is especially suited for RT when surgery may result in microstomia or require complex reconstruction for lesions occupying more than one-third of the lips; patients can be easily treated with orthovoltage RT after insertion of a lead oral cavity shield with expected cure rates similar to surgery. Patients may also benefit from postoperative RT if excision is incomplete and re-excision is not considered possible. In an Australian study of 217 patients with early lower lip SCC (considered as a sun-induced skin cancer), patients undergoing local adjuvant RT (50 Gy to 55 Gy in 20 to 25 fractions) in the setting of close ( T2) SCC and BCC, 4-year locoregional control rates were 86% and 58% for SCC and BCC, respectively.54 Despite this, RT may still remain the best option. One of the disadvantages of RT compared with surgery is the time required to undergo a course of treatment. The typical course of fractionated RT ranges from 10 to 25 daily 10-minute outpatient treatments (or fractions). However, fewer fractions (3 to 5) may be recommended in older patients with comorbid illnesses. Another disadvantage is that RT cannot be delivered a second time to the same site because of the risk of potential late complications, such as soft-tissue and cartilage necrosis. Reirradiation is rarely ever considered an option, but may be considered carefully if surgical salvage is not possible. Lesions located below the knee (i.e., lower leg) ideally should not be irradiated secondary to the genuine risk of poor wound healing. Similarly, surgical wounds, especially graft sites, should be completely healed prior to commencing RT. Although the initial cosmetic result after RT is excellent, fibrosis, soft-tissue or epidermal atrophy, and in-field pigmentation changes may become apparent over time (Fig. 47.10). Unprotected sun exposure to irradiated sites is likely to exacerbate these changes, and

Fig. 47.10 A 76-year-old man having 3 years previously received definitive radiotherapy (RT) (40 Gy in 10 fractions) to the right posterior lower nose for a nodular basal cell carcinoma. Note the well-demarcated in-field hypopigmentation and epidermal atrophy (smooth skin). He has minimal telangiectasia (small blood vessels) present.

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patients should be warned to take appropriate measures. When RT is delivered to younger patients, daily fraction sizes of 2 Gy to 2.5 Gy are recommended (e.g., 55 Gy in 25 fractions) to minimize late changes. This should apply whether treatment is delivered in the definitive or adjuvant setting. The risk of developing a late in-field radiation-induced malignancy after RT is rare and poorly documented in the literature. Alternative treatments should be considered for younger patients, however, because many develop further skin cancers as they age. However, there is no absolute contraindication for offering RT to younger patients if the patient and clinician agree this is the optimal modality.

Regional Nodes Elective nodal treatment is never indicated for BCC or low-risk SCC because of the low incidence of lymphatic spread. However, select patients with high-risk SCC of the head and neck may occasionally warrant elective treatment (surgery or RT) of clinically node-negative regional nodes in conjunction with treatment of the primary, although consensus is lacking on who would benefit from this nonstandard approach.20,55 For example, a patient with a recurrent temple SCC in whom adjuvant RT is recommended in the setting of a positive deep margin, or extensive PNI, may also be considered for the parotid nodes to be included electively en bloc in the RT field (Fig. 47.11). Patients who develop metastatic cutaneous SCC to the parotid gland and/or neck are optimally treated with surgery and adjuvant RT with few exceptions.56 The aim of adjuvant RT is to reduce the risk of regional relapse because most patients have unfavorable features, such as multiple metastatic nodes, extranodal spread, close margins, or the presence of PNI. Despite combined treatment, 10% to 15% develop in-field recurrence, often in the parotid bed or skull-base region. Most will be inoperable and incurable. With surgery and adjuvant RT, 5-year overall survival is 70% to 75%. Patients considered medically or technically

Fig. 47.11 A 73-year-old white man had wide-field adjuvant radiotherapy (RT) to a high-risk squamous cell carcinoma (recurrent and positive deep margin) with the field electively encompassing his parotid lymph nodes. The patient received 50 Gy in 20 fractions using orthovoltage energy photons.

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inoperable can still be treated with RT alone, although the likelihood of cure is reduced. No evidence indicates that the addition of concurrent chemotherapy to adjuvant RT improves outcome. Perineural invasion. The role of surgery and RT (adjuvant or definitive) in patients with PNI is unclear. Patients with asymptomatic (microscopic) PNI, detected postoperatively, may benefit from wide field local adjuvant RT without the need to treat neural pathways. Patients with symptomatic (clinical) PNI may, however, require more extensive volumes irradiated to encompass involved neural pathways, including intracranial extension. Doses of 50 to 60 Gy may be required and attention paid to the tolerance of structures such as the orbital contents and optic chiasm. The use of modern RT delivery (IMRT, SRS, SBRT, IMPT) allows for a more conformal delivery of high-dose RT while limiting the dose delivered to critical structures. Whether patients benefit from excision of involved nerves in addition to RT is controversial but recommended by some skull-base surgeons.57 Sentinel lymph node biopsy. The role of SLNB in NMSC is unclear because the overall incidence of metastatic nodal disease is low. In a study of 57 Australian patients, all having at least one pre-defined high-risk feature (size > 2 cm, poorly differentiated, locally recurrent or the presence of PNI), all patients underwent SLNB. The mean tumor diameter was 25 mm, depth of invasion 9.2 mm, and PNI present in 39%. In total 12% had subclinical nodal metastasis at the time of SLNB, consistent with other studies. However, local recurrence occurred in 14%, despite appropriate local treatment, and 11% died from SCC, with the majority of cancer deaths occurring in the SLNB-negative group. Therefore the impact that SLNB has on improving survival remains unclear.58

Merkel Cell Carcinoma The initial treatment for MCC is usually surgery to establish tissue diagnosis. The role of RT in the treatment of MCC has been evaluated since the early 1980s because of the high rate of locoregional relapse in this very radiosensitive disease. With few exceptions, most studies report a marked benefit to locoregional control and survival with the addition of adjuvant RT.59 An analysis of 6908 patients with MCC on the National Cancer Database documented a significant benefit in overall survival with the addition of adjuvant RT for patients with localized node-negative MCC, but not in those patients who were node positive.59 In a study of 171 patients with nonmetastatic MCC with most (98%) undergoing wide local excision plus or minus adjuvant RT, the addition of RT was associated with an improved 3-year local control (91% vs. 77%; p = 0.01) and overall survival (73% vs. 66%; p = 0.02).60 The routine use of adjuvant chemotherapy is unproven and not recommended. No convincing evidence suggests that cytotoxic chemotherapy improves outcome by decreasing the development of distant metastases. Many patients with MCC should proceed to wide-field adjuvant RT when a diagnosis has been confirmed. Given the high risk of local recurrence, RT margins around a primary lesion (or excision site) of at least 3 cm to 4 cm are recommended. Most wide-field treatment fields should encompass, as a minimum, the primary site, in-transit tissue (if technically feasible), and first-echelon nodes (if not investigated).61,62 RT should not be delayed by the need for further surgery even if excision margins are involved. The risk of occult nodal metastases at presentation is 30% to 50%, and, if left untreated, patients may develop clinical nodal metastases, which carries a poor prognosis.62 Thus, optimally all patients should have the draining lymph nodes either investigated with SLNB or treated electively, usually with RT in association with RT, to the primary site. Patients who may be considered for close observation because of the relatively low risk of recurrence

Fig. 47.12 An elderly farmer who 6 months previously underwent excision of a Merkel cell carcinoma from his left cheek (crossed line) without being recommended further treatment. He subsequently developed nodal relapse in his right parotid and proceeded to 5 weeks of RT to his right parotid and neck. At 3 years post RT he remains clinically well and disease free.

include those with small lesions (80 years of age) and/or in poor general condition, hypofractionation (e.g., 32 Gy in 4 fractions, 21 Gy in 3 fractions, 35 Gy in 5 fractions, or a single dose of 15 Gy to 20 Gy) may be used, still with the expectation of excellent control rates. Delivering large fractions using superficial energy photons or orthovoltage energy photons can take 20 to 30 minutes, and an uncooperative patient may need to be lightly sedated. In a systematic review of hypofractionated RT, most series documented over 90% local control rate and limited side effects.79 The dose for treatment with x-rays is specified at Dmax. The dose for irradiation with electrons is typically prescribed at 90%. Prescription of electron doses at 90% versus Dmax for superficial x-rays allows for the difference in relative biologic effectiveness between the two beam qualities. After resection of a nodal basin (e.g., parotid or neck), patients with multiple positive nodes (or a single node with extranodal spread) usually receive radiation in 2 Gy fractions to a dose of 60 Gy because of the large treatment volume. Similarly, for patients with inoperable nodal disease treated with RT alone, 2 Gy to 2.5 Gy fractions to a total dose of 60 Gy to 70 Gy is used unless the intent is palliative.

The general principles of patient setup and beam arrangement are as outlined for BCC and SCC. As primary treatment, RT is administered, with the options including wide-field electrons or IMRT (plus bolus), in 2-Gy to 2.5-Gy fractions to a cumulative dose of 45 Gy to 55 Gy for elective irradiation, plus consideration of a boost dose of 10 Gy in 5 fractions to the gross disease. A cumulative dose of 60 Gy to 66 Gy may be recommended for the treatment of bulky, inoperable primary tumors. Older patients of relatively poor performance status who are unsuitable for an extended course of RT may still benefit from shorter hypofractionated schedules, such as 30 Gy to 36 Gy in 5 to 6 fractions delivered 2 to 3 times per week. Radiation regimens used for adnexal carcinoma are 60 Gy to 70 Gy in 30 to 35 fractions, depending on the site and target volume. The volume is generally reduced to encompass areas of known gross disease after 50 Gy to 54 Gy.

Patient Care During and After Radiotherapy A tumoricidal dose of RT produces moist desquamation of the irradiated skin by the end of, and shortly after, treatment. The irradiated skin area should be protected from heat, cold, sunlight, friction, disinfectants, and other sources of irritation to avoid additional tissue injury. During RT, the daily application of a bland emollient is recommended. When moist desquamation occurs, the area should be kept clean to prevent secondary infection and may require the application of a burn-type dressing (e.g., silver sulfadiazine cream) for at least 2 to 3 weeks. Patients are instructed to use sunscreen over the irradiated area after completion of treatment during times of high sun exposure. Patients should also be informed about the specific acute and late side effects of treatment, such as mucositis of the nasal passages and upper lip, nasal dryness, synechiae (when treating nostril lesions), and conjunctivitis and loss of eyelashes (when treating eyelid cancers). After treatment involving the lacrimal canaliculi, irrigation of the ducts during the healing phase helps to prevent synechiae. Regular follow-up examinations should include evaluation of the treated area for late complications and a search for new lesions. The latter develop in up to 50% of treated patients occasionally in proximity to a previous treatment field. Late side effects include in-field hypopigmentation, hyperpigmentation, scattered telangiectasia, and skin atrophy. Skin retraction at the lower eyelid may result in ectropion. These are rarely serious after properly administered RT.

DIAGNOSTIC AND TREATMENT ALGORITHMS Basal Cell Carcinoma and Squamous Cell Carcinoma Fig. 47.16 illustrates the diagnostic and treatment algorithm for BCC and SCC. The choice of treatment for individual patients is determined by factors such as the lesion site and size, anticipated functional and cosmetic results, treatment time, treatment cost, and patient preference.

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Disease Sites Surgical approaches are preferred for most patients with resectable tumors, but RT may yield better functional and cosmetic results for lesions of the nose, lower eyelids, and ears (Fig. 47.17). A combination of surgery and adjuvant RT is indicated in larger tumors or tumors with inadequate excision, PNI, invasion of bone or cartilage, extensive skeletal muscle infiltration, or nodal metastasis.

SCC !2 cm BCC or SCC T1N0

Physical examination and imaging to stage local, nodal, and perineural spread #

H Zone RT

Surgical modality local excision No adverse features Follow up

Merkel Cell Carcinoma and Adnexal Carcinoma

" Wide excision " nodal dissection Adverse features Postoperative RT

Fig. 47.16 Diagnostic and treatment algorithm for cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). RT, Radiotherapy.

A combination of surgery (respecting form and function) and wide-field elective or adjuvant RT is recommended for most patients with MCC and adnexal carcinoma. In select situations, there should be elective treatment, usually RT, of first echelon lymph nodes. The role of adjuvant chemotherapy for the treatment of MCC is unproven and not recommended without high-level supportive evidence of a benefit. RT alone still offers a potential cure for inoperable patients or patients refusing surgery. Evidence suggests that PET/CT scanning in patients with MCC may alter management or prognosis, or both, in 30% to 40% of patients and should be considered as best practice for staging most patients. Patients with nodal metastases at presentation or who are immunosuppressed benefit most from a staging PET/CT scan.80,81

CRITICAL REFERENCES

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B Fig. 47.17 (A) A 72-year-old man with a large 3.5-cm left temple squamous cell carcinoma in close proximity to his left eye. The patient declined surgery. He received 55 Gy in 25 fractions using orthovoltage energy photons and required the insertion of an internal eye shield. (B) At 4 months post radiotherpy the patient has achieved an excellent outcome with complete clinical regression.

6. Cheng JY, Li FY, Ko CJ, Colegio OR. Cutaneous squamous cell carcinomas in solid organ transplant recipients compared with immunocompetent patients. JAMA Dermatol. 2018;154:60–66. 20. Veness MJ, Goedjen B, Jambusaria-Pahlajani A. Perioperative management of high risk primary cutaneous SCC: role of radiologic imaging, elective lymph node dissection, sentinel lymph node biopsy, and adjuvant radiotherapy. Curr Dermatol Rep. 2013;2:77–83. 21. Roscher I, Falk RS, Vos L, et al. Validating 4 staging systems for cutaneous squamous cell carcinoma using population-based data: a nested case-control study. JAMA Dermatol. 2018;Epub ahead of print. 22. Badlani J, Gupta R, Smith J, et al. Metastases to the parotid gland-A review of the clincopathological evolution, molecular mechanisms and management. Surg Oncol. 2018;27:44–53. 30. Becker JC, Stang A, DeCaprio JA, et al. Merkel cell carcinoma. Nat Rev Dis Primers. 2017;Epub ahead of print. 31. Foote M, Veness M, Zarate D, et al. Merkel cell carcinoma: the prognostic implications of an occult primary in stage 3B (nodal) disease. J Am Acad Dermatol. 2012;67:395–399. 40. Warren TA, Whiteman DC, Porceddu SV, Panizza BJ. Insight into the epidemiology of cutaneous squamous cell carcinoma with perineural invasion. Head Neck. 2016;38:1416–1420. 50. Kyrgidis A, Tzellos TG, Kechagias N, et al. Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival. Eur J Cancer. 2010;46:1563–1572. 51. Veness MJ. The important role of radiotherapy in patients with non-melanoma skin cancer and other cutaneous entities. J Med Imaging Radiat Oncol. 2008;52:278–286. 52. Najim M, Cross S, Gebski V, et al. Early stage squamous cell carcinoma of the lip: the Australian experience and the benefits of radiotherapy in improving outcome in resected high-risk patients. Head Neck. 2013;35: 1426–1430. 56. Wang J, Palme C, Morgan G, et al. Predictors of outcome in patients with metastatic cutaneous head and neck cutaneous squamous cell carcinoma involving cervical lymph nodes: improved survival with the addition of adjuvant radiotherapy. Head Neck. 2012;34:1524– 1528. 58. Gore SM, Shaw D, Martin RCW, et al. Prospective study of sentinel node biopsy for high-risk cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2016;38(suppl 1):E884–E889. 61. Strom T, Naghavi AO, Messina JL, et al. Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck. Head Neck. 2017;39:48–55.

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CHAPTER 47 62. Howle JR, Hughes TM, Gebski V, et al. Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck. Head Neck. 2017;39:48–55. 63. Gunaratne D, Howle JR, Veness MJ. Definitive radiotherapy for Merkel cell carcinoma confers clinically meaningful in-field locoregional control: a review and analysis of the literature. J Am Acad Dermatol. 2017;Epub ahead of print. 67. Al-Othman MOF, Mendenhall WM, Amdur RJ. Radiotherapy alone for clinical T4 skin carcinoma of the head and neck with surgery reserved for salvage. Am J Otolaryngol. 2001;22:387–390. 68. Matthiesen C, Thompson JS, Forest C, et al. The role of radiotherapy for T4 non-melanoma skin carcinoma. J Med Imaging Radiat Oncol. 2011;55:407–416. 71. Barnes EA, Breen D, Culleton L, et al. Palliative radiotherapy for non-melanoma skin cancer. Clin Oncol. 2010;22:844–849. 72. Rudnick EW, Thareja S, Cherpelis B. Oral therapy for nonmelanoma skin cancer in patients with advanced disease and large tumor burden: a

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review of the literature with focus on a new generation of targeted therapies. Int J Dermatol. 2016;55:249–258. 74. Khan L, Choo R, Breen D, et al. Recommendations for CTV margins in radiotherapy planning for non melanoma skin cancer. Radiother Oncol. 2012;104:263–266. 75. Ko HC, Gupta V, Mourad WF, et al. A contouring guide for head and neck cancers with perineural invasion. Pract Radiat Oncol. 2014;4:e247–e258. 79. Gunaratne DA, Veness MJ. Efficacy of hypofractionated radiotherapy in patients with non- melanoma skin cancer: results of a systematic review. J Med Imaging Radiat Oncol. 2018;Epub ahead of print.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 47

REFERENCES 1. Perera E, Gnaneswaran N, Staines C, et al. Incidence and prevalence of non-melanoma skin cancer in Australia: a systematic review. Australas J Dermatol. 2015;56:258–267. 2. Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972;105:107–110. 3. Kyllo RL, Brady KL, Hurst EA. Sebaceous carcinoma: review of the literature. Dermatol Surg. 2015;41:1–15. 4. Boukamp P. Non-melanoma skin cancer: what drives tumor development and progression? Carcinogenesis. 2005;26:1657–1667. 5. Paulson KG, Iyer JG, Warton EM, et al. Systemic immune suppression predicts diminished Merkel cell carcinoma - Specific survival independent of stage. J Invest Dermatol. 2013;133:642–646. 6. Cheng JY, Li FY, Ko CJ, Colegio OR. Cutaneous squamous cell carcinomas in solid organ transplant recipients compared with immunocompetent patients. JAMA Dermatol. 2018;154:60–66. 7. Di Giovanna JJ, Kraemer KH. Shining a light on Xeroderma Pigmentosum. J Invest Dermatol. 2012;132:785–796. 8. John AM, Schwartz RA. Basal cell naevus syndrome: an update on genetics and treatment. Br J Dermatol. 2016;174:68–76. 9. Sanchez G, Nova J, Rodriguez-Hernandez AE, et al. Sun protection for preventing basal and squamous cell skin cancers. Cochrane Database Syst Rev. 2016;(7):CD011161. 10. Baxter JM, Patel AN, Varma S. Facial basal cell carcinoma. BMJ. 2012;345:e5342. 11. Connolly KL, Nehal KS, Disa JJ. Evidence-based medicine: cutaneous facial malignancies: nonmelanoma skin cancer. Plast Reconstr Surg. 2017;139:181e–190e. 12. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet. 2010;375:673–685. 13. Soyer P, Rigel D, Wurm E. Actinic keratosis, basal cell carcinoma and squamous cell carcinoma. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. New York: Elsevier Science; 2012:1773–1793. 14. Caccialanza M, Piccinno R, Cuka E, et al. Radiotherapy of morphea-type basal cell carcinoma: results in 127 cases. J Eur Acad Dermatol Venereol. 2014;28:1751–1755. 15. Lin C, Tripcony L, Keller J, et al. Perineural invasion of cutaneous squamous carcinoma and basal cell carcinoma without clinical features. Int J Radiat Oncol Biol Phys. 2012;88:334–340. 16. Outcome following radiotherapy for head and neck basal cell carcinoma with ‘aggressive’ features. Oral Oncol. 2017;72:157–164. 17. Tang S, Thompson S, Smee R. Metastatic basal cell carcinoma: case series and review of the literature. Australas J Dermatol. 2017;58: e40–e43. 18. Werner RN, Sammain A, Erdmann R, et al. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169:502–518. 19. Bath-Hextall FJ, Matin RN, Wilkinson D, Leonardi-Bee J. Interventions for cutaneous Bowen’s disease. Cochrane Database Syst Rev. 2013;(6):CD007281. 20. Veness MJ, Goedjen B, Jambusaria-Pahlajani A. Perioperative management of high risk primary cutaneous SCC: role of radiologic imaging, elective lymph node dissection, sentinel lymph node biopsy, and adjuvant radiotherapy. Curr Dermatol Rep. 2013;2:77–83. 21. Roscher I, Falk RS, Vos L, et al. Validating 4 staging systems for cutaneous squamous cell carcinoma using population-based data: a nested case-control study. JAMA Dermatol. 2018;Epub ahead of print. 22. Badlani J, Gupta R, Smith J, et al. Metastases to the parotid gland-A review of the clincopathological evolution, molecular mechanisms and management. Surg Oncol. 2018;27:44–53. 23. Goh A, Howle J, Hughes M, et al. Managing patients with cutaneous squamous cell carcinoma metastatic to the axilla or groin lymph nodes. Australas J Dermatol. 2010;51:113–117. 24. Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol. 2008;58:375–381. 25. Fitzgerald TL, Dennis S, Kachare SD, et al. Dramatic increase in the incidence and mortality from Merkel cell carcinoma in the United States. Am Surg. 2015;81:802–806.

Cutaneous Carcinoma

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26. Merkel F. Tastzellen und Tastkoerperchen bei den haushieren und beim menschen. Arch Mikr Anat. 1875;11:636–652. 27. Lebbe C, Becker JC, Grob JJ, et al. Diagnosis and treatment of Merkel cell carcinoma. European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51:2396–2403. 28. Schadendorf D, Lebbe C, zur Hausen A, et al. Merkel cell carcinoma: epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer. 2017;71:53–69. 29. Amber K, McLeod MP, Nouri K. The Merkel cell polyomavirus and its involvement in Merkel cell carcinoma. Dermatol Surg. 2013;39: 232–238. 30. Becker JC, Stang A, DeCaprio JA, et al. Merkel cell carcinoma. Nat Rev Dis Primers. 2017;Epub ahead of print. 31. Foote M, Veness M, Zarate D, et al. Merkel cell carcinoma: the prognostic implications of an occult primary in stage 3B (nodal) disease. J Am Acad Dermatol. 2012;67:395–399. 32. Arron ST, Canavan T, Yu SS. Organ transplant recipients with Merkel cell carcinoma have reduced progression-free, overall, and disease-specific survival independent of stage of presentation. J Am Acad Dermatol. 2014;71:731–737. 33. Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol. 2005;50:103–120. 34. Dowd M, Kumar RJ, Sharma R, et al. Diagnosis and management of sebaceous carcinoma: an Australian experience. Aust N Z J Surg. 2008;78:158–163. 35. Wick MR, Goellner JR, Wolfe JT, et al. Adnexal carcinomas of the skin: II. extraocular sebaceous carcinomas. Cancer. 1985;56:1163–1172. 36. Kampshoff JL, Cogbill TH. Unusual skin tumors: merkel cell carcinoma, eccrine carcinoma, glomus tumors, and dermatofibrosarcoma protuberans. Surg Clin North Am. 2009;89:727–738. 37. Urso C, Bondi R, Paglierani M, et al. Carcinomas of sweat glands: report of 60 cases. Arch Pathol Lab Med. 2001;125:498–505. 38. Fischer S, Breuninger H, Metzier G, et al. Microcystic adnexal carcinoma: an often misdiagnosed, locally aggressive growing skin tumor. J Craniofac Surg. 2005;16:53–58. 39. Leibovitch I, Huilgol SC, Selva D, et al. Microcystic adnexal carcinoma: treatment with Mohs micrographic surgery. J Am Acad Dermatol. 2005;52:295–300. 40. Warren TA, Whiteman DC, Porceddu SV, Panizza BJ. Insight into the epidemiology of cutaneous squamous cell carcinoma with perineural invasion. Head Neck. 2016;38:1416–1420. 41. Roh J, Muelleman T, Tawfik O, Thomas SM. Perineural growth in head and neck squamous cell carcinoma: a review. Oral Oncol. 2015; 51:16–23. 42. Baulch J, Gandhi M, Sommerville J, Panizza B. 3T MRI evaluation of large nerve perineural spread of head and neck cancers. J Med Imaging Radiat Oncol. 2015;59:578–585. 43. Chen VH, Hayek BR, Grossniklaus HE, et al. Review of periorbital nerve enlargement and biopsy techniques. Orbit. 2017;36:293–297. 44. Karia PS, Morgan FC, Califano JA, Schmults CD. Comparison of tumor classifications for cutaneous squamous cell carcinoma of the head and neck in the 7th vs 8th edition of the AJCC Cancer Staging Manual. JAMA Dermatol. 2017;Epub ahead of print. 45. Karia PS, Jambusaria-Pahlajani A, Harrington DP, et al. Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. 2014;32:327–334. 46. Liu J, Ebrahimi A, Low TH, et al. Predictive value of the 8th edition American Joint Commission on Cancer (AJCC) nodal staging system for patients with cutaneous squamous cell carcinoma of the head and neck. J Surg Oncol. 2017;Epub ahead of print. 47. Moeckelmann N, Ebrahimi A, Dirven R, et al. Analysis and comparison of the 8th edition American Joint Committee on Cancer (AJCC) nodal staging system in cutaneous and oral squamous cell carcinoma of the head and neck. Ann Surg Oncol. 2018;Epub ahead of print. 48. Harms KL, Healy MA, Nghiem P, et al. Analysis and prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system. Ann Surg Oncol. 2016;11:3564–3571.

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805.e2

SECTION III

Disease Sites

49. Chitwood K, Etzkorn J, Cohen G. Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons. Dermatol Surg. 2013;Epub ahead of print. 50. Kyrgidis A, Tzellos TG, Kechagias N, et al. Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival. Eur J Cancer. 2010;46:1563–1572. 51. Veness MJ. The important role of radiotherapy in patients with non-melanoma skin cancer and other cutaneous entities. J Med Imaging Radiat Oncol. 2008;52:278–286. 52. Najim M, Cross S, Gebski V, et al. Early stage squamous cell carcinoma of the lip: the Australian experience and the benefits of radiotherapy in improving outcome in resected high-risk patients. Head Neck. 2013;35:1426–1430. 53. Marconi DG, da Costa Resende B, Rauber E, et al. Head and neck non-melanoma skin cancer treated by superficial x-ray therapy: an analysis of 1021 cases. PLoS ONE. 2016;11:e0156544. 54. Kwan W, Wilson D, Moravan V. Radiotherapy for locally advanced basal cell and squamous cell carcinomas of the skin. Int J Radiat Oncol Biol Phys. 2004;60:406–411. 55. Martinez JC, Cook JL. High-risk cutaneous squamous cell carcinoma without palpable lymphadenopathy: is there a therapeutic role for elective neck dissection? Dermatol Surg. 2007;33:410–420. 56. Wang J, Palme C, Morgan G, et al. Predictors of outcome in patients with metastatic cutaneous head and neck cutaneous squamous cell carcinoma involving cervical lymph nodes: improved survival with the addition of adjuvant radiotherapy. Head Neck. 2012;34:1524–1528. 57. Gupta A, Veness M, De’Ambrosis B, et al. Management of squamous cell and basal cell carcinomas of the head and neck with perineural invasion. Australas J Dermatol. 2016;57:3–13. 58. Gore SM, Shaw D, Martin RCW, et al. Prospective study of sentinel node biopsy for high-risk cutaneous squamous cell carcinoma of the head and neck. Head Neck. 2016;38(suppl 1):E884–E889. 59. Bhatia S, Storer BE, Iyer JG, et al. Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: survival analysis of 6908 cases from the National Cancer Data Base. Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: survival analysis of 6908 cases from the National Cancer Data Base. J Natl Cancer Inst. 2016;108:djw042. 60. Strom T, Carr M, Zager JS, et al. Radiation therapy is associated with improved outcomes in Merkel cell carcinoma. Ann Surg Oncol. 2016;23:3572–3578. 61. Strom T, Naghavi AO, Messina JL, et al. Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck. Head Neck. 2017;39:48–55. 62. Howle JR, Hughes TM, Gebski V, et al. Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck. Head Neck. 2017;39:48–55. 63. Gunaratne D, Howle JR, Veness MJ. Definitive radiotherapy for Merkel cell carcinoma confers clinically meaningful in-field locoregional control: a review and analysis of the literature. J Am Acad Dermatol. 2017;Epub ahead of print. 64. Wang LS, Handorf E, Wu H, et al. Surgery and adjuvant radiation for high-risk skin adnexal carcinoma of the head and neck. Am J Clin Oncol. 2017;40:429–432.

65. Shayna G, Fischer C, Martin A, et al. Microcystic adnexal carcinoma: a review of the literature. Dermatol Surg. 2017;43:1012–1016. 66. Robson A, Greene J, Ansari N, et al. Eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases. Am J Surg Pathol. 2001;25:710–720. 67. Al-Othman MOF, Mendenhall WM, Amdur RJ. Radiotherapy alone for clinical T4 skin carcinoma of the head and neck with surgery reserved for salvage. Am J Otolaryngol. 2001;22:387–390. 68. Matthiesen C, Thompson JS, Forest C, et al. The role of radiotherapy for T4 non-melanoma skin carcinoma. J Med Imaging Radiat Oncol. 2011;55:407–416. 69. Romeser PB, Cahlon O, Scher E, et al. Proton beam radiation therapy results in significantly reduced toxicity compared with intensitymodulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiother Oncol. 2016;118:286–292. 70. Kramkimel N, Dendale R, Bolle S, et al. Management of advanced non-melanoma skin cancers using helical tomotherapy. J Eur Acad Dermatol Venereol. 2014;28:641–650. 71. Barnes EA, Breen D, Culleton L, et al. Palliative radiotherapy for non-melanoma skin cancer. Clin Oncol. 2010;22:844–849. 72. Rudnick EW, Thareja S, Cherpelis B. Oral therapy for nonmelanoma skin cancer in patients with advanced disease and large tumor burden: a review of the literature with focus on a new generation of targeted therapies. Int J Dermatol. 2016;55:249–258. 73. Sekulic A, Midgen MR, Basset-Sequin N, et al. Long-term safety and efficacy in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017;17:332. 74. Khan L, Choo R, Breen D, et al. Recommendations for CTV margins in radiotherapy planning for non melanoma skin cancer. Radiother Oncol. 2012;104:263–266. 75. Ko HC, Gupta V, Mourad WF, et al. A contouring guide for head and neck cancers with perineural invasion. Pract Radiat Oncol. 2014;4:e247–e258. 76. Van Hezewijk M, Creutzberg CL, Putter H, et al. Efficacy of a hypofractionated schedule in electron beam radiotherapy for epithelial skin cancer: analysis of 434 cases. Radiother Oncol. 2010;95:245–249. 77. Gauden R, Pracy M, Avery AM, et al. HDR brachytherapy for superficial non-melanoma skin cancer. J Med Imaging Radiat Oncol. 2013;57:212–217. 78. Bhatnagar A, Patel R, Werschler WP, et al. High-dose rate electronic brachytherapy: a nonsurgical treatment alternative in nonmelanoma skin cancer. J Clin Aesthet Dermatol. 2016;9:16–22. 79. Gunaratne DA, Veness MJ. Efficacy of hypofractionated radiotherapy in patients with non- melanoma skin cancer: results of a systematic review. J Med Imaging Radiat Oncol. 2018;Epub ahead of print. 80. Concannon R, Larcos G, Veness M. The impact of 18F-FDG PET-CT scanning for staging and management of Merkel cell carcinoma: results from Westmead Hospital, Sydney, Australia. J Am Acad Dermatol. 2010;62:76–84. 81. Poulsen M, Macfarlane D, Veness M, et al. Prospective analysis of the utility of 18-FDG PET in Merkel cell carcinoma of the skin: a Trans Tasman Radiation Oncology Group Study, TROG 09:03. J Med Imaging Radiat Oncol. 2018;Epub ahead of print.

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48 Malignant Melanoma Matthew T. Ballo

KEY POINTS Incidence It was estimated that in 2018 there would be 91,270 new cases of melanoma diagnosed and 9320 deaths in the United States. Biological Characteristics Sun exposure is clearly associated with the development of cutaneous melanoma. Inherited mutations may also play a role in some cases. The natural history of melanoma is usually characterized by early, stepwise dissemination from a primary tumor to regional lymph node lesions and then to lesions at distant sites. The main determinants of survival are the thickness of the primary tumor (measured in millimeters), the presence or absence of primary ulceration, the status of regional lymph nodes, and the sites of distant disease. Staging Evaluation For evaluating localized disease, a thorough history and physical examination, including dermoscopy, can suffice. For patients with nodal spread, the staging evaluation should include serum level measurement of lactate dehydrogenase and imaging with contrast-enhanced computed tomography (CT) and positron emission tomography (PET). Magnetic resonance imaging (MRI) of the brain should be considered, and it should be routine for patients with distant metastases. Primary Therapy Treatment of a primary melanoma lesion that is less than 0.8 mm thick is wide local excision alone. Sentinel lymph node biopsy is generally recommended for any lesion that is 1 mm or thicker or if ulceration exists in a lesion that is greater

than or equal to 0.8 mm and less than 1 mm. If the sentinel node is not involved, the patient may be observed, but if it is involved, complete lymph node dissection should be considered because it offers a survival benefit in patients who are node positive. If complete lymph node dissection is not possible because of medical comorbidities, elective radiotherapy to the involved nodal basin is preferred to observation. Adjuvant Therapy For patients at risk of nodal spread in whom sentinel lymph node biopsy will not alter subsequent management because of medical comorbidities, regional irradiation (i.e., elective irradiation) is preferred compared to observation. Indications for postdissection nodal radiotherapy are high-risk pathological features, including nodal extracapsular extension, lymph nodes measuring 3 cm or more in the widest diameter, at least two involved lymph nodes, and recurrent nodal disease after previous dissection for pathologically involved lymph nodes. Adjuvant CTLA-4 blockers and BRAF inhibitors improve relapse-free survival and overall survival for patients with nodal metastases. However, like interferon alpha, which it replaced, immunotherapy is associated with significant toxicity. Locally Advanced Disease and Metastases Palliative radiotherapy reduces symptoms in more than 80% of patients with inoperable disease or metastatic masses. Significant improvements in overall survival (OS) are seen in patients receiving systemic CTLA-4 blockers and BRAF inhibitors.

Malignant melanoma remains a predominantly surgically treated disease; most patients with early-stage disease are cured by simple excision of the primary lesion. By the time growth of the primary tumor reaches a few millimeters, however, the risk of nodal and distant spread increases rapidly, and the role of adjuvant radiotherapy and systemic therapy takes on increasing importance. As for many diseases, radiotherapy is often recommended as an adjuvant to surgical dissection of locally advanced disease or as a palliative treatment of distant metastases. Until recently, the acceptance of radiotherapy as part of a standard treatment algorithm for patients with melanoma has been marred by controversy. In the early 1930s, melanoma was considered to be categorically radioresistant. This belief was perpetuated by popular textbooks of the time until laboratory data showed that the reputed radioresistance of melanoma might reflect a broad shoulder in the low-dose portion of the cell survival curve. The data suggested that melanoma cells might be more sensitive to radiation delivered as a large dose per fraction (i.e., hypofractionation regimen). Although a randomized trial performed

by the Radiation Therapy Oncology Group (RTOG) did not confirm clinical superiority for hypofractionation in a heterogeneous group of patients receiving palliative radiotherapy, these types of regimens are favored by clinicians specializing in melanoma radiotherapy.1 Retrospective reviews of clinical experiences have suggested that the hypofractionated regimens are effective and can be safely delivered in a short period of time to a group of patients for whom survival is ultimately dictated by the risk of distant metastasis.2,3 Although hypofractionated radiotherapy has been shown to be effective in several clinical settings, the perceived risk of distant metastatic disease and concern over the rate of long-term radiation-related toxicity often precludes its use regardless of effectiveness. In this chapter, we present the rates of local failure, regional failure, distant failure, and long-term treatment-related toxicity for patients with melanoma and provide data supporting the use of radiotherapy in a defined group of patients. Only by balancing the competing risks of failure and treatmentrelated toxicity can physicians appropriately integrate radiotherapy into the management of patients with malignant melanoma.

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CHAPTER 48

ETIOLOGY AND EPIDEMIOLOGY For 2018, 91,270 new cases of cutaneous malignant melanoma were estimated to occur in the United States, or 5% of all newly diagnosed cancers.4 Although the incidence of malignant melanoma more than doubled between 1975 and 2000, new cases of melanoma are being diagnosed earlier in the course of the disease because of increased public awareness, and the mortality rate has steadily decreased.4 The reason for the rise in incidence has not been explained. The number of deaths resulting from melanoma in 2018 is estimated to be 9320. Several lines of evidence link sun or ultraviolet (UV) radiation exposure to the development of cutaneous melanoma.5,6 There is a higher incidence of melanoma in populations with high levels of sun exposure, among sun-sensitive people, on sun-exposed body sites, in populations with high sun exposure, among people with other sun-related skin conditions,7,8 and in those using artificial sources of UV radiation, such as sunbeds. The development of melanoma may also be reduced by protection of the skin against sun exposure.7 Analysis of patients with familial clustering of melanoma has identified two genes, CDKN2A and CDK4, that confer increased susceptibility to melanoma development.9 Although only a small percentage of patients with melanoma has a mutation in CDKN2A, carriers of this mutation have an almost 70% chance of developing melanoma by the age of 80 years.10,11 The presence of an increasing number of nevi also represents a well-accepted risk factor for the development of melanoma.12 Whether the type of nevi (i.e., common, atypical, or dysplastic) is also important or merely reflects the degree of previous sun-related damage remains controversial.

PREVENTION AND EARLY DETECTION Advocates of early detection and screening programs generally assume that early detection and treatment will significantly affect the mortality rate and quality of life, particularly in melanoma, for which the association between tumor thickness and survival is well documented. Unfortunately, there are no randomized clinical trials to support routine screening of the general population. In the United States, routine screening of high-risk populations is still generally recommended, and educational efforts have been directed to clinicians and the public to promote early recognition of suspicious skin lesions. Periodic separate or mass screening for high-risk individuals consists of a total cutaneous examination and a 2- to 3-minute visual inspection of the entire integument by adequately trained physicians. Risk factors include a family history of skin cancer, fair skin, multiple nevi, and a history of melanoma or other skin cancers. Recognized signs of melanoma include the ABCDs of early diagnosis: A, asymmetry; B, border irregularity; C, color variation; and D, a diameter greater than 6 mm. The US Preventive Services Task Force (USPSTF)13 performed a thorough review of the medical literature and issued a practice policy statement regarding skin cancer prevention counseling. Recommended preventive measures include avoidance of sunlight exposure—particularly limiting time spent outdoors between 10 am and 3 pm—and wearing protective physical barriers, such as hats and clothing and sunscreens that are opaque or that block UVA and UVB radiation.

CLINICAL MANIFESTATIONS, PATHOBIOLOGY, AND PATHWAYS OF SPREAD Clinical Presentation and Pathology Primary cutaneous melanoma may develop in or adjacent to one of the precursor lesions (e.g., lentigo maligna, dysplastic nevus) or in

Malignant Melanoma

807

normal skin, and it can manifest clinically in four major growth patterns.14 The most prevalent variant is superficial spreading melanoma, which constitutes approximately 70% of cases.15,16 Superficial spreading melanoma often arises in a junctional nevus, where it first appears as a deeply pigmented area, progressing gradually to a flat induration, generally over several years. As the lesion grows, the surface and perimeter may become irregular, with amelanotic patches. On histological examination, it is characterized by a prominent intraepidermal proliferation of malignant melanocytes similar to Paget disease; hence, this pattern is called pagetoid melanoma.17 The malignant cell may be confined to the lower portion of the epidermis or may spread up into the granular cell layer of the epidermis, which is frequently hyperplastic. As the lesion enlarges, clusters of malignant cells invade the dermis and subcutaneous tissues. Nodular melanoma is the second most common variant (15%-25% of melanoma lesions).15,16 Nodular melanoma develops more frequently de novo on the trunk, head, or neck of middle-aged individuals. In contrast to superficial spreading melanoma, the nodular variant affects men more than women. It manifests as a raised or dome-shaped, blueblack lesion, which is usually darker than superficial spreading melanoma. Approximately 5% of nodular variants manifest as nonpigmented, fleshy nodules—this type of lesion is called amelanotic melanoma. Histological testing shows that nodular melanoma is characterized by an expansile nodule centered at the papillary dermis, with little or no epidermal component, composed of epithelioid cells. Spindle cells, small epithelioid cells, and mixtures of cells may be present. Deeper invasion of the dermis and subcutis occurs as the lesion grows. Lentigo maligna melanoma is seen in less than 10% of malignant melanoma lesions.16,18 This variant occurs most frequently on the face or neck of whites older than 50 years, and it arises from a precursor lesion of melanoma in situ called lentigo maligna (i.e., Hutchinson’s melanotic freckle).19 It manifests as a relatively large (> 3 cm), flat, tan-colored (with different shades of brown) lesion that often has been present for more than 5 years. The border becomes irregular as the lesion enlarges. On histological examination, an invasive tumor is usually composed of spindle-like cells. These cells may be embedded in a fibrous stroma (i.e., desmoplastic pattern) or may form fascicles displaying neural features and infiltrating endoneural and perineural structures of the cutaneous nerves.19,20 Acral lentiginous melanoma occurs characteristically on the palms or soles or beneath nail beds.21-23 The relative frequency of acral lentiginous melanoma varies substantially with race. It represents about 5% of melanomas in whites and 35% to 60% in dark-skinned individuals.24,25 Most acral lentiginous melanomas occur on the foot sole in individuals older than 60 years. They generally start as tan or brown stains and evolve over a period of years to reach an average diameter of 3 cm before a diagnosis is established.22,23 Histological testing reveals that early-stage acral lentiginous melanoma is composed of large, highly atypical, pigmented cells along the dermoepidermal junction in an area of hyperplastic epidermis. At the invasive stage, infiltrating cells may be epithelioid or spindle shaped.20 Sometimes, infiltration to deeper structures occurs, predominantly through the eccrine ducts.17

Biology and Patterns of Spread Superficial spreading and lentigo maligna melanomas generally grow slowly over many years (i.e., radial growth phase). Left untreated, however, these lesions gradually invade the dermis and subcutis (i.e., vertical growth phase) and acquire metastatic potential. Acral lentiginous melanomas—particularly, nodular melanomas—have a shorter natural history, with rapid progression to the vertical growth pattern. Previously, two microstaging systems were used. The Breslow system classifies lesions by the vertical thickness between the granular layer of

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808

SECTION III

Disease Sites

the epidermis and the deepest part of invasion, measured with an ocular micrometer. In ulcerated lesions, measurements are made from the surface to the deepest part.26 The Clark method categorizes lesions into five groups by the level of dermal or subcutis invasion: level 1, confined to the epidermis; level 2, invasion to the papillary dermis; level 3, invasion to the papillary-reticular dermal interface; level 4, invasion to the reticular dermis; and level 5, invasion to the subcutaneous tissue.15 Of the two systems, tumor thickness is more accurate in predicting outcome,

TABLE 48.1

although level of invasion remains prognostic for patients with lesions less than 1 mm thick.27 In an analysis of more than 46,000 patients with melanoma, several clinical and histological variables were found to be of prognostic value and now form the basis for the eighth edition of the American Joint Committee on Cancer (AJCC) staging system27,28 (Table 48.1). For patients without clinical evidence of nodal spread, primary thickness and ulceration remain the most important prognostic features. The

American Joint Committee on Cancer Staging System for Melanoma of the Skin

Primary Tumor (T)

Clinical Stage Grouping

TX

Primary tumor thickness cannot be assessed (e.g., diagnosis by curettage)

Stage 0 Stage IA

TisN0M0 T1aN0M0

Stage IB

T1bN0M0

T0

No evidence of primary tumor (e.g., unknown primary or completely regressed melanoma)

Tis

Melanoma in situ

T1 T1a

Melanoma ≤ 1.0 mm thick, unknown or unspecified ulceration status Melanoma < 0.8 mm thick, without ulceration

T1b

Melanoma < 0.8 mm thick with ulceration, 0.8-1.0 mm with or without ulceration

T2a T2b

Melanoma > 1.0-2.0 mm thick, unknown or unspecified ulceration Melanoma > 1.0-2.0 mm thick, without ulceration Melanoma > 1.0-2.0 mm thick, with ulceration

T3a T3b

Melanoma > 2.0-4.0 mm thick, unknown or unspecified ulceration Melanoma > 2.0-4.0 mm thick, without ulceration Melanoma > 2.0-4.0 mm thick, with ulceration

T4a T4b

Melanoma > 4.0 mm thick, unknown or unspecified ulceration Melanoma > 4.0 mm thick, without ulceration Melanoma > 4.0 mm thick, with ulceration

T2aN0M0 Stage IIA

Stage IIC

T2bN0M0 T3aN0M0 T3bN0M0 T4aN0M0 T4bN0M0

Stage III

Any T, Tis ≥N1M0

Stage IV

Any T, Any N,M1

Stage IIB

T2

T3

T4

Regional Lymph Nodes (N)

Pathologic Stage Grouping

NX

Regional lymph nodes cannot be assessed (e.g., SLN biopsy not performed, regional nodes previously removed for another reason) Exception: pathological N category is not required for T1 melanomas, use cN. No in-transit, satellite, and/or microsatellite metastases.

Stage 0 Stage IA

TisN0M0 T1aN0M0 T1bN0M0

N0

No regional lymph node metastasis; no in-transit, satellite, and/or microsatellite metastases

Stage IB

T2aN0M0

N1

One tumor-involved node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes One clinically occult (i.e., detected by SLN biopsy) node No in-transit, satellite, and/or microsatellite metastases One clinically detected node; no in-transit, satellite, and/or microsatellite metastases

Stage IIA

T2bN0M0

N1a N1b N1c

No regional lymph node disease, in-transit, satellite, and/or microsatellite metastases

N2

Two or three tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with one tumor-involved node

N2a N2b N2c

Two or three clinically occult nodes (i.e., detected by SLN biopsy); no in-transit, satellite, and/or microsatellite metastases Two or three—at least one of which is clinically detected—nodes; no in-transit, satellite, and/or microsatellite metastases One clinically occult or clinically detected node; in-transit, satellite, and/or microsatellite metastases

T3aN0M0 Stage IIB Stage IIC Stage IIIA

Stage IIIB

Stage IIIC

T3bN0M0 T4aN0M0 T4bN0M0 T1a/b-T2aN1a or N2aM0

T0N1b, N1cM0 T1a/b-T2aN1b/c or N2bM0 T2b/T3aN1a-N2bM0 T0N2b, N2c, N3b, or N3c, M0 T1a-T3aN2c or N3a/b/cM0 T3b/T4a, Any N >=N1, M0 T4b, N1a-N2c, M0

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CHAPTER 48

TABLE 48.1

Skin—cont’d

Four or more tumor-involved nodes, or in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases

N3a

Four or more clinically occult (i.e., detected by SLN biopsy); no in-transit, satellite, and/or microsatellite metastases

N3b

Four or more—at least one of which was clinically detected—or presence of any number of matted nodes; no in-transit, satellite, and/or microsatellite metastases

N3c

Two or more clinically occult or clinically detected and/or presence or any number of matted nodes, in-transit, satellite, and/or microsatellite metastases

Distant Metastasis (M) M0

No evidence of distant metastasis

M1 M1a

Evidence of distant metastasis Distant metastasis to skin, soft tissue, including muscle, and/or nonregional lymph node; LDH not recorded or unspecified M1a(0) LDH not elevated M1a(1) LDH elevated Distant metastasis to lung with or without M1a sites of disease; LDH not recorded or unspecified M1b(0) LDH not elevated M1b(1) LDH elevated Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease; LDH not recorded or unspecified M1c(0) LDH not elevated M1c(1) LDH elevated

M1c

M1d

809

American Joint Committee on Cancer Staging System for Melanoma of the

N3

M1b

Malignant Melanoma

IIID IV

T4bN3a/b/cM0 Any T, Tis, Any N, M1

Stage IIIC

T1-4bN1bM0 T1-4bN2bM0 T1-4bN2cM0

Stage IV

TanyN3M0 TanyNanyM1

Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease; LDH not recorded or unspecified M1d(0) LDH normal M1d(1) LDH elevated

Suggested staging guidelines for patients with melanoma are shown in Table 48.3. Clinical evaluation of patients with melanoma consists of inspection and palpation of the involved area of skin and the regional lymph nodes. Patients with primary lesions 1 mm thick or larger are generally staged at the time of wide local excision with sentinel lymph node biopsy. Patients with thinner lesions may still be at risk of nodal disease and may benefit from sentinel lymph node biopsy if the primary

0.9 0.8 0.7

99%

96%

96%

92%

748 1590

93%

88%

94%

88%

T4a

1150 538

86% 90%

81% 83%

T4b

691

82%

75%

T2b T3a T3b

4 5 7 8 9 10 6 Years since diagnosis Fig. 48.1 Kaplan-Meier melanoma-specific survival curves according to T subcategory for patients with stages I and II melanoma. (From Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidencebased changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:472-492.) 1

2

N 5-YR 10-YR 5225 99% 98% 2495 3254

T1b

0.6

Melanoma-specific survival probability

PATIENT EVALUATION AND STAGING

T1a T2a

0.0 0.5

10-year melanoma-specific mortality increases proportionally as the thickness of the primary tumor increases (Fig. 48.1) and as the burden of nodal disease increases27 (Fig. 48.2). For patients with documented nodal metastases, the most important prognostic feature was the number of involved lymph nodes, but primary tumor ulceration and burden of nodal disease (clinically occult compared with clinically apparent) remained of prognostic significance on multivariate analysis27 (Table 48.2). Patients with metastases are further subdivided into three distinct subgroups: those with skin, soft tissue or nonregional lymph nodes; those with non–central nervous system (CNS) visceral metastases; and those with CNS metastases.27

1.0

CNS, Central nervous system; LDH, lactate dehydrogenase; SLN, sentinel lymph node. From Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010.

3

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810

SECTION III

Disease Sites

Five-Year Survival Rates for Patients With Stage III (Nodal Metastases) Disease Stratified by Number of Metastatic Nodes, Ulceration, and Tumor Burden

TABLE 48.2

MICROSCOPIC NODAL DISEASE (NO. INVOLVED)

MACROSCOPIC NODAL DISEASE (NO. INVOLVED)

1 Node, % ± SE

No.

2-3 Nodes, % ± SE

No.

> 3 Nodes, % ± SE

No.

1 Node, % ± SE

No.

2-3 Nodes, % ± SE

No.

>3 Nodes, % ± SE

Absent

69 ± 3.7

252

63 ± 5.6

130

27 ± 9.3

57

59 ± 4.7

122

46 ± 5.5

93

27 ± 4.6

109

Present

52 ± 4.1

217

50 ± 5.7

111

37 ± 8.8

46

29 ± 5.0

98

25 ± 4.4

109

13 ± 3.5

104

Melanoma Ulceration

No.

1.0

Disease Presentation

Workup

Primary lesion < 1 mm, and Clark levels 2-3, and not ulcerated

History and physical examinationa

Primary lesion ≥ 1 mm, or Clark levels 4-5, or ulcerated

History and physical examinationa Sentinel lymph node biopsy

Microscopic nodal metastases

History and physical examinationa Chest radiograph and serum LDH level Further imaging if warranted

Macroscopic nodal metastases

History and physical examinationa Serum LDH level CT imaging of chest, abdomen, pelvis CT imaging of head and neck if primary tumor is above clavicles Consider brain MRI Further imaging if warranted

Distant metastases

History and physical examinationa Chest radiograph and serum LDH level CT imaging of chest, abdomen, pelvis CT imaging of head and neck if primary tumor is above clavicles Brain MRI Further imaging if warranted

0.2

0.4

0.6

0.8

Staging Guidelines and Diagnostic Algorithm

TABLE 48.3

N

5-YR

10-YR

N1

2669

82%

75%

N2

1354

76%

68%

N3

685

57%

47%

0.0

Melanoma-specific survival probability

SE, Standard error. From Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients. Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622-3634.

1

2

3

4 5 6 7 8 9 10 Year since diagnosis Fig. 48.2 Kaplan-Meier melanoma-specific survival curves according to N catagories. (From Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:472-492.)

lesion is ulcerated, is associated with satellitosis, or is Clark level 4 or 5. If the sentinel node is involved, CT scanning of the lungs, abdomen, and pelvis is warranted as a baseline evaluation.29 Chest radiography plays little or no role in the initial management of patients with localized disease. Positron emission tomography (PET) scans and magnetic resonance imaging (MRI) of the brain are indicated for patients with multiple or clinically palpable nodal metastases and for all patients with documented distant disease.

PRIMARY THERAPY AND RESULTS Primary Tumor Standard treatment for localized melanoma (stages I and II) is wide local excision. Wide local excision is a therapeutic intervention, but it also establishes tissue diagnosis and provides accurate microstaging. Six randomized trials have examined the appropriate width of excision for primary melanoma.30-34 The recommended skin margins vary from 1 cm to 2 cm depending on lesion thickness and location.34,35 Sentinel lymph node biopsy is recommended according to the aforementioned criteria (see the earlier section entitled “Patient Evaluation and Staging”). This diagnostic procedure involves injection of the primary site with a dye and radiotracer-tagged colloid that localizes to the first draining lymph node or nodes after a short period of time. These nodes are then removed, serially sectioned, and examined with immunohistochemical staining techniques. Patients without involved

a

Attention must be paid to comprehensive skin and nodal basin examination. CT, Computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging.

lymph nodes are spared a comprehensive lymph node dissection. The procedure provides not only accurate nodal staging but may be sufficiently therapeutic to allow patients with a positive sentinel node to undergo serial ultrasound follow-up evaluation in lieu of complete lymph node dissection or nodal radiotherapy. The rate of nodal spread according to primary thickness is shown in Table 48.4; it is less than 5% for lesions 0.75 mm or smaller, 10% for lesions 0.76 to 1.5 mm, 20% for lesions 1.51 to 4 mm, and 30% to 50% for lesions larger than 4 mm.36-47 Radiotherapy is not indicated as definitive management of primary malignant melanoma. An exception to this rule is large facial lentigo maligna melanomas for which wide surgical resection may require extensive reconstruction. In a series of 25 patients treated at the Princess Margaret Hospital with primary radiotherapy using orthovoltage x-rays (100-250 KeV) and followed for a period of 6 months to 8 years (median, 2 years), local control was achieved in 23 patients (92%).48 Regimens used were 35 Gy in 5 fractions over 1 week for lesions smaller than

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CHAPTER 48

Malignant Melanoma

811

Percentage of Patients With Positive Sentinel Lymph Nodes by Primary Melanoma Thickness

TABLE 48.4

PATIENTS (%) BY TUMOR THICKNESS (mm) Study Krag et al.36 37

≤ 0.75

0.76-1.5

1.51-4

>4

≤1

1.01-2.0

2.01-4.0

>4

4

3

22

27

—

—

—

—

0

7

18

30

—

—

—

—

Mraz-Gernhard et al.38

—

—

22

28

—

—

—

—

Haddad et al.39

0

15

19

29

—

—

—

— —

Joseph et al.

40

5

5

19

34

—

—

—

Statius Muller et al.41

0

15

26

57

—

—

—

—

Bachter et al.42

—

7

21

44

—

—

—

—

Blumenthal et al.43

—

9

64

27

—

—

—

—

Gershenwald et al.

44

2

4

17

39

—

—

—

—

Vuylsteke et al.45

—

—

—

—

6

16

34

55

McMasters et al.46

—

—

—

—

—

15

30

45

Rousseau et al.47

—

—

—

—

4

12

28

44

Weighted average (%)

1

7

21

33

4

14

29

45

Caprio et al.

From Bonnen MD, Ballo MT, Myers JN, et al. Elective radiotherapy provides regional control for patients with cutaneous melanoma of the head and neck. Cancer. 2003;100:383-389.

Local Recurrence After Surgery Alone for Primary Tumor According to High-Risk Pathological Characteristics

TABLE 48.5

Characteristic

%

References

Breslow thickness ≥4 mm

6-14

35,49-53

Head and neck location

5-17

32,49,50,52,54-58

Ulceration

10-17

32,35,50,52

Satellitosis

1416

59,60

Modified from Ballo MT, Ang KK. Radiotherapy for cutaneous malignant melanoma. Rationale and indications. Oncology. 2004;18:99–107.

3 cm, 45 Gy in 10 fractions over 2 weeks for primary tumors of 3 cm to 4.9 cm, and 50 Gy in 15 to 20 fractions over 3 to 4 weeks for tumors 5 cm or larger. Radiotherapy is rarely recommended as an adjuvant to wide local excision, as local recurrence rates are generally low (< 10%). High-risk features—such as primary thickness greater than 4 mm, head or neck primary site, and primary ulceration or satellitosis—have been reported to significantly increase the risk of local recurrence, but few series report recurrence rates much higher than 15%32,49-60 (Table 48.5). One variant of melanoma, the desmoplastic subtype with neurotropism, has historically been associated with recurrence rates as high as 50% after wide local excision alone.61-68 In a nonrandomized series specifically examining the role of radiotherapy in 150 patients with desmoplastic melanoma, a recurrence rate of 24% (14 of 59 patients) was reported without irradiation and 7% (5 of 71 patients) with irradiation.67

Regional Nodes

Elective Nodal Treatment The role of elective nodal therapy at the time of wide local excision of the primary tumor has been disputed extensively. Advocates of elective lymph node dissection argued that melanoma progresses in a stepwise

fashion from the primary lesion to regional nodes and then to distant sites, whereas opponents suggested that positive regional lymph nodes are only indicators of systemic spread. Results of an early nonrandomized study by the Sydney Melanoma Unit69 involving 1319 patients suggested that elective lymph node dissection improved the survival rates of patients with intermediately thick melanomas (0.76-4.0 mm); however, four prospective Phase III trials did not confirm these results.70-73 The surgical community has embraced sentinel lymph node biopsy with selective lymph node dissection as a replacement to elective lymph node dissection, despite no reported therapeutic benefits in terms of OS. This choice depends on several lines of reasoning.74,75 The status of the sentinel lymph node is a powerful determinant of subsequent survival and provides prognostic information to the patient; it identifies patients with early regional lymph node metastases that might benefit from nodal dissection as a way of avoiding advanced regional recurrence; and it identifies patients who may be candidates for investigational systemic therapy trials. Morton et al.76 randomly assigned 1269 patients with intermediatethickness primary melanoma to wide excision and postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred or to wide excision and sentinel lymph node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy. This trial, known as the Multicenter Selective Lymphadenectomy Trial (MSLT-I), reported improved 5-year disease-free survival (DFS) when patients undergoing sentinel lymph node biopsy with selective lymph node dissection were compared with patients who were observed. There were no differences in melanoma-specific survival. In a subgroup analysis confined to patients with nodal metastases, there was improved melanoma-specific survival in patients undergoing immediate lymphadenectomy compared with those in whom delayed lymphadenectomy was required for recurrent disease. Although the validity of this postrandomization analysis has been questioned by many,77 the prognostic information provided by sentinel lymph node biopsy was confirmed. A second Multicenter Selective Lymphadenectomy Trial (MSLT-II) compared ultrasound in the staging of patients who are clinically node negative and randomized patients with involved sentinel lymph nodes to completion lymph node dissection or observation

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812

SECTION III

Disease Sites

with periodic ultrasonography.78 Immediate completion lymph node dissection was not associated with increased melanoma-specific survival; however, it did increase the rate of regional disease control. Although sentinel lymph node biopsy remains the standard approach to patients with early-stage melanoma, there are some patients with significant medical comorbidities for whom detailed prognostic information is of little relevance and enrollment in a clinical trial is unlikely. For these patients, elective nodal irradiation is superior to observation, which places the patients at unnecessary risk of regional recurrence.79 In a retrospective analysis from the M. D. Anderson Cancer Center, Bonnen et al.80 reviewed 157 patients with stage I or II cutaneous melanoma of the head and neck who received elective regional irradiation instead of lymph node dissection after wide local excision of the primary site. Indications for regional irradiation included primary thickness of 1.5 mm or greater or Clark level 4 or 5 disease. There were 15 regional failures (89% regional control at 10 years) despite estimation that 33 to 40 patients had microscopically involved regional nodes (based on data from Table 48.4). Six percent of patients required medical care for a clinically significant complication, with moderate hearing loss being the most common complaint (5 patients). Although elective nodal irradiation has the same limitations as elective lymph node dissection, it can effectively provide regional control for patients at risk for regional recurrence while avoiding surgical dissection.

Therapeutic Nodal Approaches For most patients, nodal dissection results in more than an 80% likelihood of regional control. For patients with certain clinicopathological features, however, the surgical literature suggests regional recurrence rates as high as 80% and, therefore, a need for additional regional therapy. Although nodal extracapsular extension remains the strongest predictor of subsequent regional recurrence after surgery alone, several series have reported elevated recurrence rates if at least four lymph nodes are involved, the lymph nodes measure at least 3 cm in diameter, they are located in the cervical basin, or they are detected during a therapeutic dissection (as opposed to elective dissection or at the time of sentinel lymph node biopsy).81-86 Although less well described in the literature, nodal recurrence after previous dissection for involved regional nodes also places the patient at increased risk of subsequent relapse. Patients with 1 of these 6 clinicopathological features have a 30% to 50% rate of subsequent regional recurrence after nodal dissection alone (Table 48.6). There are substantial retrospective data supporting the effectiveness of regional radiotherapy for patients with one of the aforementioned high-risk features. Relapse rates after adjuvant radiotherapy range from 5% to 20%, compared with the much higher range seen without adjuvant irradiation.84,87-97 The Trans-Tasman Radiation Oncology Group and the Australia and New Zealand Melanoma Trials (TROG/ANZMTG) group completed a randomized trial comparing nodal observation with radiotherapy after lymphadenectomy in patients with palpable nodal disease and high-risk features.98 High risk features included 1 or more involved parotid nodes, 2 or more involved cervical or axillary nodes, or 3 or more involved inguinal nodes; presence of extranodal tumor spread; or the maximum diameter of the largest metastatic lymph node was 3 cm or more (for a cervical node) or 4 cm or more (for an axillary or inguinal node). Patients received 48 Gy in 20 fractions over 4 weeks to standard conventional fields. Although there was no improvement in OS, this trial reports acceptable acute toxicity and 5-year regional control of 77% with radiotherapy compared with 60% without it (p = 0.023). Tolerance to adjuvant radiotherapy is generally excellent and early toxic effects are infrequent and minor. Most patients receiving comprehensive neck irradiation experience transient parotid swelling after the first radiation fraction that typically lasts 1 day. For most sites, brisk erythema with patches of moist skin desquamation, particularly

Regional Relapse Rates After Surgery Alone for Nodal Disease According to High-Risk Pathological Characteristics

TABLE 48.6

Nodal Characteristic

Study

Year

Relapse Rate (%)

Extracapsular extension

Calabro et al.81 Lee et al.82 Monsour et al.83 Shen et al.84

1989 2000 1993 2000

28a 63a 54 31a

≥ 4 involved lymph nodes

Calabro et al.81 Lee et al.82 Miller et al.85

1989 2000 1992

17-33a 46-63 53a

Lymph node ≥ 3 cm

Lee et al.82 Shen et al.84

2000 2000

42-80 14

Cervical lymph node location

Bowsher et al.86 Lee et al.82 Monsour et al.83

1986 2000 1993

33 43a 50

Therapeutic dissection

Byers55 O’Brien et al.57 Lee et al.82 Shen et al.84

1986 1991 2000 2000

50 34 36 20

a

Significant on multivariate analysis.

within the axilla and the groin, are common. In the TROG/ANZMTG randomized trial, late radiation-related complications were distinctly uncommon, except for an increase in subcutaneous fibrosis in the adjuvant radiotherapy arm. Clinically significant extremity lymphedema (requiring some form of medical management, such as a compressive sleeve or physical therapy) occurs in a minority of patients. It is more common after groin dissection than after cervical or axillary dissection, and it appears to moderately increase further in the setting of adjuvant irradiation, particularly for patients with locally advanced groin metastases86,94-103 (Table 48.7). In one series examining the timing of lymphedema, however, half of the patients had developed lymphedema before starting adjuvant groin irradiation.96 This suggested that the higher rate of lymphedema was, to some extent, a consequence of locally advanced disease and its surgical treatment and not solely the result of the radiotherapy. In this same series, there was a correlation between body mass index and the development of chronic lymphedema, suggesting that patient factors need to be incorporated into rational treatment guidelines.96 In the randomized trial there were no differences in quality of life, although regional symptoms were worse in those patients receiving radiotherapy.

Distant Disease and Adjuvant Systemic Therapy A great amount of resources has been directed toward developing effective systemic therapy for patients with melanoma. Although surgical resection with selective use of adjuvant radiotherapy results in satisfactory local and regional control for most patients, even thin melanomas have significant metastatic potential. Most early research initiatives focused on interferon alpha-2b (IFN) or vaccines, or combinations of both. European investigators examined the role of low-dose IFN therapy, and US investigators focused primarily on high-dose regimens. Three randomized Eastern Cooperative Oncology Group (ECOG) trials were used to support the administration of adjuvant IFN to patients with a high risk of recurrence.104-106 The first trial (ECOG 1684) enrolled 287 patients with primary melanomas thicker than 4 mm without palpable nodes, lymph node

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CHAPTER 48

Clinically Significant Lymphedema According to Site of Regional Disease and Treatment

TABLE 48.7

Nodal Basin Cervical

Axilla

Groin

SURGERY AND RADIATIONa

SURGERY ALONEa Study

Year

%

Urist et al.99 Wrightson et al.100

1983 2003

0 0

Urist et al.99 Wrightson et al.100 Bowsher et al.86

1983 2003

1 5

1986

3

Bowsher et al.86 Karakousis et al.101 Hughes et al.102 Wrightson et al.100

1986

18

1994

10

2000

19

2003

32

Study

Year

%

Ballo et al.94 Burmeister et al.103 Burmeister et al.97

2002 2002

0 0

2006

0

Ballo et al.95 Burmeister et al.103 Burmeister et al.97

2003 2002

16 7

2006

9

Burmeister et al.103 Ballo et al.96

2002

45

2004

27

Burmeister et al.97

2006

19

a

Clinically significant lymphedema required some form of medical management (e.g., compressive device or physical therapy).

metastasis detected at elective lymph node dissection, a clinically palpable regional lymph node with primary melanoma of any stage, or regional lymph node recurrence at any interval after appropriate surgery for primary melanoma of any depth.104 This prospective study revealed a significant prolongation of relapse-free survival (RFS; 5-year actuarial, 37% vs. 26%; p = 0.002) and OS (5-year, 46% vs. 37%; p = 0.02) associated with high-dose IFN therapy. The second trial (ECOG 1690) compared high-dose IFN for 1 year or low-dose IFN for 2 years versus observation and reported a modest improvement in RFS only.105 A third trial (ECOG 1694) comparing high-dose IFN with a ganglioside GM2 melanoma vaccine suggested that the only benefit of IFN was in the patients with T4N0 disease.106 Debate over the merits of routine IFN therapy has focused on the inconsistent subgroup analysis findings and concerns about the toxicity of IFN, but it is still not unreasonable to recommend 1 year of IFN for patients with thick tumors (> 4 mm thick), ulceration, a high mitotic rate (≥ 1/mm2), or nodal metastases, although there are now more effective regimens for the latter group (see later discussion).107 Frequently observed regression of primary melanoma, and even occasionally metastatic disease, has suggested an important role for the immune system. This has fueled a long-standing search for active immunotherapies against melanoma. Interleukin-2 has shown durable response rates in 15% of patients and is considered a reasonable first option for patients with metastatic disease, with sufficient performance status to tolerate its significant toxicity. Until recently, none of the immunological approaches had demonstrated clinical efficacy in terms of OS. However, the US Food and Drug Administration recently approved new drugs as treatment for metastatic melanoma based on Phase III trial data reporting improvement in OS. The BRAF kinase inhibitor vemurafenib blocks the mitogen-activated protein kinase (MAPK) signaling pathway that normally promotes

Malignant Melanoma

813

cell proliferation and contains BRAF kinase as one of its components. Oncogenic (i.e., abnormal) BRAF kinase has been reported in almost 50% of cutaneous melanomas resulting in uncontrolled activation of the MAPK pathway. In 675 patients randomized to either vemurafenib or dacarbazine, there was an improvement in the 6-month OS (84% vs. 64%, p < 0.001) with vemurafenib and a response rate of 48%.108 Vemurafenib should be considered in patients with untreated metastatic disease, but genetic mutation analysis is essential to verify that the appropriate BRAF mutation (V600E) is present. A second BRAF inhibitor, dabrafenib, was also tested against dacarbazine in 250 patients with the V600E mutation and resulted in improved progression-free survival.109 The human monoclonal antibody ipilimumab blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and stimulates an antitumor T-cell response. In 676 patients with stage III or IV disease, ipilimumab was given either alone or with gp100 vaccine and compared to a third group receiving gp100 vaccine alone. The median survival was improved in both groups receiving the ipilimumab when compared to the gp100 group (10 vs. 6.4 months, p < 0.001).110 In a second trial of 502 patients with untreated metastatic melanoma, ipilimumab was given with dacarbazine and compared to dacarbazine plus placebo and resulted in significantly improved OS at 3 years (20.7% vs. 12.2%, p < 0.001).111 Ipilimumab can be considered in patients with untreated receptor-negative (e.g., BRAF, cKit) metastatic disease. Given the dramatic results reported for patients with metastatic disease, ipilimumab has also been tested in the adjuvant setting for patients with stage III disease. In a randomized Phase III trial of ipilimumab or placebo in 951 patients with stage III cutaneous melanoma, the RFS was 40.8% in the ipilimumab group compared with 30.3% in the placebo group (p < 0.001) and the OS was 65.4% and 54.4% (p < 0.001), respectively.112 However, grade 3 or 4 toxicity was observed in 54.1% of the ipilimumab patients and there were 5 immune-related deaths. As an alternative to ipilimumab, the PD-1 inhibitor nivolumab has now been compared in a Phase III randomized trial of 906 patients with completely resected stage IIIB, IIIC, or IV disease.113 The RFS was 70.5% in the nivolumab group and 60.8% in the ipilimumab group (p < 0.001) while the treatment-related grade 3 or 4 adverse events were only 14.4% in the nivolumab group and 45.9% in the ipilimumab group. When temporally combined with radiation, ipilimumab has been reported to result in regression of disease distant from the irradiated site, suggesting the possibility of an immunologically mediated abscopal effect.114 Trials involving combinations of targeted therapy and radiotherapy are underway to determine whether responses can be improved.

LOCALLY ADVANCED DISEASE AND PALLIATION Radiotherapy can reduce symptoms for more than 80% of patients with advanced inoperable or metastatic disease. The recommended dose-fractionation schedule for external beam therapy depends on the tumor’s location and the patient’s life expectancy. The most frequently used regimens are 30 Gy given in 10 fractions over 2 weeks for skeletal or multiple cerebral metastasis, 36 Gy in 12 fractions for pathological fracture of extremity bones (after internal fixation), 50 Gy in 25 fractions for solitary metastases after resection or radiosurgery (brain), and 36 Gy in 6 fractions over 3 weeks (twice each week) for dermal or subcutaneous melanoma masses or for neck node metastasis. Conventional fractionation schedules may always be considered if tumor lies near critical structures. The use of stereotactic ablative radiotherapy has gained considerable attention recently for the management of oligometastases from melanoma in the brain, lung, bones, spine, and liver. Dose schedules vary according to the tumor volume and site of disease but are generally well tolerated.

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814

SECTION III

Disease Sites

RADIOTHERAPY TECHNIQUES Target Volume Adjuvant radiotherapy for primary melanoma should encompass the primary site scar with a 3- to 4-cm margin, depending on the anatomic site and surrounding critical structures. The target volume for patients receiving elective nodal irradiation for head and neck primary sites includes the primary lesion, preauricular and postauricular lymph nodes (for high facial and scalp primary tumors), and the ipsilateral lymph nodes from levels 1 through 5, including the ipsilateral supraclavicular fossa (Fig. 48.3). For patients receiving therapeutic nodal irradiation for one of the aforementioned high-risk nodal features, the target volume is essentially the same, including the dissection scar, except that the primary tumor bed is irradiated only if regional relapse occurred less than 1 year after excision of the primary disease. For axillary nodal metastases, radiation fields include the axillary lymph nodes from levels 1 through 3 (Fig. 48.4). The supraclavicular fossa and low cervical lymph nodes may be included if they exhibit bulky high axillary disease but otherwise do not need to be treated. At a minimum, a field for groin lymph node metastases covers the nodal regions that have pathologically confirmed nodal disease and usually includes the entire surgical scar (Fig. 48.5). Judgment must be used regarding elective irradiation of adjacent nodal regions (i.e., external iliac coverage in the setting of confirmed inguinal disease) because of concern about the increased toxicity associated with groin irradiation, particularly for patients who are obese. Unlike the cervical or axillary regions, where electrons and flashing photon fields, respectively, generally deliver a full dose to the skin, special attention must be paid to delivering a full dose to the groin scar.

treated with two or three fields depending on the distance between the primary tumor and the parotid nodes. Matching electron fields are used to treat the primary site, the parotid and lower neck nodes. The junctions between the fields are moved (0.5-1.0 cm) after the second and fourth treatments to improve dose homogeneity. A tissue-equivalent beveled bolus is placed over a line connecting the lateral canthus and the mastoid tip to spare the temporal lobe, and an additional piece of bolus may be placed over the larynx. The thickness of this bolus depends on the electron energy used. Elective or adjuvant radiation treatment is administered to a total dose of 48 Gy in 20 daily fractions (Monday through Friday) or 30 Gy at 6 Gy per fraction, twice each week (Monday and Thursday or Tuesday and Friday) over 2.5 weeks. Electron doses are specified at maximal depth dose (Dmax) and care is always taken to ensure that the dose to the spinal cord does not exceed 40 Gy at 2.4 Gy per fraction or 24 Gy at 6 Gy per fraction. For axillary treatment, the patient is immobilized in a supine position with the treatment arm akimbo. Laser lines that include the upper and lower torso ensure a reproducible treatment setup. Typically, anterior and posterior photon fields are used to deliver the dose to the levels 1, 2, and 3 axillary lymph nodes. Dose homogeneity is ensured using a field-within-a-field technique (using multileaf collimators). The radiation dose is 48 Gy in 20 daily fractions or 30 Gy at 6 Gy per fraction, twice each week over 2.5 weeks. If necessary, the dose may be prescribed to a volume such that the isocenter dose is 3% to 6% lower than the

Setup, Field Arrangement, and Dose-Fractionation Schedule For patients with cervical disease, an open-neck position provides access to the primary site and parotid and cervical lymphatics, allowing treatment delivery with electrons of appropriate energy. Lesions of frontal, temporal, and preauricular areas; the auricle; and the cheek are usually

Fig. 48.3 Typical external beam radiation treatment field for a patient with cervical lymph node metastases. A similar field is used for a patient requiring elective irradiation. (Courtesy NL Visual Art © 2005, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.)

Fig. 48.4 Typical external beam radiation treatment field for a patient with axillary lymph node metastases. Numbers correspond to the ribs. The upper border of the field typically ends at the superior aspect of the clavicle, but the supraclavicular and cervical lymph nodes may be irradiated if clinically involved. AP/PA, Anteroposterior/posteroanterior. (Courtesy NL Visual Art © 2005, University of Texas M. D. Anderson Cancer Center, Houston, Texas.)

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CHAPTER 48

Malignant Melanoma

815

disease would predict a poor OS. Similar techniques used in the postoperative setting can be used with surgery to follow 10 to 12 weeks later if the patient continues to have localized disease.

Patient Care During and After Radiotherapy Electron field

AP/PA photons

Electron field

Patients are informed of the specific acute side effects of treatment, such as mucositis and parotiditis after irradiation of the cervical basin and moist desquamation after irradiation of the axilla or groin. When moist desquamation occurs, cleaning the area with mild soap and water to prevent secondary infection is recommended. Regular follow-up examinations include evaluation of the treated area for late complications and a search for potential relapse. The most common late side effects include hypopigmentation, hyperpigmentation, telangiectasia, and skin and subcutaneous tissue atrophy. After cervical irradiation, monitoring for subclinical hypothyroidism and the signs and symptoms of hearing loss, although relatively uncommon, is essential. Acute lymphedema is managed early and aggressively with physical therapy and compressive devices to avoid chronic lymphedema.

TREATMENT ALGORITHMS AND CLINICAL TRIALS Elective Nodal Treatment

Fig. 48.5 Typical external beam radiation field for a patient with groin lymph node metastases. AP/PA, Anteroposterior/posteroanterior. (Courtesy NL Visual Art © 2005, University of Texas M. D. Anderson Cancer Center, Houston, Texas.)

prescribed dose, as dose heterogeneity can result in unacceptable toxicity at these doses per fraction. To irradiate the groin, patients are immobilized in a unilateral frog-leg position, eliminating any inguinal skin folds. Photons or electrons can be used depending on the patient’s contour, extent of surgical bed, and whether the pelvic nodes are included as part of the target volume. Lower-energy electron fields can be used superiorly and inferiorly to cover the full extension of the scar. If a photon technique is selected, a tissue-equivalent bolus is used over the scar, and the dose is weighted anteriorly. Doses are either 48 Gy in 20 daily fractions or 30 Gy at 6 Gy per fraction, twice each week over 2.5 weeks. Appropriate reductions are made to limit the small-bowel dose to 40 Gy at 2.4 Gy per fraction or 24 Gy at 6 Gy per fraction. For all sites of regional disease, intensity-modulated radiotherapy (IMRT) may also be used to cover the aforementioned regions.115-117 Just as it has for nonmelanoma diagnoses, IMRT has consistently shown lower dose heterogeneity and lower doses to critical structures. These dosimetric advantages, however, have yet to translate into truly meaningful reductions in clinical toxicity; thus, the decision to use one technique over another should be determined by the experience of the clinician.

Sentinel lymph node biopsy has obviated routine elective treatment of the draining lymphatics of patients with thick primary melanomas. Although retrospective studies of elective irradiation have verified the effectiveness of this approach, sentinel lymph node biopsy has become accepted as the standard of care. For patients whose medical comorbidities preclude sentinel lymph node biopsy (and the option of comprehensive dissection if the sentinel node is involved), elective nodal irradiation is favored over observation, which reduces the risk of regional recurrence with its associated morbidity. Although this approach is still investigational, it is suggested that patients with a positive sentinel lymph node biopsy result who refuse subsequent dissection be referred for regional irradiation. Observation in the setting of an involved sentinel lymph node is not appropriate, and systemic therapy is not a substitute for completing regional therapy.

Therapeutic Nodal Approaches Therapeutic nodal dissection is the standard treatment for patients with lymph node metastases; available data support the use of systemic, high-dose adjuvant IFN. Adjuvant postoperative irradiation is also indicated to reduce the regional recurrence rate in patients with high-risk clinicopathological features. Although some of the same features that predict regional failure, such as extracapsular extension and number of involved lymph nodes, also predict distant failure, the importance of regional control should not be underestimated, and radiotherapy should not be systematically avoided because the risk of distant metastasis is perceived to be too high. We have developed radiation treatment guidelines that account for the complex clinical interaction between the risks of regional recurrence, regional toxicity, and distant metastatic disease (Fig. 48.6). For patients with cervical disease, the threshold for irradiation may be lowered to include those with at least two involved lymph nodes or those with tumors measuring at least 2 cm in diameter. For patients with groin metastases, the threshold may be raised so that combinations (two or more) of the high-risk features must be present before adjuvant irradiation is given.

Radiotherapy for Bulky or Inoperable Nodal Disease

Acknowledgments

Radiotherapy can be considered for bulky or inoperable nodal disease in which surgery is likely to be incomplete or the extent of the nodal

Thanks go to James D. Cox, MD for providing vision, support, and encouragement.

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SECTION III

Disease Sites

Clinically Apparent Nodal Metastases

Cervical

Axillary

Any 1 indication ECE !2 cm !2 involved Recurrent disease

Any 1 indication ECE !3 cm !4 involved Recurrent disease

BMI "25 kg/m2

Groin/pelvis

BMI !25 kg/m2

ECE plus 1 indication Any 1 indication !3 cm ECE !4 involved !3 cm !4 involved Recurrent disease Fig. 48.6 Treatment algorithm for patients with nodal metastases from melanoma. Typically, the threshold for irradiating patients with cervical lymph node metastases is lower than for those with inguinal lymph node metastases, for which the risk of long-term lymphedema is higher. BMI, Body mass index; ECE, extracapsular extension.

CRITICAL REFERENCES 1. Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys. 1986;12:1839–1842. 2. Ballo MT, Ang KK. Radiation therapy for malignant melanoma. Surg Clin North Am. 2003;83:323–342. 3. Chang DT, Amdu RJ, Morris CG, et al. Adjuvant radiotherapy for cutaneous melanoma. Comparing hypofractionation to conventional fractionation. Int J Radiat Oncol Biol Phys. 2006;66:1051–1055. 8. Tucker MA, Goldstein AM. Melanoma etiology. Where are we? Oncogene. 2003;22:3042–3052. 27. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma Staging: evidence-based changes in the American Joint Committee on Cancer eight edition cancer staging manual. CA Cancer J Clin. 2017;67:472–492. 34. Thomas JM, Newton-Bishop J, A’Hern R, et al. Excision margins in high-risk malignant melanoma. N Engl J Med. 2004;350:757–766. 45. Vuylsteke RJ, van Leeuwen PA, Statius Muller MG, et al. Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection. Long-term follow up results. J Clin Oncol. 2003;21:1057–1065. 46. McMasters KM, Wong SL, Edwards MJ, et al. Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery. 2001;130:151–156. 67. Guadagnolo BA, Prieto V, Weber R, et al. The role of adjuvant radiotherapy in the management of desmoplastic melanoma. Cancer. 2014;120(9):1361–1368. doi:10.1002/cncr.28415. 72. Balch CM, Soong S, Ross MI, et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0-4.0 mm). Ann Surg Oncol. 2000;7:87–97.

73. Cascinelli N, Morabito A, Santinami M, et al. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk. A randomised trial. Lancet. 1998;351:793–796. 75. McMasters KM. What good is sentinel lymph node biopsy for melanoma if it does not improve survival? Ann Surg Oncol. 2004;11:810–812. 76. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel–node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307–1317. 77. Thomas JM, A’Hern RP, Grichnik JM, et al. Sentinel-node biopsy in melanoma. N Engl J Med. 2007;356:418. 78. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastases in melanoma. N Engl J Med. 2017;376:2211–2222. 80. Bonnen MD, Ballo MT, Myers JN, et al. Elective radiotherapy provides regional control for patients with cutaneous melanoma of the head and neck. Cancer. 2003;100:383–389. 82. Lee RJ, Gibbs JF, Proulx GM, et al. Nodal basin recurrence following lymph node dissection for melanoma. Implications for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys. 2000;46:467–474. 94. Ballo MT, Strom EA, Zagars GK, et al. Adjuvant irradiation for axillary metastases from malignant melanoma. Int J Radiat Oncol Biol Phys. 2002;52:964–972. 95. Ballo MT, Bonnen MD, Garden AS, et al. Adjuvant irradiation for cervical lymph node metastases from melanoma. Cancer. 2003;97:1789–1796. 96. Ballo MT, Zagars GK, Gershenwald JE, et al. A critical assessment of adjuvant radiotherapy for inguinal lymph node metastases from melanoma. Ann Surg Oncol. 2004;11:1079–1084. 98. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lympadenectomy for melanoma: a randomized trial. Lancet Oncol. 2012;13:589–597. 105. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alpha-2b in high-risk melanoma. First analysis of intergroup trial E1690/s9111/c9190. J Clin Oncol. 2000;18:2444–2458. 107. Kaufman HL, Kirkwood JM, Hodi FS, et al. The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol. 2013;10(10):588–598. 108. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516. 109. Hauschild A, Grob J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–365. 110. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723. 111. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–2526. 112. Eggermont AMM, Chiarion-Sileni V, Grob J, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–1855. 114. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–931.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 48

REFERENCES 1. Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys. 1986;12:1839–1842. 2. Ballo MT, Ang KK. Radiation therapy for malignant melanoma. Surg Clin North Am. 2003;83:323–342. 3. Chang DT, Amdu RJ, Morris CG, et al. Adjuvant radiotherapy for cutaneous melanoma. Comparing hypofractionation to conventional fractionation. Int J Radiat Oncol Biol Phys. 2006;66:1051–1055. 4. Siegal RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. 5. Beral V, Evans S, Shaw H, et al. Cutaneous factors related to the risk of malignant melanoma. Br J Dermatol. 1983;109:165–172. 6. Gellin GA, Kopf AW, Garfinkel L. Malignant melanoma. A controlled study of possibly associated factors. Arch Dermatol. 1969;99:43–48. 7. English DR, Armstrong BK, Kricker A, et al. Sunlight and cancer. Cancer Causes Control. 1997;8:271–283. 8. Tucker MA, Goldstein AM. Melanoma etiology. Where are we? Oncogene. 2003;22:3042–3052. 9. Hussussian CJ, Struewing JP, Goldstein AM, et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994;8:15–21. 10. Aitken J, Welch J, Duffy D, et al. CDKN2A variants in a populationbased sample of Queensland families with melanoma. J Natl Cancer Inst. 1999;3:446–452. 11. Bishop DT, Demanais F, Goldstein AM, et al. Geographical variation in the penetrance of CDKN2A mutation in melanoma. J Natl Cancer Inst. 2002;94:894–903. 12. Bliss JM, Ford D, Swerdlow AJ, et al. Risk of cutaneous melanoma associated with pigmentation characteristics and freckling. Systematic overview of 10 case controlled studies. The International Melanoma Analysis Group (IMAGE). Int J Cancer. 1995;62:367–376. 13. Moyer VA. Behavioral counseling to prevent skin cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;157:59–65. 14. Gruber SB, Barnhill RL, Stenn KS, et al. Nevomelanocytic proliferations in association with cutaneous melanoma. A multivariate analysis. J Am Acad Dermatol. 1989;21:773–780. 15. Clark WH, Ainsworth AM, Bernardino EA. The developmental biology of primary human malignant melanomas. Semin Oncol. 1975;2:83–103. 16. McGovern VJ, Murad TM. Pathology of melanoma: an overview. In: Balch CM, Milton GW, eds. Cutaneous Melanoma: Clinical Management and Treatment Results Worldwide. Philadelphia: JB Lippincott; 1985:29–53. 17. Barnhill RL, Mihm MC. Histopathology of malignant melanoma and its precursor lesions. In: Balch CM, Houghton AN, Milton GW, et al, eds. Cutaneous Melanoma. Philadelphia: JB Lippincott; 1992:234–263. 18. Urist MM, Balch CM, Soong SJ. Head and neck melanoma in 534 clinical stage I patients. A prognostic factor analysis and results of surgical treatment. Ann Surg. 1984;200:769–775. 19. Clark WH, Mihm MC. Lentigo maligna and lentigo-maligna melanoma. Am J Pathol. 1969;55:39–67. 20. Reed RJ. The pathology of human cutaneous melanoma. In: Malignant Melanoma I. The Hague: Martinus Nijhoff; 1983:85–116. 21. Arrington JH, Reed RJ, Ichinose H, et al. Plantar lentiginous melanoma. A distinctive variant of human cutaneous malignant melanoma. Am J Surg Pathol. 1977;1:131–143. 22. Coleman WP, Loria PR, Reed RJ, et al. Acral lentiginous melanoma. Arch Dermatol. 1980;116:773–776. 23. Krementz ET, Feed RJ, Coleman WP, et al. Acral lentiginous melanoma. A clinicopathologic entity. Ann Surg. 1982;195:632–645. 24. Seiji M, Takahashi M. Acral melanoma in Japan. Hum Pathol. 1982;13:607–609. 25. Reintgen DS, McCarty KM, Cox E, et al. Malignant melanoma in black American and white American populations. A comparative review. JAMA. 1982;248:1856–1859. 26. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:902–908.

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27. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma Staging: evidence-based changes in the American Joint Committee on Cancer eight edition cancer staging manual. CA Cancer J Clin. 2017;67:472–492. 28. Amin MB, Edge S, Greene F, et al, eds. AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer; 2017. 29. Buzaid AC, Tinoco L, Ross MI, et al. Role of computed tomography in the staging of patients with local-regional metastases of melanoma. J Clin Oncol. 1995;13:2104–2108. 30. Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm [Erratum: N Engl J Med. 325:292, 1991]. N Engl J Med. 1988;318:1159–1162. 31. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al. Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer. 2000;89:1495–1501. 32. Balch CM, Soong S, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm versus 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8:101–108. 33. Khayat D, Rixe O, Martin G, et al. Surgical margins in cutaneous melanoma (2 cm versus 5 cm) for lesions measuring less than 2.1-mm thick. Long-term results of a large European multicentric phase III study. Cancer. 2003;97:1941–1946. 34. Thomas JM, Newton-Bishop J, A’Hern R, et al. Excision margins in high-risk malignant melanoma. N Engl J Med. 2004;350:757–766. 35. Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (>4 mm) primary melanoma. Ann Surg Oncol. 1998;5:322–328. 36. Krag DN, Meijer SJ, Weaver DL, et al. Minimal-access surgery for staging of malignant melanoma. Arch Surg. 1995;130:654–658. 37. Joseph E, Brobeil A, Glass F, et al. Results of complete lymph node dissection in 83 melanoma patients with positive sentinel nodes. Ann Surg Oncol. 1998;5:119–125. 38. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, et al. Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol. 1998;134:983–987. 39. Haddad FF, Stall A, Messina J, et al. The progression of melanoma nodal metastasis is dependent on tumor thickness of the primary lesion. Ann Surg Oncol. 1999;6:144–149. 40. Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience. The prognostic value of sentinel lymph node status in 612 stage I and II melanoma patients. J Clin Oncol. 1999;17:976–983. 41. Statius Muller MG, Borgstein PJ, Pijpers R, et al. Reliability of the sentinel node procedure in melanoma patients. Analysis of failures after long-term follow-up. Ann Surg Oncol. 2000;7:461–468. 42. Bachter D, Michl C, Büchels H, et al. The predictive value of the sentinel lymph node in malignant melanomas. Recent Results Cancer Res. 2001;58:129–136. 43. Blumenthal R, Banic A, Brand CU, et al. Morbidity and outcome after sentinel lymph node dissection in patients with early-stage malignant cutaneous melanoma. Swiss Surg. 2002;8:209–214. 44. Caprio MG, Carbone G, Bracigliano A, et al. Sentinel lymph node detection by lymphoscintigraphy in malignant melanoma. Tumori. 2002;88:S43–S45. 45. Vuylsteke RJ, van Leeuwen PA, Statius Muller MG, et al. Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection. Long-term follow up results. J Clin Oncol. 2003;21:1057–1065. 46. McMasters KM, Wong SL, Edwards MJ, et al. Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery. 2001;130:151–156. 47. Rousseau DL, Ross MI, Johnson MM, et al. Revised American Joint Committee on Cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients. Ann Surg Oncol. 2003;10:569–574.

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SECTION III

Disease Sites

48. Harwood AR. Conventional fractionated radiotherapy for 51 patients with lentigo maligna and lentigo maligna melanoma. Int J Radiat Oncol Biol Phys. 1983;9:1019–1021. 49. Urist MM, Balch CM, Soong S, et al. The influence of surgical margins and prognostic factors predicting the risk of local recurrence in 3445 patients with primary cutaneous melanoma. Cancer. 1985;55:1398–1402. 50. Ames FC, Balch CM, Reintgen D. Local recurrence and their management. In: Balch CM, Houghton AN, Milton GW, et al, eds. Cutaneous Melanoma. Philadelphia: JB Lippincott; 1992:287–294. 51. Roses DF, Harris MN, Rigel D, et al. Local and in-transit metastases following definitive excision for primary cutaneous malignant melanoma. Ann Surg. 1983;198:65–69. 52. Karakousis CP, Balch CM, Urist MM, et al. Local recurrence in malignant melanoma. Long-term results of the multiinstitutional randomized surgical trial. Ann Surg Oncol. 1996;3:446–452. 53. Ng AK, Jones WO, Shaw JH. Analysis of local recurrence and optimizing excision margins for cutaneous melanoma. Br J Surg. 2001;88:137–142. 54. Neades GT, Orr DJ, Hughes LE, et al. Safe margins in the excision of primary cutaneous melanoma. Br J Surg. 1993;80:731–733. 55. Byers RM. The role of modified neck dissection in the treatment of cutaneous melanoma of the head and neck. Arch Surg. 1986;121:1338–1341. 56. Loree TR, Spiro RH. Cutaneous melanoma of the head and neck. Am J Surg. 1989;158:388–391. 57. O’Brien CJ, Coates AS, Petersen-Schaefer K, et al. Experience with 998 cutaneous melanomas of the head and neck over 30 years. Am J Surg. 1991;162:310–314. 58. Fisher SR, O’Brien CJ. Head and neck melanoma. In: Balch CM, Houghton AN, Sober AJ, et al, eds. Cutaneous Melanoma. St Louis: Quality Medical Publishing; 1998:163–174. 59. Kelly JW, Sagebiel RW, Calderon W, et al. The frequency of local recurrence and microsatellites as a guide to reexcision margins for cutaneous malignant melanoma. Ann Surg. 1984;200:759–763. 60. Leon P, Daly JM, Synnestvedt M, et al. The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg. 1991;126:1461–1468. 61. Egbert B, Kempson R, Sagebiel R. Desmoplastic malignant melanoma. A clinicohistopathologic study of 25 cases. Cancer. 1988;62:2033–2041. 62. Beenken S, Byers R, Smith JL, et al. Desmoplastic melanoma. Arch Otolaryngol Head Neck Surg. 1989;115:374–379. 63. Smithers BM, McLeod GR, Little JH. Desmoplastic melanoma. Patterns of recurrence. World J Surg. 1992;16:186–190. 64. Calson JA, Dickersin GR, Sober AJ, et al. Desmoplastic neurotropic melanoma. A clinicopathologic analysis of 28 cases. Cancer. 1995;75:478–494. 65. Quinn MJ, Crotty KA, Thompson JF, et al. Desmoplastic and desmoplastic neurotropic melanoma. Experience with 280 patients. Cancer. 1998;83:1128–1135. 66. Payne WG, Kearney R, Wells K, et al. Desmoplastic melanoma. Am Surg. 2001;67:1004–1006. 67. Guadagnolo BA, Prieto V, Weber R, et al. The role of adjuvant radiotherapy in the management of desmoplastic melanoma. Cancer. 2014;120(9):1361–1368. doi:10.1002/cncr.28415. 68. Jaroszewski DE, Pockaj BA, DiCaudo DJ, et al. The clinical behavior of desmoplastic melanoma. Am J Surg. 2001;182:590–595. 69. Milton GW, Shaw HM, McCarthy WH, et al. Prophylactic lymph node dissection in clinical stage I cutaneous malignant melanoma. Results of surgical treatment in 1319 patients. Br J Surg. 1982;69:108–111. 70. Veronesi U, Adamus J, Bandiera DC, et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer. 1982;49:2420–2430. 71. Sim FH, Taylor WF, Pritchard DJ, et al. Lymphadenectomy in the management of stage I malignant melanoma. A prospective randomized study. Mayo Clin Proc. 1986;61:697–705. 72. Balch CM, Soong S, Ross MI, et al. Long-term results of a multiinstitutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0-4.0 mm). Ann Surg Oncol. 2000;7:87–97.

73. Cascinelli N, Morabito A, Santinami M, et al. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk. A randomised trial. Lancet. 1998;351:793–796. 74. Doubrovsky A, de Wilt JH, Scolyer RA, et al. Sentinel node biopsy provides more accurate staging than elective lymph node dissection in patients with cutaneous melanoma. Ann Surg Oncol. 2004;11:829–836. 75. McMasters KM. What good is sentinel lymph node biopsy for melanoma if it does not improve survival? Ann Surg Oncol. 2004;11:810–812. 76. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel–node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307–1317. 77. Thomas JM, A’Hern RP, Grichnik JM, et al. Sentinel-node biopsy in melanoma. N Engl J Med. 2007;356:418. 78. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastases in melanoma. N Engl J Med. 2017;376:2211–2222. 79. Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys. 1994;30:795–798. 80. Bonnen MD, Ballo MT, Myers JN, et al. Elective radiotherapy provides regional control for patients with cutaneous melanoma of the head and neck. Cancer. 2003;100:383–389. 81. Calabro A, Singletary SE, Balch CM. Patterns of relapse in 1001 consecutive patients with melanoma nodal metastases. Arch Surg. 1989;124:1051–1055. 82. Lee RJ, Gibbs JF, Proulx GM, et al. Nodal basin recurrence following lymph node dissection for melanoma. Implications for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys. 2000;46:467–474. 83. Monsour PD, Sause WT, Avent JM, et al. Local control following therapeutic nodal dissection for melanoma. J Surg Oncol. 1993;54:18–22. 84. Shen P, Wanek LA, Morton DL. Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol. 2000;7:554–559. 85. Miller EJ, Synnestvedt M, Schultz D, et al. Loco-regional nodal relapse in melanoma. Surg Oncol. 1992;1:333–340. 86. Bowsher WG, Taylor BA, Hughes LE. Morbidity, mortality and local recurrence following regional node dissection for melanoma. Br J Surg. 1986;73:906–908. 87. Burmeister BH, Smithers BM, Poulsen M, et al. Radiation therapy for nodal disease in malignant melanoma. World J Surg. 1995;19:369–371. 88. O’Brien CJ, Petersen-Schaefer K, Stevens GN, et al. Adjuvant radiotherapy following neck dissection and parotidectomy for metastatic malignant melanoma. Head Neck. 1997;19:589–594. 89. Corry J, Smith JG, Bishop M, et al. Nodal radiation therapy for metastatic melanoma. Int J Radiat Oncol Biol Phys. 1999;44:1065–1069. 90. Fenig E, Eidelevich E, Njuguna E, et al. Role of radiation therapy in the management of cutaneous malignant melanoma. Am J Clin Oncol. 1999;22:184–186. 91. Morris KT, Marquez CM, Holland JM, et al. Prevention of local recurrence after surgical debulking of nodal and subcutaneous melanoma deposits by hypofractionated radiation. Ann Surg Oncol. 2000;7:680–684. 92. Cooper JS, Chang WS, Oratz R, et al. Elective radiation therapy for high-risk malignant melanoma. Cancer J. 2001;7:498–502. 93. Fuhrmann D, Lippold A, Borrosch F, et al. Should adjuvant radiotherapy be recommended following resection of regional lymph node metastases of malignant melanomas? Br J Dermatol. 2001;144:66–70. 94. Ballo MT, Strom EA, Zagars GK, et al. Adjuvant irradiation for axillary metastases from malignant melanoma. Int J Radiat Oncol Biol Phys. 2002;52:964–972. 95. Ballo MT, Bonnen MD, Garden AS, et al. Adjuvant irradiation for cervical lymph node metastases from melanoma. Cancer. 2003;97:1789–1796. 96. Ballo MT, Zagars GK, Gershenwald JE, et al. A critical assessment of adjuvant radiotherapy for inguinal lymph node metastases from melanoma. Ann Surg Oncol. 2004;11:1079–1084. 97. Burmeister BH, Smithers M, Burmeister E, et al. A prospective phase II study of adjuvant postoperative radiation therapy following nodal

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CHAPTER 48 surgery in malignant melanoma. Trans Tasman Radiation Oncology Group (TROG) study 96.06. Radiother Oncol. 2006;81:136–142. 98. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lympadenectomy for melanoma: a randomized trial. Lancet Oncol. 2012;13:589–597. 99. Urist MM, Maddox WA, Kennedy JE, et al. Patient risk factors and surgical morbidity after regional lymphadenectomy in 204 melanoma patients. Cancer. 1983;51:2152–2156. 100. Wrightson WR, Wong SL, Edwards MJ, et al. Complications associated with sentinel lymph node biopsy for melanoma. Ann Surg Oncol. 2003;10:676–680. 101. Karakousis CP, Driscoll DL, Rose B, et al. Groin dissection in malignant melanoma. Ann Surg Oncol. 1994;1:271–277. 102. Hughes TM, A’Hern RP, Thomas JM. Prognosis and surgical management of patients with palpable inguinal lymph node metastases from melanoma. Br J Surg. 2000;87:892–901. 103. Burmeister BH, Smithers BM, Davis S, et al. Radiation following nodal surgery for melanoma. An analysis of late toxicity. ANZ J Surg. 2002;72:344–348. 104. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma. The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7–17. 105. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alpha-2b in high-risk melanoma. First analysis of intergroup trial E1690/s9111/c9190. J Clin Oncol. 2000;18:2444–2458. 106. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alpha-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma. Results of intergroup trial E1694/S9512/ C509801. J Clin Oncol. 2001;19:2370–2380. 107. Kaufman HL, Kirkwood JM, Hodi FS, et al. The Society for Immunotherapy of Cancer consensus statement on tumour

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immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol. 2013;10(10):588–598. 108. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516. 109. Hauschild A, Grob J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–365. 110. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723. 111. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–2526. 112. Eggermont AMM, Chiarion-Sileni V, Grob J, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–1855. 113. Weber J, Mandla M, Del Vecchio MD, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–1835. 114. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–931. 115. Hallemeier CL, Garces YI, Neben-Wittich MA, et al. Adjuvant hypofractionation intensity modulated radiation therapy after resection of regional lymph node metastases in patients with cutaneous melanoma of the head and neck. Prac Radiat Oncol. 2013;3:e71–e77. 116. Adams G, Foote M, Brown S, et al. Adjuvant external beam radiotherapy after therapeutic groin lymphadenectomy for patients with melanoma: a dosimetric comparison of three-dimensional conformal and intensitymodulated radiotherapy techniques. Melanoma Res. 2017;27:50–56. 117. Mattes MD, Zhou Y, Berry SL, et al. Dosimetric comparison of axilla and groin radiotherapy techniques for high-risk and locally advanced skin cancer. Radiat Oncol J. 2016;34:145–155.

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PART C

Thoracic Neoplasms

49 Overview Jeffrey A. Bogart

Primary thoracic neoplasms are reviewed in detail in the chapters of this section. In this overview, we consider developments and controversies in the diagnosis and treatment of non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), thymic tumors, pulmonary carcinoid, and mesothelioma.

and women.9 Thymic carcinomas account for a minority of all thymic neoplasms,10 and they are more aggressive than thymomas.11 Thymic carcinoids represent less than 5% of anterior mediastinal tumors, but they have a higher rate of regional lymph node metastases on presentation compared with carcinoids found in other locations in the body.12

EPIDEMIOLOGY

Pulmonary Carcinoid

Lung Cancer Lung cancer is the most common and deadliest thoracic malignancy, accounting for approximately 3000 deaths each week in the United States.1 Exposure to tobacco smoke is the most common cause of lung cancer, with 85% to 90% of cases directly linked to active or passive tobacco exposure.2 Lung cancer mortality rates have been trending downward in men because of reductions in smoking prevalence dating back to the mid-1960s, whereas mortality rates in women started to stabilize only in 2003. There is substantial geographic variation in the United States, with California the only state with decreasing lung cancer incidence and death rates in women.3 Exposures to several occupational respiratory carcinogens have been controlled in developed nations, but environmental exposure to radon, the second-leading cause of lung cancer death, remains problematic.4 Lung cancer in never-smokers is increasingly recognized as a distinct entity, described in greater detail in Chapter 51, and is the seventh most common cause of cancer worldwide. Most of these cancers occur in women; geographic, cultural, and genetic differences and hormonal factors have been implicated.5 The median age of patients who present with lung cancer is 70 years.6 Lung cancer is broadly separated into SCLC and NSCLC types. NSCLC accounts for approximately 80% to 85% of cases. Less than 50% of patients with NSCLC have resectable disease on initial presentation, and 25% of patients present with locally advanced (regional lymph node involvement without distant metastases) disease. Approximately 30% of patients with SCLC have limited-stage disease on presentation.7

Thymic Neoplasms Thymoma is the most common tumor in the anterior mediastinum. Most thymic neoplasms arise in the epithelial cells of the thymus. The incidence of thymoma in the United States is estimated to be 0.13 to 0.15 per 100,000 people.8 The median age of patients with thymoma is older than 50 years, and thymomas are diagnosed equally in men

Pulmonary or bronchial carcinoid tumors are often low-grade neoplasms that arise from bronchial mucosal cells known as enterochromaffin cells or Kulchitsky cells.13 These specialized cells are capable of producing bioactive amines, which cause carcinoid syndrome if released into the bloodstream by the tumor. The respiratory tract is the second most common site for carcinoids (after the gastrointestinal tract). Pulmonary carcinoid tumors are often centrally located and confined to the main or lobar bronchi.14 The incidence of bronchopulmonary carcinoids in the United States is estimated to be 0.6 per 100,000 people.15 Carcinoid tumors tend to occur at a younger age than other lung cancers, with a median age ranging from 50 to 56 years at diagnosis. In contrast to NSCLC and SCLC, bronchial carcinoids are more common in women.

Mesothelioma The incidence of mesothelioma in the United States is estimated to be 10 per 1 million people,16 or approximately 3000 patients per year, and the rate is expected to increase to about 4000 cases per year by 2025. Approximately 90% of mesotheliomas can be attributed to prior occupational asbestos exposure; a lag of 20 to 40 years between asbestos exposure and diagnosis is typical.17 Mesothelioma occurs predominantly in men, but secondary asbestos exposure from a spouse or parent can be as significant as environmental exposure. Major histological subtypes of mesothelioma include epithelioid, biphasic, and sarcomatoid. Although epithelioid tumors are most common and have a better prognosis than other histological types, the prognosis for most patients with mesothelioma remains poor.18

BIOLOGY Lung Cancer Lung cancers have a propensity to disseminate early and have a high rate of relapse despite aggressive treatment with surgery, chemotherapy,

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radiotherapy (RT), or combinations of these modalities. Molecular characteristics of NSCLC and SCLC are described in Chapters 50 and 51. Although NSCLC has traditionally been treated as a single disease, there is increasing recognition that histological and molecular characteristics may help direct therapy. Targeted drugs are now considered first-line therapy for advanced NSCLC with specific epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) gene rearrangements, and, more recently, ROS1 rearrangement and BRAF V600E mutation.19–21 Enhancing tumor-specific T-cell immunity programmed death ligand 1 (PD-L1) inhibition has recently demonstrated improved survival in metastatic and locally advanced NSCLC, though PD-L1 tumor expression has a variable relationship with tumor response.22,23 Efforts to take advantage of molecular abnormalities in SCLC in developing more effective treatment have been more challenging, though PD-L1 inhibition has been effective despite relatively low tumor expression of PD-L1.24

Thymus Tumors The cause of thymic neoplasms is unclear. Environmental factors that contribute to the development of thymic neoplasms may include Epstein-Barr virus infection25 and exposure to ionizing irradiation.26 The translocation of chromosomes 15 and 19 has been observed in thymic carcinoma.27 Benign thymoma has been associated with deletion of the short arm of chromosome 6. Abnormalities in TP53, epidermal growth factor, and EGFR may contribute to the development of thymoma.28,29 Thymic carcinoma displays features that are similar to features of carcinoma arising in other body sites. It has a higher rate of capsular invasion, involvement of the regional lymph nodes, and systemic metastases compared with invasive thymomas.30 Features of thymic carcinomas may include expression of high levels of EGFR, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor.31,32 CD70 positivity may serve as a marker for thymic carcinoma.33 In contrast to lung cancer, thymic carcinomas usually do not express transcription termination factor-1.34

Pulmonary Carcinoid Although most pulmonary carcinoids are nonfunctional, some can secrete various substances, which can lead to paraneoplastic syndromes, including carcinoid and Cushing syndrome.35 Serotonin is the most common substance released by carcinoid tumors, but corticotropin, histamine, dopamine, substance P, neurotensin, prostaglandins, and kallikrein may also be involved.36 Typical carcinoids usually display an indolent clinical course, but atypical carcinoids have a higher rate of regional and systemic involvement on presentation.37 Most familial pulmonary carcinoids have been reported in patients with multiple endocrine neoplasia type I.38 In atypical carcinoids, there seems to be a higher rate of inactivation of TP53.39 Other genetic alterations in lung carcinoids include losses of 3p, 5p, 9p, 10q, and 13q.40

STAGING AND WORKUP Lung Cancer The evaluation should start with a careful history and physical examination. Emphasis should be placed on the duration of symptoms and signs related to the thoracic neoplasm and the overall baseline medical condition of the patient. Diagnosis and staging should be accomplished in an orderly and cost-effective manner. Although sputum cytology reveals a diagnosis in only a small percentage of patients, it is a simple and noninvasive evaluation that should be considered for patients with respiratory

symptoms and a suspicious lung mass. Traditionally, bronchoscopy has been employed for biopsy of central lesions, whereas transthoracic needle biopsy is often the first consideration for peripheral lesions. Endobronchial ultrasound is increasingly used to obtain tissue from mediastinal lymph nodes or parenchymal lung lesions; esophageal ultrasound may be used for biopsy of paraesophageal lymph nodes. Staging evaluation is often initiated before a definitive pathological diagnosis has been established. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) combined with computed tomography (CT) imaging is indicated in most patients with localized NSCLC and SCLC and can replace the traditional workup that included CT imaging of the chest and abdomen plus a bone scan. The use of 18F-FDG-PET imaging has been shown to reduce the number of futile thoracotomies for patients with NSCLC and has a substantial impact on the radiation treatment plan for NSCLC and SCLC, particularly when an approach of involved field RT is used.41,42 Generally, biopsy of suspected distant metastatic sites should be considered in lieu of biopsy of the primary lung lesion because this would confirm both histology and stage. 18 F-FDG-PET imaging is typically not warranted in patients presenting with evidence of distant metastases (on other imaging studies) because treatment would not likely be altered by the PET results. Magnetic resonance imaging (MRI) of the brain should be obtained in patients with localized SCLC and patients with lymph node–involved NSCLC in addition to patients presenting with neurological symptoms. The TNM (primary tumor, regional nodes, metastases) staging system by the American Joint Committee on Cancer (AJCC) for bronchogenic cancer continues to evolve to better correlate stage with clinical outcome. The eighth edition further refines T stage according to tumor size, including subdividing tumors previously classified as T1b (1-3 cm) as either T1b (1-2 cm) or T1c (2-3 cm). Stage IIIC (T4 N3 M0 or T3 N3 M0 N3) is a new designation, as is the use of M1c for multiple extrathoracic metastases (see Table 51.2). Although the AJCC system has been proposed for use in staging patients with both SCLC and NSCLC, it is more common to use the 1973 Staging System of the Veterans Administration Lung Cancer Study Group for staging SCLC. It distinguishes disease extent as limited versus extensive,43 with limited-stage SCLC often described as treatable with a “reasonable” RT portal to encompass the known disease. That said, outcomes in limited SCLC correlate with stage, with potential to bias clinical trial outcomes if stage is not taken into account in study design. Mediastinal staging is indicated for most patients with early-stage clinical node-negative NSCLC because CT and 18F-FDG-PET imaging have a false-negative rate (in the mediastinum) ranging from 10% to greater than 25%.44 Combined anatomic and functional imaging is generally sufficient to assess mediastinal lymph node involvement for the subset of patients with peripheral stage I NSCLC.45 Comprehensive mediastinal lymph node sampling with endobronchial ultrasound has been successfully used in experienced hands but is unlikely to completely replace mediastinoscopy.46

Thymic Tumors Approximately 10% to 15% of patients with myasthenia gravis have thymoma, and 30% to 45% of patients with thymoma have myasthenia gravis.47 Serum alpha-fetoprotein and beta-human chorionic gonadotropin levels should be obtained in young men to exclude nonseminomatous germ cell tumors.47 Thymic carcinoids may also be associated with Cushing syndrome, Eaton-Lambert syndrome, syndrome of inappropriate secretion of antidiuretic hormone, and hypercalcemia.48 Symptoms of classic carcinoid syndrome are rare in patients with thymic carcinoids. A routine chest radiograph examination can detect 30% to 40% of patients with thymic neoplasms.49 CT is the most valuable radiological

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CHAPTER 49 study in the workup of thymic tumors.50 It can establish the initial clinical staging and response to treatment. MRI has not been shown to be more accurate than CT in assessing anterior mediastinal tumors.51 18 F-FDG-PET has not been established as routine in the workup of thymic neoplasms. The risk of tumor spillage and pleural seeding during biopsy of thymoma is uncertain, although current guidelines suggest that biopsy may be avoided for resectable tumors if thymoma is strongly suspected by clinical and radiographical features. Thymomas histologically display epithelial and lymphatic cell types. They can be classified according to the degree of the epithelial and lymphatic cell combination. The neoplastic cells are the epithelial cells, but there is no consistent correlation between the histology of thymomas and their malignant potential or systemic syndromes. The degree of invasion of the capsule and adjacent tissues defines malignancy.52 The Masaoka staging system53 is used widely and is based on the anatomic extent of disease at the time of surgery. The first AJCC staging system for thymic neoplasms was recently introduced with the eighth edition.54 Thymic carcinoma histology is cytologically not different from carcinomas in other sites. Thymic carcinomas often involve the pleura and locoregional lymph nodes. Distant metastases to the lungs, liver, brain, and bone can also develop.55

Pulmonary Carcinoid Pulmonary carcinoids are often located centrally within the tracheobronchial tree, and approximately 10% to 20% are in the peripheral lung parenchyma.56 The AJCC lung staging system (TNM) is commonly used for lung carcinoids. Most patients with typical carcinoid present with early-stage disease, and less than 5% have evidence of distant spread. Approximately 20% of patients with atypical carcinoids have stage IV disease at presentation. Functioning carcinoids may be diagnosed by showing an increase in urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid. In addition to anatomic CT imaging, targeted radioactive octreotide or pentetreotide has been used to stage carcinoids.57 Such targeted imaging against type 2 somatostatin receptors may be useful in 80% of carcinoids. The utility of 18F-FDG-PET imaging is controversial, although PET imaging using alternative tracers seems promising.58,59

Mesothelioma A detailed history of asbestos exposure should be investigated for any patient with mesothelioma. Thoracentesis and percutaneous fine-needle aspiration biopsy have a low diagnostic sensitivity because mesothelioma can be difficult to differentiate from benign pleural disease and other malignancies.60 Video-assisted thoracoscopic biopsy seems to be the most accurate means to establish a pathological diagnosis.61 Contrast-enhanced CT imaging of the chest is indicated as part of initial staging but can underestimate the extent of the disease. MRI may be more accurate in predicting the extent of chest wall and diaphragm invasion. Additional invasive studies, such as laparoscopy and peritoneal lavage, may be indicated to document resectability. The AJCC staging system, which is based on the International Mesothelioma Interest Group staging system, is commonly used. The most common sites of metastatic disease are the peritoneum, contralateral pleura, and lung.62

NORMAL-TISSUE TOXICITY CONSIDERATIONS The spinal cord, lung, esophagus, and heart are the dose-limiting structures in RT for thoracic malignancy. Generally, functioning subunits of an organ may be arranged as an in-series or in-parallel structure. Normal tissue, such as the lung, is an example of an in-parallel structure in which critical numbers of functioning units must be damaged before the organ is impaired.63 Organ failure occurs when functional subunits

Overview

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are damaged beyond a critical level. The gastrointestinal tract and spinal cord represent in-series structures in which a loss of a single functioning subunit may lead to organ impairment or development of clinical symptoms. Current grading systems for toxicities include Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) from the National Cancer Institute. Although many reports suggest limited toxic effects after stereotactic body radiotherapy (SBRT) for early-stage NSCLC, treatment-related fatalities have been reported.64 Phase II data from Indiana University initially showed an increased risk of toxic deaths after SBRT for centrally located lesions, although a statistically significant difference in severe toxicity was not seen between central and peripheral lesions with longer follow-up.65,66 Nevertheless, central tumors were excluded from the subsequent multi-institutional Radiation Therapy Oncology Group (RTOG) Phase II study (RTOG 0236); caution should be used in treating central lesions with SBRT outside of a clinical study.67 No treatmentrelated deaths were reported in RTOG 0236, which was reported with a 34-month median follow-up, although 14% grade 3 and 4% grade 4 protocol-specified toxicity was observed, and 6 additional patients had severe toxicity that was not classified prospectively as protocol specified. Rigorous quality assurance was mandated. In addition to tumor location, size of the gross tumor volume was a significant predictor of severe toxicity in the Indiana University trial.68 In other experience, fatalities have been observed secondary to fistula (tracheoesophageal or bronchopulmonary), pneumonitis, pleural effusion, and hemoptysis.69 Several more recent SBRT reports have also shown higher than expected skin, rib, soft-tissue, and brachial plexus toxicity.70,71 More recently, the classification of ultracentral location has been proposed as a particularly high risk of toxicity after traditional SBRT dose fractionation for tumors in this location.72 Dose constraints for SBRT regimens have been suggested by the RTOG/NRG and National Comprehensive Cancer Network (NCCN). The following sections are generally based on data derived with conventionally fractionated RT and may not apply when large doses per fractions are used, such as in SBRT. Routine integration of conformal RT planning has facilitated the assessment of dose-volume relationships for conventionally fractionated RT. A systematic review of the literature found that an ideal dose-volume parameter predicting for pulmonary toxicity has not been identified,73 although the most widely used measures are the total lung volume receiving at least 20 Gy (i.e., V20) and the mean lung dose.74,75 Other metrics, including baseline pulmonary function and perfusion abnormalities, have also been used. It is also likely that multiple physical and biological factors are important in predicting the risk of pulmonary toxicity.76,77 Barriers to describing accurately the relationship between treatment and its resultant toxicity include the use of imperfect metrics and the inaccurate reporting of toxic effects. The latter may be particularly relevant for patients with underlying pulmonary toxicity, as it may be difficult to determine whether a functional decline is attributable to the effects of therapy. The dose-volume relationship may also be affected by the integration of systemic chemotherapy, and the sequencing of therapies may have a significant impact on the toxic effects of therapy.78 Most current prospective combined modality trials have adopted V20 as a treatment planning parameter and limit V20 to a maximum 30% to 40% of the total lung volume. Current NCCN guidelines recommend limiting the V20 lung to less than 37% and the mean lung dose to less than 20 Gy. There is also recognition of the potential impact of exposing relatively large volumes of lung to low doses of 5 Gy or 7 Gy, which is particularly relevant when intensity-modulated radiotherapy (IMRT) techniques are employed for lung cancer or mesothelioma.79 Esophageal toxicity is generally the major clinically relevant acute toxicity during thoracic RT. The implementation of conformal techniques

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Disease Sites

may affect esophageal toxicity by reducing the volume of esophagus irradiated, particularly for patients without extensive mediastinal adenopathy. The risk of radiation-induced acute esophageal toxicity varies according to fractionation; increased acute toxicity has been observed with hyperfractionated and accelerated RT regimens.80 The integration of concurrent chemotherapy with thoracic RT results in significantly increased severe esophagitis compared with primary RT or sequential therapy. Dosimetric parameters that may correlate with esophageal toxicity include the length of esophagus treated to greater than 40 to 50 Gy, the volume of esophagus receiving greater than 50 Gy, and the mean esophageal dose.81–83 Current NCCN guidelines recommend keeping the mean esophageal dose less than 34 Gy if possible, but esophageal dose guidelines are not absolute and acute esophagitis should be treated aggressively with pain management and nutritional support. It is crucial that the patient’s treatment plan not be compromised because of a generally temporary toxic effect of therapy. The role of “radioprotective” agents is unclear; the RTOG conducted a randomized trial to test the ability of amifostine to reduce esophagitis in locally advanced NSCLC treated with concurrent RT and chemotherapy.84 Amifostine was associated with higher rates of acute nausea, vomiting, cardiovascular toxicity, and infection or febrile neutropenia. Amifostine is not recommended in combination with thoracic RT outside of a clinical trial. Spinal cord radiation injury, covered in detail in Chapter 35, is a serious but rare complication of thoracic RT. Most contemporary clinical trials of concurrent fractionated RT and chemotherapy for thoracic malignancies limit the maximum point dose to the spinal cord to 45 to 50 Gy. The risk of radiation-induced cardiovascular disease had received relatively little attention for patients treated for locally advanced lung cancer in part due to the guarded prognosis. The importance of cardiac dose constraints is being increasingly recognized, as a post-hoc analysis of RTOG 0617 demonstrated a negative impact of increasing heart dose on overall survival (OS) in patients with locally advanced NSCLC.85 Most prior data relating to cardiovascular toxicity is derived from patients with Hodgkin disease and breast cancer. Multiple studies have shown that patients with Hodgkin disease are at higher risk for the development of cardiovascular disease after mediastinal irradiation and that fatal myocardial infarction is the leading cause of noncancer death in this population.86 Although the total dose used to treat Hodgkin disease has been reduced over the years, it is not yet clear whether this results in a reduced risk of myocardial infarctions. The increased risk of cardiac mortality for patients treated with RT for breast cancer has been defined by the Early Breast Cancer Trialists’ Collaborative Group meta-analyses of randomized clinical trials, which showed that patients treated with RT have a 1.27 relative risk of mortality from cardiac disease compared with patients not receiving RT.87 The treatment of left-sided breast cancer and the treatment of internal mammary lymph nodes seem to increase the risk of cardiac morbidity further.88 There seems to be a decline in RT-induced cardiac disease with modern RT planning. The implementation of advanced treatment technique—including conformal therapy, IMRT, image guidance, and respiratory gating—should reduce the risk of cardiac toxicity through improved sparing of cardiac structures in treating thoracic cancers.

TREATMENT CONSIDERATIONS Non–Small Cell Lung Cancer The standard of care for fit patients with early-stage I NSCLC is anatomic resection (lobectomy). Patients with borderline cardiopulmonary function should be assessed for rehabilitation and smoking cessation before being deemed to be medically inoperable. In a Phase III trial conducted during

the 1980s for fit patients with peripheral stage I (< 3 cm) NSCLC, limited resection was associated with a substantially higher risk of local tumor relapse and increased risk of death from cancer compared with lobectomy.89 Evidence has emerged supporting the use of limited resection for peripheral NSCLC smaller than 2 cm, although most experience comes from Asia, where the biology of small peripheral lesions may differ from the biology in North America and Europe.90 North American and Japanese Phase III trials studying limited resection for lesions less than 2 cm have completed accrual and should soon be reported.91 Alternatively, provocative results with SBRT have been reported in certain fit patients with early-stage NSCLC. Prospective Phase II trials of SBRT in operable patients have been completed in North America and Japan. RTOG 0618 demonstrated promising results but only 26 patients were evaluable, highlighting the need for further study.92 Phase III trials comparing SBRT and surgery in this population have not successfully met accrual goals, though new efforts are ongoing.93,94 Treatment of patients with early-stage NSCLC and cardiopulmonary dysfunction has rapidly evolved. Sublobar resection and SBRT are the most common considerations; there is more limited experience with radiofrequency ablation.95,96 Local tumor control approaching 90% has been reported in several trials of SBRT for stage I NSCLC, although some trials with aggressive SBRT regimens restrict entry to lesions in the lung periphery owing to concerns about severe toxicity.68 Accelerated hypofractionated RT regimens, with daily fractions given over 3 to 4 weeks, also seem promising; a randomized trial in Canada is comparing SBRT with hypofractionated therapy.97–99 Although traditional dose escalation is feasible with modern treatment planning, protracted regimens do not seem to be as effective as accelerated regimens and are more burdensome for patients.100–102 Although pilot experience suggested that the addition of Iodine-125 (125I) brachytherapy might reduce local relapse for high-risk patients treated with sublobar resection for stage I NSCLC, a Phase III American College of Surgeons Oncology Group (ACOSOG) trial failed to show a benefit with intraoperative 125 103 I. The relative merit of SBRT and sublobar resection in high-risk early-stage NSCLC remains unclear. Phase III trials comparing SBRT and sublobar resection for high-risk peripheral stage I NSCLC have been difficult to complete, though the ongoing STABLE-MATES modified randomized design allows patients to opt out of their assigned treatment and still remain on study. Radiofrequency ablation has also been prospectively studied in early-stage disease, though the local tumor-free recurrence rate was only 59.8% at 2 years.104 Large randomized studies show that adjuvant chemotherapy improves survival for patients with resected NSCLC, although the benefit diminishes over time.105 The role of adjuvant chemotherapy for early-stage node-negative NSCLC is controversial. A Cancer and Leukemia Group B (CALGB) trial did not show a benefit for adjuvant chemotherapy for T2 NSCLC, although there was a suggestion of improved survival for tumors larger than 4 cm.106 Whether chemotherapy should be given to patients treated with primary RT for node-negative NSCLC is an area for future investigation. The role of surgery for patients with stage IIIA NSCLC is unclear despite the reporting of mature results of a Phase III trial comparing concurrent chemotherapy and definitive RT (61 Gy) with induction concurrent chemotherapy and RT (45 Gy) followed by surgical resection.107 Improved relapse-free survival, but not OS, was observed for patients assigned to receive surgery. Nevertheless, surgical resection is currently used in certain patients with stage IIIA NSCLC, although it is recognized that induction therapy should be administered. Whether induction therapy should consist of chemotherapy or combined chemotherapy and RT remains controversial. The cornerstone of treatment for patients with “unresectable” locally advanced NSCLC is concurrent systemic doublet chemotherapy and

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CHAPTER 49 thoracic RT, as described in Chapter 51. Adjuvant immunotherapy with durvalumab recently emerged as standard treatment based on the results of the PACIFIC trial (described below).23 Controversies regarding the optimal treatment of this population are described later.

Chemotherapy Regimen and Schedule During Radiotherapy The landmark Phase III studies supporting concurrent chemotherapy and RT over a sequential approach used cisplatin-based chemotherapy in a schedule similar to that administered when chemotherapy is given for systemic disease.108 Nevertheless, several Phase III trials have adopted a regimen of weekly paclitaxel and carboplatin as standard of care despite a lack of level 1 evidence.109 Whether the weekly chemotherapy schedule or the substitution of carboplatin for cisplatin affects outcomes is unknown, though the excellent results from the standard (60 Gy) arm of RTOG 0617 lend support to the considering weekly concurrent paclitaxel and carboplatin as an acceptable standard therapy.85

Sequencing and Timing of Radiotherapy and Chemotherapy Trials conducted in the 1980s first showed that giving cisplatin-based chemotherapy before thoracic RT improved OS compared with RT alone. Subsequent trials showed that concurrent administration of chemotherapy and RT was better than sequential treatment.110 Additional chemotherapy is frequently given in clinical practice (and included as standard on clinical trials) after concurrent therapy, although more recent Phase III randomized trials failed to show benefit for either induction chemotherapy or consolidation chemotherapy.111,112 Toxicity was enhanced in the cohorts receiving longer-duration chemotherapy. The question of whether to give adjuvant chemotherapy, particularly when weekly low-dose chemotherapy is used concurrent with radiotherapy, may reemerge given that adjuvant immunotherapy for 1 year has become standard of care for locally advanced disease.113

Radiation Dose Escalation and Fractionation The standard RT regimen for NSCLC, 60 Gy in daily 2-Gy fractions, was defined by an RTOG trial conducted in the 1970s.114 The emergence of conformal RT planning ushered in several dose escalation studies. Encouraging outcomes of Phases I and II studies led to development of a Phase III trial, RTOG 0617, testing 74 Gy compared with 60 Gy with weekly carboplatin and paclitaxel chemotherapy.115,116 Unexpectedly, results of this seminal trial demonstrate that higher doses of RT result in significantly worse survival and provides strong evidence against dose-escalated RT outside of a clinical trial.85 Altered fractionation has been tested in several Phase III trials of locally advanced NSCLC. Regimens that accelerate the time to complete therapy by giving multiple daily treatments have shown promise, although the utility of these regimens is limited by difficulty in integrating concurrent chemotherapy and the logistic challenge for many centers to treat patients up to three times a day.117,118 The use of hyperfractionated RT seems to have no benefit if the time to complete treatment is not shortened.119,120 The emergence of advanced treatment technologies, which facilitate limiting radiation dose to critical normal tissue, has resulted in increased interest in studying accelerated hypofractionated regimens. There may be further rationale to study hypofractionation in the context of immunotherapy with PD-L1 inhibition. Prospective trials have demonstrated encouraging results. While large randomized studies comparing hypofractionated RT and standard RT have not been reported, recent results of a European Organization for Research and Treatment of Cancer (EORTC) study using 24 fractions of 2.75 Gy reported encouraging outcomes, with median survival of 30 to 33 months.121 Although there is limited experience treating locally advanced NSCLC with proton therapy, the increase in proton facilities in the United States

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and worldwide has started to provide prospective data. An initial randomized trial did not demonstrate improved local tumor control or reduced pneumonitis with proton therapy as compared with IMRT.122 A larger Phase III trial comparing photon and proton RT concurrent with chemotherapy is being conducted by the RTOG.

Radiation Target Volumes The role of elective nodal irradiation (ENI) is controversial; current practice has generally evolved such that clinically uninvolved lymph node regions are not intentionally targeted.123,124 Studying the impact of ENI and accurately documenting sites of relapse in locally advanced NSCLC is challenging, although a modest-sized Chinese study showed less toxicity without a detriment in survival with involved field treatment compared with ENI.125 The potential influence of ENI may be lessened in the era of routine 18 F-FDG-PET staging, and most ongoing prospective trials do not include ENI.

Integration of Novel Systemic Agents A Phase III trial conducted by the Southwestern Oncology Group (SWOG) from 2001 to 2005 demonstrated worse survival with maintenance EGFR inhibitor gefitinib after chemoradiotherapy in locally advanced NSCLC,126 curbing enthusiasm for large-scale study of targeted agents in potentially curable populations. Pilot data from CALGB showed gefitinib concurrent with chemoradiotherapy results in poor outcomes, although encouraging results were observed with concurrent administration of gefitinib with RT if concurrent chemotherapy was not given.127 A subsequent Phase II trial assessing erlotinib and RT for patients who were a poor risk with stage III NSCLC failed to reach the primary survival endpoint, although the median survival of 17 months was reasonable for a poor-risk population.128 Additionally, although Phase II studies showed that combining cetuximab (a monoclonal antibody against EGFR) with concurrent chemotherapy and RT yielded encouraging outcomes,129,130 cetuximab did not improve survival in the recently reported Phase III RTOG 0617 trial.85 Routine administration of targeted agents do not appear to have a role in the treatment of unselected patients, but the role of targeted therapy in patients with locally advanced NSCLC harboring mutations or gene rearrangements remains unclear. A randomized study assessing the role of induction targeted therapy, with either erlotinib (EGFR mutated tumors) or crizotinib (ALK rearrangements), was unfortunately recently terminated prematurely owing to slow accrual, and evidence is lacking to justify routinely using these agents in the treatment of stage III disease. The addition of the VEGF inhibitor bevacizumab to doublet chemotherapy improves survival for patients with advanced non–squamous cell carcinoma.131 Although there was initial enthusiasm for studying bevacizumab in locally advanced disease, an increased risk of tracheoesophageal fistula has been shown with bevacizumab for both NSCLC and SCLC. Administration of bevacizumab months to years after completion of thoracic RT has been linked to fistula formation.132 These agents should not be used in combination with RT outside of a clinical trial.

Immune Checkpoint Inhibitors Updated results from the PACIFIC trial were recently published. After completion of at least 2 cycles of chemotherapy with definitive concurrent radiotherapy, patients were randomized to either durvalumab, a monoclonal antibody that blocks PD-L1, or observation. Two-year OS was significantly longer in the durvalumab group, 66.3% versus 55.6% (p = 0.005), and median progression-free survival was also improved (17.2 months vs. 5.6 months). A post-hoc analysis found that PD-L1 status appeared to correlate with outcomes, and patients were unlikely to benefit

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Disease Sites

from durvalumab if PD-L1 expression was less than 1%. Several active trials are testing immune checkpoint inhibitors that should further define optimal patient selection, sequencing, and duration of therapy.23

Prophylactic Cranial Irradiation The role of prophylactic cranial irradiation (PCI) was assessed in four early trials for locally advanced NSCLC,133–136 with the general conclusion that PCI reduces brain metastases but does not improve OS. Results of an RTOG-led intergroup study confirm this observation, although the trial was terminated prematurely because of poor accrual.137

Postoperative Radiotherapy Meta-analyses of postoperative RT have been roundly criticized on many counts, including the use of outdated technology, inclusion of patients with early-stage disease, and administration of excessive RT doses.138 Nevertheless, a survival detriment was shown for postoperative RT in early-stage node-negative NSCLC, with an unclear benefit in patients who are node positive. Current efforts have generally focused on assessing postoperative RT for resected N2 disease, and a more recent Surveillance, Epidemiology, and End Results (SEER) analysis supports the contention that postoperative RT may be beneficial in N2 disease when delivered with modern technology in appropriate doses (e.g., 50 Gy in 2-Gy fractions).139 A Phase III European study assessing postoperative RT is ongoing.140

Small Cell Lung Cancer Treatment of limited-stage SCLC includes the concurrent administration of RT and chemotherapy. Standard practice includes delivery of full-dose, cisplatin-based systemic chemotherapy during accelerated hyperfractionated thoracic RT (1.5 Gy twice daily to 45 Gy over 3 weeks). PCI is indicated after completion of thoracic RT and chemotherapy in patients with a good tumor response. Given the recently reported outcomes with immunotherapy checkpoint inhibitors in extensive-stage disease, randomized trials assessing PD-L1 inhibition are planned in limited-stage disease.24 Classic issues that remain unresolved in the standard treatment of limited SCLC are described next.

Thoracic Radiotherapy Dose and Fractionation Although high clinical response rates are expected with combinedmodality therapy, durable local tumor control is poor when modest-dose, conventionally fractionated thoracic RT is employed. Intensifying the RT course by accelerating the time to complete treatment seems to be an effective strategy in limited-stage SCLC. Intergroup trial 0096 randomly assigned patients to receive 4500 cGy in either conventional (180 cGy daily fractions) or hyperfractionated, accelerated (150 cGy twice-daily fractions) regimens.141 Thoracic RT was initiated with the first cycle of etoposide and cisplatin chemotherapy. Mature results favored accelerated RT. With accelerated RT, 5-year survival was 26% compared with 16% for patients receiving conventional RT. The major increased toxicity of the accelerated regimen was a doubling of the grades 3 to 4 acute esophagitis rate (e.g., 16% vs. 32%). Despite this result, the regimen of 45 Gy twice daily has not been well accepted in clinical practice, with fewer than 12% of patients receiving twice-daily treatment in recent National Cancer Database analysis.142 Reluctance to accept accelerated RT may be in part as a result of the increased acute toxicity and practical issues involved with treating patients twice each day. However, the results of the study have also been questioned because of the inclusion of relatively low-dose (45-Gy) daily RT as the standard treatment. The CALGB has examined high-dose daily thoracic RT in multiple studies demonstrating the feasibility of delivering 70 Gy in 2-Gy fractions concurrent with chemotherapy. An initial Phase II study suggested

encouraging survival with less apparent toxicity than was observed in studies using twice-daily fractions to 45 Gy.143 Two Phase III trials have now compared standard twice-daily RT against high-dose once-daily RT in limited-stage SCLC. The European Concurrent Once-daily Versus Twice-daily radiotherapy trial (CONVERT), tested whether 66-Gy once-daily RT was superior to 45-Gy twice-daily RT. OS was not significantly different between the arms, and the median survival for once-daily and twice-daily arms were 25 months and 30 months, respectively.144 As the once-daily arm did not prove superior, the authors concluded that twice-daily radiotherapy should remain standard of care. It is noteworthy that severe toxicity was lower than in prior trials, including 19% esophagitis in each arm, likely reflecting advances in radiotherapy planning. An unplanned subset analysis suggested improved efficacy with twice-daily RT in patients with N3 disease, as 5-year OS was 18% with twice-daily RT and only 3% with once-daily RT. A similar Phase III trial, CALGB 30610/RTOG 0538, is comparing standard thoracic RT (1.5 Gy twice daily) with the CALGB 70-Gy, once-daily regimen and should complete accrual in early 2019.145

Timing of Radiotherapy The optimal timing of thoracic RT relative to chemotherapy is controversial. CALGB 8083 randomly assigned patients to receive initial RT plus chemotherapy, delayed RT plus chemotherapy, or chemotherapy alone. Mature results showed that survival with chemotherapy alone was inferior to both thoracic RT arms. A significant difference was not observed between early and delayed RT, although there was a trend favoring delayed thoracic RT (p = 0.14).146 Conversely, a Phase III trial from the National Cancer Institute of Canada showed a benefit for initiating RT, 40 Gy in 3 weeks, with the second chemotherapy cycle compared with the sixth cycle of chemotherapy.147 In the early thoracic RT cohort, 5-year survival was 20% compared with 11% in the late thoracic RT arm; the difference was ascribed to a reduction in brain metastases because local tumor control did not differ between arms. Additional studies have attempted to address the timing of thoracic RT. Meta-analyses have been published addressing this issue.148,149 Although definitive conclusions cannot be reached, there is general consensus that the early initiation of thoracic RT (e.g., first through third cycle) may be beneficial, particularly in the context of intensive thoracic RT.

Treatment Volume The issue of optimal thoracic RT volume in limited-stage SCLC therapy has not been well studied in comparative trials. Investigators from the SWOG found that targeting postchemotherapy tumor volume instead of tumor volume on presentation did not result in increased failure rates.150 More recent prospective trials using delayed (e.g., third- or fourth-cycle) chemotherapy incorporated reduced-volume thoracic RT for all patients.151,152 Mature patterns of failure data from the North Central Cancer Treatment Group, showing that only 2 of 90 local relapses may have occurred outside the postinduction volume but inside the preinduction volume, indicate that reduced-field thoracic RT may be an acceptable strategy.152 Data attesting to the role of ENI for limited-stage SCLC are lacking. Most prospective trials have included selected bilateral mediastinal stations as part of the initial target volume, although elective inclusion of the supraclavicular regions and contralateral hilum is not indicated. Whether implementation of 18F-FDG-PET imaging can reduce the role of ENI for SCLC has not been well studied, though small trials from the Netherlands suggest that promising results can be obtained with FDG-PET–guided involved-field RT.153

Prophylactic Cranial Irradiation The meta-analysis by the Prophylactic Cranial Irradiation Overview Collaborative Group154 showed a convincing survival benefit (5.4% at

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CHAPTER 49 3 years) for the addition of PCI following a complete response to therapy. A Phase III trial compared standard dose (25 Gy in 10 fractions) and high dose (36 Gy in either once-daily or twice-daily fractions) in limited-stage SCLC. Higher doses of PCI did not further reduce brain metastases, but increased mortality was observed in the patients receiving high doses.155 Given the lack of benefit of PCI in a recent Japanese study for extensive-stage SCLC, the role of PCI for limited-stage patients has been called into question.156 A randomized study assessing close MRI surveillance versus PCI is currently in development in the North American cooperative groups.

Systemic Therapy Regimen SCLC is exquisitely sensitive to systemic chemotherapy. The combination of cisplatin and etoposide became standard frontline therapy in the 1980s because of its clinical activity and tolerability in combination with concurrent thoracic irradiation. Efforts to improve outcomes by adding a third chemotherapy agent have been disappointing. A Phase III trial showed increased severe toxicity without a survival benefit when paclitaxel was added to etoposide and cisplatin for first-line therapy in extensive SCLC.157 While a Japanese study demonstrated improved OS using cisplatin and irinotecan, the result was not reproduced in North America trials.158,159 Given the success with immunotherapy in NSCLC, there have been several studies integrating immune checkpoint inhibitors in the treatment of extensive-stage disease. Initial trials demonstrated promising outcomes for treatment with ipilumumab in combination with nivolumab or nivolumab alone for relapsed disease.160 The recently published IMpower133 trial demonstrated improved survival and progression-free survival with the addition of atezolizumab to first-line chemotherapy with carboplatin and etoposide in extensive-stage disease.24 Median survival was improved from 10.3 months with standard therapy to 12.3 months in the atezolizumab arm.

Thymoma The initial treatment of choice for thymic tumors is surgery. Adjuvant RT or chemotherapy should be considered for patients at high risk for recurrence. Complete en bloc surgical resection is the standard of care for resectable thymomas. The primary determinants of clinical outcome are surgical-pathological staging, tumor size, histology, and extent of surgical resection. Complete resection of thymoma can lead to low recurrence and excellent survival rates.161 Although prospective, randomized data on the value of adjuvant RT after resection of invasive thymoma are lacking, certain retrospective studies have shown improvements in local tumor control and survival in patients receiving RT for invasive disease.162–164 However, conflicting results regarding the utility of adjuvant RT have been reported from analyses of large multi-institutional series, including the SEER database. A more recent analysis of SEER data showed postoperative RT had no advantage in patients with localized thymoma (Masaoka stage I), but a possible survival benefit was suggested in patients with regional disease (Masaoka stages II-III).165 The strongest data supporting postoperative RT were in the population of patients with nonextirpative surgery. In contrast, Kondo and Monden10 reported a large multi-institutional, retrospective study of 1320 patients with stage II or III thymic epithelial tumors for whom no significant benefit of adjuvant irradiation after surgery was found. While the benefit of adjuvant RT remains controversial in stage II disease, most series suggest benefit for adjuvant RT following resection of more locally advanced tumors.166 Primary RT has been administered to select patients with unresectable thymoma with reasonable results, including approximately 65% local

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control and 5-year survival rate of 40% to 50%.167 Likewise, salvage RT for patients with recurrent thymoma may achieve a 7-year survival rate of approximately 70%.168 Similar to the treatment for thymomas, surgery remains the predominant treatment for patients with thymic carcinomas, which are treated similarly to carcinomas found in other body sites. Adjuvant RT is commonly administered after surgery.169 There may be a trend toward improved survival and local control with adjuvant therapy, but it is difficult to show given the relatively low frequency of thymic carcinoma.170 There are reports of promising OS rates for patients who received irradiation after surgery, and systemic chemotherapy is also often considered.171

Pulmonary Carcinoid Surgery is the primary treatment for typical and atypical pulmonary carcinoids, and long-term results after complete resection are excellent.172 Clinical symptoms such as flushing can be relieved with ondansetron, a serotonin 5-HT3 antagonist. Somatostatin analogs, inhibitors of neuropeptide release, relieve the symptoms of carcinoids by binding to somatostatin receptors.173 Long-acting analogs of somatostatin, such as octreotide and lanreotide, are used to control diarrhea and flushing; they have an approximately 70% chance of improving symptoms. Typical carcinoids do not require adjuvant therapy after curative resection.174 Patients with a tumor greater than 3 cm in diameter, lymph node metastasis, atypical histology, or residual disease may benefit from RT.175 Experience with SBRT for small parenchymal lung lesions in patients at high risk for resection may be considered though there is limited clinical experience. Tumor targeting with radioactive somatostatin analogs has been used in patients with carcinoids with inconclusive results.176 Interferon-α, alone or in combination with octreotide, has resulted in symptomatic relief in some patients.177 Chemotherapy results have been inconclusive, with a possible role for cisplatin and etoposide in patients with atypical carcinoids.178 RT may palliate symptoms in patients with locally advanced or metastatic disease.179

Mesothelioma Because mesothelioma usually involves the visceral and parietal pleural surfaces of the lung and extends into the pleural-lined pulmonary fissures, it can be difficult to perform a complete resection without an extrapleural pneumonectomy (EPP). EPP includes en bloc removal of tissues in the hemithorax, including the parietal and visceral pleura, involved lung, mediastinal lymph nodes, diaphragm, and pericardium. Given the aggressive nature of the surgery, EPP is considered only for patients with localized disease of epithelial subtype who have minimal comorbid medical problems. Even with EPP, complete resections cannot typically be accomplished, and the relative value of EPP compared with lesser resection remains unclear.180,181 The multi-institutional mesothelioma and radical surgery (MARS) randomized feasibility trial conducted in the United Kingdom found a possible detriment to EPP in the context of trimodality therapy, although only 50 patients ended up being randomized.182 The value of RT in mesothelioma remains controversial and most data are subject to patient selection factors. A report from Cancer Care Ontario’s Program in Evidence-based Care suggested that there was little evidence in the published literature to support a role for RT in the management of mesothelioma.183 A recent prospective study, SAKK 17/04, did not show a benefit to local radiotherapy after neoadjuvant chemotherapy and EPP, though only 27 patients were assigned to receive RT.184 Alternatively, a SEER database review identified epithelioid histology, pneumonectomy, and RT as predictive of increased survival.185 Median survival for patients treated with pneumonectomy with and

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SECTION III

Disease Sites

without RT was 19 months and 13 months (p = 0.01). Additional institutional studies have suggested improved local tumor control when RT is administered after EPP. Systemic therapy with pemetrexed and cisplatin is considered standard of care for patients with advanced (unresectable) mesothelioma.186 The expected median survival in patients treated with the regimen approaches 12 months. The addition of bevacizumab is considered in eligible patients with unresectable disease.187 Carboplatin is frequently substituted for cisplatin, often owing to medical comorbidity, without an apparent decrease in efficacy. Chemotherapy has now routinely been integrated as part of trimodality therapy for patients with resectable mesothelioma based primarily on promising results in select series.178 Based on early results from prospective studies, NCCN guidelines now include consideration of immunotherapy with pembrolizumab or nivolumab with or without ipilimumab for patients with relapsed malignant pleural mesothelioma (MPM).188,189 Trials in progress are testing the efficacy of adding checkpoint inhibitors to initial therapy; preliminary results of the DREAM trial suggested improved disease-free survival and response rates with the addition of durvalumab to cisplatin and pemetrexed.190 RT treatment of the ipsilateral hemithorax with IMRT after EPP has been associated with a high rate of toxic deaths in several singleinstitution experiences.191,192 Fatal pneumonitis has been related to radiation exposure of the contralateral lung; NCCN guidelines suggest that the mean lung dose be limited to 8.5 Gy and the V5 lung be kept as low as possible. Subsequent series suggest IMRT can be used with acceptable toxicity if normal tissue dose constraints are strictly followed. Treatment of the ipsilateral hemithorax after lung-preserving surgery with pleurectomy or decortication is particularly challenging, though data from experienced centers suggest that treatment may be tolerable with meticulous treatment planning and if total dose is guided by normal-tissue constraints.193,194 Tumor seeding along the biopsy tract is a well described phenomenon in mesothelioma. Evidence that palliative RT may have a role in reducing the rate of chest wall tumor seeding is conflicting, and a current randomized trial in Europe is assessing the impact of 21 Gy in 3 fractions on chest wall tract relapse.195

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A complete reference list can be found online at ExpertConsult.com.

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REFERENCES 1. Jemal A, Siegal R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2009;59:225–249. 2. Alberg AJ, Ford JG, Samet JM. Epidemiology of lung cancer: ACCP evidence based clinical practice guidelines (2nd edition). Chest. 2007;132:29S–55S. 3. Egleston BL, Meireles SI, Flieder DB, et al. Population-based trends in lung cancer incidence in women. Semin Oncol. 2009;36:506–515. 4. Neuberger JS, Gesell TF. Residential radon exposure and lung cancer: risk in nonsmokers. Health Phys. 2002;83:1–18. 5. Samet JM, Avila-Tang E, Boffetta P, et al. Lung cancer in never smokers: clinical epidemiology and environmental risk factors. Clin Cancer Res. 2009;15:5626–5645. 6. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Available from: http://seer.cancer.gov/csr/1975_2000/ sections.html. 7. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A metaanalysis. J Clin Oncol. 1992;10:890–895. 8. Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer. 2003;105:546–551. 9. Batata MA, Martini N, Nuvos AG, et al. Thymomas: clinicopathologic features, therapy, and prognosis. Cancer. 1974;34:389. 10. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg. 2003;76:878–884. 11. Hsu CP, Chen CY, Chen CL, et al. Thymic carcinoma: ten years’ experience in twenty patients. J Thorac Cardiovasc Surg. 1994;107:615–620. 12. Economopoulos GC, Lewis JW, Lee MW, et al. Carcinoid tumors of the thymus. Ann Thorac Surg. 1990;50:58–61. 13. Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma: an ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol. 1991;15:529–553. 14. Mendonca C, Baptista C, Ramos M. Typical and atypical lung carcinoids: clinical and morphological diagnosis. Microsc Res Tech. 1997;38:468–472. 15. Godwin JD 2nd. Carcinoid tumors: an analysis of 2,837 cases. Cancer. 1975;36:560–569. 16. Connelly RR, Spirtas R, Myers MH, et al. Demographic patterns for mesothelioma in the United States. J Natl Cancer Inst. 1997;78:1053–1060. 17. Weill H, Hughes JM, Churg AM. Changing trends in US mesothelioma incidence. Occup Environ Med. 2004;61:438–441. 18. Robinson BW, Lak RA. Advances in malignant mesothelioma. N Engl J Med. 2005;353:1591–1603. 19. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–957. 20. Neal JW. Histology matters: individualizing treatment in non–small cell lung cancer. Oncologist. 2010;15:3–5. 21. Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7:596–609. 22. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1- positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–1833. 23. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Eng J Med. 2018. 24. Liu S, Mansfield A, Szczesna S, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N End J Med. 2018. 25. Patton DP, Ribeiro RC, Jenkins JJ, et al. Thymic carcinoma with a defective Epstein-Barr virus encoding the BZLF1 transactivator. J Infect Dis. 1994;170:7–12. 26. Jensen MO, Antonenko D. Thyroid and thymic malignancy following childhood irradiation. J Surg Oncol. 1992;50:206–208.

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27. Lee ACW, Kwong YL, Fu KH, et al. Disseminated mediastinal carcinoma with chromosomal translocation (15:19). Cancer. 1993;72:2273–2276. 28. Herens C, Radermecker M, Servais A, et al. Deletion (6:22,25) is a recurrent anomaly of thymoma: report of a second case and review of the literature. Cancer Genet Cytogenet. 2003;146:66–69. 29. Hayashi Y, Ishii N, Obayashi C, et al. Thymoma: tumour type related to expression of epidermal growth factor (EGF), EGF-receptor, p53, v-erb B and ras p21. Virchows Arch. 1995;426:43–50. 30. Jung KJ, Lee KS, Han J, et al. Malignant thymic epithelial tumors: CT-pathologic correlation. AJR Am J Roentgenol. 2001;176:433–439. 31. Fukai I, Masaoka A, Hashimoto T, et al. Cytokeratins in normal thymus and thymic epithelial tumors. Cancer. 1993;71:99–105. 32. Oyama T, Osaki T, Mitsudomi T, et al. P53 alteration, proliferating cell nuclear antigen, and nucleolar organizer regions in thymic epithelial tumors. Int J Mol Med. 1998;1:823–826. 33. Hishima T, Fukayama M, Hayashi Y, et al. CD70 expression in thymic carcinoma. Am J Surg Pathol. 2000;24:742–746. 34. Fukai I, Masaoka A, Hashimoto T, et al. The distribution of epithelial membrane antigen in thymic epithelial neoplasms. Cancer. 1992;70:2077–2081. 35. Mendonca C, Baptista C, Ramos M. Typical and atypical lung carcinoids: clinical and morphological diagnosis. Microsc Res Tech. 1997;38:468–472. 36. Feldman JM, O’Dorisio TM. Role of neuropeptides and serotonin in the diagnosis of carcinoid tumors. Am J Med. 1986;81:41–48. 37. Thomas CF Jr, Tazelaar HD, Jett JR. Typical and atypical pulmonary carcinoids: outcome in patients presenting with regional lymph node involvement. Chest. 2001;119:1143–1150. 38. Debelenko LV, Brambilla E, Agarwal SK, et al. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet. 1997;6:2285–2290. 39. Sugio K, Osaki T, Oyama T, et al. Genetic alteration in carcinoid tumors of the lung. Ann Thorac Cardiovasc Surg. 2003;9:149–154. 40. Onuki N, Wistuba II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer. 1999;85:600–607. 41. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med. 2009;361:32–39. 42. Spratt DE, Diaz R, McElmurray J, et al. Impact of FDG PET/CT on delineation of the gross tumor volume for radiation planning in non–small-cell lung cancer. Clin Nucl Med. 2010;35:237–243. 43. Stahel RA, Ginsberg R, Havermann K, et al. Staging and prognostic factors in small cell lung cancer: a consensus. Lung Cancer. 1989;5:119–126. 44. Cerfolio RJ, Bryant AS, Ojha B, et al. Improving the inaccuracies of clinical staging of patients with NSCLC: a prospective trial. Ann Thorac Surg. 2005;80:1207–1213. 45. Meyers BF, Haddad F, Siegel BA, et al. Cost-effectiveness of routine mediastinoscopy in computed tomography- and positron emission tomography-screened patients with stage I lung cancer. J Thorac Cardiovasc Surg. 2006;131:822–829. 46. Gress FG, Savides TJ, Sandler A, et al. Endoscopic ultrasonography, fine-needle aspiration biopsy guided by endoscopic ultrasonography, and computed tomography in the preoperative staging of non–small cell lung cancer: a comparison study. Ann Intern Med. 1997;127:604–612. 47. Morgenthaler TI, Brown LR, Colby TV, et al. Thymoma. Mayo Clin Proc. 1993;68:1110–1123. 48. Hoffman OA, Gillespie DJ, Aughenbaugh GL, et al. Primary mediastinal neoplasms (other than thymoma). Mayo Clin Proc. 1993;68:880–891. 49. Wick MR, Rosai J. Neuroendocrine neoplasms of the mediastinum. Semin Diagn Pathol. 1991;8:35–51. 50. Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg. 2004;77:1860–1869. 51. Casamassima F, Villari N, Fargnoli R, et al. Magnetic resonance imaging and high-resolution computed tomography in tumors of the lung and the mediastinum. Radiother Oncol. 1988;11:21–29. 52. Eng TY, Fuller CD, Jagirdar J, et al. Thymic carcinoma: State of the art review. Int J Radiat Oncol Biol Phys. 2004;59:654–664. 53. Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981;48:2485–2492.

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Disease Sites

54. Kondo K. The thymic epithelial tumor staging system. J Thorac Oncol. 2017;12(1S):S31–S33. 55. Lee JD, Choe KO, Kim SJ, et al. CT findings in primary thymic carcinoma. J Comput Assist Tomogr. 1991;15:429–433. 56. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer. 1997;79:813–829. 57. Kaltsas G, Korbonits M, Heintz E, et al. Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors. J Clin Endocrinol Metab. 2001;86:895–902. 58. Anderson CJ, Dehdashti F, Cutler PD, et al. 64Cu-TETA-octreotide as a PET imaging agent for patients with neuroendocrine tumors. J Nucl Med. 2001;42:213–221. 59. Prasad V, Ambrosini V, Hommann M, et al. Detection of unknown primary neuroendocrine tumours (CUP-NET) using (68)Ga-DOTANOC receptor PET/CT. Eur J Nucl Med Mol Imaging. 2010;37: 67–77. 60. Renshaw AA, Dean BR, Antman KH, et al. The role of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma. Chest. 1997;111:106–109. 61. Bueno R, Reblando J, Glickman J, et al. Pleural biopsy: a reliable method for determining the diagnosis but not subtype in mesothelioma. Ann Thorac Surg. 2004;78:1774–1776. 62. Bonomi M, De Filippis C, Lopci E, et al. Clinical staging of malignant pleural mesothelioma: current perspectives. Lung Cancer (Auckl). 2017;8:127–139. 63. Marks LB. The impact of organ structure on radiation response. Int J Radiat Oncol Biol Phys. 1996;4:1165–1171. 64. Chi A, Liao Z, Nguyen NP, et al. Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non–small-cell lung cancer: clinical implications. Radiother Oncol. 2010;94:1–11. 65. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006;24:4833–4839. 66. Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body radiation therapy for early-stage non–small-cell lung carcinoma: Four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys. 2009;75:677–682. 67. Timmerman R, Hu C, Michalsky J, et al. Long-term results of RTOG 0236: a phase II trial of stereotactic body radiation therapy (SBRT) in the treatment of patients with medically inoperable stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;90:S30. 68. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303:1070–1076. 69. Forquer JA, Fakiris AJ, Timmerman RD, et al. Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: Dose-limiting toxicity in apical tumor sites. Radiother Oncol. 2009;93:408–413. 70. Pettersson N, Nyman J, Johansson KA. Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy of non–small cell lung cancer: a dose- and volume-response analysis. Radiother Oncol. 2009;91:360–368. 71. Dunlap NE, Cai J, Biedermann GE, et al. Chest wall volume receiving >30 Gy predicts risks of severe pain and/or rib fracture after lung stereotactic. Int J Radiat Oncol Biol Phys. 2010;76:796–801. 72. Murrell DH, Laba JM, Erickson A, et al. Stereotactic ablative radiotherapy for ultra-central lung tumors: prioritize target coverage or organs at risk? Radiat Oncol. 2018;13:57. 73. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys. 2010;76(suppl):S70–S76. 74. Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non–small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 1999;45:323–329. 75. Kwa SL, Lebesque JV, Theuws JC, et al. Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys. 1998;42:1–9.

76. Hope AJ, Lindsay PE, El Naqa I, et al. Modeling radiation pneumonitis risk with clinical, dosimetric, and spatial parameters. Int J Radiat Oncol Biol Phys. 2006;65:112–124. 77. Anscher MS, Kong FM, Andrews K, et al. Plasma transforming growth factor beta1 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 1998;41:1029–1035. 78. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non–smallcell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005;23:5883–5891. 79. Kristensen CA, Nottrup TJ, Berthelsen AK, et al. Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma. Radiother Oncol. 2009;92:96–99. 80. Singh AK, Lockett MA, Bradley JD. Predictors of radiation-induced esophageal toxicity in patients with non–small cell lung cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2003;55:337–341. 81. Werner-Wasik M, Pequignot E, Leeper D, et al. Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: a multivariate analysis of patients with lung cancer treated with non-operative therapy. Int J Radiat Oncol Biol Phys. 2000;48:689–696. 82. Rose J, Rodrigues G, Yaremko B, et al. Systematic review of dose-volume parameters in the prediction of esophagitis in thoracic radiotherapy. Radiother Oncol. 2009;91:282–287. 83. Liao Z, Cox JD, Komaki R. Radiochemotherapy of esophageal cancer. J Thorac Oncol. 2007;2:553–568. 84. Movsas B, Scott C, Langer C, et al. Randomized trial of amifostine in locally advanced non- small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation Therapy Oncology Group trial 98-01. J Clin Oncol. 2005;23:2145–2154. 85. Bradley JD, Paulus R, Komaki R, et al. A randomized phase III comparison of standard-dose (60GY) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non–small lung cancer: results on radiation dose in RTOG. J Clin Oncol. 2013;31:7501. 86. Aleman BM, Belt-Dusebout AW, Klokman WJ, et al. Long-term cause-specific mortality of patients treated for Hodgkin’s disease. J Clin Oncol. 2003;21:3431–3439. 87. Early Breast Cancer Trialists’ Collaborative Group. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;366:2087–2106. 88. Borger JH, Hooning MJ, Boersma LJ, et al. Cardiotoxic effects of tangential breast irradiation in early breast cancer patients: the role of irradiated heart volume. Int J Radiat Oncol Biol Phys. 2007;69:1131–1138. 89. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non–small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 1995;60:615–622. 90. Watanabe T, Okada A, Imakiire T, et al. Intentional limited resection for small peripheral lung cancer based on intraoperative pathologic exploration. Jpn J Thorac Cardiovasc Surg. 2005;53:29–35. 91. National Cancer Institute (NCI). Phase III randomized study of lobectomy versus sublobar resection in patients with small peripheral stage IA non–small cell lung cancer. Available from: http://www.cancer. gov/clinicaltrials/CALGB-140503. 92. Timmerman RD, Paulus R, Pass HI, et al. Stereotactic body radiation therapy for operable early-stage lung cancer findings from the NRG oncology RTOG 0618 trial. JAMA Oncol. 2018;4(9):1263–1266. 93. Hiraoka M, Ishikura S. A Japan clinical oncology group trial for stereotactic body radiation therapy of non–small cell lung cancer. J Thorac Oncol. 2007;2(7 suppl 3):S115–S117. 94. Available from: https://www.vacsp.research.va.gov/CSP_2005/CSP_2005. asp. Accessed September 29, 2018. 95. Haasbeek CJ, Senan S, Smit EF, et al. Non–small cell lung cancer: a critical review of nonsurgical treatment options for stage I. Oncologist. 2008;13:309–319.

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CHAPTER 49 96. Powell JW, Dexter E, Scalzetti EM, et al. Treatment advances for medically inoperable non–small-cell lung cancer: emphasis on prospective trials. Lancet Oncol. 2009;10:885–894. 97. Bogart JA, Hodgson L, Seagren SL, et al. Phase I study of accelerated conformal radiotherapy for stage I non–small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904. J Clin Oncol. 2010;28:202–206. 98. Cheung P, Faria S, Ahmed S, et al. Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25. J Natl Cancer Inst. 2014;106:106. 99. Swaminath A, Wierzbicki M, Parpia S, et al. Canadian phase III randomized trial of stereotactic body radiotherapy versus conventionally hypofractionated radiotherapy for stage I, medically inoperable non–small-cell lung cancer – Rationale and protocol design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE trial. Clin Lung Cancer. 2017;18(2):250–254. 100. Chen M, Hayman JA, Ten Haken RK, et al. Long-term results of high-dose conformal radiotherapy for patients with medically inoperable T1-3N0 non–small-cell lung cancer: is low incidence of regional failure due to incidental nodal irradiation. Int J Radiat Oncol Biol Phys. 2006;64:120–126. 101. Rosenzweig KE, Fox JL, Leibel SA, et al. Results of a phase I doseescalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non small cell lung carcinoma. Cancer. 2005;103:2118–2127. 102. Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of RTOG9311: a phase I-II dose escalation study using three-dimensional conformal radiotherapy in patients with inoperable non–small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2005;61:318–328. 103. Fernando HC, Landreneau RJ, Mandrekar SJ, et al. Impact of brachytherapy on local recurrence after sublobar resection: results from ACOSOG Z40322 (Alliance), a phase III randomized trial for high-risk operable non–small cell lung cancer (NSCLC). J Clin Oncol. 2013;31(7502). 104. Dupuy DE, Fernando HC, Hillman S, et al. Radiofrequency ablation of stage IA NSCLC in medically inoperable patients: results from the ACOSOG Z4033 (Alliance) trial. Cancer. 2015;121:3491–3498. 105. Arriagada R, Dunant A, Pignon JP, et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatinbased chemotherapy in resected lung cancer. J Clin Oncol. 2010;28:35–42. 106. Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non–small-cell lung cancer: CALGB 9633 with Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008;31:5043–5051. 107. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non–small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379–386. 108. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452–1460. 109. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non–small cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005;23:5883–5891. 110. Blackstock AW, Govindan R. Definitive chemoradiation for the treatment of locally advanced non–small-cell lung cancer. J Clin Oncol. 2007;25:4146–4152. 111. Vokes EE, Herndon JEII, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non–small-cell lung cancer: cancer and Leukemia Group B. J Clin Oncol. 2007;25:1698–1704. 112. Hanna N, Neubauer M, Ansari R, et al. Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel (D) in patients (pts) with inoperable

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stage III non–small cell lung cancer (NSCLC) HOG LUN01-24/ USO-023. Proc Am Soc Clin Oncol. 2007;25. 113. Coate LE, Shepherd FA. Maintenance therapy in advanced non–small cell lung cancer. J Thorac Oncol. 2008;26:4849–4850. 114. Perez CA, Stanley K, Rubin P, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung: preliminary report by the Radiation Therapy Oncology Group. Cancer. 1980;45:2744–2753. 115. Rosenman JG, Halle JS, Socinski MA, et al. High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non–small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys. 2002;54:348–356. 116. Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non–small-cell lung cancer: CALGB 30105. J Clin Oncol. 2008;2026:2457–2463. 117. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non–small-cell lung cancer: a randomised multicentre trial. Chart Steering Committee. Lancet. 1997;350:161–165. 118. Belani CP, Wang W, Johnson DH, et al. Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non–small-cell lung cancer. Eastern Cooperative Oncology Group. J Clin Oncol. 2005;23:3760–3767. 119. Sause W, Kolesar P, Taylor S IV, et al. Final results of phase III trial in regionally advanced unresectable non–small cell lung cancer. Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000;117:358–364. 120. Bonner JA, McGinnis WL, Stella PJ, et al. The possible advantage of hyperfractionated thoracic radiotherapy in the treatment of locally advanced non small cell lung carcinoma: results of a North Central Cancer Treatment Group Phase III Study. Cancer. 1998;82:1037–1048. 121. Walraven I, Van Den Heuvel M, Van Diessen J, et al. Long-term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab. Radiother Oncol. 2016;118:442–446. 122. Liao Z, Lee JJ, Komaki R, et al. Adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non–small-cell. Lung Cancer J Clin Oncol. 2018;36(18):1813–1822. 123. Kepka L, Bujko K, Zolciak-Siwinska A. Risk of isolated nodal failure for non–small cell lung cancer (NSCLC) treated with the elective nodal irradiation (ENI) using 3D-conformal radiotherapy (3D-CRT) techniques—a retrospective analysis. Acta Oncol. 2008;47:95–103. 124. Emami B, Mirkovic N, Scott C, et al. The impact of regional nodal radiotherapy (dose/volume) on regional progression and survival in unresectable non–small cell lung cancer: an analysis of RTOG data. Lung Cancer. 2003;41:207–214. 125. Yuan SP, Sun XMD, Li MP, et al. A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III non small cell lung cancer. Am J Clin Oncol. 2007;30:239–244. 126. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non–small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008;26:2450–2456. 127. Ready N, Janne PA, Bogart J, et al. Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALGB) 30106, a CALGB-Stratified phase II trial. J Thorac Oncol. 2010;5(9):1382–1390. 128. Lilenbaum R, Samuels M, Wang X, et al. A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor-risk stage III non–small-cell lung cancer: results of CALGB 30605 (Alliance)/RTOG 0972 (NRG). J Thorac Oncol. 2015;10(1):143–147.

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Disease Sites

129. Blumenschein GR, Paulus R, Curran WJ, et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non–small-cell lung cancer: RTOG 0324. J Clin Oncol. 2011;29(17):2312–2318. 130. Govindan R, Bogart J, Stinchcombe T, et al. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non–small-cell lung cancer: cancer and leukemia group B trial 30407. J Clin Oncol. 2011;29(23):3120–3125. doi:10.1200/JCO.2010.33.4979. 131. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. 132. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol. 2010;1:43–48. 133. Mira JG, Miller TP, Crowley JJ. Chest irradiation (RT) vs. chest RT + chemotherapy + prophylactic brain RT in localized non small cell lung cancer: a Southwest Oncology Group randomized study [abstract]. Am Soc Ther Radiol Oncol. 1990;43(19):145. 134. Cox JD, Stanley K, Petrovich Z, et al. Cranial irradiation in cancer of the lung of all cell types. JAMA. 1981;245:469–472. 135. Russell AH, Pajak TE, Selim HM, et al. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1991;21:637–643. 136. Umsawasdi T, Valdivieso M, Chen TT, et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease non–small cell lung cancer. J Neurooncol. 1991;2:253–259. 137. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol. 2011;29:272–278. 138. PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non–small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet. 1998;352:257–263. 139. Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non small cell lung cancer using the surveillance, epidemiology and end results database. J Clin Oncol. 2006;24:2998–3006. 140. Phase III study comparing post-operative conformal radiotherapy to no post-operative radiotherapy in patients with completely resected non–small cell lung cancer and mediastinal N2 involvement (EORTC 22055-08053). Available from: http://public.ukcrn.org.uk/search/ StudyDetail.aspx?StudyID=5686. 141. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340:265–271. 142. Schreiber D, et al. Utilization of Hyerfractionated Radiation in Small-Cell Lung cancer and Its Impact on Survival. J Thorac Oncol. 2015;10(12):1770–1775. 143. Bogart JA, Herndon JE 2nd, Lyss AP, et al. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys. 2004;59:460–468. 144. Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18:1116e1125. 145. Alliance for Clinical Trials in Oncology (Cancer and Leukemia Group B). Phase III randomized study of three different thoracic radiotherapy regimens in patients with limited-stage small cell lung cancer receiving cisplatin and etoposide. Available from: http://www.clinicaltrials.gov/ct/ show/NCT00632853. 146. Perry MC, Herndon JE 3rd, Eaton WL, et al. Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol. 1998;16:2466–2467.

147. Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1993;11:336–344. 148. De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, et al. Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol. 2006;17:543–552. 149. Huncharek M, McGarry R. A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited stage small cell lung cancer. Oncologist. 2004;9:665–672. 150. Kies MS, Mira JG, Crowley JJ, et al. Multimodal therapy for limited small cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders, and with wide-field versus reduced-field radiation in partial responders. A Southwest Oncology Group study. J Clin Oncol. 1987;5:592–600. 151. Bonner JA, Sloan JA, Shanahan TG, et al. Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol. 1999;17:2681–2691. 152. Schild SE, Bonner JA, Shanahan TG, et al. Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;59:943–951. 153. Baas P, Belderbos JS, Senan S, et al. Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study. Br J Cancer. 2006;94:625–630. 154. Aupérin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341:476–484. 155. Le Pechoux C, Dunant A, Senan S, et al. Standard-dose versus higherdose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009;10:467–474. 156. Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:663–671. 157. Niell HB, Herndon JE 2nd, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: cancer and Leukemia Group B Trial 9732. J Clin Oncol. 2005;23:3752–3759. 158. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346:85–91. 159. Lara PN Jr, Natale R, Crowley J, et al. Phase III trial of irinotecan/ cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol. 2009;15:2530–2535. 160. Hellmann M, Ott P, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): first report of a randomized expansion cohort from CheckMate 032. J Clin Oncol. 2017;35:s8503. 161. Safieddine N, Liu G, Cuningham K, et al. Prognostic factors for cure, recurrence and long-term survival after surgical resection of thymoma. J Thorac Oncol. 2014;9(7):1018–1022. 162. Girard N, Mornex F, Van Houtte P, et al. Thymoma: a focus on current therapeutic management. J Thorac Oncol. 2009;4:119–126. 163. Urgesi A, Monetti U, Rossi G, et al. Role of radiation therapy in locally advanced thymoma. Radiother Oncol. 1990;19:273–280. 164. Haniuda M, Miyazawa M, Yoshida K, et al. Is postoperative radiotherapy for thymoma effective? Ann Surg. 1996;224:219–224.

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CHAPTER 49 165. Forquer JA, Rong N, Fakiris AJ, et al. Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease. Int J Radiat Oncol Biol Phys. 2010;76:440–445. 166. Rimner A, Yao X, Huang J, et al. Postoperative radiation therapy is associated with longer overall survival in completely resected stage II and III thymoma—an analysis of the international thymic malignancies interest group retrospective database. J Thorac Oncol. 2016;11(10):1785–1792. 167. Giannopoulou A, Gkiozos I, Harrington KJ, Syrigos KN. Thymoma and radiation therapy: a systematic review of medical treatment. Expert Rev Anticancer Ther. 2013;13:759–766. 168. Urgesi A, Monetti U, Rossi G, et al. Aggressive treatment of intrathoracic recurrences of thymoma. Radiother Oncol. 1992;24:221–225. 169. Eng TY, Fuller CD, Jagirdar J, et al. Thymic carcinoma: State of the art review. Int J Radiat Oncol Biol Phys. 2004;59:654–664. 170. Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: results of an international analysis. J Thorac Cardiovasc Surg. 2015;149:95. 171. Jackson MW, Palma DA, Camidge DR, et al. The impact of postoperative radiotherapy for thymoma and thymic carcinoma. J Thorac Oncol. 2017;12:734. 172. Filosso PL, Rena O, Donati G, et al. Bronchial carcinoid tumors: surgical management and long-term outcome. J Thorac Cardiovasc Surg. 2002;123:303–309. 173. Kubota A, Yamada Y, Kagimoto S, et al. Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors. J Clin Invest. 1994;93:1321–1325. 174. Beasley MB, Thunnissen FB, Brambilla E, et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol. 2000;31:1255–1265. 175. Carretta A, Ceresoli GL, Arrigoni G, et al. Diagnostic and therapeutic management of neuroendocrine lung tumors: a clinical study of 44 cases. Lung Cancer. 2000;29:217–225. 176. Granberg D, Eriksson B, Wilander E, et al. Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol. 2001;12:1383–1391. 177. Oberg K, Astrup L, Eriksson B, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Acta Oncol. 2004;43:617–625. 178. Flores RM, Krug LM, Rosenzweig KE, et al. Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial. J Thorac Oncol. 2006;1:289–295. 179. Schupak KD, Wallner KE. The role of radiation therapy in the treatment of locally unresectable or metastatic carcinoid tumors. Int J Radiat Oncol Biol Phys. 1991;20:489–495. 180. Verma V, Ahern CA, Berlind CG, et al. National cancer database report on pneumonectomy versus lung-sparing surgery for malignant pleural mesothelioma. J Thorac Oncol. 2017;12(11):1704–1714. 181. Batirel HF, Metintas M, Caglar HB, et al. Adoption of pleurectomy and decortication for malignant mesothelioma leads to similar survival as extrapleural pneumonectomy. J Thorac Cardiovasc Surg. 2016;151(2):478–484.

Overview

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182. Treasure T, Lang-Lazdunski L, Waller D, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol. 2011;12(8):763–772. 183. Ung YC, Yu E, Falkson C, et al. The role of radiation therapy in malignant pleural mesothelioma: a systematic review. Radiat Oncol. 2006;80:13–18. 184. Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol. 2015;16(16):1651–1658. 185. Li L, Lally B, Egleston BL, et al. Significant increased survival in mesothelioma patients treated with radiation and surgery: an analysis of the SEER registry [abstract 2700]. Int J Radiat Oncol Biol Phys. 2009;S496–S497. 186. Santaro A, O’Brien ME, Stahel RA, et al. Pemetrexed plus cisplatin or pemetrexed plus cardioplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol. 2008;3:756–763. 187. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10026):1405–1414. 188. Scherpereel A, Mazieres J, Greillier L, et al. Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: results of the IFCT-1501 MAPS2 randomized phase II trial. J Clin Oncol. 2017;35:18. 189. Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017;18:623–630. 190. Nowak A, Kok P, Livingstone A, et al. DREAM - A Phase 2 Trial of durvalumab with First Line chemotherapy in mesothelioma with a Safety Run In. J Thorac Oncol. 2017;12:S1086–S1087. 191. Allen AM, Den R, Wong JS, et al. Influence of radiotherapy technique and dose on patterns of failure for mesothelioma patients after extrapleural pneumectomy. Int J Radiat Oncol Biol Phys. 2007;68:1366–1374. 192. Patel PR, Yoo S, Broadwater G, et al. Effect of increasing experience on dosimetric and clinical outcomes in the management of malignant pleural mesothelioma with intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2012;83:362. 193. Minatel E, Trovo M, Bearz A, et al. Radical radiation therapy after lung-sparing surgery for malignant pleural mesothelioma: survival, pattern of failure, and prognostic factors. Int J Radiat Oncol Biol Phys. 2015;93(3):606–613. 194. Rimner A, Zauderer MG, Gomez DR, et al. Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma. J Clin Oncol. 2016;34(23):2761–2768. 195. Bayman N, Ardron D, Ashcroft L, et al. Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention. BMJ Open. 2016;6:e010589.

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50 Small Cell Lung Cancer Michael Mix and Jeffrey A. Bogart

KEY POINTS Incidence Small cell lung cancer (SCLC) represents about 15% of over 230,000 annual lung cancer diagnoses in the United States. Only about one-third present without metastatic disease. Biological Characteristics SCLC is a high-grade tumor of the lung, with ultrastructural characteristics consistent with its neuroendocrine differentiation. P53 and pRB are mutated in nearly all cases, and additional mutations are acquired, leading to the final metastatic phenotype. It has known associations with paraneoplastic syndromes. Staging Evaluation Computed tomography (CT) of the chest with contrast, positron emission tomography/computed tomography (PET/CT), and magnetic resonance imaging (MRI) of the brain are essential to the workup following histological diagnosis. The eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging is reported, but clinical decision-making is largely based on the widely used dichotomous limited versus extensive staging system. Primary Therapy in Limited-Stage Disease Treatment consists of chemotherapy in all cases, generally 4 cycles of cisplatin and etoposide. Thoracic radiation therapy (TRT) is delivered concurrently; the current standard is 45 Gy in 30 twice-daily fractions for those with limited-stage disease. However, the optimal dosing will be defined by long-term results of recently closed and accruing Phase III trials (CALGB 30610 and

CONVERT). TRT is given early in the course, concurrent with cycle 1 or 2 if possible. Gross disease is targeted, and elective nodal irradiation has been largely abandoned. Prophylactic cranial irradiation (PCI) is routinely recommended for patients who have had a response to initial therapy. Primary Therapy in Extensive-Stage Disease Chemotherapy is the backbone of treatment, again consisting of cisplatin and etoposide, typically six cycles. Consideration is given to consolidative TRT for those who have a good response to chemotherapy, often 30 Gy in 10 fractions, although this dose remains to be clearly defined. PCI has been recommended following completion of chemotherapy, but its use has become more controversial recently given conflicting results of Phase III studies regarding presence of overall survival benefit. Methods of mitigating toxicity from brain radiation while garnering benefit of PCI are being investigated in Phase III studies, including hippocampal avoidance. Improvement in outcomes overall has been slow to develop over the past several decades, but emerging research regarding targeted therapies provides hope for the future. Immunotherapy with checkpoint inhibitors is currently used for refractory or recurrent disease, and Phase III data supporting PD-L1 inhibition as a component of first-line therapy have recently emerged.

INTRODUCTION

and treatment of SCLC, it was identified as a recalcitrant cancer by the director of the National Cancer Institute (NCI) within the last decade, denoting the need for increased funding and research. Relative to NSCLC, advances in management, both local and systemic, have been few and far between.

Small cell lung cancer (SCLC) is a subset of lung cancer with a natural history generally more aggressive than non–small cell lung cancer (NSCLC), its more common counterpart. In the 1970s, note was made of the frequent propensity for distant metastasis early in the course of SCLC.1 Since that era, SCLC has been largely treated with chemotherapy and radiation, with surgery being reserved for only a very small minority of cases. Following definitive treatment, consideration is given to prophylactic cranial irradiation (PCI) given high incidence of brain metastases. Despite good rates of response to initial therapy, relapse is the rule rather than the exception. Survival rates remain relatively poor, especially in those who present with disseminated disease. With standardof-care therapy, median survival is about 28 months2 and 15 months3 for localized and metastatic disease, respectively. About one-third of those who present with chest-confined disease will be alive at 5 years. Long-term survival in those with disseminated disease is exceedingly uncommon. Due to a general lack of progress in screening, diagnosis,

ETIOLOGY AND EPIDEMIOLOGY In 2018, there were estimated to be a total of 234,000 new cases of lung cancer diagnosed in the United States.4 Worldwide, lung cancer represents the most common malignancy and most common cause of cancer-related death.5 SCLC represents approximately 15% of all lung cancer diagnoses. There has been a decline in incidence over time,6 largely attributed to a decline in smoking rates. Tobacco smoking remains the dominant risk factor for development of SCLC. The vast majority of those with the disease have a heavy smoking history. Unlike in NSCLC, additional environmental risk factors are felt to play a smaller role, although there is some evidence to suggest

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826

SECTION III

Disease Sites

that radon can increase risk, as it does in NSCLC.7 In the prototypical case, repeated exposure to inhaled cigarette smoke leads to a multitude of genomic abnormalities that drive carcinogenesis, discussed later.

PREVENTION AND EARLY DETECTION Abstinence from smoking or cessation represents the only meaningful prevention of SCLC. No effective screening system exists. One could speculate that the use of low-dose computed tomography (CT) for screening in NSCLC may lead to an upward shift in localized diagnoses of SCLC, but current data are not supportive.8 Generally speaking, SCLC does not fit the typical mold for a diagnosis that can benefit from screening because of its short preclinical latency, biological aggressiveness, and propensity for early systemic metastasis. Finally, given the relative rarity compared to NSCLC, the number needed to screen may be prohibitive. Patients who do achieve durable control of their disease are at significant risk of developing second primary cancers, particularly those related to smoking.9 Thus, emphasis should be placed on smoking cessation both at the time of diagnosis and in the surveillance period.

BIOLOGICAL CHARACTERISTICS/MOLECULAR BIOLOGY SCLC was identified as a distinct entity from other lung cancers in the mid-20th century.10 Based initially on ultrastructural characteristics11 and ultimately verified in vitro with note of secretory capabilities,12 SCLC became classified as a neuroendocrine lung tumor. It is the most aggressive member of the class that also includes (in order of decreasing aggressiveness) large cell neuroendocrine carcinoma (LCNEC), atypical carcinoid, and typical carcinoid.13 Atypical carcinoid tumors have 2 to 11 mitoses per high-power field; anything greater is a criterion for diagnosis of SCLC or LCNEC. Distinction between these two high-grade entities is made based on morphological features, of course, including cell size. With light microscopy, a positive diagnosis identifies “a malignant epithelial tumor consisting of small cells, with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli.”13 Supporting immunohistochemical stains, which can be helpful but are not required for diagnosis, include CD56, chromogranin, synaptophysin, and TTF-1, which are positive in a vast majority.14,15 There is a distinct entity known as combined small cell carcinoma variant, which refers to SCLC with an admixed component NSCLC (squamous, adenocarcinoma, and so on). To meet this definition, 2004 World Health Organization (WHO) criteria dictate the presence of at least 10% large cells. Like all epithelial cancers, SCLC traverses a series of acquired mutations, ultimately leading to the final malignant and metastatic state. Tobacco carcinogenesis is felt to play a crucial role in this evolution. TP53 and RB1 are the most commonly mutated genes in SCLC, and are altered in nearly all cases.16 Additional genetic hits are generally required, though, often including PTEN and NFIB.17 NFIB, in particular, is associated with the development of metastatic potential.18 Another frequent finding is the deletion of allelic 3p.19 Many additional tumor suppressor genes have been identified; investigation into the role they play is ongoing.20 Notch signaling is frequently dysregulated thanks to mutations in Notch pathway genes or by expression of inhibitors.21,22 MYC amplifications are common,23 but amplification of kinase signaling pathways (e.g., EGFR, ALK) is less frequent compared to lung adenocarcinomas. A majority of SCLC cells are believed to express KIT—or its ligand, stem cell factor24-26—though imatinib has shown little antitumor activity.27 Vascular endothelial growth factor (VEGF) expression is increased in SCLC, but despite enthusiasm in targeting

angiogenesis, trials attempting to do so with monoclonal antibodies or tyrosine kinase inhibitors have been largely negative. Beyond genetic mutations, there has also been interest in the potential role of epigenetic changes and their mechanistic involvement in carcinogenesis.20 Compared with NSCLC, SCLC tumor expression of PD-L1 is generally considered to be low, but there have been varying reports regarding positivity.28-31 Regardless, as expression does not necessarily correlate with treatment response, there is significant optimism for improvement in outcomes with checkpoint inhibitors. Clinical outcomes will be discussed in more detail later. Markers predictive for response have been highly sought; one method showing promise is degree of tumor mutational burden. There was suggestion of increased benefit to dual therapy with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) versus the former alone in tumors categorized in the highest tertile of burden.32

CLINICAL MANIFESTATIONS, PATIENT EVALUATION, AND STAGING SCLC is notorious for early dissemination, bulky nodal disease, and widespread metastases. This is due in large part to rapid proliferation. As noted earlier, a majority of patients present with metastatic disease at diagnosis, and only very few (< 5%) present with true node-negative disease. Given a rapid doubling rate, patient often present with thoracic symptoms that progress rapidly. Shortness of breath, cough, postobstructive infection, and superior vena cava syndrome are among the most common presentations. Functional neuroendocrine characteristics and/or antibody crossreactivity can lead to disrupted homeostasis in remote systems—so-called paraneoplastic syndromes. These can be the result of ectopic hormone production or antibodies directed against neural antigens. These syndromes are well described and represent a notable source of morbidity in this patient population. Lambert Eaton myasthenic syndrome (LEMS), encephalomyelitis, and sensory neuropathy represent typical neurological syndromes. LEMS is a clinical syndrome in which antibodies directed at presynaptic calcium channels interfere with normal acetylcholine release. The result is slowly progressing proximal muscle weakness and depressed deep tendon reflexes. Endocrine dyscrasias include the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Cushing syndrome, with the ectopic production of ADH and cortisol, respectively. Management depends on the syndrome present and is in conjunction with (if not solely consisting of) the antineoplatic therapy.33 Superior vena cava (SVC) syndrome is the progressive occlusion of the SVC by bulky mediastinal adenopathy or occasionally from a parenchymal-based mass invading the mediastinum. Patients exhibit signs of restricted venous emptying in the face and upper extremities, including swelling, plethora, bluish/purplish discoloration, pain with recumbency, and development of collateral vasculature over the chest if vascular occlusion is gradual. SVC syndrome is a presentation frequently seen in newly diagnosed SCLC given its tendency to exhibit bulky mediastinal adenopathy. Given the chemosensitive nature, expeditious initiation of chemotherapy is often the therapy of choice as opposed to delivering palliative radiotherapy (RT) upfront. There are data suggesting equivalent outcome without using RT at the outset in patients presenting with SVC syndrome.34,35 Tissue diagnosis should be obtained with haste and prior to initiation of therapy if feasible, as treatment recommendations may differ substantially from that of NSCLC. While percutaneous needle biopsy is sometimes appropriate, bronchoscopy with ultrasound (endobronchial ultrasound [EBUS]) offers the advantage of obtaining a diagnosis as well as ascertaining the stage if nodal involvement is identified. Following routine laboratory evaluation, CT with contrast of the chest should be

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CHAPTER 50 obtained as well as magnetic resonance imaging (MRI) of the brain given the high propensity for brain metastases. If no metastatic disease is identified, positron emission tomography/computed tomography (PET/CT) is recommended. PET/CT has been shown to improve the ability to detect extrathoracic metastases and has improved sensitivity significantly compared with CT alone.36-38 Ten to twenty percent of patients are upstaged with the addition of PET/CT. The American Joint Committee on Cancer (AJCC) lung cancer staging is recommended, as it is for NSCLC; official implementation of the eighth edition occurred in January 2018. However, practical clinical decision-making has been made for decades based on the dichotomous limited- versus extensive-staging system. That said, AJCC staging is prognostic and could potentially impact clinical trial outcomes if not taken into account. Thus, it is vital to underscore the importance of its routine clinical use. The US Veterans Administration (VA) Lung Study Group initially developed the limited/extensive definition in the latter half of the 20th century; limited was defined as disease confined to one hemithorax that could be targeted with a reasonable radiation treatment field.39 Extensive stage included anything not qualifying as limited. In current practice, the extent of disease that qualifies as limited is much more subjective, due in large part to developments made in conformal RT delivery. No strict correlation with the AJCC system exists; however, M1a disease is generally considered extensive. Ipsilateral supraclavicular (N3) involvement is frequently included within the limited-stage treatment paradigms, while contralateral hilar or supraclavicular involvement is more controversial and represents typical exclusion criteria from most, but not all, contemporary clinical trials enrolling patients with limited-stage disease.

PRIMARY THERAPY, LOCALLY ADVANCED DISEASE, COMBINED-MODALITY THERAPY Surgery for Small Cell Lung Cancer Unlike in NSCLC, surgery has played a very limited role in SCLC. The 10-year results of a Medical Research Council (MRC) trial from the United Kingdom suggested that survival outcomes were superior with RT compared with surgical resection.40 Patients (n = 144) with resectable disease without evidence of extrathoracic metastases who were fit enough to undergo either treatment were eligible. The surgeries were extensive (included pneumonectomy in all cases), and there was no chemotherapy delivered in either arm. Survival was superior in the radical RT arm, 300 days versus 199 days (p = 0.04). This was based

TABLE 50.1

Small Cell Lung Cancer

827

on an intention-to-treat analysis, a fact important to note considering that the one long-term survivor in the surgery arm never actually had surgery and received only palliative RT. Nevertheless, the results led the authors to conclude that RT was the preferred choice for patients who fit the inclusion criteria. Surgical resection was largely removed from the treatment algorithms for SCLC following these results. A more contemporary trial run by the Lung Cancer Study Group (LCSG) randomized patients after response to cyclophosphamide, doxorubicin, and vincristine (CAV) to inclusion or omission of pulmonary resection.41 All patients received thoracic radiation (50 Gy in 25 fractions) therapy and PCI (30 Gy in 15 fractions). No improvement in survival or local control was seen with the addition of surgery. An attempted subgroup analysis with regard to disease extent did not identify a cohort that might benefit from surgery. Diagnosis was made bronchoscopically in all cases; thus, no patients with peripheral tumors and negative bronchoscopy were included in this trial. A number of retrospective analyses, small single-arm early-phase trials, and database studies have attempted to further elucidate a potential role for surgical resection in early-stage disease. Five-year survival rates in many of these series are promising, in the 40% to 70% range. Several of these studies are summarized in Table 50.1. In many instances, RT was not used or its use was not detailed, making comment on any effect of RT difficult. The National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of surgical resection for T1-2N0, following negative mediastinal staging.42 In a Surveillance, Epidemiology, and End Results (SEER) Program database analysis of over 1900 patients with stage I SCLC, only 28% underwent resection,43 suggesting that resection is not common practice despite the NCCN recommendation. There appeared to be a benefit from more extensive nodal sampling in that patients who had four or more lymph nodes removed had better overall survival (OS). In a small Japanese study, 11% of patients were deemed inoperable owing to mediastinal involvement uncovered by mediastinoscopy.44 Of these patients, 18% were found to have pN2 disease after negative mediastinoscopy, suggesting limited sensitivity and underscoring the import of invasive mediastinal staging prior to definitive resection. In cases in which resection is performed, adjuvant chemotherapy is recommended. A National Cancer Database (NCDB) analysis suggested improved survival with the addition of chemotherapy, with or without radiation, following resection.45 This analysis also suggested that use of chemotherapy with brain-directed RT was associated with improved survival. Currently, PCI remains a standard recommendation for patients

Selected Series of Surgical Resection in Small Cell Lung Cancer

Author (Date)

Type

Schreiber (2010)112

SEER

863

Yu (2010)113

SEER

247a

I

NR

50%

Varlotto (2011)

SEER

436

I-II

NR

47% (lobar resection) 29% (sublobar resection)

Takei (2014)115

Retrospective

243

I-IV

11% IND 65% Adj

53%

Yang (2016)45

NCDB

954

I

57% Adj

47%

Combs (2015)116

NCDB

2476

I-III

68%

51%, 25%, and 18% for stages I-III, respectively

Wakeam (2017)117

NCDB

2619

I-IIIA

59% Adj

MS of 39, 23, and 22 mo, for stages I-III, respectively

49

NCDB

943

I

54%

3-y OS, 62%

114

Paximadis (2018)

N

Stage(s) I-III

Chemo

5-Y Overall Survival

28%

35%

a

Selected patients who underwent lobectomy. Adj, Adjuvant; Chemo, chemotherapy; IND, induction; MS, median survival; NCDB, retrospective review of National Cancer Database; NR, not reported; OS, overall survival; SEER, retrospective review of Surveillance Epidemiology and End Results database.

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828

SECTION III

Disease Sites

TABLE 50.2

Series of SBRT for Early Stage SCLC

Author (Date)

Type

N

Chemo

PCI

RT Dose

DFS/PFS

Median OS

OS

Multi-Inst Retrospective

74

56% yes

23%

Median 50/5

Median 61.3 mo Median 9 mo

31.4 mo

3 y, 34%

23.5 mo

5 y, 22%

NR

3 y, 40%

Verma (2017)

118,119

44% no Stahl (2017)120

NCDB

Shioyama (2018)121

Retrospective

Paximadis (2018)49

NCDB

285

46% yes

NR

Most commona 50/5, 21% 48/4, 16% 60/3, 14% 54/3, 12%

NR

43

19% yes

19%

48-60 in 4-8 fx

2 y 45%

140

51% yes

NR

Most common* 50/5, 25% 48/4, 20% 60/3, 15% 54/3, 13%

NR

14.3 mo

2 y, 72%

a

(%) of entire cohort Chemo, chemotherapy; DFS/PFS, disease-/progression-free survival; multi-inst, multi-institutional; NCDB, retrospective review of National Cancer Database; NR, not reported; OS, overall survival; PCI, prophylactic cranial irradiation.

in remission following resection and adjuvant chemotherapy,42,46 although there are retrospective data suggesting that there may be no benefit in pathological stage I patients.47,48 There are no prospective data to answer this question definitively. Given the widespread use of stereotactic body radiation therapy (SBRT) for medically inoperable stage I NSCLC, it is not surprising that patients with early-stage SCLC have been offered this treatment, especially if deemed high risk for resection. A few series have detailed the increasing utilization of SBRT in this scenario (Table 50.2). Outcomes compare favorably with the surgical literature when allowing for the small retrospective designs and the probable presence of comorbidities. In an NCDB analysis of T1-2N0 SCLC, 5938 patients were categorized as having surgery (35%), conventionally fractionated external beam radiation therapy (EBRT; 60%), or SBRT (5%).49 Median 2- and 3-year OS rates were 62% and 50%, respectively. Surgery was classified as definitive (lobectomy, pneumonectomy) or limited (less than lobectomy). Most common EBRT regimens were 60 Gy in 30 fractions (14%), 45 Gy in 30 twice-daily (BID) fractions (11%), and 59.4 Gy in 33 fractions (7%). Most common SBRT regimens were 50 Gy in 5 fractions (25%), 48 Gy in 4 fractions (20%), 60 Gy in 3 fractions (15%), and 54 Gy in 3 fractions (13%). Of those patients undergoing surgery, 83% had pathological nodal assessment versus 6% for SBRT/EBRT cases. The 2- and 3-year OS rates for patients receiving surgery, EBRT, and SBRT were 72% and 62%, 56% and 44%, and 56% and 40%, respectively. Definitive resection was associated with improved survival compared with limited resection, and SBRT was associated with better survival compared with EBRT. In a multivariate model, resection was superior to RT, but benefit did not exist when comparing SBRT to limited resection. The impact of nodal assessment in surgical cases certainly plays a role in the perceived benefit of surgery over radiation, as does the presence of comorbidity (or lack thereof). Additional study will be required before definitive conclusions can be made regarding a role for SBRT in the treatment of SCLC.

Thoracic Radiotherapy in Limited-Stage Small Cell Lung Cancer The current standard of care for limited-stage SCLC (L-SCLC) is thoracic RT delivered concurrently with systemic chemotherapy. Two

meta-analyses confirmed an OS benefit with the addition of thoracic RT to chemotherapy.50,51 Both suggested an absolute survival difference at 2 years of 5.4%. Warde and Payne51 also found a significant reduction in local recurrence (LR) with the addition of RT. These are critical findings because they demonstrate that although SCLC is considered to be a disease quick to metastasize, local treatment—and, therefore, local control (LC)—can impact survival. The impact of thoracic RT (TRT) is even more remarkable given that both the staging methods and treatment regimens used at the time that this benefit was established would be considered suboptimal by modern standards.

Dose and Fractionation in Limited Stage Small Cell Lung Cancer Since the utility of localized irradiation was established in improving survival, several fractionation schemes have been investigated. Initial trials evaluating the use of TRT in limited-stage disease published in the late 1970s and 1980s investigated nominal doses of 40 to 50 Gy in varying fractionations, with split course in some instances.50 The first significant advancement in fractionation came with the publication of the long-term follow-up of the Intergroup 0096 trial in 1999.52 Patients were randomized to receive 45 Gy in 1.5 Gy BID fractions over 3 weeks or 45 Gy in 1.8 Gy daily (QD) fractions over 5 weeks. This was started concurrently with the first of four cycles of cisplatin and etoposide (PE) chemotherapy. Treatment volumes included gross disease and elective coverage of the ipsilateral hilum and bilateral mediastinum. PCI (25 Gy in 10 fractions) was given to those with complete response (CR). There was a significant improvement in median survival (MS) associated with the BID regimen, 23 months versus 19 months (p = 0.04). Two- and 5-year OS increased from 41% to 47% and 16% to 26%, respectively. There was an associated doubling of grade 3+ esophagitis (16% vs. 32%, p < 0.001). The trial has drawn criticisms, primarily owing to the relatively low biologically effective dose (BED) used in the standard arm. The argument is made that the increase in survival that is seen may not have occurred if a somewhat higher dose had been used. A second Phase III study conducted in the 1990s by the North Central Cancer Treatment Group (NCCTG) evaluated the use of BID RT.53 Patients with limited-stage disease received three cycles of PE, and those

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CHAPTER 50 without progression were randomized to receive one of two radiation regimens concurrently with two more cycles of the same chemotherapy. The experimental arm was 48 Gy in 32 fractions BID, with a 2.5-week break after the initial 24 Gy. Alternatively, patients received 50.4 Gy in 28 fractions, delivered once daily without this break. A sixth and final cycle of chemotherapy was given after RT, and PCI (30 Gy in 15 fractions) was delivered to those who achieved CR. Those in the BID arm experienced more high-grade esophagitis (12% vs. 5.3%, p = 0.05). There were no significant differences noted in LC or survival. Thus, no benefit was seen with BID fractionation without acceleration of time to complete radiotherapy. The Cancer and Leukemia Group B (CALGB) reported a study seeking to find the maximum tolerated dose (MTD) in both QD and BID fractionation54 starting with the fourth cycle of chemotherapy. The MTD for QD radiation was not technically reached, as the highest dose evaluated was considered safe—70 Gy in 35 fractions. For the BID cohort, 45 Gy in 30 fractions was the MTD, given unacceptable rates of esophagitis with higher dose regimens. This led to a Phase II trial by the CALGB, consisting of 63 patients treated with 70 Gy in 35 daily fractions with cycle 1 of concurrent carboplatin and etoposide (CE) following induction paclitaxel and topotecan.55 In addition to gross disease, the ipsilateral hilum and mediastinum were treated electively, and PCI was offered to those with CR or “good PR.” The regimen was well tolerated, and MS was 22.4 months. Tolerable Phase I results56 led the Radiation Therapy Oncology Group (RTOG) to investigate a concomitant boost technique in a Phase II trial, RTOG 0239.57 Patients received 61.2 Gy over 5 weeks, 5 days per week (QD 1.8 Gy fractions on days 1-22, then BID 1.8 Gy fractions on days 23-33). This started concurrently with the first of four cycles of PE. Those who achieved CR were offered PCI. While locoregional tumor control was good, 2-year OS was disappointing at 37%. The regimen was tolerable, and rates of toxicity were in line with the BID and CALGB regimens. This led to the development of a three-armed Phase III trial, evaluating both the 70-Gy daily approach and the RTOG concomitant boost technique compared to the 45-Gy BID standard. This CALGB 30610/RTOG 0538 trial was designed with plans to discontinue the experimental arm with the worst toxicity profile. As of this writing, the concomitant boost arm has been discontinued after a planned interim analysis, and the trial is near completion of accrual with a target of > 700 patients. The primary endpoint is median survival and 2-year OS. A similar Phase III trial was conducted in Europe and Canada, testing the hypothesis that high-dose QD RT was superior to BID RT with regard to OS—The CONVERT (Concurrent Once-daily Versus twice-daily RadioTherapy) trial.2 Sixty percent received PET staging. Randomization was to 45 Gy in 30 fractions BID or 66 Gy in 33 fractions QD. There was no elective nodal irradiation, and about one of six patients were treated with intensity-modulated radiation therapy (IMRT). Patients received 4 to 6 cycles of PE; RT began with cycle 2. Median OS did not differ significantly: 30 months and 25 months for the BID and QD cohorts, respectively. Nor did 2- or 5-year OS differ significantly, which was 56% versus 51% and 34% versus 31%, respectively. There were no significant differences in nonhematological toxicity, although more grade 4 neutropenia was seen in the BID arm (49% vs. 38%, p = 0.05). Rates of grades 3 and 4 esophagitis were 18% to 19%, and high-grade pneumonitis was noted in about 2% of both arms. The authors concluded that toxicity was similar, and survival outcomes did not differ between regimens. However, given its design to show superiority, which it failed to do, the BID regimen should remain standard of care, when feasible. Despite the results of the Intergroup 0096 trial, use of BID fractionation remains low according to available literature. In an NCDB analysis of patients treated between 1999 and 2012, overall BID use across all centers was 11%, with the rate being somewhat higher (18%) in academic/

Small Cell Lung Cancer

829

research institutions.58 The use of BID radiation was associated with improved OS even when compared to QD dosing ≥ 60 Gy. Inconvenience and perceived inferiority of the standard arm in INT-0096 are among the purported explanations. In 2013, Kong et al. published American College of Radiology (ACR) Appropriateness Criteria, stating a preference for the 45-Gy BID regimen when feasible.59 This was before the publication of the CONVERT trial results. Current NCCN guidelines recommends use of higher doses (60-70 Gy) if opting for daily treatment, but does not voice a preference relative to the BID regimen.42 Whether there is a dose response with once-daily RT in limited-stage disease is not clear. While retrospective analyses have suggested improved outcomes, including OS with higher doses, there is not substantiating evidence of a dose response with daily dose-escalated regimens in prospective comparative studies (Table 50.3). While there is room for improvement regarding in-field and locoregional control, caution is advised when pursuing dose escalation outside the context of a clinical trial. Similar treatment volumes were dose escalated in the setting of locally advanced NSCLC in RTOG 0617.60 Here, not only did 74 Gy versus 60 Gy fail to improve LC, there was suggestion of inferior survival. Analogously, increasing the definitive dose for esophageal cancer to 64.8 Gy from 50.4 Gy did not improve locoregional control and potentially led to worse survival.61 When it comes to relative value of dose for LC, more is not always better. In these authors’ opinion, 45 Gy BID should remain the preferred standard in those who are able to comply, as current literature has not shown superiority of dose-escalated daily regimens.

Timing and Sequencing of Radiotherapy in Limited-Stage Small Cell Lung Cancer Giving multiple cycles (4-6) of chemotherapy has long been the standard; the optimal timing to deliver RT has been investigated extensively. While definitive Phase III evidence supporting concurrent chemotherapy and radiotherapy over sequential treatment is lacking, concurrent therapy has long been adopted as the standard of care in patients with good performance status. This is due in large part to the fact that trials including concurrent therapy have generally reported higher median and long-term survival rates compared with trials using sequential therapy. The optimal timing of initiating TRT relative to chemotherapy has been more controversial. The classic study supporting the early use of TRT was conducted by the National Cancer Institute of Canada (NCIC), which demonstrated that delivering 40 Gy in 15 daily fractions at week 3 (cycle 2) as opposed to with the final cycle (week 15) improved both overall and progression-free survival (PFS).62 Five-year OS was 20% with early RT and 11% with late RT. Interestingly, the improvement in survival appeared to be related to reduced brain metastases in the early RT arm rather than improved response rate or local tumor control. Chemotherapy consisted of alternating cycles of CAV with PE, and antiquated RT planning was used, including posterior spinal cord blocking. A trial aiming to confirm these results was conducted by the London Lung Cancer Group (UK) using a similar treatment protocol.63 The early RT arm in this trial underperformed, with MS of only 13.7 months, potentially due to less receipt of intended chemotherapy. No difference in early versus late RT was seen regarding survival. In contrast to the NCIC study, long-term follow-up from a CALGB trial evaluating chemotherapy alone versus chemotherapy with either early or late RT had trending results in favor of delayed RT.64 Two-year failure-free survival was 25% with late RT, 15% with early RT, and 8% with chemotherapy alone. It should be noted that this study also employed chemotherapy no longer considered standard of care. The Japan Clinical Oncology Group (JCOG) conducted a Phase III trial evaluating the use of 45 Gy in 30 BID fractions over 3 weeks starting concurrent with the first cycle of PE or after the fourth cycle.65

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830

SECTION III

TABLE 50.3

Disease Sites

Select Phase III and Phase II Prospective Trials

Years

N

Chemo

TRT

TRT Duration

TRT Start

1989-1992

417

PE × 4

45 Gy QD (25 fx) 45 Gy BID (30 fx)

5 wk 3 wk

Cycle 1 Cycle 1

19 23

41% (16% 5-y) 47% (26% 5-y)

NCCTG122

1990-1996

262

PE × 6

50.4 Gy QD (28 fx) 48 Gy BID (32 fx)

5.5 wk 5 wk

Cycle 4 Cycle 4

21.9a 19.9a

47%a (34% 3-y) 45%a (29% 3-y)

CALGB 9235123

1993-1999

307

PE × 5 TamPE × 5

50 Gy (25 fx) 50 Gy (25 fx)

5 wk 5 wk

Cycle 4 Cycle 4

20.6 18.4

RTOG 960991

1996-1998

55

ECOG 2596124

1997-1998

SWOG 9713125

1998-1999

8987

CALGB 39808

1999-2000

SWOG 0222126

2003-2006

CALGB 30002127 CALGB 30206128

Trial INT 0096

52

55

57

Med OS (mo)

2-Y OS

PET × 4

45 Gy BID (30 fx)

3 wk

Cycle 1

24.7

54.7%

PET × 4

63 Gy (35 fx)

7 wk

Cycle 3

15.7

23.8%

PE × 2 − TC × 3

61 Gy (33 fx)

7 wk

Cycle 1

17

33%

75

TTpo × 2 − CE × 3

70 Gy (35 fx)

7 wk

Cycle 3

22.4

48%

68

TpzPE × 5

61 Gy (33 fx)

7 wk

Cycle 1

21

45% (est)

2001-2003

65

TETpo × 2 − CE × 3

70 Gy (35 fx)

7 wk

Cycle 3

20

35%

2003-2005

78

PIrin × 2 − CE × 3

70 Gy (35 fx)

7 wk

Cycle 3

18.1

31%

PE × 4

61.2 Gy CB

5 wk

Cycle 1

19

36%

PE × 4 or 6

45 Gy BID (30 fx) 66 Gy QD (33 fx)

3 wk 6.5 wk

Cycle 2

30 25

56% 51%

RTOG 0239

2003-2006

72

CONVERT2

2008-2013

547

a

Includes only patients without disease progression randomized after third cycle of chemotherapy. C, Carboplatin; CB, concomitant boost; Chemo, chemotherapy; E, etoposide; est, estimated; fx, fractions; INt, intergroup; Irin, irinotecan; Med, median; ns, not started; OS, overall survival; P, Cisplatin; T, paclitaxel; Tam, tamoxifen; Tpo, topocan; Tpz, tiripazemine; TRT, thoracic radiotherapy.

While the findings were not statistically significant, there appeared to be a benefit of concurrent therapy, with MS of 27 months compared with 19.7 months. Severe esophagitis was 9% in the concurrent arm versus 4% in the sequential arm. Moreover, the study results are challenging to interpret within the timing discussion because RT was given sequential to chemotherapy rather than concurrent. These results have been used, however, to support concurrent therapy as standard of care. Finally, a Korean trial suggested noninferiority of starting TRT with cycle 3 of PE as opposed to cycle 1 with regard to disease response and survival.66 Patients received 52.5 Gy in 25 fractions, 2.1 Gy per fraction followed by PCI (25 Gy in 10 fractions) assuming CR or very good partial response. A meta-analysis of selected Phase III trials evaluating RT with concurrent platinum-based regimens suggested that, in addition to early timing of RT, the time from start of any treatment until the end of radiotherapy (SER) was an important factor impacting 5-year OS.67 The SER was also associated with increased incidence of severe esophagitis. The authors hypothesized that this parameter is meaningful, as it takes accelerated repopulation into account from chemotherapy as well, not just that seen during RT. Interestingly, the SER was not predictive for local tumor control. This analysis combined four trials, including only those trials that used platinum-based regimens and those with available 5-year OS results, trying to limit the influence of salvage systemic therapy. Much of the result was driven by the Intergroup 0096 trial, which was not a pure test of early versus late RT, as described earlier.52 A second meta-analysis, which was more inclusive, but necessarily more heterogeneous, also sought to evaluate the influence of early versus late RT.68 Early RT was defined as beginning prior to 9 weeks after initiation of chemotherapy; late RT was defined as beginning after 9 weeks or after the beginning of the third cycle of chemotherapy. Results suggest significant OS benefit to early RT at 2 years (risk ratio [RR], 1.17; 95% confidence interval [CI], 1.02-1.35; p = 0.03) that continued to trend but lost statistical significance at 3 years (RR, 1.13; 95% CI, 0.92-1.39; p = 0.23). This corresponds to an absolute survival benefit of 5% at 2

years. The benefits were amplified in those receiving platinum-based chemotherapy and hyperfractionated RT. Similar to the previous metaanalysis, timing of RT did not impact disease response. Important to consider here is the inclusion of the Japanese trial65 in which the late RT arm was not delivered concurrently and, as was mentioned earlier, was actually a test of concurrent versus sequential RT. This trial largely influenced the results of the analysis. In fact, none of the trials included in the meta-analysis employed a treatment plan that would be considered standard therapy by today’s standards in both arms (4-6 cycles of cisplatin and etoposide with concurrent RT). Table 50.3 summarizes many of the randomized and prospective trials, detailing chemotherapy as well as RT timing and dose fractionation. It is worth noting that despite the findings of the two aforementioned meta-analyses on timing of RT, survival outcomes have not changed appreciably over the past 2 decades, and the importance of early RT may be overstated. A recently published survey of US radiation oncologists suggests that nearly 75% recommend beginning TRT with cycle 1, while their actual practice was closer to a 50-50 split between cycles 1 and 2. Half of the respondents believed that initiation of RT with cycle 1 led to a survival advantage, and knowledge of data supporting a later start was more associated with flexibility in their recommendation.69 While INT 0096 initiated RT with the first cycle of chemotherapy, this was prior to routine use of CT simulation and 3D treatment planning. The advent of modern treatment planning has, in fact, resulted in a delay in being able to initiate RT in many centers—starting TRT with the second cycle of chemotherapy is commonplace. TRT was initiated with chemotherapy cycle 2 for all patients in the CONVERT trial and CALGB 30610 allows RT to start with either the first or second cycle of chemotherapy. Many past cooperative group trials have waited until the third cycle of chemotherapy (or later) to start RT (see Table 50.3). Taken together, these findings suggest that RT is likely best delivered concurrently and early in the course (i.e., with cycle 1 or 2) if feasible. Given the aforementioned issues with the combined analyses and the

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CHAPTER 50 discordant results of the individual studies, however, it may be reasonable to wait until later to begin RT if clinically indicated.

Prophylactic Cranial Irradiation Given the high propensity for brain metastases in SCLC, the use of PCI has been advocated in both limited- and extensive-stage disease for decades. Benefits include reduction in incidence of brain metastases and improvement in survival, although the latter has come into question and become more controversial in recent years. A survival benefit was first suggested in a review of patients treated in the 1970s, also hypothesizing that it might be limited to those who achieve a CR of disease outside the brain.70 Since that time, multiple additional studies have been performed, and two meta-analyses have addressed the role of PCI. The first, from Auperin et al., suggested a 5.4% absolute benefit in survival at 3 years (15.3% vs. 20.7%), in those who achieved a CR.71 The cumulative incidence of brain metastases at 3 years was reduced from 59% to 33%. Patients were treated from 1965 to 1995 (majority after 1985), and most had limited-stage disease. Given the time period, the ability to properly screen for metastases was somewhat limited, a critique common to much of the more dated literature on PCI. A second systematic review was published in 2001, confirming the presence of a survival benefit.72 These data are quoted often to substantiate the benefit of PCI in L-SCLC; its use remains widespread as of this writing. In a survey of US radiation oncologists, greater than 95% reported recommending PCI in the setting of limited-stage disease.73 The use of PCI in extensive-stage SCLC (E-SCLC) was investigated by the European Organization for Research and Treatment of Cancer (EORTC).74 This trial randomized 286 patients to either receive or omit PCI after response to 4 to 6 cycles of chemotherapy. Brain imaging was not standard and was used only if symptoms were suggestive of brain metastases. Allowable treatment regimens ranged from 20 to 30 Gy in 5 to 12 fractions. Cumulative rates of brain metastases at 1 year were reduced from 40% to 15% with the use of PCI. Median survival improved from 5.4 months to 6.7 months, and survival at 1 year favored the use of PCI—27% versus 13%. The results of this important trial are subject to criticism, however, largely due to the lack of standardized brain imaging prior to delivery of PCI. Without that imaging, the possibility exists that much of the observed benefit was derived from the treatment of macroscopic, but clinically occult, disease (i.e., what would be seen if an MRI were obtained). A contemporary trial conducted in Japan aimed to further clarify the role of PCI in extensive-stage disease by requiring brain imaging prior to enrollment.75 In this study, 224 patients

Small Cell Lung Cancer

831

were randomized after any response to platinum-containing doublet chemotherapy, without evidence of brain metastases on MRI. Treatment was 25 Gy in 10 fractions. Patients were surveilled at 3-month intervals for 1 year and spaced out thereafter. The study was terminated early after crossing the futility boundary with regard to OS, which served as the primary endpoint. Median survival was 11.6 months and 13.7 months in the PCI and observation arms, respectively. At the time of final analysis, the cumulative rate of brain metastases was 48% in the PCI group and 69% in the observation groups. These numbers are higher than that seen in the EORTC study, likely due to the mandated MRI surveillance. These results have reinvigorated the debate about the clinical utility of PCI in general, but especially in extensive-stage disease. Regardless of disease stage, the aforementioned benefits need to be carefully weighed against potential toxicities, ideally in the form of shared decision-making between patient and radiation oncologist. The most notable sequela is delayed neurocognitive toxicity. In a multinational intergroup study, increased-dose PCI (36 vs. 25 Gy) failed to improve survival or reduce total incidence of brain metastases.76 Those patients enrolled through the RTOG 0212 portion of the study were analyzed for delayed neurocognitive outcomes; there appeared to be a doseresponse relationship in that those receiving high-dose PCI had a 25% increase in chronic neurotoxicity.77 One can be informed by the results of the standard-dose arm. Greater than 60% of patients receiving 25 Gy in 10 fractions were experiencing neurocognitive toxicity at 1 year. Due to declining availability (and, thus, power) of neurocognitive and quality-of-life survey results throughout the survey period, no statistically significant conclusions could be drawn when comparing 12-month results to baseline. However, a trend was evident. Findings are summarized in Table 50.4. Approaches to mitigate the risk of delayed neurotoxicity are being actively investigated, including the use of memantine, which has documented benefit in the setting of WBRT for brain metastases,78 and the use of IMRT for hippocampal avoidance.79 Detailed discussions between the patient and radiation oncologist should transpire regarding potential benefit versus risks.

Definitive Treatment in the Elderly Though the median age of patients with SCLC approximates 70 years, elderly patients have been underrepresented in clinical trials. Several trials, including Intergroup 0096, suggest that elderly patients may benefit from and tolerate combined-modality therapy relatively well, although severe hematological toxicity may be more likely. A substantial population of elderly patients with limited-stage disease are not treated with TRT in

Incidence of Neurological Deterioration and Chronic Neurotoxicity at 12 Months Following PCI From RTOG 021277

TABLE 50.4

ABSENT

PRESENT

n

%

n

%

95% CI of ND/CNt (%)

p Value

Neurological deterioration

25 Gy in 10 fx 36 Gy in 18 fx 36 Gy in 24 BID fx

17 3 2

38 15 11

28 17 17

62 85 89

(50-74) (72-98) (78-100)

0.03

Chronic neurotoxicity

25 Gy in 10 fx 36 Gy in 18 fx 36 Gy in 24 BID fx

18 3 2

40 15 11

27 17 17

60 85 89

(48-72) (72-98) (78-100)

0.02

95% CI, 95% Confidence interval; cNT, chronic neurotoxicity, defined as ND without development of brain metastases; fx, fractions; ND, neurologic deterioration, defined as performance decline on at least one neurocognitive test regardless of brain metastasis; PCI, prophylactic cranial irradiation; RTOG, Radiation Therapy Oncology Group. Neurocognitive tests: Hopkins Verbal Learning Test (HVLT)-recall, HVLT-recognition, HVLT-delayed recall, Controlled Oral Word Association Test (COWAT), Trail Making Test (TMT).

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832

SECTION III

Disease Sites

clinical practice. A recent NCDB review included 8637 patients aged ≥ 70 years; only 56% received combined TRT and chemotherapy, with the remainder treated with chemotherapy alone.80 Multivariate analysis suggested that treatment with combined therapy had the greatest impact on OS and this association remained on subsequent propensity score matching. The survival benefit with TRT remained for patients > 80 years as well as for the population with defined comorbidity. These data strongly suggest that TRT should be the first consideration in the management of elderly patients. The use of PCI in the elderly is likewise controversial with less clear data to guide the decision-making process. Retrospective data suggest that PCI is not routinely recommended at a rate comparable with younger patients.81 While the risk of PCI-related neurosequelae appears to increase with increasing age,82 SEER data and analysis of clinical trial data suggest that patients > 70 years old still derive a survival benefit from PCI.83, 84 It is important to ensure that conversations with elderly patients regarding definitive therapy are inclusive of all potential options and not abbreviated based on age alone.

Role of Non–Central Nervous System Radiotherapy in Extensive-Stage Small Cell Lung Cancer While the utility of TRT in L-SCLC has been firmly established, its use in E-SCLC disease as a routine part of the definitive management has been more controversial. Proof of concept was seen in a small Phase I/II trial evaluating the use of sequential hemibody RT following 7 cycles of cyclophosphamide-based chemotherapy.85 Although the regimen was quite toxic (2 fatalities following lower hemibody RT), 5-year OS was 16% (3 of 20 patients). Seeing survivors at 5 years was suggestive that radiation following chemotherapy in this scenario might improve outcomes given an otherwise dismal prognosis. A prospective trial from Yugoslovia randomized patients with complete or partial response in the chest and CR elsewhere after 3 cycles of PE to receive TRT concurrent with CE or CE alone.86 All patients went on to receive PCI and an additional 2 cycles of PE. Those with less than the aforementioned response to the initial 3 cycles were also included in the trial and received TRT after 5 total cycles but did not undergo randomization. RT targeted all gross disease, the ipsilateral hilum, entire mediastinum, and bilateral supraclavicular fossae. Total dose was 54 Gy in 36 fractions over 3.5 weeks. In the randomized cohort, radiation improved median survival from 11 to 17 months, and 5-year OS from 3.7% to 9.1%. A multinational European trial (CREST) led by the Dutch evaluating the role of TRT in E-SCLC was published in 2014.87 Extensive-stage patients without brain metastases who had a response to initial chemotherapy (4-6 cycles of platinum/etoposide) were eligible and were randomized to receive PCI alone or PCI with consolidative TRT. Treatment was 30 Gy in 10 fractions targeting postchemotherapy volumes and involved mediastinal/hilar nodal stations regardless of response. Dose of PCI was 20 to 30 Gy in 10 to 15 fractions. The primary endpoint was OS at 1 year, which was not significant (33% vs. 28%) but favored the use of TRT with regard to 2-year OS in a secondary analysis (13% vs. 3%, p = 0.004). PFS at 6 months also favored the use of TRT (24% vs. 7%, p = 0.001). While its primary endpoint was not met, these data are often cited when considering use of TRT following response to chemotherapy in E-SCLC, despite the small number of patients alive at 2 years (19 of 495). In an accompanying response from the authors, a secondary analysis was discussed regarding the potential impact of residual thoracic disease on outcome.88 Of the patients, 88% had residual thoracic disease after chemotherapy as assessed on CT. As these patients composed the majority of the cohort, the overall results were echoed in this group—not surprisingly. However, no benefit was seen when looking at those with CR to initial chemotherapy (the other 12%). The question is raised as to whether there is a benefit of TRT in those who have had CR in the chest, but the small numbers likely leave this question

unanswered with these data. The CREST trial and the Yugoslavian trial were examined together in a meta-analysis, confirming the presence of a survival benefit in favor of TRT after chemotherapy for E-SCLC (hazard ratio [HR], 0.81; 95% CI, 0.69-0.96, p = 0.014).89 The role of extrathoracic consolidation was investigated in a prospective randomized trial led by the RTOG.3 Patients with one to four extrathoracic metastases (excluding brain) were eligible after response to 4 to 6 cycles of platinum-based chemotherapy, and all patients received PCI consisting of 25 Gy in 10 fractions. The experimental group received consolidative RT to chest and to each metastatic site (cRT) in a dose of 45 Gy in 15 fractions. Ninety-seven patients were randomized of an intended 154 prior to a premature closure due to the primary endpoint of 1 year OS crossing the futility boundary. Almost 75% of the patients had either one or two metastases. OS rates at 1 year were nonsignificant but notably high at 60% and 51% for the experimental and control groups, respectively. Time to progression was significantly different between arms, however, and PFS at 3 months favored those receiving cRT (53% vs. 15%). Median PFS was 2.9 versus 4.9 months (p = 0.04); thus, the responses were not particularly durable. The role of consolidative TRT in E-SCLC appears to be cemented for the time being, but defining a population that may benefit from consolidative treatment to metastatic sites remains a challenge. A small series did suggest that patients with brain-only metastatic disease may fare better and have prognoses that approach that of L-SCLC.90 Further study will be needed to ascertain who may benefit from extrathoracic consolidation and whether local therapy in an oligometastatic state is worthwhile.

Optimal Systemic Therapy Cisplatin and etoposide represent the de facto standard in both limited and extensive-stage disease as first-line therapy. Carboplatin and etoposide represent the most common alternative, and the addition of irinotecan to either platinum agent is also endorsed by the NCCN in E-SCLC.42 In early trials, additional regimens included CML (cyclophosphamide, methotrexate, and lomustine) alternating with VAP (vincristine, doxorubicin, and procarbazine), CAV (cyclophosphamide, doxorubicin, and vincristine), and variations thereof. Other regimens have been evaluated in more contemporary trials. Ettinger et al. published the results of an RTOG Phase II study investigating the addition of paclitaxel to PE in L-SCLC patients receiving standard BID RT to 45 Gy.91 The authors deemed the regimen to be tolerable and effective, but unlikely to improve survival outcomes above and beyond the 2-drug regimen. The addition of paclitaxel in E-SCLC disease was the question of an intergroup trial led by the CALGB.92 Patients received cisplatin/etoposide alone or with the addition of paclitaxel for a total of 6 cycles. Median survival was 9 to 10 months in both arms, and toxicity was considered unacceptable. In Japan, a Phase III trial found a survival benefit (13 vs. 9.4 months MS, p = 0.002) favoring use of irinotecan/cisplatin (PI) compared to PE in E-SCLC.93 Two subsequent trials did not confirm the benefit.94,95 The larger of the two was led by the Southwestern Oncology Group (SWOG) and had over 300 evaluable patients per arm. Median PFS and OS was 5.8 and 9.9 versus 5.2 and 9.1 months, respectively, for the PI and PE arms.95 All studies suggested a mixed toxicity profile between regimens. A Cochrane meta-analysis of 32 studies sought to compare platinumcontaining regimens versus those without platinum.96 All stages were included. A statistically significant improvement in survival and overall tumor response could not be found, but platinum-containing regimens led to increased CR rates despite an increased rate of adverse events, including nausea, vomiting, anemia, and thrombocytopenia. One might interpret these data as an alert to a lack of quality of evidence supporting the current standard of platinum-based regimens. Carboplatin is generally

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CHAPTER 50 considered a reasonable alternative to cisplatin and is a common substitution in clinical practice. Available evidence suggests no difference in efficacy between the drugs apart from suggestion of higher overall response rate noted in one study97 but rather a different toxicity profile. Cisplatin is associated with higher rates of nonhematological toxicity (e.g., ototoxicity and nephrotoxicity), while carboplatin is associated with higher rates of hematological toxicity.98 There has been some investigation in recent years into alternative cytotoxic agents, including the novel anthracycline, amrubicin, which has shown some promise in Phase II trials when combined with platinum agents in both limited- and extensive-stage disease.99-101 Alternatively, palifosfamide (an active metabolite of ifosfamide) did not suggest improvement of outcome in a small Phase III trial102 when added to carboplatin/etoposide. As introduced earlier, checkpoint inhibitors are showing notable promise among the newer-generation targeted therapies, much like in NSCLC. Nivolumab was recently granted a priority review in SCLC based on the results of the Phase I/II CheckMate-032 study.28,103 In the SCLC cohort, 216 patients with recurrent disease received nivolumab or a combination of nivolumab and ipilimumab. Two-year survival was 17% with nivolumab and up to 30% with nivolumab/ipilimumab. Response was not dependent on PD-L1 expression, and a minority had expression > 1%. Based on these data, NCCN guidelines include nivolumab or nivolumab/ipilimumab as options for relapsed SCLC. As of August 2018, nivolumab became the first agent approved by the US Food and Drug Administration for metastatic SCLC. Recent Phase III trial data (IMpower 133) suggest that adding atezolizumab to first-line chemotherapy in E-SCLC improves outcomes and with a median follow-up of 13.9 months, median OS was 12.3 months in the atezolizumab group and 10.3 months with chemotherapy alone (HR for death, 0.70; 95% CI, 0.54 to 0.91; p = 0.007).103a Early studies have not been unanimously positive, however. A Phase II study of maintenance pembrolizumab after induction chemotherapy in E-SCLC did not appear to improve PFS compared with historical control.104 Nevertheless, there is significant enthusiasm that these agents will lead to a long-awaited improvement in outcomes.

Techniques of Irradiation The delivery of TRT has evolved significantly over the years. The prior standard of two-dimensional RT has long been supplanted by threedimensionally based planning and IMRT. Historical treatment techniques are worth noting, however, as much of the data that guides us today is taken from previous eras. The practice-changing INT 0096 trial targeted gross disease with the aid of previously obtained chest CT as well as ipsilateral hilum and bilateral mediastinum electively.52 The inferior border extended to include the hilum or 5 cm below the carina, whichever was lower. The supraclavicular fossa was not irradiated unless involved. The identified volume was expanded 1.0 to 1.5 cm, and conventional simulators were used to design treatment ports (two-dimensional RT). Treatment in the BID arm was with opposed anterior-posterior fields (AP/PA) for both treatments during week 1 (fractions 1-10), and in the mornings of weeks 2 and 3. Afternoon treatments were opposed oblique fields with the goal of avoiding the spinal cord. Per protocol, the maximum point dose to the spinal cord was not to exceed 36 Gy. This approach was standard at the time that this trial was enrolling patients. CT-based planning is now the norm. Simulation also includes use of IV contrast in many cases to better elucidate mediastinal and hilar targets as well as four-dimensional CT (4DCT) for assessment of target motion with repiration. Fusion of simulation imaging with PET/CT aids in target planning, especially in cases in which tumor and surrounding soft tissue are hard to distinguish on CT alone—a relatively common occurrence given the cancer’s propensity to be located centrally and lead to

Small Cell Lung Cancer

833

downstream atelectasis. Known areas of disease involvement are identified as gross tumor volume (GTV) based on available diagnostic imaging, bronchoscopic findings, and any pathological results from mediastinal sampling. Malignant adenopathy is targeted, including what is fluorodeoxyglucose (FDG)-avid on PET and enlarged by CT criteria (> 1.0 cm in short axis). Whereas in the past elective nodal coverage was considered routine, its use has become less and less common. In the era of PET staging, omission of elective nodal coverage has not been shown to decrease locoregional control or survival rates.105-107 In the recently published CONVERT trial (discussed earlier), elective coverage was not allowed.108 In the enrolling CALGB 30610 study, only the ipsilateral hilum is instructed to be covered above and beyond involved gross disease. Creation of a clinical target volume (CTV) is often considered, but practice is somewhat variable. In the US CALGB trial, CTV is specified to include the ipsilateral hilum and potentially areas considered still at risk if volumes are modified following a second (mid-course) simulation scan. In the CONVERT trial, the CTV represents an isotropic 5-mm expansion from GTV, with permitted adjustment in the vicinity of the spinal cord. PTV expansions, as usual, should be based on institutional tolerance, use of 4DCT during simulation, confidence in daily immobilization to reduce intra- and interfraction motion, and use of image-guided radiotherapy (IGRT). Both 3DCRT and IMRT are used in common practice today, with the latter being favored especially in cases in which organ-at-risk (OAR) tolerances cannot be met (Fig. 50.1). The relationship between lung dose and pulmonary toxicity was evaluated in a combined analysis of three prospective CALGB studies in L-SCLC.109 Patients received varying regimens of induction chemotherapy followed by concurrent chemoradiation to 70 Gy in 2 Gy per day fractionation, with concurrent carboplatin and etoposide. CT planning was used, followed by 2D or 3D RT. These trials predated routine use of 4DCT or IMRT. Of those included in dosimetric analysis, only 3% experienced grade 3 pulmonary complications, and there were no grade 4 or grade 5 events. Increased age and smaller lung volume were associated with likelihood of toxicity. As expected, volume of lung receiving low (5 and 10 Gy), intermediate (20 and 40 Gy), and high (60 Gy) doses was also correlated with development of toxicity. For example, median V20 (volume of lung receiving 20 Gy) of those with and without toxicity was 50% and 35%, respectively (p = 0.04). Thirty patients had lung V20 over 40%, and nine were over 50%. These data emphasize the importance of limiting the dose of radiation to healthy lung but should defend decisions to treat above commonly used V20 metrics (i.e., 37%) when limited-stage disease extent requires it, as overall rates of pneumonitis are very low in this population (Fig. 50.2). Variability in contouring also likely plays a significant role in both treatment planning and interpretation of normal-tissue complication rates based on dosimetry. An analysis from the CONVERT study group suggested that up to 75% to 80% patients experienced an increase in heart dose when “gold standard” heart contouring was applied, suggesting that this OAR is often undercontoured.110

TREATMENT ALGORITHM(S), CONTROVERSIES, PROBLEMS, CHALLENGES, FUTURE POSSIBILITIES, AND CLINICAL TRIALS There are many ongoing clinical trials, which should further shape the landscape of SCLC in the years to come. The Alliance/NRG trial (CALGB 30610/RTOG 0538) should provide additional evidence regarding the potential role for dose-escalated daily RT relative to the current standard of 45 Gy with BID fractionation. Multiple Phase II and Phase III studies are underway investigating targeted agents with hopes of adding additional systemic options to the arsenal. Checkpoint inhibitors, poly ADP ribose polymerase (PARP)

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834

SECTION III

Disease Sites

Fig. 50.1 Contours and dosimetry of a patient with N3 limited-stage small cell lung cancer treated with intensity-modulated radiation therapy to 70 Gy in 35 fractions, enrolled and treated on CALGB 30610/RTOG 0538. Dark shaded blue = planning target volume (PTV). Red line = gross tumor volume (GTV). Upper right panel is dose volume histogram: brown line = esophagus; magenta line = spinal cord; lower left dark blue line = combined lung; pink line = heart; and upper right dark blue and red lines represent PTV and GTV, respectively.

Histological Diagnosis (TTNB, EBUS with FNA) Staging & Initial Steps

Limited SCLC

Extensive SCLC

)

Fig. 50.2 Treatment algorithm for small cell lung cancer. ASAP, As soon as possible; BID, twice daily; EBUS, endobronchial ultrasound with biopsy; FNA, fine-needle aspiration; PCI, prophylactic cranial irradiation; PFT, pulmonary function test; TRT, thoracic radiotherapy; TTNB, transthoracic needle biopsy.

inhibitors, and tyrosine kinase inhibitors (TKIs) are among those being evaluated, just to name a few.20 Given the activity of checkpoint inhibitors in recent trials noted earlier, there is strong interest in studying agents in limited-stage disease. A cooperative group trial led by NRG is planned assessing adjuvant immunotherapy and, interestingly, either once-daily or twice-daily TRT will be permitted. Whether the details of TRT remain as important to curative therapy in the burgeoning immunotherapy era remains to be determined. A Phase II/III trial from NRG (CC-003) is investigating the use of hippocampal avoidance in an attempt to improve neurocognitive outcomes following PCI in both limited and extensive-stage SCLC. A similar trial is being conducted in Europe. The use of PCI in general will likely continue to be a controversial issue, one that generates polarizing opinions. With the publication of the Japanese Phase III trial without an OS benefit,75 the debate about use of PCI in extensive-stage disease seems to be reinvigorated and the recommendation for PCI in extensive-stage patients was softened in the most recent NCCN guidelines.42 Additional studies aiming to elicit the truth of the matter in modern practice are being considered in cooperative groups. Database analyses provide some preliminary signal that there may be a role for management of brain metastases with stereotactic radiosurgery alone, without whole-brain RT.111 It would not be surprising to see a shift toward use of focal irradiation for limited metastases as opposed to whole-brain RT if support for PCI fades over time. Opinions on these controversial subjects are actively evolving.

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CHAPTER 50

CRITICAL REFERENCES 2. Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18(8):1116–1125. 3. Gore EM, Hu C, Sun AY, et al. Randomized phase II study comparing prophylactic cranial irradiation alone to prophylactic cranial irradiation and consolidative extracranial irradiation for extensive-disease small cell lung cancer (ED SCLC): NRG oncology RTOG 0937. J Thorac Oncol. 2017;12(10):1561–1570. 13. Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol. 2005;40(2):90–97. 20. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer. 2017;17(12):765. 36. Bradley JD, Dehdashti F, Mintun MA, et al. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol. 2004;22(16):3248–3254. 40. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet. 1973;2(7820):63–65. 41. Lad T. The comparison of CAP chemotherapy and radiotherapy to radiotherapy alone for resected lung cancer with positive margin or involved highest sampled paratracheal node (stage IIIA). LCSG 791. Chest. 1994;106(6 suppl):302S–306S. 45. Yang CF, Chan DY, Speicher PJ, et al. Role of adjuvant therapy in a population-based cohort of patients with early-stage small-cell lung cancer. J Clin Oncol. 2016;34(10):1057–1064. 50. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med. 1992;327(23):1618–1624. 52. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265–271. 55. Bogart JA, Herndon JE 2nd, Lyss AP, et al. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys. 2004;59(2):460–468. 62. Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1993;11(2):336–344. 63. Spiro SG, James LE, Rudd RM, et al. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol. 2006;24(24):3823–3830. 64. Perry MC, Herndon JE 3rd, Eaton WL, et al. Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of

65.

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Cancer and Leukemia Group B Study 8083. J Clin Oncol. 1998;16(7):2466–2467. Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002;20(14):3054–3060. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol. 2006;24(7):1057–1063. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341(7):476–484. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357(7):664–672. Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(5):663–671. Le Pechoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009;10(5):467–474. Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011;81(1):77–84. Corso CD, Rutter CE, Park HS, et al. Role of chemoradiotherapy in elderly patients with limited-stage small-cell lung cancer. J Clin Oncol. 2015;33(36):4240–4246. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol. 1999;17(7):2092–2099. Slotman BJ, van Tinteren H, Praag JO, et al. Radiotherapy for extensive stage small-cell lung cancer - Authors’ reply. Lancet. 2015;385(9975):1292–1293. Salama JK, Pang H, Bogart JA, et al. Predictors of pulmonary toxicity in limited stage small cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904. Lung Cancer. 2013;82(3):436–440.

A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 50

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20. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer. 2017;17(12):765. 21. Meder L, Konig K, Ozretic L, et al. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer. 2016;138(4):927–938. 22. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136. 23. Johnson BE, Brennan JF, Ihde DC, et al. MYC family DNA amplification in tumors and tumor cell lines from patients with small-cell lung cancer. J Natl Cancer Inst Monogr. 1992;13:39–43. 24. Hibi K, Takahashi T, Sekido Y, et al. Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer. Oncogene. 1991;6(12):2291–2296. 25. Sekido Y, Obata Y, Ueda R, et al. Preferential expression of c-kit protooncogene transcripts in small cell lung cancer. Cancer Res. 1991;51(9):2416–2419. 26. Wang WL, Healy ME, Sattler M, et al. Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. Oncogene. 2000;19(31):3521–3528. 27. Johnson BE, Fischer T, Fischer B, et al. Phase II study of imatinib in patients with small cell lung cancer. Clin Cancer Res. 2003;9(16 Pt 1):5880–5887. 28. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883–895. 29. Chang YL, Yang CY, Huang YL, et al. High PD-L1 expression is associated with stage IV disease and poorer overall survival in 186 cases of small cell lung cancers. Oncotarget. 2017;8(11):18021–18030. 30. Ishii H, Azuma K, Kawahara A, et al. Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol. 2015;10(3):426–430. 31. Komiya T, Madan R. PD-L1 expression in small cell lung cancer. Eur J Cancer. 2015;51(13):1853–1855. 32. Hellmann MD, Callahan MK, Awad MM, et al. Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell. 2018;33(5):853–861, e854. 33. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85(9):838–854. 34. Chan RH, Dar AR, Yu E, et al. Superior vena cava obstruction in small-cell lung cancer. Int J Radiat Oncol Biol Phys. 1997;38(3):513–520. 35. Spiro SG, Shah S, Harper PG, et al. Treatment of obstruction of the superior vena cava by combination chemotherapy with and without irradiation in small-cell carcinoma of the bronchus. Thorax. 1983;38(7):501–505. 36. Bradley JD, Dehdashti F, Mintun MA, et al. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol. 2004;22(16):3248–3254. 37. Brink I, Schumacher T, Mix M, et al. Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging. 2004;31(12):1614–1620. 38. Fischer BM, Mortensen J, Langer SW, et al. A prospective study of PET/ CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis. Ann Oncol. 2007;18(2):338–345. 39. Zelen M. Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 3. 1973;4(2):31–42. 40. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet. 1973;2(7820):63–65. 41. Lad T. The comparison of CAP chemotherapy and radiotherapy to radiotherapy alone for resected lung cancer with positive margin or

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SECTION III

Disease Sites

involved highest sampled paratracheal node (stage IIIA). LCSG 791. Chest. 1994;106(6 suppl):302S–306S. 42. NCCN Guidelines. Small Cell Lung Cancer - Version 2; 2018. www.nccn. org/professionals/physician_gls/pdf/sclc.pdf. Accessed August 21, 2018. 43. Ahmed Z, Kujtan L, Kennedy KF, et al. Disparities in the management of patients with stage I small cell lung carcinoma (SCLC): a surveillance, epidemiology and end results (SEER) analysis. Clin Lung Cancer. 2017;18(5):e315–e325. 44. Inoue M, Nakagawa K, Fujiwara K, et al. Results of preoperative mediastinoscopy for small cell lung cancer. Ann Thorac Surg. 2000;70(5):1620–1623. 45. Yang CF, Chan DY, Speicher PJ, et al. Role of adjuvant therapy in a Population-Based cohort of patients with Early-Stage Small-Cell lung cancer. J Clin Oncol. 2016;34(10):1057–1064. 46. National Comprehensive Cancer Network. Small Cell Lung Cancer (Version 1.2015). http://www.nccn.org/professionals/physician_gls/pdf/ sclc.pdf. Accessed October 29, 2014. 47. Xu J, Yang H, Fu X, et al. Prophylactic cranial irradiation for patients with surgically resected small cell lung cancer. J Thorac Oncol. 2017;12(2):347–353. 48. Yang Y, Zhang D, Zhou X, et al. Prophylactic cranial irradiation in resected small cell lung cancer: a systematic review with meta-analysis. J Cancer. 2018;9(2):433–439. 49. Paximadis P, Beebe-Dimmer JL, George J, et al. Comparing treatment strategies for stage I Small-cell lung cancer. Clin Lung Cancer. 2018. 50. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med. 1992;327(23):1618–1624. 51. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A metaanalysis. J Clin Oncol. 1992;10(6):890–895. 52. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265–271. 53. Bonner JA, Sloan JA, Shanahan TG, et al. Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol. 1999;17(9):2681–2691. 54. Choi NC, Herndon JE 2nd, Rosenman J, et al. Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol. 1998;16(11):3528–3536. 55. Bogart JA, Herndon JE 2nd, Lyss AP, et al. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys. 2004;59(2):460–468. 56. Komaki R, Swann RS, Ettinger DS, et al. Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for patients with limited small-cell lung cancer: report of Radiation Therapy Oncology Group (RTOG) protocol 97-12. Int J Radiat Oncol Biol Phys. 2005;62(2):342–350. 57. Komaki R, Paulus R, Ettinger DS, et al. Phase II study of accelerated high-dose radiotherapy with concurrent chemotherapy for patients with limited small-cell lung cancer: Radiation Therapy Oncology Group protocol 0239. Int J Radiat Oncol Biol Phys. 2012;83(4):e531–e536. 58. Schreiber D, Wong AT, Schwartz D, et al. Utilization of hyperfractionated radiation in Small-Cell lung cancer and its impact on survival. J Thorac Oncol. 2015;10(12):1770–1775. 59. Kong FM, Lally BE, Chang JY, et al. ACR Appropriateness Criteria® radiation therapy for small-cell lung cancer. Am J Clin Oncol. 2013;36(2):206–213. 60. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-bytwo factorial phase 3 study. Lancet Oncol. 2015;16(2):187–199.

61. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20(5):1167–1174. 62. Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1993;11(2):336–344. 63. Spiro SG, James LE, Rudd RM, et al. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol. 2006;24(24):3823–3830. 64. Perry MC, Herndon JE 3rd, Eaton WL, et al. Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol. 1998;16(7):2466–2467. 65. Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002;20(14):3054–3060. 66. Sun JM, Ahn YC, Choi EK, et al. Phase III trial of concurrent thoracic radiotherapy with either first- or third-cycle chemotherapy for limited-disease small-cell lung cancer. Ann Oncol. 2013;24(8):2088–2092. 67. De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol. 2006;24(7):1057–1063. 68. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol. 2004;22(23):4837–4845. 69. Farrell MJ, Yahya JB, Degnin C, et al. Timing of thoracic radiation therapy with chemotherapy in Limited-stage Small-cell lung cancer: survey of US radiation oncologists on current practice patterns. Clin Lung Cancer. 2018. 70. Rosen ST, Makuch RW, Lichter AS, et al. Role of prophylactic cranial irradiation in prevention of central nervous system metastases in small cell lung cancer. Potential benefit restricted to patients with complete response. Am J Med. 1983;74(4):615–624. 71. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341(7):476–484. 72. Meert AP, Paesmans M, Berghmans T, et al. Prophylactic cranial irradiation in small cell lung cancer: a systematic review of the literature with meta-analysis. BMC Cancer. 2001;1:5. 73. Farrell MJ, Yahya JB, Degnin C, et al. Prophylactic cranial irradiation for Limited-Stage Small-Cell lung cancer: survey of US radiation oncologists on current practice patterns. Clin Lung Cancer. 2018;19(4):371–376. 74. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357(7):664–672. 75. Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(5):663–671. 76. Le Pechoux C, Dunant A, Senan S, et al. Standard-dose versus higherdose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009;10(5):467–474. 77. Wolfson AH, Bae K, Komaki R, et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with

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CHAPTER 50 limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011;81(1):77–84. 78. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15(10):1429–1437. 79. Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32(34):3810–3816. 80. Corso CD, Rutter CE, Park HS, et al. Role of chemoradiotherapy in elderly patients with Limited-Stage Small-Cell lung cancer. J Clin Oncol. 2015;33(36):4240–4246. 81. Ludbrook JJ, Truong PT, MacNeil MV, et al. Do age and comorbidity impact treatment allocation and outcomes in limited stage small-cell lung cancer? A community-based population analysis. Int J Radiat Oncol Biol Phys. 2003;55(5):1321–1330. 82. Gondi V, Paulus R, Bruner DW, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys. 2013;86(4):656–664. 83. Eaton BR, Kim S, Marcus DM, et al. Effect of prophylactic cranial irradiation on survival in elderly patients with limited-stage small cell lung cancer. Cancer. 2013;119(21):3753–3760. 84. Schild SE, Foster NR, Meyers JP, et al. Prophylactic cranial irradiation in small-cell lung cancer: findings from a North Central Cancer Treatment Group Pooled Analysis. Ann Oncol. 2012;23(11):2919–2924. 85. Bonner JA, Eagan RT, Liengswangwong V, et al. Long term results of a phase I/II study of aggressive chemotherapy and sequential upper and lower hemibody radiation for patients with extensive stage small cell lung cancer. Cancer. 1995;76(3):406–412. 86. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol. 1999;17(7):2092–2099. 87. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015;385(9962):36–42. 88. Slotman BJ, van Tinteren H, Praag JO, et al. Radiotherapy for extensive stage small-cell lung cancer - Authors’ reply. Lancet. 2015;385(9975):1292–1293. 89. Palma DA, Warner A, Louie AV, et al. Thoracic radiotherapy for extensive stage Small-Cell lung cancer: a Meta-Analysis. Clin Lung Cancer. 2016;17(4):239–244. 90. Kochhar R, Frytak S, Shaw EG. Survival of patients with extensive small-cell lung cancer who have only brain metastases at initial diagnosis. Am J Clin Oncol. 1997;20(2):125–127. 91. Ettinger DS, Berkey BA, Abrams RA, et al. Study of paclitaxel, etoposide, and cisplatin chemotherapy combined with twice-daily thoracic radiotherapy for patients with limited-stage small-cell lung cancer: a Radiation Therapy Oncology Group 9609 phase II study. J Clin Oncol. 2005;23(22):4991–4998. 92. Niell HB, Herndon JE 2nd, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: cancer and Leukemia Group B Trial 9732. J Clin Oncol. 2005;23(16):3752–3759. 93. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346(2):85–91. 94. Hanna N, Bunn PA Jr, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006;24(13):2038–2043. 95. Lara PN Jr, Natale R, Crowley J, et al. Phase III trial of irinotecan/ cisplatin compared with etoposide/cisplatin in extensive-stage small-cell

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lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol. 2009;27(15):2530–2535. 96. Amarasena IU, Chatterjee S, Walters JA, et al. Platinum versus nonplatinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev. 2015;(8):CD006849. 97. Jiang J, Liang X, Zhou X, et al. A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancer. Lung Cancer. 2007;57(3):348–358. 98. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30(14):1692–1698. 99. Morikawa N, Inoue A, Sugawara S, et al. Randomized phase II study of carboplatin plus irinotecan versus carboplatin plus amrubicin in patients with chemo-naive extensive-stage small-cell lung cancer: North Japan Lung Cancer Study Group (NJLCG) 0901. Lung Cancer. 2017;111:38–42. 100. Sekine I, Harada H, Yamamoto N, et al. Randomized phase II trial of weekly dose-intensive chemotherapy or amrubicin plus cisplatin chemotherapy following induction chemoradiotherapy for limiteddisease small cell lung cancer (JCOG1011). Lung Cancer. 2017;108:232–237. 101. Spigel DR, Hainsworth JD, Shipley DL, et al. Amrubicin and carboplatin with pegfilgrastim in patients with extensive stage small cell lung cancer: a phase II trial of the Sarah Cannon Oncology Research Consortium. Lung Cancer. 2018;117:38–43. 102. Jalal SI, Lavin P, Lo G, et al. Carboplatin and etoposide with or without palifosfamide in untreated Extensive-Stage Small-Cell lung cancer: a multicenter, adaptive, randomized phase III study (MATISSE). J Clin Oncol. 2017;35(23):2619–2623. 103. Hellman MD, Ott P, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): first report of a randomized expansion cohort from CheckMate 032. J Clin Oncol. 2017;35(15_suppl):8503. 103a. Horn L, Mansfield AS, Szcz sna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–2229. 104. Gadgeel SM, Pennell NA, Fidler MJ, et al. Phase II study of maintenance pembrolizumab in patients with Extensive-Stage small cell lung cancer (SCLC). J Thorac Oncol. 2018. 105. Colaco R, Sheikh H, Lorigan P, et al. Omitting elective nodal irradiation during thoracic irradiation in limited-stage small cell lung cancer– evidence from a phase II trial. Lung Cancer. 2012;76(1):72–77. 106. Han TJ, Kim HJ, Wu HG, et al. Comparison of treatment outcomes between involved-field and elective nodal irradiation in limited-stage small cell lung cancer. Jpn J Clin Oncol. 2012;42(10):948–954. 107. Hu X, Bao Y, Zhang L, et al. Omitting elective nodal irradiation and irradiating postinduction versus preinduction chemotherapy tumor extent for limited-stage small cell lung cancer: interim analysis of a prospective randomized noninferiority trial. Cancer. 2012;118(1):278–287. 108. Faivre-Finn C, Falk S, Ashcroft L, et al. Protocol for the CONVERT trial-Concurrent ONce-daily VErsus twice-daily RadioTherapy: an international 2-arm randomised controlled trial of concurrent chemoradiotherapy comparing twice-daily and once-daily radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status. BMJ Open. 2016;6(1):e009849. 109. Salama JK, Pang H, Bogart JA, et al. Predictors of pulmonary toxicity in limited stage small cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904. Lung Cancer. 2013;82(3):436–440. 110. Groom N, Wilson E, Faivre-Finn C. Effect of accurate heart delineation on cardiac dose during the CONVERT trial. Br J Radiol. 2017;90(1073):20170036. 111. Robin TP, Jones BL, Amini A, et al. Radiosurgery alone is associated with favorable outcomes for brain metastases from small-cell lung cancer. Lung Cancer. 2018;120:88–90.

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Disease Sites

112. Schreiber D, Rineer J, Weedon J, et al. Survival outcomes with the use of surgery in limited-stage small cell lung cancer: should its role be re-evaluated? Cancer. 2010;116(5):1350–1357. 113. Yu JB, Decker RH, Detterbeck FC, et al. Surveillance epidemiology and end results evaluation of the role of surgery for stage I small cell lung cancer. J Thorac Oncol. 2010;5(2):215–219. 114. Varlotto JM, Recht A, Flickinger JC, et al. Lobectomy leads to optimal survival in early-stage small cell lung cancer: a retrospective analysis. J Thorac Cardiovasc Surg. 2011;142(3):538–546. 115. Takei H, Kondo H, Miyaoka E, et al. Surgery for small cell lung cancer: a retrospective analysis of 243 patients from Japanese Lung Cancer Registry in 2004. J Thorac Oncol. 2014;9(8):1140–1145. 116. Combs SE, Hancock JG, Boffa DJ, et al. Bolstering the case for lobectomy in stages I, II, and IIIA small-cell lung cancer using the National Cancer Data Base. J Thorac Oncol. 2015;10(2):316–323. 117. Wakeam E, Varghese TK Jr, Leighl NB, et al. Trends, practice patterns and underuse of surgery in the treatment of early stage small cell lung cancer. Lung Cancer. 2017;109:117–123. 118. Verma V, Simone CB 2nd, Allen PK, et al. Multi-Institutional experience of stereotactic ablative radiation therapy for stage I small cell lung cancer. Int J Radiat Oncol Biol Phys. 2017;97(2):362–371. 119. Verma V, Simone CB 2nd, Allen PK, et al. Outcomes of stereotactic body radiotherapy for T1-T2N0 small cell carcinoma according to addition of chemotherapy and prophylactic cranial irradiation: a multicenter analysis. Clin Lung Cancer. 2017;18(6):675–681 e671. 120. Stahl JM, Corso CD, Verma V, et al. Trends in stereotactic body radiation therapy for stage I small cell lung cancer. Lung Cancer. 2017;103:11–16. 121. Shioyama Y, Onishi H, Takayama K, et al. Clinical outcomes of stereotactic body radiotherapy for patients with stage I Small-Cell lung cancer: analysis of a subset of the Japanese Radiological Society Multi-Institutional SBRT Study Group database. Technol Cancer Res Treat. 2018;17.

122. Schild SE, Bonner JA, Shanahan TG, et al. Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;59(4):943–951. 123. McClay EF, Bogart J, Herndon JE 2nd, et al. A phase III trial evaluating the combination of cisplatin, etoposide, and radiation therapy with or without tamoxifen in patients with limited-stage small cell lung cancer: cancer and Leukemia Group B Study (9235). Am J Clin Oncol. 2005;28(1):81–90. 124. Horn L, Bernardo P, Sandler A, et al. A phase II study of paclitaxel + etoposide + cisplatin + concurrent radiation therapy for previously untreated limited stage small cell lung cancer (E2596): a trial of the Eastern Cooperative Oncology Group. J Thorac Oncol. 2009;4(4):527–533. 125. Edelman MJ, Chansky K, Gaspar LE, et al. Phase II trial of cisplatin/ etoposide and concurrent radiotherapy followed by paclitaxel/ carboplatin consolidation for limited small-cell lung cancer: Southwest Oncology Group 9713. J Clin Oncol. 2004;22(1):127–132. 126. Le QT, Moon J, Redman M, et al. Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limited-stage small-cell lung cancer: SWOG 0222. J Clin Oncol. 2009;27(18):3014–3019. 127. Miller AA, Wang XF, Bogart JA, et al. Phase II trial of paclitaxeltopotecan-etoposide followed by consolidation chemoradiotherapy for limited-stage small cell lung cancer: CALGB 30002. J Thorac Oncol. 2007;2(7):645–651. 128. Kelley MJ, Bogart JA, Hodgson LD, et al. Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206. J Thorac Oncol. 2013;8(1):102–108.

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51 Non–Small Cell Lung Cancer Jordan A. Torok, Jeffrey M. Clarke, Betty C. Tong, and Joseph K. Salama

KEY POINTS Incidence In the United States, approximately 228,150 cases of lung cancer and approximately 142,670 deaths were projected from lung cancer in 2019. Incidence is decreasing in the United States while increasing worldwide, reflecting patterns in tobacco use. Routine lung cancer screening with low-dose computed tomography (CT) is recommended for patients with a significant tobacco history. Biological Characteristics The predominant histological classifications of NSCLC are adenocarcinoma and squamous cell carcinoma. Unique and actionable “driver” molecular events are best characterized in adenocarcinoma, which includes EGFR mutation and EM4-ALK translocation. NSCLCs are also known to respond to immune checkpoint inhibition, with the PD-L1 assay being the most common test to predict responsiveness. Staging Evaluation High resolution CT of the chest is needed to determine the thoracic extent of disease. Intravenous contrast is helpful for central lesions and/or those with suspected nodal involvement. Positron emission tomography/computed tomography is recommended for all cases to not only detect occult metastatic disease but also to better evaluate the mediastinum. Patients with more advanced disease should also have a brain magnetic resonance imaging scan given the propensity for brain metastases. Biopsies should be done to prove stage and may include a surgical approach with mediastinoscopy or less invasive approaches, including bronchoscopy, endobronchial ultrasound, or transthoracic needle aspiration. The American Joint Committee on Cancer’s Cancer Staging Manual,

8th edition is used to categorize the staging information for optimal treatment approaches. Primary Therapy For early-stage disease, anatomic resection with a lobectomy when feasible and mediastinal lymph node dissection are the preferred treatment options for medically operable patients. Medically inoperable patients are often well suited for stereotactic body radiotherapy. Adjuvant Therapy Following curative-intent resection with hilar or occult mediastinal lymph node involvement, adjuvant chemotherapy is recommended. The role of postoperative radiotherapy is clearly indicated for incomplete resections but is controversial in completely resected lung cancer with N2 involvement. Locally Advanced Disease Multimodality treatment is necessary for optimal results. For some operable patients with limited mediastinal involvement, neoadjuvant chemotherapy with or without radiation followed by resection is appropriate. For inoperable cases, radiation to a minimum dose of 60 Gy concurrent with chemotherapy is recommended, followed by consolidation with the immune checkpoint inhibitor durvalumab. Palliation Hypofractionated regimens result in effective palliation for a variety of symptoms, with the performance status of the patient influencing the preferred dose/fractionation. Longer-course regimens appear to have less immediate but more durable symptom palliation and may extend survival in patients with good performance status. More aggressive extracranial treatment is indicated in patients with oligometastatic disease.

INTRODUCTION

tobacco-associated NSCLC; these differences can have significant clinical and therapeutic implications. Owing to the latency between tobacco exposure and cancer development, the burden of lung cancer will remain for decades even if aggressive cessation efforts are successful. Routine screening of high-risk populations is essential, with current practice shaped by the National Lung Screening Trial (NLST), which demonstrated a reduction in lung cancer deaths with low-dose computed tomography (CT) screening of high-risk populations.4 Although current therapies have considerable room for improvement, they must not be viewed nihilistically. Adjuvant systemic therapy in resected NSCLC has resulted in a modest but statistically significant and clinically meaningful survival improvement, especially in those with nodal involvement. In locally advanced NSCLC, concurrent chemotherapy and radiotherapy has substantially increased long-term

It was estimated that lung cancer would kill around 142,670 men and women in the United States in 2019, more than colon, breast, prostate, and pancreatic cancers combined.1 More than 80% of these cases were caused by habitual or environmental exposure to tobacco smoke.2 This common origin, as well as markedly improved outcomes following treatment of early- versus advanced-stage lung cancer, makes it a disease better suited to prevention and early detection rather than treatment. Tobacco-cessation efforts on both national and hospital/community levels are necessary to assist with prevention. However, non–tobaccoassociated lung cancer (NTLC) is not a rare disease, representing approximately 20% and 10% of lung cancers in women and men, respectively.3 NTLC frequently differs at a molecular level from

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CHAPTER 51

Non–Small Cell Lung Cancer

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survival. Recently, the addition of immunotherapy has transformed the care of lung cancer patients. Adjuvant immunotherapy following concurrent chemotherapy and radiotherapy dramatically improves progressionfree survival (PFS) and overall survival (OS) in locoregionally advanced NSCLC patients, while immunomodulating agents alone or in combination with cytotoxins and biologics have improved PFS and OS in metastatic or recurrent NSCLC. Finally, improvements in supportive care have both prolonged survival and enhanced quality of life (QoL). These incremental improvements in therapy have helped many individuals diagnosed with NSCLC. The key to improving treatment for lung cancer is the integration of diagnostic and treatment modalities by a dedicated team well versed in the application of the appropriate modalities and with the ability to combine them without undue bias. This interdisciplinary approach and the expertise, dedication, and collaboration that it mandates are essential to optimize therapy for patients. Furthermore, advances in molecular characterization have enabled the identification and targeted treatment of oncogenic-driven cancers, bringing the concept of personalized medicine to fruition. From a radiotherapy standpoint, refinements in imaging and delivery technologies have improved the accuracy and reproducibility of therapy, thereby enhancing the therapeutic ratio. The development of interventions to facilitate such continuity of care and communication with patients and other care providers is gaining attention. A growing advocacy effort similar to what is done for patients with breast and prostate cancer will also focus attention and research efforts on lung cancer patients.

in the incidence of second primary lung cancers, and improved survival.8 Although risk estimates are much lower, secondhand exposure is also a clear risk factor.9 Beyond tobacco, other agents that have been associated with lung cancer include arsenic, beryllium, cadmium, chromium, nickel, asbestos, silica, radon, smoke from cooking/heating, and diesel fumes. There is often a synergistic effect in the risk of these agents in populations that also smoke. These agents are also implicated in the development of lung cancer in never smokers. Worldwide, up to 20% to 25% of lung cancer cases occur in never smokers, particularly in women.10 A study in an Asian population found a significant association with indoor pollution from heating/cooking methods.11 Particulate outdoor pollution has also been associated with a modest but significant risk for the development of lung cancer. An inherited component of risk may be present for some individuals, especially younger patients with no smoking history and multiple affected family members.12,13 The genetic component is likely complex and may represent a combination of factors, including susceptibility loci, alterations of genes involved in the dependency on nicotine, metabolism of carcinogens, cell cycle progression, and DNA repair or even specific oncogenic germline mutations such as EGFR T790M and HER2 G660D.14-16 The clinical and molecular characteristics of lung cancer arising in persons who have never smoked or in minimal smokers are generally distinct from those of tobacco-associated lung cancer.17

ETIOLOGY AND EPIDEMIOLOGY

The single most important preventive action for lung cancer is the complete abstinence or cessation of tobacco smoking. Preventive action occurs on a national/international level with public education programs about the potential harms of tobacco use as well as programs to support tobacco cessation. However, it also should occur on the physician-patient level; the US Preventive Services Task Force (USPSTF) recommends that clinicians ask all adults about tobacco use.18 Active smokers should be advised to stop and provided behavioral interventions and pharmacotherapy to assist with a quit attempt. Enrollment in a formal smoking cessation program is preferred if available. In the United States, a free telephone quit line (800-QUIT-NOW) or web-based program (www.smokefree.gov) is provided to facilitate these efforts. In addition to behavioral counseling and support, several US Food and Drug Administration (FDA)–approved medications have been shown to increase the chance of a quit attempt. Preferred options include nicotine replacement therapy (patches, gums, lozenges, and the like), varenicline, or bupropion. Randomized evidence comparing all three medications shows varenicline to have the highest abstinence rates with a good safety profile.19 Many patients will consider e-cigarettes as an alternative nicotine replacement strategy. Although the reduction or cessation of tobacco smoke is preferred, the health risks of e-cigarettes have not been fully characterized and there are no current guidelines that recommend their use in helping patients quit smoking.20 At present, no agent or combination of agents has been proven to delay or prevent the development of lung cancer in high-risk populations. The emphasis in this population has been early detection, previously with chest radiographs and now most notably with low-dose screening chest CT (Fig. 51.1). NSCLC is a disease well suited for a comprehensive screening program for a number of reasons. The disease is common and represents a significant health problem, especially in a high-risk population that has a clearly identifiable risk factor of tobacco exposure. Lung cancer is often asymptomatic until the disease is advanced, at which point it has a high mortality rate even with treatment. Effective therapies are available for early-stage lung cancer. As tumor size and stage are highly prognostic, it is most advantageous to diagnose the

An estimated 2,093,876 cases of lung cancer were diagnosed worldwide in 2018, with 1,761,007 deaths.5 Among men, age-standardized rates are highest in central/eastern Europe and Eastern Asia. In contrast, age-standardized rates for women are highest in North America. Incidence is decreasing in developed countries, including the United States, attributable to declining trends in tobacco use. Unfortunately, the tobacco epidemic is rising in East Asia. In the United States alone, the annual American Cancer Society (ACS) cancer statistics report projected 234,030 new cases will be diagnosed in 2018 with an estimated 154,050 deaths.1 Incidence in US men continues to decline. For women, a clear decrease is now apparent following nearly 2 decades of stable incidence. The number of deaths remains staggering and represents a quarter of all cancer deaths, greater than breast, prostate, and colorectal cancers deaths combined. Based on the ACS report, 5-year OS for lung cancer (including small cell) is approximately 20%. The poor survival is related in part to the fact that approximately 60% of patients present with metastatic disease. Fortunately, the mortality rate is decreasing, which is likely a result of a combination of factors, including increased screening, improved staging, and therapeutic advances. The etiology of lung cancer involves modifiable risk factors as well as the individual susceptibility to those exposures. Cigarette use is the most significant preventable risk factor for developing lung cancer and is thought to be associated with more than 80% of cases.2 This is attributed to the many carcinogens in tobacco smoke, including nitrosamines and polycyclic aromatic hydrocarbons. The amount and length of time that tobacco is smoked correlates with risk, with estimates ranging from a 10- to 30-fold risk depending on the exposure.6 A useful metric in quantifying this exposure is known as pack years smoked, which is the amount of packs per day multiplied by the length of time in years smoking. Up to 90% of the risk attributable to tobacco exposure can be avoided with early tobacco cessation.7 Even among patients who have been treated for lung cancer, smoking cessation has several benefits including a reduction in recurrence of the primary tumor, reduction

EARLY DETECTION AND PREVENTION

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838

SECTION III

Disease Sites

Fig. 51.1 Computed tomography scan of a 78-year-old man with a screen detected cT1c N0 non–small cell lung cancer.

disease as early as possible. A sensitive screening test is essential to an effective screening program that preferably has limited morbidity, is accessible to the at-risk population, and is economical relative to the consequences of an unscreened population. Initial trials with chest radiographs and sputum cytology suggested a potential benefit of early detection,21 but in the large Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, there was no survival benefit from chest radiographs compared with usual care.22 Improved anatomic resolution with low-dose chest CT was compared with conventional chest radiographs in the NLST, which represents the most important screening trial influencing early detection practices in the modern era. Patients aged 55 to 74 years with at least a 30 pack-year history were eligible for the NLST, including active smokers or those who had quit within 15 years. Exclusion criteria included a prior diagnosis of lung cancer, chest CT within 18 months of enrollment, or any symptoms suggestive of lung cancer, including hemoptysis or unexplained weight loss. In the CT arm, low-dose noncontrast multidetector CT (LD-CT) was used to reduce radiation exposure (average effective dose of 1.5 mSv compared with 8 mSv for diagnostic CT) but obtain high-resolution thin-cut images. In both groups, imaging was obtained at baseline and for two subsequent consecutive years. A positive result was defined as a noncalcified nodule (at least 4 mm in the LD-CT group) or other suspicious findings, including a pleural effusion or regional adenopathy. Approximately 53,000 patients from 33 centers were randomly assigned and, after a median follow-up of 6.5 years, LD-CT was associated with a 20% and 6.7% relative reduction in lung cancer–specific and overall mortality, respectively.4 Of detected lung cancers, 50% were stage I with LD-CT while only 30% were stage I with chest radiography. An important observation from this trial was the high false-positive rate of screening. In the LD-CT arm, 24% of CT scans met criteria for an abnormal result, of which over 95% were deemed false positive. In most cases, false-positive results were confirmed by serial imaging; invasive procedures were necessary to characterize the abnormality in others. A protocol-defined management approach to pulmonary nodules was not implemented in the trial, however. A criticism of the NLST was that it did not compare CT to a truly unscreened population, but in

considering the results of the PLCO trial, it suggests that LD-CT would have similar benefits over usual care. Ongoing questions for screening include the appropriate population to screen, the optimal duration and interval of screening examinations, and the most appropriate workup of an abnormal result. While most expert groups recommend screening a population similar to that of the NLST protocol, patients older than 74 years but in good health who would be eligible for definitive treatment may warrant screening. Refinements in risk prediction may eventually better select patients; however, at present, age and tobacco exposure remain the primary criteria. The NELSON trial randomly assigned 15,822 high-risk patients in Europe to increasing screening intervals with CT (1, 2, and 2.5 years) versus no screening. In contrast to the NLST, NELSON incorporates volume doubling time in the nodule management algorithm. While the primary analysis for mortality reduction with screening is still pending, it has been observed that the longer-interval screening is associated a higher proportion of advanced-stage disease and interval cancer diagnoses.23 This suggests that the screening interval should be maintained annually. Whether screening should continue beyond 3 years in patients with a negative result is unclear. The identification of a pulmonary nodule(s) on screening CT can be further classified using the lung imaging reporting and data system (Lung-RADS; Table 51.1).24 Similar to the Bi-RADS system used for breast imaging, Lung-RADS was developed in order to provide standardization for lung cancer screening reporting and management. In contrast to the NLST, solid nodules greater than 6 mm in average diameter are considered a positive finding in Lung-RADS. This system was implemented in 2015, with subsequent studies demonstrating the utility of its use in screening populations.24,25 The most important characteristics of the Lung-RADS system include nodule attenuation (i.e., solid, part-solid, or ground-glass), nodule size, and growth characteristics. Among the different attenuation types, part-solid nodules tend to have the greatest association with malignancy.26 Attenuation characteristics that strongly favor a benign etiology include benign calcification pattern (central, diffuse, or laminated) and fat attenuation, which can represent prior infection and granulomas or hamartomas, respectively. Malignancy is more likely in solid or part-solid nodules when the solid component is greater than or equal to 8 mm. While spiculated borders tend to be associated with primary lung cancer and smooth, well-defined borders can be seen with either benign or metastatic lesions, these features are not always reliable in distinguishing a primary lung cancer. When serial CT is obtained, volume doubling time can further risk stratify lung nodules. Solid nodules with a doubling time of less than 6 months are highly associated with malignancy, where part-solid and ground-glass nodules with doubling times on the order of years can still be associated with malignancy.27 Malignancies with long volume doubling times tend to be associated with more indolent histologies (adenocarcinoma in situ [AIS], minimally invasive adenocarcinoma [MIA]), which can factor into the need for intervention.28 It should be noted that volume doubling time is not part of the current Lung-RADS system. The workup and tissue confirmation of a patient with a suspected lung cancer is discussed separately. Nodules that are detected incidentally outside of a screening program are typically managed according to the Fleischner Society Guidelines most recently updated in 2017.29

PATHOLOGY AND MOLECULAR BIOLOGY OF LUNG CANCER The past decade has seen dramatic changes in our understanding of the molecular basis of lung cancers. Histopathological classification remains a critical step in not only differentiating small cell versus non–small cell

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CHAPTER 51

TABLE 51.1

Management

Non–Small Cell Lung Cancer

839

Lung-RADS Classification of Pulmonary Nodules With Recommended

Lung-RADS Category

Findings on Initial/Subsequent LD-CT

Recommendation

1-negative

No nodules; nodules with calcification

Continued annual LDCT

2-benign

Initial SN/PSN: 2 but ≤ 3 cm

T2

Tumor > 3 cm but ≤ 5 cm, or tumor with any of the following featuresb: Invades visceral pleura (T2 Visc Pl) or Involves main bronchus but not carina or associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung (T2 Centr)

T2a

Tumor > 3 cm but ≤ 4 cm

T2b

Tumor > 4 cm but ≤ 5 cm

T3

Tumor > 5 cm but ≤ 7 cm; or tumor with any of the following features: Invasion of the chest wall (includes superior sulcus tumors), pericardium, phrenic nerve (T3 Inv), or Separate tumor nodule(s) in the same lobe (T3 satell)

T4

Tumor > 7 cm or tumor with any of the following features: Invasion of the mediastinum, diaphragm, heart, great vessels, carina, trachea, recurrent laryngeal nerve, esophagus, or vertebral body (T4 Inv), or Separate tumor nodule(s) in a different ipsilateral lobe (T4 Ips Nod)

N NX

Regional Lymph Nodes Regional lymph nodes not assessed

N0

No regional lymph node metastasis

N1

Metastases in ipsilateral pulmonary and/or hilar lymph node(s); subclassified into single-station (N1a) or multistation (N1b) involvement

N2

Metastases in ipsilateral mediastinal and/or subcarinal lymph node(s); subclassified into single-station N2 without N1 involvement (N2a1), single-station N2 with N1 involvement (N2a2) and multistation N2 involvement (N2b)

N3

Metastases in contralateral mediastinal/hilar or supraclavicular lymph node(s)

M M0

Distant Metastases No distant metastases

M1

Distant metastasis

M1a

Malignant pleuralc or pericardial effusion and/or nodules (M1a Pl Dissem); or Separate tumor nodule(s) in a contralateral lobe (M1a Contr Nod)

M1b

Single extrathoracic metastasis

M1c

Multiple extrathoracic metastases (1 or > 1 organ)

a

Superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified T1a. b T2 tumors with these features are classified T2a if ≤ 4 cm or T2b if > 4 cm but ≤ 5 cm. c Can be excluded from M1a stage if multiple microscopic examinations of pleural fluid are cytologically negative for tumor, are nonbloody, transudative, and clinically judged to be non-malignant.

no further testing is needed.102 PPO lung function based on quantitative radionuclide lung perfusion imaging and the anticipated volume of lung resection may more precisely estimate pulmonary risk, especially when pneumonectomy may be required. Simple and advanced exercise testing may be necessary to further risk stratify patients who are borderline. It is important to note that there is no distinct threshold that prohibits surgery and the risks/benefits should be discussed between the patient and a board-certified thoracic surgeon. Superior patient

outcomes are reported at high volume centers, highlighting the importance of surgeon experience.103 Lobectomy currently remains the standard operation for early-stage NSCLCs. The Lung Cancer Study Group randomized trial of lobectomy versus limited resection (predominantly segmentectomy but wedge resections with ≥ 2-cm clear margins allowed) for T1N0 NSCLC found a relative tripling in local recurrence with limited resection.104 Although not statistically different, limited resection trended toward inferior

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848

SECTION III

TABLE 51.3

Categories

Disease Sites

Stage Grouping and TNM

T/M

Sub-Category

N0

N1

N2

N3

T1

T1a T1b T1c

1A1 1A2 1A3

2B 2B 2B

3A 3A 3A

3B 3B 3B

T2

T2a T2b

1B 2A

2B 2B

3A 3A

3B 3B

T3

2B

3A

3B

3C

T4

3A

3A

3B

3C

4A 4A 4B

4A 4A 4B

4A 4A 4B

4A 4A 4B

M1

M1a M1b M1c

mortality without significant improvements in pulmonary function or perioperative morbidity/mortality. This study established lobectomy as the gold standard over 2 decades ago. Practice has changed in the modern era with routine use of PET/ CT and follow-up CT for surveillance. Additionally, preoperative assessments and surgical techniques have evolved. Open thoracotomy is now usually reserved for cases in which minimally invasive techniques such as video-assisted thoracic surgery (VATS) and/or robotic surgery are not achievable. A meta-analysis of VATS versus open lobectomy has suggested similar oncological outcomes,105 with both institutional and national database series suggesting fewer complications and shorter hospital stays.106-109 Despite some retrospective studies showing higher rates of nodal upstaging with thoracotomy versus VATS lobectomy,110 patients undergoing thoracoscopic lobectomy have long-term survival that is not inferior to open thoracotomy.111 In experienced hands, significant perioperative morbidity and operative mortality are 9% and 1.4%, respectively.112 With modern staging and surgical techniques, many have again questioned the need for a lobectomy for early-stage NSCLC. Modern retrospective and nonrandomized prospective series suggest that there is still a role for limited resection, particularly in small (< 2 cm) N0 adenocarcinomas.113-116 However, some of these studies included minimally or noninvasive tumors, which inevitably reduces the locoregional recurrence event rate. At least two randomized trials are ongoing to define the role of limited resection in small peripheral tumors: Cancer and Leukemia Group B (CALGB) 140503 (NCT00499330) in the United States and JCOG0802/WJOG4607L in Japan. Each has completed accrual, but survival data are forthcoming. For proximal tumors, a sleeve lobectomy, if feasible, is preferred over pneumonectomy given the higher rates of perioperative complications and mortality with the latter.117 Moreover, quality of life has been shown to be superior with the use of parenchymal-sparing techniques such as sleeve lobectomy compared with pneumonectomy.118 Pathological mediastinal lymph node sampling should be routinely implemented prior to surgical resection for most patients. In patients who have a negative mediastinal sampling, the randomized Phase III ACOSOG Z0030 trial found no benefit from subsequent systematic mediastinal lymph node dissection.119 However, it is recommended that all patients at a minimum have complete hilar and mediastinal node mapping with sampling of at least 3 N2 stations as part of their surgery.63 The rate of locoregional recurrence after surgery depends on the pathological stage, histology, type of surgery, and the definition of recurrence (first site of failure, isolated or concomitant with distant

recurrence, crude vs. actuarial). A detailed pattern of recurrence analysis following surgical resection for early-stage NSCLC reported a 5-year actuarial local failure risk of 23%.61 Recurrence at the resection margin, ipsilateral hilum, or mediastinum was scored as local failure. Distant failures predominated, however, with 75% of all recurrences having isolated or concomitant metastatic disease.

Medically Inoperable Radiotherapy is the preferred alternative for patients with early-stage NSCLC who are either medically inoperable or refuse a surgical approach. The cause of death in untreated frail patients with early-stage disease is predominantly from their cancer and not other comorbid conditions.120 These patients should be strongly considered for curative therapy. Historical series of conventional radiotherapy predate modern staging and radiotherapy techniques, limiting their comparison with present-day outcomes. Radiotherapy was previously delivered with 2D or 3D techniques using conventional fractionation, but more modern techniques including SBRT appear to have increased survival.109 Historically, radiotherapy for this population was associated with poor local control and survival.121 To overcome this, a number of modifications to standard radiotherapy were incorporated, including elimination of elective nodal irradiation,122 dose escalation,123 and PET-directed radiotherapy.124 Based on the incorporation of these changes, the Radiation Therapy Oncology Group (RTOG) conducted a Phase I/II dose escalation trial in patients with inoperable stages I-III NSCLC. Patients were stratified into two groups based on lung volume receiving greater than or equal to 20 Gy, with group 1 patients having smaller tumors and consisting of approximately 60% stage I/II patients. Within this group, doses were escalated from 70.9 Gy in 33 fractions up to 90.3 Gy in 42 fractions (2.15 Gy/fx). While the 90.3-Gy dose was determined to be dose limiting in terms of late toxicity, there was no clear dose-response for local control, with 2-year locoregional control rates ranging between 55% and 73%.125 Investigators hypothesized that the prolonged treatment schemes with tumor repopulation may have compromised efficacy. An alternative to conventional fractionated dose escalation was hypofractionation. CALGB 39904 showed high rates of treated tumor control in a Phase I study increasing the dose per fraction while maintaining a total dose of 70 Gy.126 In current practice, the vast majority of patients with medically inoperable stage I NSCLC are now treated with SBRT, which is synonymous with stereotactic ablative radiotherapy (SABR) and hypofractionated imaged-guided radiotherapy (HIGRT). Advances in radiation simulation, planning, and delivery have facilitated the development of the SBRT platform. Target volume is minimized using personalized respiratory motion assessment and management. The ability to deliver multiple coplanar and noncoplanar beams or arcs allows for steep dose gradients, thereby permitting unconventionally high doses to the tumor while minimizing radiation dose to nearby organs at risk (OARs; Fig. 51.8). Modern linear accelerators are fitted with on-board imaging, which allows for orthogonal and/or volumetric image matching that enhances the precise delivery of highly conformal radiotherapy. Stereotaxis, or the use of an external coordinate reference system, is no longer employed. In North America, critical studies from the University of Indiana defined the maximum tolerated dose of 3-fraction SBRT to be 60 Gy (20 Gy/fx), which demonstrated a 2-year tumor control rate of 95% in the subsequent Phase II portion.127, 128 While these results were quite promising, an important observation was the development of severe toxicity with treatment of tumors within 2 cm of the proximal bronchial tree, subsequently referred to as central tumors. For these patients, grade 3 or higher toxicity approached 30%, including pneumonia, hemoptysis, decline in pulmonary function, pleural/pericardial effusions, and skin

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CHAPTER 51

Non–Small Cell Lung Cancer

849

A B

C Fig. 51.8 Stereotactic body radiotherapy plan for a patient diagnosed with a cT1c N0 non–small cell lung cancer. This patient was treated with a 2-arc volumetric-modulated arc therapy (VMAT) plan with a prescription dose of 54 Gy delivered over 3 fractions. Panels represent the axial (A), sagittal (B), and coronal (C) image planes with isodose lines superimposed.

reactions.129 Larger tumors (> 10 ccs) were also associated with higher grade toxicity. As a result, a distinction is now made between central and peripheral tumors as depicted in Fig. 51.9. The typical long-term radiographic result after SBRT is scarring of the parenchymal mass, with various additional evolving radiographic findings possible, including ground-glass opacities and consolidation (Fig. 51.10). The RTOG conducted a Phase II trial using the University of Indiana SBRT regimen but excluded patients with central tumors or those with tumors measuring > 5 cm. RTOG 0236 confirmed an excellent tumor control rate of 98% at 3 years.130 Additional outcomes included 3-year involved lobe control, locoregional control, distant progression, and OS rates of 91%, 87%, 22%, and 56%, respectively. With this carefully selected patient group, no treatment-related deaths were reported and the grades 3-4 toxicity rate was 16%. Five-year results showed a slight reduction in tumor control to 93% with corresponding values of involved lobe control, locoregional control, distant progression, and OS of 80%, 62%, 31%, and 40%, respectively.131 Despite the increase in disease-related events with longer follow up, these outcomes still compare favorably to historical studies. One important caveat is that with heterogeneity correction (which is now standard in treatment planning software), the adjusted prescription dose of this regimen is 54 Gy (18 Gy/fx). Trials from Japan and Europe using different SBRT dose fractionation schemes have also reported favorable outcomes.132, 133 Results from multi-institutional trials in Japan have established a biologically equivalent dose (BED) of 100 Gy (α/β = 10) as a critical dose threshold to achieve

a local control probability of over 90%.134 While this is achieved with the common 3- to 5-fraction SBRT regimens, more protracted courses over 8 to 10 fractions (achieving total doses ranging from 60 to 72 Gy) also reach this threshold and have similar effectiveness. The largest report on SBRT outcomes comes from VU University Medical Center, who reported on 676 patients treated with doses of 54 to 60 Gy in 3 to 8 fractions. With a median follow-up of 33 months, the 2-year local, regional, and distant recurrence rates were 5%, 8%, and 15%, respectively.135 Comparative effectiveness between the different regimens is lacking. RTOG 0915 represents the only published randomized trial that compared 34 Gy in a single fraction to 48 Gy in four fractions for peripheral early-stage NSCLC with a primary endpoint of greater than or equal to grade 3 protocol specified toxicity. Both arms achieved greater than 90% tumor control without statistical differences, but there were numerically less toxic events with 34 Gy × 1.136 The initial intent of this trial was to pick a comparator arm for 54 Gy in 3 fractions, but such a trial was never conducted. A multi-institutional Phase II study, however, compared 30 Gy × 1 with 20 Gy × 3 (without heterogeneity correction). Results presented at the American Society for Radiation Oncology (ASTRO) meeting in 2016 included a total of 98 patients and showed no statistical difference in treatment efficacy or toxicity at 2 years.137 Retrospective data suggest slight improvements in local control with 54 Gy/3 fx compared with more fractionated regimens, albeit at the risk of increased toxicity.138 A risk-adapted approach is therefore

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850

SECTION III

Disease Sites Brachial plexus

Heart

Esophagus Aorta

Lung

Heart

2 cm zone Fig. 51.9 Recommended definition of central lesion: a tumor within 2 cm in all directions of any mediastinal critical structure, including the bronchial tree, esophagus, heart, brachial plexus, major vessels, spinal cord, phrenic nerve, and recurrent laryngeal nerve. (From Chang JY, Bezjak A, Mornex F. Stereotactic ablative radiotherapy for centrally located early stage non-small-cell lung cancer: what we have learned. J Thorac Oncol. 2015;10:577–585.)

Fig. 51.10 Sequence of follow-up computed tomography scans showing tumor regression/scarring following stereotactic body radiotherapy dose 10 Gy × 5 for central NSCLC.

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CHAPTER 51 advisable.139 In our practice, 54 Gy/3 fx is reserved for small peripheral tumors without broad contact with the chest wall. When keeping the chest wall V30 < 30 ccs, the risk of severe chest wall toxicity can be minimized.140 Following the cautionary results for central tumors, there was reluctance to use SBRT for central tumors. RTOG 0813 was a prospective Phase I/II dose escalation study for central tumors using a 5-fraction regimen. The dose was escalated up to 12 Gy per fraction; final results have yet to be published. The lowest dose level, 10 Gy × 5, has been interpreted as being safe. A word of caution is notable, however, as severe toxicity and treatment-related deaths have occurred with this fractionation.141 The VU University Medical Center has shown promising local control of over 90% using the alternative regimen of 60 Gy in 8 fractions for central tumors.142 A systematic review in central tumors has confirmed the importance of a BED greater than or equal to 100 Gy (α/β = 10) for tumor control, but also that a BED greater than or equal to 210 Gy (α/β = 3) increased treatment toxicity and mortality.143 More protracted 10-fraction regimens have also been reported with high local control rates and acceptable toxicity.144, 145 Tumors that overlap main bronchi or the trachea may be termed ultracentral and have an increased risk of toxicity, with one study that used 12 fractions of 5 Gy finding a 21% grade 5 event rate.146 Similar to peripheral tumors, a risk-adapted approach is advisable, with more prolonged fractionation warranted for proximity to critical OARs. While SBRT has been adopted as the standard treatment for medically inoperable patients, there is little level 1 evidence to support this. A large propensity-matched analysis of veterans with early-stage NSCLC found that SBRT improved survival compared with conventionally fractionated radiotherapy.109 The SPACE trial was a randomized controlled trial to compare the outcome of 3-fraction SBRT with conventionally fractionated radiotherapy to a total dose of 70 Gy. There was no significant improvement in PFS or OS, but the SBRT regimen offered much more convenience, with improved tolerance of the therapy.147 An additional randomized trial comparing SBRT (54 Gy in 3 fractions or 48 Gy in 4 fractions) with conventional (66 Gy in 33 fractions) or moderate hypofractionation (50 Gy in 20 fractions) was completed by the Trans-Tasmanian Radiation Oncology Group (TROG), known as the CHISEL trial. A total of 101 participants were accrued (2 : 1 with n = 66 SBRT and n = 35 conventional). Results were presented at the 2017 World Conference on Lung Cancer showing superior freedom from local failure (HR, 0.29; 95% CI, 0.13-0.66; p = 0.002) and OS (HR, 0.51; 95% CI, 0.51-0.91; p = 0.02) in favor of SBRT.148 Radiofrequency ablation (RFA) is another potential option for patients who are marginal surgical candidates. RFA is an image-guided thermal ablation technique that locally heats tumor tissue to a lethal temperature while potentially minimizing damage to surrounding tissue. ACOSOG Z4033 reported the feasibility of RFA for inoperable stage IA tumors, with a 2-year recurrence-free rate of 60% and 2-yr OS of 70%.149 A systemic review and pooled analysis of SBRT and RFA found higher rates of tumor control for SBRT, although survival was similar.150 Compared with wedge resection, one retrospective series found a trend for reduced local recurrence with SBRT (4% vs. 20%) with no difference in cause-specific survival.151 However, other analyses could not find a cohort of patients treated with radiation who had improved tumor control or survival outcomes compared with surgically resected patients.109 While SBRT has mostly been investigated in the medically inoperable population, evidence is emerging in the medically operable population as well. RTOG 0618 was a Phase II trial of peripheral tumors treated with 54 Gy in 3 fractions. Of 26 evaluable patients (primarily T1 tumors), only 1 local failure occurred, resulting in a 4-year primary tumor and local control rate of 96%.152 The Japanese Clinical Oncology Group (JCOG) study 0403 evaluated the safety and efficacy of SBRT in both

Non–Small Cell Lung Cancer

851

operable and inoperable early-stage NSCLC. In the operable cohort, 3-year local control and OS were 85% and 77%, respectively.153 Several Phase III trials comparing SBRT with surgery were initiated but were terminated early owing to poor accrual. A combined analysis of two of these trials, the STARS and ROSEL trials, was recently reported. Combined eligibility included those with a tumor less than 4 cm, with the surgical arm requiring a lobectomy and mediastinal lymph node sampling. Central tumors were allowed on the STARS protocol, while only peripheral tumors were enrolled on the ROSEL protocol. SBRT regimens included 54 Gy in 3 fractions, 50 Gy in 4 fractions or 60 Gy in 5 fractions. A total of 58 patients were randomized; after a median follow-up of 40 months, SBRT was noted to have superior OS (3-year OS, 95% vs. 79%, p = 0.04) but similar rates of local, regional, and distant recurrencefree survival.154 The survival difference is most likely explained by the early postoperative mortality that can be associated with surgery. This trial has provided the needed equipoise to facilitate accrual of several ongoing prospective trials comparing surgery with SBRT. Multiple retrospective single-institution and large database studies have reported conflicting results in SBRT and surgical comparisons. Typically, these studies suggest inferior survival with SBRT but are not well controlled for the confounding factors that make these patients medically inoperable. Additional issues in these retrospective studies are clinical versus pathological staging, in which a subset of clinically staged patients will have occult nodal disease. Select practice-changing trials of SBRT for both medically inoperable and operable patients are listed in Table 51.4. Additional prospective randomized trials are needed to further define the role of SBRT in the medically operable patient. Two additional trials are underway: VALOR (NCT02984761) and STABLE-MATES (NCT02468024). The SABR-OS (TROG 13.03) trial is in development. Recruitment to trials with surgical versus nonsurgical arms has been a challenge in the United States, at least, in part, owing to strong patient and physician preconceived notions and potential financial incentives. The conflicting data at present, however, should provide equipoise to facilitate accrual for the next generation of trials.

Adjuvant Chemotherapy Despite curative surgery, patients with NSCLC are at a significant risk of recurrence. The Lung Adjuvant Cisplatin Evaluation (LACE) metaanalysis provides valuable information to guide adjuvant therapy recommendations. This study evaluated 5 trials including 4600 patients with completely resected NSCLC. After a median follow-up of 5 years, postoperative cisplatin-based chemotherapy was associated with an overall HR of 0.89 for death (95% CI, 0.82-0.96, p = 0.005) and a 5% absolute improvement in survival.155 When analyzed by stage, there was clear interaction with the effect of chemotherapy. Stage IA patients trended toward inferior outcomes with chemotherapy, while stages II/III patients derived the greatest benefit. Adjuvant chemotherapy is therefore not routinely recommended for stage IA patients but is indicated for most stages II/III patients. The use of chemotherapy in stage IB patients is controversial. The CALGB 9633 trial specifically addressed this population in a randomized comparison of adjuvant carboplatin and paclitaxel versus observation. The results of this study are difficult to interpret, as it was stopped early by the data safety monitoring committee and, therefore, was underpowered. There was not a statistically significant benefit in terms of survival with adjuvant chemotherapy (HR, 0.83; 95% CI, 0.64-1.08).156 Although also not significant, there was a trend for improved disease-free survival with adjuvant chemotherapy. An exploratory analysis suggested greater benefit in patients with tumors greater than or equal to 4 cm. In current practice, routine use of chemotherapy for these patients is not recommended, but a risk/benefit discussion is warranted.157 Molecular risk stratification strategies may

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852

SECTION III

Disease Sites

Select Prospective Studies of Stereotactic Body Radiation Therapy (SBRT) for Peripheral Medically Inoperable And Operable Early Stage (T1-2 N0) NSCLC, Comparator Arm of Randomized Studies Included When Applicable

TABLE 51.4

Studya

N

Dose/Fraction

Median F/u (mo)

Tumor Control

Survival

Toxicity

Medically Inoperable RTOG 0236 52

60 Gy/3 fx

48

93% (5-y)

40% (5-y)

13% Gr 3/4, no G5

JCOG 0403

100

48 Gy/4 fx

47

87% (3-y)

60% (3-y)

12% Gr3/4, no G5

RTOG 0915

39 45

34 Gy/1 fx 48 Gy/4 fx

30

97% (1-y) 93% (1-y)

61% (2-y) 78% (2-y)

10.3% Gr 3+ 13.3% Gr 3+

SPACE

49 53

66 Gy/3 fx 70 Gy/35 fx

37

42% (3-y PFS) 42% (3-y PFS)

54% (3-y) 59% (3-y)

7% G3, no G4/5 13% G3, no G4/5

Medically Operable RTOG 0618 26

54 Gy/3 fx

48

96% (4-y)

56% (4-y)

8% G3, no G4/5

JCOG 0403

64

48 Gy/4 fx

67

85% (3-y)

54% (5-y)

5 G3 events, no G4/5

STARa / ROSEL

31 27

54 Gy/3 fx, 50 Gy/4 fx or 60 Gy/5 fx Surgery

40

96% (3-y) 100% (3-y)

95% (3-y) 79% (3-y)

10% G3, no G4/5 44% G3-4, 1 (4%) G5

a

Allowed central tumors JCOG, Japanese Clinical Oncology Group; PFS, progression-free survival; RTOG, Radiation Therapy Oncology Group; SPACE, Stereotactic Precision And Conventional radiotherapy Evaluation.

guide adjuvant therapy recommendations in the near future. Several gene expression assays have shown prognostic significance,158-160 but the predictive benefit of adjuvant chemotherapy in the different risk groups needs prospective validation before routine implementation. Adjuvant chemotherapy typically consists of a cisplatin-based doublet, including pemetrexed (nonsquamous), gemcitabine, docetaxel, vinorelbine, or etoposide. Carboplatin may be substituted for those not felt to be cisplatin candidates. The use of molecularly targeted agents in the adjuvant setting requires further study. The addition of bevacizumab to adjuvant cytotoxic chemotherapy was addressed in a large randomized study and did not improve survival.161 Thus, it is not recommended in the adjuvant setting. The international RADIANT trial explored the use of adjuvant erlotinib versus placebo in patients with completely resected stage IB to IIIA NSCLC with positive EGFR expression and/ or amplification but did not require an EGFR-activating mutation. There was not a statistically significant difference in disease-free survival in the overall population.162 A subgroup of patients with EGFR-activating mutations did appear to derive a disease-free survival benefit, but this did not reach predefined statistical significance and survival has not yet been reported. The ALCHEMIST trial (NCT02194738) is screening patients with surgically resected NSCLC. Patients with an EGFR mutation or ALK rearrangement will be randomized to placebo or the appropriate TKI as adjuvant therapy. In patients without these mutations or who have squamous histology, a third arm (ANVIL) will compare adjuvant immunotherapy with nivolumab to observation.

N0 or N1 disease but found a survival improvement in those with N2 disease.164 A subset analysis of the ANITA trial confirmed a survival improvement for the N2 patients receiving PORT and, interestingly, also showed a survival benefit for patients with N1 disease who did not receive chemotherapy.165 PORT is now administered carefully using 3D and intensity-modulated techniques in more select patient populations to optimize the risk/benefit ratio. PORT for N2 disease and positive margins are the strongest indications and will be discussed in the upcoming locoregionally advanced-stage section.

Postoperative Radiotherapy

The role of surgery in patients with stage IIIA and IIIB disease is controversial. Several large prospective trials with heterogenous study designs have addressed the role of surgery (Table 51.5). In the European Organization for Research in Cancer Therapy (EORTC) trial 08941, patients with stage IIIA (N2) NSCLC received induction chemotherapy with cisplatin/etoposide and responders were randomized between definitive radiotherapy or surgery.166 Inclusion criteria was N2 involvement by non–squamous cell carcinoma or N2 involvement exceeding level 4R for right-sided tumors or level 5/6 for left-sided tumors of squamous histology. Approximately 60% (n = 332/579) of the enrolled patients had a response to induction chemotherapy and

After complete resection (R0) of NSCLC, postoperative radiotherapy is not routinely indicated in early-stage disease. Historical series of postoperative radiotherapy (PORT), including early-stage patients, have shown a potential detriment in an unselected patient population.163 These trials, however, suffered from outdated radiation techniques and atypically large fraction sizes in several studies that likely contributed to an increase in treatment-related morbidity and mortality. A Surveillance, Epidemiology, and End Results (SEER) database study further explored survival outcomes following PORT in nearly 7500 patients. Subset analyses by stage found a survival detriment in patients with

Locoregionally Advanced-Stage Non–Small Cell Lung Cancer Locoregionally advanced-stage NSCLC typically refers to stage III disease, which is a heterogeneous cohort. Based on the eighth edition of AJCC staging, there are now three categories of stage III disease that include various combinations of T and N groups. Curative therapy for these patients necessitates multimodality therapy. Medically fit patients with T3N1 are appropriately managed with the early-stage paradigm of resection and adjuvant chemotherapy assuming that the mediastinum is thoroughly staged preoperatively. T4 disease, irrespective of medical fitness, is typically synonymous with unresectability. The management of patients with N2 disease is controversial and practice patterns vary. This section will primarily focus on the management of these patients.

Preoperative Treatment for Patients With Resectable Non–Small Cell Lung Cancer

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CHAPTER 51

Select Randomized Phase III Trials of Trimodality Therapy for Stage III Non–Small Cell Lung Cancer

TABLE 51.5

5-y OS

Study

Eligibility

N

Therapy

EORTC166

3A-N2; response after PD

165

PD → RT 60-62.5 Gy; 2 Gy/fx PD → S; PORT 56 Gy if R+ (40%)

14%

PD/RT → RT boost 61 Gy → PD PD/RT → S → PD

24%

PD/RT → RT boost 65-71 Gy; 2 Gy/fx PD/RT → S

40%

167 Intergroup167

ESPATUE168

3A-N2; no progression after PD/RT 45 Gy; 1.8 Gy/fx

194

3A-N2, select 3B; no progression after PD/RT 45 Gy; 1.5 Gy/fx BID

80

202

81

16%

37%

44%

EORTC, European Organization for Research and Treatment of Cancer; OS, overall survival; PD, platinum doublet; PORT, postoperative radiotherapy; RT, radiotherapy; S, surgery.

were then randomized, 90% of whom were treated per their allocated treatment arm. Median (17.5 vs. 16.4 months) and 5-year OS (14 vs. 15.7%) were not statistically different between the radiotherapy and surgery arms, respectively. Criticisms of this trial include that nearly 50% of patients in the surgery arm received a pneumonectomy and incomplete resections were noted in nearly half of the surgical group. PORT was administered only for positive margins and 40% of the surgical patients received it. The North American Intergroup Trial INT 0139 randomized 202 patients with resectable pathological N2 disease to definitive chemoradiation (61 Gy concurrent with cisplatin/etoposide) or concurrent preoperative chemoradiation to 45 Gy followed by surgery.167 The study population included robust patients (median age of 60 years, 90% Karnofsky Performance Status [KPS] ≥ 90) with 75% having a single positive nodal station and 80% of the surgical arm undergoing a thoracotomy. In the overall population, the addition of surgery compared with radiation did not statistically improve median (23.6 vs. 22.2 months) or 5-year OS (27 vs. 20%), the primary endpoint of the study. PFS, however, was significantly improved with trimodality therapy (median PFS, 12.8 vs. 10.5 months; HR, 0.77; 95% CI, 0.62-0.96; p = 0.017), primarily resulting from a 10% absolute reduction in local-only relapse. Mortality was unexpectedly high, with pneumonectomy that may have negated a potential survival benefit. An unplanned subgroup analysis of patients treated with lobectomy and matched to the definitive radiotherapy cohort found an improved survival with lobectomy (median OS 33.6 vs. 21.7 months, 5-year OS 36 vs. 18%). The ESPATUE trial is the most modern study that included PET-staged IIIA/IIIB patients who received induction chemotherapy (cisplatin and paclitaxel × 3 cycles) and a unique preoperative chemoradiotherapy (CRT) regimen of 45 Gy in 1.5-Gy BID fractions concurrent with cisplatin/vinorelbine. At the completion of this initial therapy, patients deemed to be resectable were randomized to completion of radiotherapy (20- to 26-Gy boost delivered in daily 2-Gy fractions) or surgery. Investigators found no significant difference in survival or progression between radiotherapy or surgery, with a 5-year OS and PFS of approximately 40% and 35% in both arms, respectively.168 The improved survival in this trial may be a reflection of the routine use of PET and stage migration.

Non–Small Cell Lung Cancer

853

Collectively, these three large randomized controlled trials do not show a clear survival advantage to surgery. Broader inclusion criteria in the European trials with more advanced disease may have limited the benefit of surgery. The subgroup analysis in the Intergroup trial, however, may justify a trimodality approach in select stage IIIA patients amenable to a lobectomy. Specifically, this would include robust patients with single-station nonbulky (< 3 cm) N2 disease. When a patient is deemed a surgical candidate with N2 disease, there are currently two accepted preoperative treatment paradigms: chemotherapy or chemoradiotherapy. Nationally, practice patterns are split between these approaches.169 A clear benefit for adjuvant chemotherapy, compared with surgery alone, has been demonstrated for patients with proven nodal involvement, including N2 disease. A similar survival benefit, primarily in early-stage patients, has also been observed when chemotherapy is delivered preoperatively.170 A potential benefit of delivering chemotherapy prior to surgery is that compliance rates are significantly higher; however, in the NATCH trial, which randomized early-stage patients to adjuvant versus neoadjuvant chemotherapy, there was no clear difference in outcome.171 Several small randomized trials investigating the addition of neoadjuvant chemotherapy to surgery alone in N2 patients showed a significant improvement in survival.172,173 Several studies have specifically compared the effectiveness of induction chemotherapy versus chemoradiation. The German Lung Cancer Group conducted the largest trial to date and compared induction chemotherapy alone (cisplatin and etoposide) or chemotherapy plus concurrent radiotherapy (45 Gy BID over 3 weeks) in patients with stage IIIA/IIIB NSCLC.174 PORT was included in the induction chemotherapy arm as part of the study design, with additional radiotherapy given for positive margins. A total of 524 patients were eligible for initial treatment, but only approximately 60% went on to undergo surgery. The addition of preoperative radiotherapy significantly improved the R0 resection rate (84% vs. 77%) and mediastinal downstaging (46% vs. 29%), but it did not improve PFS (median 9.5 vs. 10 months, 5-year 16% vs. 14%), the primary endpoint of the study, or OS (median 15.7 vs. 17.6 months, 5-year 21% vs. 18%). Because postoperative radiotherapy was routinely given in the chemotherapy arm of the trial, the study essentially suggests that radiotherapy can be given in either sequence. More recently, the SAKK Lung Cancer Project Group randomized 232 patients with stage IIIA/N2 NSCLC to induction chemotherapy (cisplatin/docetaxel × 3 cycles) versus the same induction chemotherapy plus sequential RT (44 Gy in 22 fractions given over 3 weeks) followed by surgery if repeat staging did not reveal progression.175 Unlike the German trial, PORT was not mandated in the chemotherapy-alone arm and only 16% received PORT, primarily for R1 resections. The addition of preoperative radiotherapy improved the objective response rate (61% vs. 44%), increased the R0 resection rate (91% vs. 81%) and increased mediastinal downstaging (64% vs. 53%) but did not statistically improve median survival (37.1 vs. 26.2 months; HR, 1.0; 95% CI, 0.7-1.4). A criticism of the radiotherapy-alone arm was the lack of concurrent therapy, which has been shown to improve efficacy in the definitive setting. Efforts to further intensify the neoadjuvant radiation platform have been investigated. In a Phase II study, RTOG 0229 showed the feasibility of delivering 60 Gy concurrent with weekly carboplatin and paclitaxel prior to resection.176 Mediastinal clearance in this trial was 63%, with reasonable postoperative complication rates. However, some surgeons are hesitant to operate after full-dose radiotherapy owing to a potential increase in complication rates. As an alternative option, surgery could be reserved for salvage therapy in patients who otherwise have a good response but whose disease recurs locally. Retrospective series of salvage surgery after chemoradiation have reported this approach to be feasible, with promising outcomes in well-selected patients.177,178

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854

SECTION III

Disease Sites

A

B Fig. 51.11 Preoperative (A) and postoperative (B) CT scans of a patient with cT3N2 non–small cell lung cancer following induction chemotherapy, left upper lobectomy and mediastinal lymph node dissection. Note the presence of clips at the left upper lobe bronchial stump.

Superior sulcus tumors represent a unique situation owing to their location and the difficulty in achieving an R0 resection. A trimodality paradigm was investigated in this population by the prospective Phase II Intergroup Trial 0160.179 This protocol included patients with T3-T4, N0-N1 disease, with mediastinoscopy required to exclude N2 involvement. Patients were treated with induction chemotherapy (cisplatin 50 mg/ m2 days 1, 8, 29, and 36 and etoposide 50 mg/m2 days 1-5 and days 29-33) and concurrent radiotherapy to 45 Gy in 1.8-Gy daily fractions. The radiotherapy field was to include the primary disease with elective coverage of the ipsilateral supraclavicular fossa but not the mediastinum or hilum. Patients were reassessed 2 to 4 weeks after induction therapy with repeat chemotherapy and those without disease progression underwent thoracotomy. Two additional cycles of consolidation/adjuvant cisplatin and etoposide were planned. Approximately 80% of patients went on to surgery, with over 90% of these patients achieving an R0 resection. A complete response (CR) was seen in approximately one-third of patients. Median survival for the entire population and those achieving an R0 resection were 33 and 94 months, respectively.180 Median survival was not reached for the patients achieving a pathological CR. A similar approach was investigated by the JCOG in a single-arm study reporting a favorable 5-year OS of 56%.181 Although comparative evidence is lacking, retrospective and cross-study comparisons support trimodality therapy as the most effective approach compared with single or bimodality therapy.182 To summarize, the role of surgery remains controversial in N2 disease, but there is likely a subgroup that derives significant benefit from aggressive local control. Induction chemoradiation clearly increases mediastinal downstaging and R0 resection rates compared with induction chemotherapy, but randomized evidence has failed to demonstrate an improvement in treatment outcomes. When surgery is pursued, either induction strategy is appropriate. The use of PORT in patients treated with induction chemotherapy remains controversial and will be addressed in the next section. Trimodality therapy with induction chemoradiation remains the standard of care for N0-N1 superior sulcus tumors.

Postoperative Radiotherapy Locoregional recurrence following a complete resection for N2 disease is a significant risk. Reported recurrence rates vary depending on the definition applied, the stage of patients included in the study, and how local failures are reported. With the significant competing risk of distant recurrence, the true incidence of local failure is likely underestimated.

A pattern of failure analysis of completely resected N2 NSCLC treated with adjuvant chemotherapy reported an actuarial locoregional rate of 39% at 5 years.183 Areas at highest risk for locoregional recurrence include the bronchial stump (Fig. 51.11), hilum, and involved mediastinal lymph node stations. Despite this elevated locoregional risk, distant failure was the predominant pattern of first failure. This emphasizes the need for effective systemic therapy in this setting. A now historical meta-analysis of 2128 patients treated in nine randomized trials of PORT versus observation concluded that this treatment was associated with a highly significant increase in the risk of death.163 It is notable that in this meta-analysis, the increased risk of death was most significant for those patients with stage I disease and was not significant for patients with N2/stage III disease. Practice patterns have changed significantly from the time of these older studies, which included large 2D fields and fraction sizes up to 3 Gy/day without the use of chemotherapy to potentially mitigate the competing risk of distant recurrence. Subsequent analyses have suggested that cardiac toxicity with these older techniques may have contributed to the excess mortality and that modern treatment techniques appear to reduce the risk of treatment-related mortality.184-186 Unfortunately, there is no current randomized evidence that has addressed the value of PORT with modern treatment techniques. The Lung ART study, however, is an international randomized study that will specifically address the role of PORT in patients with completely resected N2 NSCLC. In the meantime, subset analyses of prospective trials and retrospective institutional and national database series provide some guidance. A review of the SEER database indicated that although survival for patients with resected NSCLC was not generally improved by the addition of PORT, it was significantly improved for patients with N2 disease (HR, 0.86; 95% CI, 0.76-0.96; p = 0.008).164 In the ANITA trial, PORT was given at the discretion of the investigators with the study randomization being the use of adjuvant chemotherapy. In a subgroup analysis, PORT was associated with a survival benefit in pN1 patients who did not receive adjuvant chemotherapy and in pN2 patients irrespective of the use of adjuvant chemotherapy.165 Most recently, a National Cancer Database (NCDB) study compared the effect of PORT in patients with N2 disease. The use of PORT resulted in a significant improvement in 5-year OS (27.8 vs. 34.1%, p < 0.001).187 Increased doses appeared to be associated with inferior outcome, however, and the authors suggested limiting PORT to a total dose to 54 Gy. Considering the known benefit of adjuvant chemotherapy in this population, this

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CHAPTER 51 treatment is administered prior to PORT if not already given preoperatively. There is not a role for the routine administration of concurrent chemoradiation postoperatively following a complete resection. RTOG 9705, a single-arm Phase II study, reported favorable outcomes compared with historical controls when carboplatin and paclitaxel were administered concurrently with PORT.188 However, a randomized ECOG trial found no improvement in outcome with the addition of concurrent chemotherapy to PORT.189 In patients with incompletely resected NSCLC, the use of PORT is clearly indicated. Although never subjected to a prospective trial, an NCDB analysis of incompletely resected stage II/III NSCLC showed a significant improvement in survival with the use of PORT.190 A historical trial found that the addition of concurrent chemotherapy to PORT improved outcomes in patients with positive resection margins or involvement of the highest sampled mediastinal lymph node.191 Another NCDB analysis specifically looked at the sequencing of PORT and CT in both completely and incompletely resected NSCLC. In completely resected N2 disease, survival was superior when the treatments were administered sequentially as opposed to concurrently (median OS 58.8 vs. 40.4 months, p < 0.001).192 For incompletely resected NSCLC, the authors did not find a significant difference between the two approaches. In summary, until the results of the Lung ART trial are available, PORT administered sequentially with modern treatment techniques appears to have value for patients with N2 disease. There is less controversy for patients with incomplete resection who should routinely be offered PORT. PORT should be sequenced sequentially with chemotherapy for most cases, but concurrent administration is a consideration for incomplete resections.

Definitive Radiotherapy for Stage IIIA/IIIB Disease The standard dose for conventionally fractionated definitive radiotherapy was established by RTOG 73-01, which randomly assigned patients into 3 treatment groups with a cumulative dose of 40, 50, or 60 Gy delivered continuously and 1 split course group of 40 Gy. In this era, radiotherapy was delivered using two-dimensional ports (anteroposterior/posterioranterior [AP/PA]) without the use of CT planning, posterior blocks were used to limit spinal cord dose, and radiographic follow-up consisted of chest radiographs. Modest improvement in 3-year survival and local control were observed in the high-dose arm, which set 60 Gy in 30 fractions as the standard dose fractionation.193 Long-term survival was rare, however, and local control was likely overestimated by the lack of 3D surveillance imaging. As radiation techniques evolved to CT-based 3D planning, it became feasible to intensify treatment via pure dose escalation or altered fractionation techniques. Various hyperfractionation and acceleration schemes using radiotherapy alone were investigated. RTOG 8311 conducted a large randomized Phases I/II study of hyperfractionated arms delivered in 1.2-Gy fractions BID with total doses of 60.0, 64.8, 69.6, 74.4, or 79.2 Gy. In stage III patients with a good performance status, there appeared to be a survival benefit when patients were treated to 69.6 Gy or above.194 This led to the Intergroup (RTOG/ECOG/SWOG) threearm randomized comparison of 60 Gy/30 fx (conventional arm), induction chemotherapy followed by conventional radiotherapy, or hyperfractionation to 69.6 Gy in 1.2-Gy BID fractions. The induction chemotherapy arm resulted in the highest survival rate,while there was no statistical difference between the conventional and hyperfractionated RT arms.195 One of the more notable altered fractionation regimens came from the Medical Research Council (MRC), defined as continuous hyperfractionated accelerated radiotherapy (CHART), which consisted of 1.5-Gy fractions given TID over 12 consecutive days to a total dose of 54 Gy. Patients with predominantly stage III (60%) NSCLC were

Non–Small Cell Lung Cancer

855

randomized to CHART versus conventional fractionation with 60 Gy in 30 fractions. Although more frequent and severe esophagitis was noted with CHART, 3-year OS was improved (20 vs. 13%) and there was a 20% relative reduction in LR. The CHARTWEL study compared a similar regimen but allowed weekends off. Compared with conventional fractionation, no survival or local control benefit was seen, but there was a trend for improved LC with hyperfractionation in the subgroup with advanced disease.196 An individual patient data meta-analysis including 2000 patients from randomized trials concluded that altered fractionation modestly improved 5-year survival by 2.5%.197 Local and distant failure remained a major issue, with 2-year rates of 50% each in both treatment groups. Another approach to intensifying treatment was by purely escalating the total dose with conventional fractionation. RTOG 9311 conducted such a study in a Phases I/II dose escalation trial using 3D conformal RT. Using a dose-adapted strategy based on the probability of lung toxicity, investigators safely escalated the dose to 83.8 Gy or 77.4 Gy in 2.15-Gy fractions in patients with V20 values of < 25% or between 25% and 36%, respectively.125 There was not an obvious dose response for LC or survival, however. Locoregional control, with events censored with distant failure, was seen in 50% to 78% at 2 years. The prolonged time to deliver the total dose (~ 8 weeks) raised concern for tumor cell repopulation. Simultaneous trials began to show benefits of integrating chemotherapy, making it clear that more than dose escalation was needed. CALGB 8433 established the benefit of induction chemotherapy prior to radiotherapy for locoregionally advanced NSCLC. This two-arm study randomized stage III NSCLC patients to conventional radiotherapy alone (60 Gy/30 fx) versus induction chemotherapy with cisplatin and vinblastine followed by the same radiotherapy regimen. The addition of induction chemotherapy significantly improved median (13.7 vs. 9.6 months) and 5-year OS (17 vs. 6%).198 The benefit of induction chemotherapy was confirmed in the previously mentioned Intergroup trial.199 Seeking to improve outcomes further, many began testing the paradigm of concurrent chemotherapy and radiotherapy compared with sequential treatment. In one of the first randomized comparisons, the West Japan Lung Cancer (WJLC) group compared sequential cisplatin, vindesine, and mitomycin with continuous radiotherapy versus the same chemotherapy concurrent with a split course of radiotherapy. Survival was significantly improved with concurrent therapy, with median survival of 16.5 versus 13.3 and 5-year OS of 16% versus 9%.200 RTOG 9410 confirmed these results with a randomized 3-arm study including the CALGB induction arm and 2 concurrent regimens: 63 Gy given in once-daily fractions over 7 weeks with cisplatin and vinblastine or 69.6 Gy given in 1.2-Gy BID fractions over 6 weeks with cisplatin and etoposide. Compared with sequential treatment, concurrent chemoradiation with once-daily conventional radiotherapy significantly improved 5-yr OS (16% versus 10%).201 There was not a statistically significant difference between the conventional or hyperfractionated chemoradiation arms. A clear benefit of concurrent over sequential chemoradiation is best illustrated in a meta-analysis by Auperin et al. Including 6 trials and approximately 1200 patients with a median follow-up of 6 years, concurrent chemotherapy resulted in an absolute OS benefit of 4.5% at 5 years (HR, 0.84; 95% CI, 0.74-0.95; p = 0.004).202 Concurrent therapy resulted in a significant reduction in local progression (5-year rate of 28.9% vs. 35%) but not in distant progression (5-year rate of 39.4% vs. 40.6%). The benefit was more pronounced in patients receiving combination chemotherapy regimens, which most often included systemically dosed cisplatin. The main disadvantage of concurrent therapy was an increase in grade 3 or 4 esophageal toxicity from 4% to 18%, with most trials in this era using elective nodal irradiation and less conformal treatment techniques.

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856

SECTION III

Disease Sites

Various concurrent chemotherapy regimens have been used, but there is little consensus on the optimal combination. In recent practice, the two more common combination regimens are cisplatin/etoposide and carboplatin/paclitaxel. A retrospective analysis using propensity score matching compared the outcomes from the two regimens of patients treated in the Veterans Health Administration (VA) database. A total of approximately 1800 patients were included in this analysis, which found increased morbidity with cisplatin and etoposide but similar survival results.203 The two concurrent combinations were directly compared in a relatively small randomized trial of approximately 200 patients, which reported a 3-year survival (41% vs. 26%) and median survival (23.3 vs. 20.7 months) in favor of cisplatin and etoposide.204 A Cochrane meta-analysis, however, came to similar conclusions as the VA study, showing no difference in overall survival.205 Cisplatin-based regimens were more often associated with nausea/vomiting and esophagitis, while carboplatin/paclitaxel was more often associated with cytopenias and pneumonitis. In general, patients with increased comorbidity better tolerate the carboplatin/paclitaxel regimen. The results of RTOG 0617, as discussed later, provide equipoise for the routine use of carboplatin/paclitaxel. Cisplatin/pemetrexed has been specifically investigated in patients with nonsquamous histology. The PROCLAIM study was a randomized comparison of concurrent and consolidation cisplatin/pemetrexed versus cisplatin/etoposide in locally advanced patients. The trial was closed early for futility after approximately 550 patients had been treated, with survival being similar between the two arms (median, 26.8 vs. 25 months; HR, 0.98; 95% CI, 0.79-1.20; p = 0.831).206 However, the cisplatin/ pemetrexed arm had a reduced incidence of any grade 3 or 4 toxicity (64% vs. 76.8%). Although clearly not superior based on the results of this trial, cisplatin or carboplatin with pemetrexed is an option for patients with nonsquamous histology. Further intensification of systemic therapy either with induction or consolidation chemotherapy was investigated in hopes of further decreasing distant failures. A randomized Phase II trial known as the Locally Advanced Multi-modality Protocol (LAMP) investigated three treatment approaches using conventionally fractionated radiotherapy: sequential induction chemotherapy with carboplatin (AUC 6) and paclitaxel (200 mg/m2) for 2 cycles followed by radiotherapy alone, the same induction chemotherapy followed by concurrent chemoradiation with carboplatin (AUC 2) and paclitaxel (45 mg/m2) administered weekly, or concurrent chemoradiation followed by 2 cycles of consolidation carboplatin and paclitaxel. The median OS times of the three arms were 13.0, 12.7, and 16.3 months, respectively.207 Although numerically different, there was no statistical difference when these were compared with a historical arm of RTOG 88-08, and all three arms had similar 3-year survival rates, ranging from 15% to 17%. CALGB 39801 randomly assigned approximately 370 patients with unresectable stage III NSCLC to induction chemotherapy or immediate concurrent chemoradiation with conventionally fractionated radiotherapy to 66 Gy (with similar dosing of carboplatin and paclitaxel as described for the LAMP study). The median survival periods for the standard and induction arms were 12 and 14 months, respectively, which was not statistically different.208 Relatively poor outcomes in both arms were attributed in part to the inclusion of patients with weight loss greater than 5%. Even after adjusting for weight loss, there was no difference in survival between arms. Distant failures were not appreciably reduced with the use of induction chemotherapy. The Southwest Oncology Group (SWOG) study S9504 investigated consolidation docetaxel following concurrent chemoradiation. In this Phase II study, median survival was promising at 26 months and consolidation chemotherapy was generally tolerable.209 In a similar design, SWOG S9712 used consolidation paclitaxel following concurrent

chemoradiation in a poor-risk population including those with borderline performance status, comorbidities or other adverse prognostic factors. Median survival in this high-risk population was 10 months, with high toxicity rates.210 The Hoosier Oncology Group (HOG LUN 01-24) conducted a Phase III trial of consolidation docetaxel following cisplatin/ etoposide chemoradiation. In this trial, all patients received cisplatin 50 mg/m2 on days 1, 8, 29, and 36 of therapy with etoposide 50 mg/ m2 given on days 1 to 5 and days 29 to 33. Radiotherapy was conventionally fractionated to a total dose of 59.4 Gy. Patients who did not progress were then randomized to observation or consolidation docetaxel (75 mg/ m2) given q3 weeks for 3 cycles. Median survival for the standard and consolidation arms was 26.1 and 24.2 months, respectively.211 These results were confirmed in a more contemporary international multicenter study in which locally advanced patients were treated with concurrent weekly cisplatin and docetaxel and randomized to observation or consolidation cisplatin/docetaxel. Median survival was nearly identical and distant metastases were not reduced with consolidation chemotherapy, still occurring in approximately 50% of patients.212 Consolidation chemotherapy has been more routinely used when carboplatin and paclitaxel are administered concurrently, with the justification being that the doses delivered during radiotherapy are not systemic. It is important to note, however, that no consolidation trial has shown a statistically significant OS benefit or reduction in distant failures, calling the routine use of consolidation carboplatin and paclitaxel into question.212,213 Radiotherapy dose escalation and altered fractionation techniques have been investigated in the setting of concurrent chemotherapy. Retrospective analyses suggested improved local control and survival with higher biologically effective doses of radiotherapy,214 setting the stage for a prospective comparison of high-dose versus standard-dose radiotherapy concurrent with chemotherapy. Cooperative group Phases I/II studies CALGB 30105,215 NCCTG N0028,216 and RTOG 0117217 demonstrated the safety and efficacy of dose escalation with concurrent chemotherapy, with 74 Gy being considered the maximum tolerated dose with conventional fractionation. RTOG 0617 randomized patients with stage III NSCLC to 60-Gy or 74-Gy radiotherapy delivered with either 3DCRT or IMRT techniques concurrent with carboplatin and paclitaxel followed by consolidation carboplatin and paclitaxel. A second randomization was introduced to additionally randomize patients to cetuximab during and following radiotherapy. Although not mandated, staging with PET was performed in 90% of patients. Patients who received high-dose CRT had an inferior outcome, with median survival of 20.3 months compared with 28.7 months for those treated with standard-dose CRT (HR, 1.38; 95% CI, 1.09-1.75; p = 0.004).218 The addition of cetuximab did not improve outcomes for the unselected population (but did benefit the subset with EGFR overexpression) and was associated with increased grade 3 or higher toxicity. The results of this trial have firmly established the dose of 60 Gy concurrent with chemotherapy as the standard. It is unclear why the higher dose was detrimental, but possible explanations were minimal use of advanced techniques to minimize heart/lung doses and the potential for tumor miss with tight margins. It is noteworthy that the median survival in the standard arm is the highest reported to date in the Phase III setting for definitive chemoradiation. This may be explained, at least in part, by stage migration with the routine use of PET. Accelerated hypofractionation with concurrent chemotherapy is under study. A prior EORTC study used a radiation regimen of 66 Gy in 2.75-Gy fractions, either concurrent with low-dose cisplatin or following induction gemcitabine and cisplatin. No significant difference in outcome was found between the arms.219 CALGB 31102 (Alliance) reported a Phase I study in which the total radiation dose remained at 60 Gy but the number of daily fractions was reduced over 4 cohorts.

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CHAPTER 51

857

Non–Small Cell Lung Cancer

Select Randomized Phase III Trials Demonstrating Incremental Improvements in the Definitive Conventionally Fractionated Platform for Stage III NSCLC

TABLE 51.6

Study

N 193

Treatment Arm

Median Survival (mo)

Actuarial Survival (%)

Statistics

RTOG 7301

93 97 91 84

40 Gy split course 40 Gy 50 Gy 60 Gy

36.8 (wk) 45.5 (wk) 41 (wk) 47.2 (wk)

6 (3-y) 6 (3-y) 10 (3-y) 15 (3-y)

NS

CALGB 8433198

77 78

60 Gy SEQ VP → 60 Gy

9.6 13.7

6 (5-y) 17 (5-y)

p = 0.01

RTOG 9410201

195 195

SEQ VP → 60 Gy 60 Gy CON VP

14.6 17.0

10 (5-y) 16 (5-y)

p = 0.05

CALGB 39801208

182 184

66 Gy CON CT CT → 66 Gy CON CT

12 14

29 (2-y) 31 (2-y)

NS

84 82

60 Gy CON PE 60 Gy CON PE → D

26.1 24.2

23.8 (5-y) 16.4 (5-y)

NS

HOG211 RTOG 0617a218

217 207

60 Gy CON CT 74 Gy CON CT

28.7 20.3

57.6 (2-y) 44.6 (2-y)

p = 0.004

PACIFIC221

473 236

54-66 Gy CON PD → Dur 54-66 Gy CON PD

NR 28.7

66.3 (2-y) 55.6 (2-y)

p = 0.005

a

Included a second randomization to cetuximab. CALGB, Cancer and Leukemia Group B; CON, concurrent; CT, carboplatin/paclitaxel; D, docetaxel; Dur, durvalumab, HOG, Hoosier Oncology Group; NR, not reach; NS, not significant; PE, cisplatin and etoposide; PD, platinum doublet; RTOG, Radiation Therapy Oncology Group; SEQ, sequential; VP, vinblastine/cisplatin.

Patients received weekly carboplatin and paclitaxel followed by consolidation chemotherapy. The maximum tolerated dose was defined as 2.5 Gy/ fraction. Whether there is an oncological advantage to accelerated hypofractionation in the setting of concurrent chemotherapy is undetermined and conventional fractionation remains the standard of care. Table 51.6 summarizes select practice-changing trials that have established the current paradigm of concurrent chemotherapy and radiotherapy. Recently, several novel approaches have been undertaken to further improve on the chemoradiation backbone. RTOG 1306 was a study designed to investigate the use of targeted agents in stage III NSCLC. In this study, patients with EGFR mutations or ALK rearrangements were planned to be randomized to either induction therapy with the appropriate molecular agent (erlotinib or crizotinib) or proceed with immediate concurrent chemoradiation. Unfortunately, this study was terminated early and the use of molecular therapy in this setting remains uncertain. The most recent paradigm change is the integration of consolidation immunotherapy. The PACIFIC study was a multicenter randomized trial investigating the addition of the anti-programmed death ligand-1 (PD-L1) antibody durvalumab for 1 year following definitive chemoradiotherapy. Patients had to receive at least 2 cycles of platinum-based chemotherapy concurrently with radiation to a dose of 54 to 66 Gy and have no evidence of disease progression at the completion of treatment. PFS, the co-primary endpoint, was significantly prolonged with durvalumab consolidation with a median PFS of 16.8 versus 5.6 months (HR, 0.52; 95% CI, 0.42-0.65; p < 0.001) and 18-month PFS of 44.2% versus 27%.220 A PFS benefit was seen irrespective of PD-L1 expression on IHC. Additional findings were a reduction in the median time to death or distant metastases (23.2 vs. 14.6 months); a higher response rate (28.4% vs. 16%), which was also more durable; and a reduction in new lesions (20.4% vs. 32.1%), including a lower incidence of brain metastases (5.5% vs. 11%). Pneumonitis or pneumonias of any grade were higher in the durvalumab arm, but grade 3 or higher

events were similar. An updated survival analysis found a significant prolongation of OS with durvalumab (HR, 0.68; 99.73% CI, 0.47-0.997; p = 0.0025), with a 24-month OS rate of 66.3% in the durvalumab group compared with 55.6% in the placebo group.221 Multiple studies are underway further investigating this platform, including a Phase III study similar to the PACIFIC study only investigating consolidation nivolumab (NCT02768558) and the Phase II NICOLAS study investigating nivolumab concurrent with definitive chemoradiation (NCT02434081). While the use of concurrent chemotherapy and radiotherapy is standard of care for most, studies establishing this regimen typically have included medically fit patients younger than 70 years old. The safety of these regimens in medically frail or elderly patients is less clear. A Japanese cooperative group study (JCOG 0301) addressed the value of single-agent carboplatin concurrent with standard radiotherapy in elderly (age > 70 years) patients with unresectable stage III NSCLC. OS, the primary endpoint of the study, was significantly improved with the addition of carboplatin (median OS, 22.4 vs. 16.9 months; HR, 0.68; 95% CI, 0.47-0.98; p = 0.02). However, this was at the expense of increased grade 3 or 4 hematological toxicity. A pooled analysis of patients treated with concurrent chemoradiation on US National Cancer Institute cooperative group studies found that elderly patients experienced similar PFS to younger patients but worse OS and grades 3 to 5 adverse events.222 Concurrent chemoradiation should not necessarily be withheld in fit elderly patients given the survival advantage over sequential therapy. In fact, patients 70 years old or older appeared to derive the greatest advantage from concurrent therapy in the RTOG 9410 study.223 That said, a cautious approach may be warranted for higher-risk patients in this population for whom sequential therapy may be a reasonable alternative. CALGB 30605 (Alliance)/RTOG 0972 (NRG) conducted a Phase II trial in stage III patients with poor performance status and/ or weight loss using sequential carboplatin/nab-paclitaxel followed by

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858

SECTION III

Disease Sites

thoracic radiation concurrent with erlotinib. The median and 1-year OS were 17 months and 57%, with the latter being below the prespecified target for significance.224 Various hypofractionated radiotherapy regimens have been reported for stage III patients who are unfit for concurrent chemotherapy. Patients with stages II to IV or recurrent NSCLC with an ECOG performance status (PS) of 2 or greater and who were ineligble for surgery, SBRT, or concurrent chemoradiation were enrolled on a prospective dose escalation trial of high conformal hypofractionated radiotherapy. Radiotherapy dose was escalated to 60 Gy in 15 fractions and was generally well tolerated.225 A multi-institutional study is comparing this hypofractionated regimen to conventional fractionation in poor performance status stages II and III patients not receiving chemotherapy. Interim results as reported at ASTRO 2016 found no difference in OS or PFS, with lower grade 3 toxicity with hypofractionation.226

RADIOTHERAPY TREATMENT PLANNING AND TECHNIQUES The goal of radiotherapy planning is to ensure optimal coverage of the primary tumor, pathologically involved lymph nodes, and associated target volume expansions, while minimizing radiation exposure of surrounding normal tissues including the esophagus, heart, spinal cord, lung, chest wall, and skin. Currently, the standard planning and treatment approach is either 3DCRT or IMRT using multiple beam arrangements. Recently, radiation dose to the heart has joined (or even surpassed) the dose to the lung and spinal cord in the importance of planning priorities impacting acute and late toxicities and survival.

Positioning and Immobilization Patients are generally positioned supine during treatment, with the torso supported and immobilized using custom devices such as an Alpha Cradle (Smithers Medical Products, North Canton, OH) or Vac-Lok bag (CIVCO Radiotherapy, Orange City, IA) or using adjustable standard immobilization such, as a wing board. Positioning the arms above the head allows for more freedom in selecting lateral or oblique beam angles or even full or partial arcs. Care must be taken to allow the arms to fit in the gantry (typically, 70 or 80 cm) of CT scanners used for radiation planning image acquisition.

Respiratory Motion Management Given the impact of respiratory motion on lung cancers, respiratory motion assessment is critical for the precise delineation of gross disease. By customizing the assessment for the patient, dose to non-target tissue can also be significantly reduced as can late cardiac, pulmonary, and esophageal toxicities.227 Formal motion assessment should be done for all curative lung cancer cases, including SBRT for early-stage disease and definitive or postoperative therapy in advanced disease. This can be accomplished a number of different ways, including fluoroscopy, a four-dimensional CT (4DCT) scan, or use of inspiratory and expiratory CT scans. The historical and least precise method was to apply the same population-wide margin to account for respiratory motion in all patients. However, significant heterogeneity in tumor motion between patients exists owing to variable tumor position (i.e., upper vs. lower lobe, proximity to diaphragm, invasion of adjacent structures) and patient factors, including comorbid disease. A population-derived margin, therefore, overestimates respiratory motion for most patients and underestimates it for others. In this section, we will highlight the individual techniques to both assess and manage respiratory motion. 4DCT is a common technique in which patients are instructed to breathe in a free and regular manner. Breathing signal is typically recorded indirectly using a belt or reflective marker placed over the abdomen while the CT acquires multiple slices at each table position. Each

individual slice is tagged to a specific phase of the respiratory cycle. This effectively results in volumetric CT datasets for each phase of the respiratory cycle.228 At the time of simulation, these datasets can be reconstructed to visualize the extent of target volume motion and a determination is made regarding whether additional respiratory motion management is needed. Our standard practice is to use the 4DCT to first assess respiratory tumor motion. If tumor motion is less than or equal to 1 cm, then no management is undertaken outside of incorporation of this information into target volume delineation. If tumor motion exceeds 1 cm, then respiratory motion management is considered. Several options are available to incorporate the respiratory assessment information into treatment planning. When deciding to treat the patient in free-breathing, the entire 4DCT dataset, including the individual respiratory phases, should be included in the treatment planning process. Although contouring on each individual CT is possible, this is often too laborious. An alternative technique is to generate composite images, including maximum intensity projection (MIP) and average intensity projection (AIP) datasets. The MIP dataset displays the maximum intensity of any given voxel throughout the entire respiratory cycle.229 For a CT dense lung tumor surrounded by air, the MIP easily identifies tumor location during respiration. This volume can be contoured and is often referred to as the internal gross target volume (IGTV). For tumors and normal tissues in the mediastinum, similar CT densities limit the usefulness of MIP in this location. In contrast to the MIP, the AIP incorporates the average intensity into every voxel. This is more useful in organs with less respiratory motion and this dataset can be used for OAR delineation and treatment planning/dose calculation. Alternatively, the free-breathing dataset can be used for this purpose. When significant target motion is identified on the initial 4DCT, efforts to manage respiratory motion include breath-hold techniques, real-time tumor tracking, or respiratory gating. Breath-hold can be voluntary, with coaching from the radiation therapist to maintain a consistent and reproducible threshold. There is, however, some uncertainty in achieving this threshold precisely throughout treatment. Active breathing control (ABC) is a system that directly monitors the respiratory cycle and involuntarily triggers a breath-hold. ABC includes a mouthpiece and nose clamp to effectively seal the system and enhance the ability to attain a threshold reproducibly. While useful for many patients, some patients are not able to tolerate the system. Alternative respiratory motion management techniques allowing patients to breathe freely are respiratory phase gating, abdominal compression, and fiducial tracking. For phase gating, typically, the end expiratory phases are selected for treatment planning and treatment delivery as intrathoracic structures are most stable during this phase. The respiratory motion assessment software is integrated into the treatment delivery console such that the beam is only on during the selected phases. Abdominal compression uses a paddle-shaped device that is applied just below the xiphoid process. The paddle is lowered to a level that is just tolerable to the patient, increasing intraabdominal pressure in order to blunt diaphragmatic motion. The paddle size and compression level is recorded for subsequent treatment visits. Real-time tumor tracking is an option on certain machines that requires the placement of a fiducial marker. This marker can be tracked with fluoroscopy as a surrogate for tumor position. This can either facilitate gating with a static gantry or even real-time treatment adjustments with a robotic gantry, such as the CyberKnife (Accuray; Sunnyvale, CA).

Definition of Target Volumes The International Commission on Radiation Units and Measurements (ICRU) specifies a series of target volumes that can be generated in a stepwise fashion. The gross tumor volume (GTV) represents the macroscopic tumor visible on imaging, including CT and PET. For the

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CHAPTER 51 primary lung tumor, CT window-leveling to either a preset “lung window” or manual adjustment (window, 850-1600; level, 650-750) facilitates identification of GTV borders in the lung parenchyma. CT volumes are good representations for the true extent of the tumor as there is good pathological correlation of surgical specimens and preoperative CT, with slight overestimation of the true pathological tumor area by CT noted in at least one study.230 A caveat to this, however, is that older CT techniques had slower acquisition times, which could lead to motion artifact and elongation of the volume. IV contrast can enhance the delineation of both nodal and primary tumor volumes, especially in central areas near the pulmonary vasculature. PET may be useful in localizing primary disease, especially when atelectasis obscures the tumor borders. RTOG 0515, a prospective single-arm effort to integrate PET into radiation treatment planning for stages II/III NSCLC, found a significant reduction in the size of the primary GTV when delineated with integrated PET-CT compared with CT alone.231 Reduction in target volumes also led to more favorable dose volume histogram (DVH) parameters. This study will be discussed in further detail with regard to implications of PET on elective nodal coverage. Owing to the spatial uncertainty with PET, it is important to not base tumor volumes entirely on PET but rather to use the metabolic information to guide volumes on CT. Following the identification of the GTV and IGTV, the next important concept of treatment planning is identification of the clinical target volume (CTV) to address microscopic extension of the tumor and potentially occult disease in lymph nodes that are not visible on routine imaging modalities. Microscopic extension (ME) can take several forms in the primary tumor, including aerogenous dissemination, direct parietoalveolar extension, invasion into the pulmonary interstitium, and lymphovascular invasion. Pathological correlate studies have been conducted to quantify the necessary CTV. Giraud et al. determined that the average distance of ME in adenocarcinoma and squamous cell carcinomas was 2.7 and 1.5 mm, respectively.232 Significant heterogeneity was noted, however; in order to account for 95% of all samples, a margin of 8 and 6 mm would be necessary for adenocarcinoma and squamous cell carcinoma, respectively (Fig. 51.12). A more recent report using PET defined a group at low risk for ME based on smaller tumor size and CT density, suggesting that the CTV may be unnecessary for some patients.233 This supports the practice of not using a CTV for SBRT/HIGRT in early-stage patients, although additional factors such as precise image guidance coupled with potent biologically effective doses at the margin also provide rationale for omitting this expansion. Contemporary treatment protocols for stages II/III NSCLC recommend a CTV margin ranging from 5 to 10 mm. There is insufficient clinical evidence in early-stage or advanced-stage NSCLC, however, to validate an optimal primary tumor CTV in terms of tumor control. For pathologically involved lymph nodes, extracapsular extension (ECE) may be present, especially for larger nodes. Yuan et al. found ECE in one-third of pathologically involved nodes and that a margin of 3 mm would incorporate 95% of cases.234 Bulky nodes (> 2-3 cm) may have more extensive ECE, requiring a larger margin (5-10 mm). In the modern era, the current standard is to treat only involved nodes without intentional elective nodal irradiation (ENI). Prior to PET, radiographic size criteria (typically > 1 cm short axis) was used to select involved lymph nodes. Additional radiographic features that suggest malignant involvement include loss of a fatty hilum, enhancement, and central necrosis. Rosenzweig et al. retrospectively reviewed their experience of involved-node irradiation based on radiographic and pathological criteria. Elective nodal failure (ENF), defined as recurrence in an initially uninvolved node in the absence of local failure, was reported as approximately 8% at 2 years.235 The 2-year LC was 50%, however, which likely underestimated the true incidence of ENF.

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% 100 95% 90 91% 80 70 60

ADC

50

SCC

40 30 20 10 0

0

1

2

3

4

5

6 7 8 9 10 11 12 13 ME (mm) Fig. 51.12 Cumulative distribution of microscopic extension (ME) in the adenocarcinoma (ADC) and in the squamous cell carcinoma (SCC) groups. (From Giraud P, Larrouy A, Milleron, et al. Evaluation of microscopic tumor extension in non–small-cell lung cancer for three-dimensional conformal radiotherapy planning. Int J Radiat Oncol Biol Phys. 2000;48(4):1015-1024.)

Similarly, in the pre-PET era, there was a randomized trial assessing the role of ENI in locoregionally advanced NSCLC patients. In this study, patients were randomized 1 : 1 to 1 of 2 target volumes: an involved-field arm, including the primary tumor and only nodes measuring greater than or equal to 1 cm in short axis or an ENI arm, including the primary tumor, ipsilateral hilum, and mediastinum spanning from the clavicular head to 5 to 8 cm below the carina. The involved-field arm was treated in a single phase to 68-74 Gy, where the ENI arm was treated initially to 44 Gy, then patients were rescanned and residual disease boosted to 60-64 Gy. Radiotherapy was concurrent with cisplatin-based chemotherapy after two cycles of induction chemotherapy. Local control, the primary endpoint of the study, was improved with dose-escalated, involved-field radiotherapy (5-year LC, 36% vs. 51%).236 Although what classified as elective nodal progression was not described, this was reported at 4% in the ENI arm and 7% in the involved-field arm. Higher rates of pneumonitis and other toxicities were noted with ENI. The difference in dose between arms limits the conclusions from this study but overall supports the concept of omitting ENI. With the potential staging benefits of PET/CT in identifying occult mediastinal involvement, PET/CT became incorporated into radiotherapy treatment planning. As mentioned previously, RTOG 0515 assessed the role of PET-directed radiotherapy planning for locoregionally advanced NSCLC. In this study, only the primary tumor and lymph nodes measuring greater than 1 cm in short axis diameter or PET avid nodes were irradiated. A specific SUV threshold was not used; rather, nodes with increased FDG uptake relative to mediastinal background were identified as GTV. While patients were treated based on PET/CT planning, target volumes were independently drawn on the CT only for comparative purposes. In terms of nodal coverage, there was only 50% agreement between the use of CT only and PET/CT-defined nodal stations. Most of this disagreement was limited to one or two stations, however. One nodal progression (2% of analyzed patients) was reported in a nontargeted lymph node, although it was unclear whether patients were censored for simultaneous locoregional or distant recurrences and median follow-up was relatively short at 13 months. Subsequent RTOG protocols have not allowed ENI. While PET/CT has improved the ability to discriminate involved lymph nodes, the inclusion of only PET-avid nodes has limitations as well. Occult nodal involvement is still possible despite a negative PET and this risk likely increases in nodes that are immediately adjacent to

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radiographically involved nodes. Selective inclusion of adjacent lymph nodes and/or stations may be appropriate in certain clinical situations, especially when more conformal treatment techniques can limit toxicity. The final step in target volume delineation is the planning target volume (PTV), a reflection of organ motion and setup uncertainty. While respiratory motion assessment and management largely accounts for the former, a small amount of unaccounted for residual motion may still be present. Rigid immobilization can help reduce interfraction isocenter deviation,237 but the most important factor in reducing setup uncertainty is the routine use of image-guided radiotherapy (IGRT) with on-board imaging devices. The use of daily IGRT allows for the smallest possible setup margin and is commonly accomplished with either orthogonal kV planar imaging or cone beam CT (CBCT). The biggest advantage of orthogonal kV imaging is rapid image acquisition and interpretation, which is most important for patients undergoing conventionally fractionated therapy. Two approaches for orthogonal kV matching are to either use osseous landmarks (vertebral bodies/ spine) or the trachea/carina as surrogates for the location of thoracic disease. Alternatively, CBCT allows for direct soft-tissue matching to the GTV. The choice of spine versus carina matching in part depends on the location/distribution of disease and its proximity to OARs. When the tumor is in close proximity to the spinal canal, vertebral body imaging would be preferred. A proximal tumor with adjacent paratracheal adenopathy would be well suited for carinal matching. One study compared to two approaches using CBCT soft-tissue matching as the reference throughout an entire course of treatment for patients with locally advanced NSCLC. Compared to vertebral body matching, carina matching reduced greater than 5 mm displacements for both the primary tumor and lymph nodes.238 CBCT allows for direct soft-tissue matching to the target, which results in the most accurate positioning. The logistical drawbacks of CBCT are a longer acquisition time and the more complex interpretation of volumetric data, potentially requiring the presence of the physician to interpret and appropriately match the images. When treating multiple targets, such as a primary tumor and lymph nodes, an optimal CBCT match can be challenging as the primary tumor and lymph nodes can be displaced independently. At a minimum, weekly CBCT for locally advanced patients as a supplement to daily kV image guidance can identify structural thoracic changes (i.e., pleural effusions, atelectasis, tumor displacement outside the PTV, and significant tumor volume reduction) that can inform modifications to the treatment plan (Fig. 51.13).239 The authors recommend a setup margin of 5 mm when

A

daily IGRT is used for locally advanced cases. In precise treatments such as SBRT/HIGRT, in which CBCT matching prior to treatment is the essential component in localization, the PTV margins are typically 3 to 5 mm. The clinical value of respiratory motion assessment/management and IGRT has been investigated in several studies. Shumway et al. compared their experience using advanced treatment planning techniques with standard practice in the setting of trimodality therapy, in which the dose and chemotherapy regimen were relatively constant. They found higher rates of mediastinal downstaging and pathological CR rates in patients treated with advanced planning techniques (i.e., 4DCT and IGRT).240 In another retrospective study, the use of IGRT resulted in a significant reduction in locoregional recurrence compared with non-IGRT treatment.241 The use of respiratory gating was specifically compared to standard planning techniques in a randomized clinical trial. The use of gating significantly increased lung volume and decreased the mean lung dose, lung V20, and need for subsequent hospitalizations.227 Therefore, evidence supports efforts to employ these advanced planning techniques to not only minimize geographic miss but also to reduce normal tissue toxicity.

Individualized Radiation Dosing An experimental approach to treatment is adaptive therapy, in which the prescription dose is tailored to the patient’s response. RTOG 1106/ ACRIN 6697 is a randomized Phase II trial of individualized adaptive radiotherapy using during-treatment FDG-PET. In this study, both arms get a PET/CT scan between fractions 18 and 19, but only the experimental arm is resimulated and subsequent treatment is adapted based on the response, including the potential to boost to a total dose of 80.4 Gy if dosimetric criteria are met. A subset of this study will also investigate the utility of 18F-fluoromisonidazole (FMISO)-PET in detecting tumor hypoxia.

Treatment Planning Techniques Radiotherapy delivery has evolved considerably over the past several decades from simple 2D portals to advanced 3D conformal techniques, including intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). While no randomized trials have been conducted between 3DCRT and IMRT for NSCLC, a secondary analysis of RTOG 0617 provides some insight into the benefit of IMRT. In this study, 3DCRT and IMRT were allowed in both the standard and doseescalated arms and were nearly evenly distributed. Despite the IMRT

B Fig. 51.13 Pretreatment planning computed tomography (A) and midtreatment cone beam computed tomography after 36 Gy (B) showing regression of the primary lung mass. Magenta line represents the primary tumor internal target volume.

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CHAPTER 51 subgroup consisting of larger and more advanced tumors, these patients had lower V20 values and heart dose metrics and had significantly lower rates of grade 3 or higher pneumonitis.242 Therefore, we advocate for the routine use of IMRT to reduce the potential for normal tissue toxicity. Proton therapy has a unique physical property, known as the Bragg peak, in which particles deposit maximal energy at a defined depth with minimal exit dose. Considering the proximity of important normal tissues in the mediastinum, proton therapy is under investigation to potentially improve the therapeutic ratio of thoracic radiotherapy. The two basic modes of proton delivery are passive scattering proton therapy (PSPT), which is delivered analogous to 3DCT, and pencil beam scanning (PBS), which can be optimized for intensity-modulated proton therapy (IMPT).243 While IMPT often results in superior dose distributions, its application has been limited to cases with strict respiratory management owing to the range uncertainty of protons, which is further complicated by organ motion. Promising Phase II data using PSPT concurrent with chemotherapy resulted in favorable clinical outcomes and toxicity compared with historical controls.244 A subsequent randomized trial in patients with inoperable stages IIB-IIIB NSCLC compared PSPT versus photon IMRT with co-primary endpoints of grade 3 or greater pneumonitis and local failure. No significant difference was found between the two treatment techniques in terms of the primary endpoints, although heart dosimetry was improved with PSPT.245 Larger studies are needed to clarify the role of proton therapy in NSCLC. RTOG 1308, a Phase III trial comparing proton beam to photon beam radiotherapy in the context of concurrent chemotherapy for locally advanced NSCLC (NCT01993810) is currently recruiting. The primary endpoint is overall survival with an estimated enrollment of 560 patients.

Toxicity of Thoracic Radiotherapy Treatment of patients with aggressive multimodality therapy exposes them to potential acute and late toxicity. Several of these toxicities have been well characterized and dosimetric criteria developed in an effort to reduce the normal-tissue complication probability (NTCP). Radiation esophagitis (RE) is one of the most common and challenging acute toxicities encountered by patients with proximal tumors and/or mediastinal disease. The pathogenesis relates to denudation of the esophageal mucosa with the clinical manifestation being pain and/ or difficulty with swallowing. This can progress to a degree that patients are unable to tolerate swallowing and require a feeding tube for support. As the esophagus is a serial organ, damage to any part can result in symptoms. The risk and severity of RE is a function of dose/volume parameters, the use of accelerated fractionation, and concurrent chemotherapy.246, 247 Palma et al. performed an individual patient data meta-analysis in patients treated with concurrent chemoradiation to identify predictors for RE. Grade 2 or higher RE was common, occurring in 50% of patients, but no RE-related deaths were observed.248 On multivariable analysis, the esophageal volume receiving greater than or equal to 60 Gy (V60) was the best predictor of grade 3 or higher RE. The risk was highest in patients with a V60 greater than or equal to 17%; thus, efforts to minimize V60 are warranted. Conformal therapy with IMRT can allow for significant esophageal sparing, with one study showing a reduction of the average V60 from 21% with 3DCRT to 6.5% with IMRT in patients planned with both techniques.249 The use of conformal therapy to avoid high-dose circumferential irradiation of the esophagus also appears to be important in reducing severe RE.250 The management of RE consists of supportive care, including dietary modification (soft, bland foods with neutral temperatures); antisecretory therapy (proton pump inhibitor); use of topical analgesics, such as lidocaine; and systemic narcotics. Patients should be followed closely to maintain stable weight and address pain management. Treatment

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breaks should be avoided if at all possible owing to the established reduction in survival when treatment time is prolonged.251 Efforts to prevent or reduce RE with the radioprotector amifostine or with alternative agents such as Manuka honey have failed to show benefit in randomized controlled trials.252, 253 While most patients will have resolution of esophagitis 2 to 3 weeks following treatment, some patients can develop late esophageal toxicity, including esophageal strictures or, rarely, ulceration/fistula. Radiation pneumonitis (RP) is another well-established complication of treatment but is more often subacute, typically occurring between 1 to 6 months after radiotherapy is completed. The pathogenesis for RP is multifactorial, with both direct pulmonary cytotoxicity and indirect aberrant cell signaling and cytokine release being implicated. The disease exists on a spectrum from more acute lung injury to a chronic fibrotic reaction. The clinical presentation most commonly consists of a chronic nonproductive cough, dyspnea, and/or low-grade fever. In rare cases, the impact on breathing can be severe enough to result in fatal reactions. RP is a clinical diagnosis and one of exclusion, for which no single test is necessarily sensitive or specific. Patients with NSCLC often have coexisting COPD and may experience COPD exacerbations mimicking RP. Progressive tumor-related symptoms, including obstruction or the development of pleural effusion, can also lead to similar symptoms, while postobstructive pneumonia may be differentiated by a higher fever or productive/purulent cough. Workup typically includes a chest CT scan, preferably a pulmonary angiogram study to also rule out pulmonary embolism. The use of CT is primarily to exclude other etiologies, including tumor progression and PE. While ground-glass opacities corresponding to the treatment field align with a diagnosis of RP, they are not required to make the diagnosis. The most important modifiable risk factors for RP are the radiation dose and volume of lung irradiated, with lung V20 (volume of lung receiving 20 Gy or more) and mean lung dose (MLD) being validated in early studies.254 Consistency in lung volumes is important for reporting purposes, with the preferred method being total lung volume minus GTV. In one of the most comprehensive analyses, a multi-institutional individual patient data meta-analysis investigated dosimetric predictors for RP in patients treated with concurrent chemoradiation. This study reported symptomatic RP in 30% of treated patients, with fatal RP reported in 2%.255 The most important predictors for RP included V20, older age, and carboplatin/paclitaxel chemotherapy. It is unclear how much carboplatin/paclitaxel contributes to lung toxicity, as patients who tend to receive this combination are often more frail and may have more advanced baseline lung impairment. It is important to note that there is no safe threshold that prevents RP; rather, the risk for both symptomatic and fatal RP is continuous with increasing V20 parameters. V20 as a continuous variable was also validated in a subgroup analysis of RTOG 0617.242 In this analysis, treatment with IMRT was associated with a significantly lower risk of RP despite having a higher V5, which had been associated with RP in prior studies. Thus, the goal for radiation treatment planning is to achieve the lowest V20 and mean lung dose possible, while V5 does not appear to be a critical variable. Commonly cited metrics include a V20 less than 35% and MLD less than 20 Gy, but lower doses are often achievable with modern treatment planning strategies. When these metrics are high despite optimal conformal therapy, options for further reductions are to include respiratory motion management if not already addressed, decreasing margins or even potentially induction chemotherapy. Patients with interstitial lung disease (ILD) should be treated with caution, as higher rates of symptomatic and fatal pneumonitis have been reported in this patient population.256 Management of patients with moderate to severe RP includes supportive care and the use of oral corticosteroids, such as prednisone.

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Prednisone doses are typically initiated at 50 to 60 mg/day and gradually tapered depending on response. Supplemental oxygen is indicated in the hypoxic patient, with hospital admission indicated for severe cases. The development of late cardiac toxicity has been increasingly recognized in NSCLC. Cardiac toxicity encompasses a variety of adverse events, including ischemic heart disease/acute coronary events, heart failure, valvular dysfunction, arrhythmias, and pericardial effusions. RTOG 0617 showed a continuous negative association between the heart dose metrics V5 and V30 with OS.218 Subsequent analyses have sought to further characterize the dose-volume relationships with cardiac toxicity, with two studies finding baseline cardiac risk factors and a mean heart dose to be predictive of events.257,258 The heart is a complex organ with compartmentalized functions; thus, mean heart dose and dose-volume metrics of the whole heart may not entirely inform specific toxicities. One analysis specifically looked at dose-volume parameters for heart subvolumes and their association with three different types of cardiac toxicity: arrhythmias, ischemia events, and pericardial toxicity. While whole-heart V30 correlated with all three toxicities, left and right atrial V30 correlated with pericardial events and arrhythmias while left ventricle V30 correlated with ischemic toxicity.259 Although further study is needed to better characterize cardiac toxicity, conformal therapy to minimize heart V30 is indicated. Secondary prevention of cardiac events should be pursued, including smoking cessation, control of blood pressure/cholesterol, and routine exercise. The authors’ recommended dose-volume constraints for conventionally fractionated thoracic radiotherapy are listed in Table 51.7.

SYSTEMIC AND LOCAL MANAGEMENT OF METASTATIC DISEASE Approximately 60% of patients with NSCLC present with metastatic disease.1 Although long-term survival is rare in this population, updated staging reflects a cohort of limited metastatic patients with M1a disease having a 5-year survival of 10%.260 Furthermore, the menu of standard systemic therapies has been transformed by identifying and treating actionable driver mutations and integrating agents augmenting the immune system’s response. Finally, for patients with limited metastases or limited metastatic progression on systemic therapy, advanced radiation planning and delivery techniques allow for the treatment of all known and/or progressing disease. Goals of treatment for patients with metastatic disease are to prolong survival, alleviate disease-related symptoms, and maintain or improve quality of life while limiting treatment toxicity. The optimal patientcentered treatment approach takes into account a number of factors— including age, performance status, comorbidity, symptom burden, molecular analysis of tumor biopsies, number and location of metastases, and the goals and expectations of the patient and the family. With any approach, early implementation of formal palliative care management is important as it not only improves quality of life but also extends quantity of life in patients with advanced NSCLC.261

Systemic Therapy The systemic approach to NSCLC requires careful analysis of the biopsy specimen to determine the presence or absence of actionable mutations and/or immune markers to determine the optimal treatment paradigm (Table 51.8). If the biopsy is adequate, NSCLC specimens can be assessed for PD-L1 status considering the known survival benefit of patients with a PD-L1 expression greater than or equal to 50% treated with single-agent immunotherapy.262 For nonsquamous histologies, genotyping for oncogenic driver mutations, including at least ALK and ROS1 gene rearrangements and EGFR and BRAF V600E mutations, should also be assessed. Matching targeted therapies with the appropriate driver

Authors’ Recommended Thoracic Dose-Volume Constraints for Conventionally Fractionated Radiotherapy

TABLE 51.7

Organ

DVH Metric

Clinical Endpoint

Spinal cord

Max point dose ≤ 50 Gy

Myelopathy

Lung

V20 ≤ 35%, mean dose ≤ 20 Gy

Pneumonitis

Heart

V30 < 50%

Cardiovascular toxicity

Esophagus

V60 < 17%

Esophagitis

Brachial plexus

Max dose ≤ 66 Gy

Brachial plexopathy

Common Actionable Mutations and Their Corresponding Drugsa

TABLE 51.8 Mutation

Drug(s)

EGFR

Osimertinib, erlotinib, afatinib, gefitinib

EML4-ALK

Alectinib, ceritinib, crizotinib, brigatinib

ROS1

Crizotinib, ceritinib

BRAF V600E

Dabrafenib/trametinib

a

Bold lettering denotes the preferred first-line therapy when multiple agents are indicated.

mutation generally prolongs survival in the metastatic setting.263 This can be comprehensively assessed with next-generation sequencing, often using less tissue than single-gene assays. For other rare targetable mutations, a number of clinical investigations—including the NCI-Match trial (NCT02465060)—are assessing the response of tumors to novel targeted therapies, which will facilitate the investigation in small subsets of patients. The use of frontline immunotherapy in previously untreated metastatic NSCLC was established by the KEYNOTE 024 clinical trial in which patients with PD-L1 high expressing tumors (≥ 50%) without an EGFR mutation or ALK rearrangement were randomized to receive either single-agent pembrolizumab or standard cytotoxic chemotherapy. Patients receiving frontline immunotherapy demonstrated significant improvement in both PFS (median, 10.3 vs. 6.7 months) as well as OS (median note reached; HR, 0.60; 95% CI, 0.41-0.89; p = 0.005) and showed a superior objective response rate (ORR) of 45%.262 Importantly, long-term follow-up from this study confirmed durable survival with a median OS of over 30 months with pembrolizumab compared to 14.2 months with chemotherapy.264 A similar trial conducted with nivolumab was negative, but this was likely a result of a lower PD-L1 threshold.265 Although severe adverse reactions occur less compared with cytotoxic chemotherapy, unique adverse reactions have been reported with immunotherapy. These immune-related adverse events include dermatological changes, colitis, hepatotoxicity, pneumonitis, and endocrinopathies. While some adverse reactions resolve with discontinuation of immunotherapy and/or corticosteroids, they can be permanent. How radiotherapy interacts with these effects is largely unknown. Regardless of PD-L1 status, patients with metastatic nonsquamous NSCLC benefit from frontline immunotherapy in combination with cytotoxic chemotherapy. This was confirmed in the large Phase III clinical trial KEYNOTE 189 of platinum and pemetrexed chemotherapy with or without pembrolizumab, which resulted in an improvement in 1-year OS (69% vs. 49%) and a 4-month increase in median PFS.266 Notably, improved clinical outcomes were seen in all PD-L1 subgroups in this

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CHAPTER 51 study. Similarly, the IMpower150 clinical trial showed improved median PFS (8.3 vs. 6.8 months) and OS (19.2 vs. 14.7 months) with the addition of atezolizumab to combination bevacizumab, platinum, and paclitaxel in treatment-naïve nonsquamous NSCLC.267 Interestingly, patients with refractory EGFR and ALK mutations were included and also benefited from the combination therapy. Similar clinical trials are currently ongoing with combination chemotherapy and immunotherapy, including patients with squamous histology. KEYNOTE 407 and IMpower131 are investigating the addition of immunotherapy to cytotoxic chemotherapy in metastatic squamous NSCLC, with early results presented at ASCO 2018 suggesting a PFS benefit in both trials across all PD-L1 subgroups.268, 269 Lastly, tumor mutational burden has become an increasingly recognized predictive biomarker for immunotherapy. In a prespecified analysis of the Checkmate 227 Phase III clinical trial, nivolumab and ipilimumab improved PFS and OS compared with chemotherapy alone in patients with high tumor mutational burden (≥ 10 mutations per megabase) irrespective of PD-L1 status.270 The response rate for patients receiving doublet immunotherapy in this study was 45% compared with 27% with chemotherapy alone. Historically, in unselected patients with NSCLC, the addition of cytotoxic chemotherapy to supportive care improved survival, with an approximate 10% absolute improvement at 1 year.271 While meaningful survival benefits can be achieved with single-agent therapy, the combination of two chemotherapy agents doubles response rates and further improves survival.272 Platinum-containing doublets (i.e., cisplatin or carboplatin) are preferred, but whether one is superior to the other is controversial and the choice of therapy must take into account patient age and comorbidity.272,273 Options for a second agent include paclitaxel, docetaxel, etoposide, vinorelbine, gemcitabine, or pemetrexed. The choice of this agent is influenced by histology, with cisplatin-pemetrexed showing improved efficacy in nonsquamous NSCLC compared with cisplatin-gemcitabine.274,275 The addition of a third cytotoxic agent does not consistently improve survival at the expense of additional toxicity. Integration of bevacizumab for patients with nonsquamous histology—a monoclonal antibody to vascular endothelial growth factor (VEGF)—improved ORR, PFS, and median OS (12.3 vs. 10.3 months) in the ECOG 4599 clinical trial when used with initial combination carboplatin and paclitaxel followed by maintenance bevacizumab compared with the cytotoxic combination alone.276 Cytotoxic chemotherapy is typically administered for 4 to 6 cycles. In those with nonsquamous histology and responsive or stable disease, maintenance therapy with pemetrexed or bevacizumab is often considered. This paradigm is changing based on the immunotherapy data; however, the existing data in the context of cytotoxic chemotherapy is as follows. The addition of pemetrexed maintenance appears to modestly prolong both PFS and OS: median survival was extended approximately 3 months.277,278 Trials adding bevacizumab to doublet therapy have typically included bevacizumab as maintenance. In the PointBreak trial, maintenance bevacizumab following carboplatin and paclitaxel resulted in similar OS compared with maintenance bevacizumab and pemetrexed following initial treatment with this combination and carboplatin.279 In the AVAPERL trial, the addition of maintenance pemetrexed to bevacizumab doubled PFS compared with bevacizumab alone, with a trend toward improved OS.280 An ongoing ECOG trial is comparing three maintenance strategies: pemetrexed alone, bevacizumab alone, and the combination of the two. The role of maintenance therapy is less clear in squamous histology and it is not routinely recommended. A criticism of the maintenance trials are the low crossover rates in the placebo arms; thus, close observation with early salvage may be a reasonable strategy. In patients with limited metastatic disease, another alternative to maintenance chemotherapy is radiotherapy to known

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sites of disease. This is detailed further in the oligometastases section that follows. In patients who progress following cytotoxic chemotherapy, the PD-1 antibodies nivolumab and pembrolizumab and the PD-L1 antibody atezolizumab have prolonged survival with less adverse effects in comparison with single-agent docetaxel.281-283 The KEYNOTE 010 trial found a median survival of 10.4 to 12.7 months in 2 dose cohorts of pembrolizumab compared with 8.5 months with docetaxel alone in patients with PD-L1 expression greater than or equal to 1%. There was no PFS benefit in the overall population. When including patients with PD-L1 expression greater than or equal to 50%, PFS was increased modestly (4 vs. 5 months) but a more significant difference in OS was noted (median, 14.9-17.3 vs. 8.2 months). Another key observation was the “tail” seen in the PFS and OS curves, indicating durable responses in a subset of patients. Grades 3 to 5 toxicity was halved with the use of immunotherapy compared with docetaxel. Similar observations were seen with nivolumab, with 2-year absolute OS improvements of 13% to 15% and similar reductions in severe toxicity.281 Likewise, atezolizumab demonstrated an improvement in median OS compared with single-agent docetaxel regardless of PD-L1 expression and is currently FDA approved for chemotherapy-refractory disease.283 EGFR TKI is indicated in the first-line treatment of patients with TKI-sensitive EGFR mutations. Recently, osimertinib has supplanted the early-generation TKIs (erlotinib, gefitinib, and afatinib) as the preferred first-line agent. The use of EGFR TKI was initially based on multiple prospective Phase III trials showing high response rates and significant improvements in PFS compared with standard platinum-based chemotherapy.34 Similar results have been obtained with both the first-generation EGFR TKIs erlotinib284 and gefitinib285 and the secondgeneration EGFR TKI afatinib.286 These trials did not show survival improvements, likely as a result of the high crossover rate being part of the study design. Median survival on many of these trials was impressive at approximately 20 months. Nearly all patients will progress owing to a variety of EGFR TKI–resistance mechanisms, with the T790M secondary mutation being one of the best characterized, occurring in approximately 50% to 60% of patients. Osimertinib was initially approved for patients with T790M mutations that progressed after first-line EGFR TKI. More recently, a randomized trial compared osimertinib with standard EGFR TKI (gefitinib or erlotinib) in previously untreated EGFR-mutant metastatic NSCLC and found a significant improvement in PFS (18.9 vs. 10.2 months) with lower severe adverse effects.287 Interestingly, a subgroup of patients with CNS metastases also derived significant benefit, suggesting improved CNS penetration of osimertinib compared with the standard EGFR TKIs. These results have now moved osimertinib into the first-line setting for EGFR-mutant NSCLC. Cetuximab, a chimeric monoclonal antibody targeting EGFR, has failed to demonstrate efficacy in unselected patients.288-291 Necitumumab, a human monoclonal antibody to EGFR, modestly improved survival at the expense of increased serious adverse events in a randomized trial of patients with advanced squamous cell carcinoma.292 By the same token, patients whose tumors harbor EML4/ALK rearrangement warrant therapy with a matched TKI. Crizotinib was the first-generation TKI to be compared with platinum doublet chemotherapy in patients with ALK-positive NSCLC and significantly improved PFS (10.9 vs. 7 months) and ORR (74% vs. 45%) while having no effect on OS.50 Similar to the issues with early-generation EGFR TKIs, most patients with an ALK rearrangement will develop resistance to crizotinib. Ceritinib is a second-generation agent with increased potency and can be used in the first-line setting or following progression on crizotinib. Alectinib has been compared directly with crizotinib in the first-line setting and showed superior efficacy with less severe adverse events.293 Alectinib also induced higher response rates in the CNS and reduced

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intracranial progression compared with crizotinib, highlighting the potential efficacy of this agent for brain metastases. Brigatinib has also been approved for patients who have progressed on frontline crizotinib and is currently being evaluated in the frontline setting.294 Additional genotypes with approved targeted therapies include ROS1 translocations and BRAF mutations. Crizotinib remains the primary initial therapy for ROS1 translocation. Ceritinib also has activity in the setting but has not been compared directly with crizotinib. Alectinib does not have ROS1 activity. Similar to the treatment of melanoma, BRAF V600E mutant NSCLC is treated with combination dabrafenib and trametinib. Although this has not been studied in a Phase III study, Phase II data suggest activity with this combination with a 64% response rate.295 Targeted therapies for these mutations are continued until disease progression. Currently, assays to identify actionable molecular mutations are routinely based on tumor biopsies. Furthermore, the widespread availability and routine use of next-generation sequencing allows for multiplexed genotyping to be performed on a limited amount of tissue, yielding an integrated biomarker report. However, the ability to identify and quantitate genomic changes in tumor by analysis of circulating tumor DNA may soon change this paradigm and reduce the need for invasive biopsy procedures. The feasibility of such a “liquid biopsy” has been demonstrated extensively in qualitatively identifying EGFR mutations. Although false-negative rates are approximately 30%, specificity is very high.296 This technology has also shown promise in detecting the T790M resistance mutation in EGFR-mutant NSCLC.297 Beyond this important qualitative information, the ability to quantify mutations may serve as a useful biomarker to further tailor therapy.

Management of the Patient With Oligometastatic Disease The oligometastatic state refers to patients with metastases limited in both number and organ involvement. In these patients, it may be feasible to address all sites of disease with metastasis-directed therapy to prolong disease-free intervals and even cure a select group. Metastasis-directed therapy is most often achieved with surgical metastasectomy or ablative radiotherapy techniques with thermal ablation and cryotherapy as additional options. The oligometastatic state can occur at presentation, as recurrence following treated primary disease, or following systemic therapy for multifocal metastatic disease in which a limited number of lesions either do not respond to initial therapy or subsequently progress afterward. At present, there is no consensus on the number of lesions or organs that qualifies as oligometastatic but, generally, most studies have used five or fewer lesions involving no more than three organs. The incidence of oligometastases varies depending on the definition applied and presentation (e.g., de novo stage IV, recurrent, oligoprogressive), but most series have reported an incidence of approximately 50%.298,299 The favorable prognosis of the oligometastatic state has been reported in several studies,298,300,301 but it was unclear whether local therapy would improve outcomes in this more indolent group. Additional rationale for local therapy in these patients is that progression often occurs at initially involved sites following treatment with systemic therapy.299 Multiple retrospective and single-arm prospective studies have reported on the feasibility and favorable, better-than-expected outcome of patients treated with aggressive local therapy.302-305 Despite promising results compared with historical outcomes, many patients do ultimately progress. To better select patients for aggressive local therapy, characteristics such as metachronous versus synchronous metastases and N0 versus N1/N2 thoracic involvement may help predict disease course.306 Two small prospective randomized studies now provide clear evidence of a significant tripling of PFS in consolidating all sites of disease in

patients with limited metastases and at least stable disease following initial chemotherapy.307,308 In both of these studies, patients were randomized after standard first-line platinum doublet cytotoxicity chemotherapy to standard maintenance chemotherapy or consolidative local therapy to the primary disease and all known metastatic sites. Gomez et al. allowed EGFR/ALK TKI for those with EGFR mutations or ALK rearrangements and surgery could be used to consolidate local sites, although radiotherapy was used in the vast majority of patients. Radiotherapy doses varied in these studies depending on the treatment site and institutional practice. Primary disease was treated with SBRT if feasible, but both conventional fractionation with or without concurrent chemotherapy and hypofractionated regimens (e.g., 45-60 Gy in 15 fractions) were used for more advanced thoracic disease. Median PFS was 9.7 to 11.9 months with local consolidation and 3.5 to 3.9 months with maintenance chemotherapy. Local consolidation shifted patterns of failure to occurring predominantly at new sites, which were delayed in comparison with maintenance therapy. Consolidation was delivered without a significant increase in toxicity. Survival results from these trials are maturing, but the crossover design may minimize a potential survival benefit. This treatment strategy is gaining significant momentum and will be subject to further study in the randomized Phases II/III NRG-LU002. A recent survey polling radiation oncologists found that over 60% would recommend SBRT for patients with less than or equal to 3 extracranial metastases.309 When using this approach, the principle of treating all sites of involvement deserves further emphasis. A propensity-matched study found a significant OS and PFS benefit when all sites were comprehensively treated.310 With better systemic control from immune checkpoint inhibition281,282 and molecularly targeted agents,50, 287 the control of existing metastatic and primary tumors will become increasingly important. Radiotherapy may also augment immune-mediated responses, with a subset analysis of the KEYNOTE 001 Phase I trial showing improved survival in patients who previously received radiotherapy.311 Aggressive treatment of oligoprogressive disease is also an attractive treatment strategy, as some but not all tumors may develop resistance to the systemic agent. SBRT has been shown to control progressing lesions and allow continued use of an otherwise effective systemic regimen.312 In those who are intolerant of systemic therapy, radiotherapy may at least delay the need for additional chemotherapy.313

Palliative Radiotherapy For patients with advanced NSCLC not amenable to definitive intent therapy, a multidisciplinary approach is warranted. As discussed in the systemic therapy section earlier, a major goal in these patients is to alleviate symptom burden and improve quality of life. The benefits of early palliative care cannot be overstated in this regard. The benefits of systemic therapy and palliative radiotherapy are complimentary, with the former facilitating additional cytoreduction to alleviate symptoms from a particular site. This section will primarily address palliation of thoracic disease, but histology-specific treatment recommendations for brain metastases are covered briefly. Most patients with advanced lung cancer have symptoms from their intrathoracic disease. These symptoms commonly include cough, dyspnea, hemoptysis, or chest pain. Several unique syndromes can develop from advanced primary disease, including superior vena cava syndrome and Pancoast syndrome. Radiotherapy has long been the mainstay of treatment for advanced primary disease, with relatively high rates of palliation. A number of historical randomized controlled studies inform the dose-response relationships for palliation in this patient population. In general, longer courses of radiotherapy are associated with improved survival in patients with good performance status, typically at the expense of increased toxicity in the form of dysphagia/odynophagia. Therefore,

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CHAPTER 51 it is important to balance the symptomatic benefits of treatment with factors including the patient’s performance status, ability to tolerate adverse effects, and accessibility to the treatment center. In discussing the palliative thoracic radiotherapy trials, one must recognize that these trials included heterogeneous patient populations, and what was considered palliative decades ago may be treated with more aggressive intent in the modern era. The MRC conducted numerous trials between short and long courses of radiotherapy. In one of the earlier trials, a 2-fraction regimen of 8.5 Gy per fraction given 1 week apart was compared with conventional multifractionated regimens, typically 30 Gy in 10 fractions.314 Of the 369 patients, nearly all presented with cough and the majority had other symptoms, including hemoptysis, chest pain, anorexia, anxiety, and depression. More than half of all patients experienced symptomatic relief. The palliation of hemoptysis was the most successful, with 80% having symptom resolution that was maintained through follow-up in most patients. Cough, chest pain, anorexia, depression, and anxiety were also improved in 60% to 80% of patients, with cough being the least likely to resolve completely at 40%. Palliation was durable for approximately 50% of survival, with a median survival of 6 months. There was no difference in palliation or survival between the two treatment arms. The 2-fraction regimen was then compared with a single fraction of 10 Gy in poor-performance-status patients. Palliative outcomes were similar to those reported in the earlier MRC trial without statistical differences between the two arms.315 The 2-fraction regimen, however, was associated with higher rates of dysphagia (56% versus 23%). The investigators concluded that single-fraction radiotherapy was preferred in poor-performance-status patients. The MRC then sought to determine the optimal regimen in good-performance-status patients without metastatic disease but with symptomatic local disease extent that precluded definitive doses of radiotherapy. A total of 509 patients were randomized to 17 Gy in 2 fractions versus 39 Gy in 13 fractions. Longcourse radiotherapy was associated with a significant improvement in survival (median, 7 vs. 9 months; 1 year OS, 31% vs. 36%).316 Other important findings were similar overall symptom palliation (which occurred earlier in the two-fraction arm) and similar rates of treatmentrelated dysphagia (although it lasted twice as long with extended fractionation). Studies from other countries have mostly come to similar conclusions. A Norwegian study compared 3 treatment arms in 421 patients: 17 Gy in 2 fractions, 42 Gy in 15 fractions, or 50 Gy in 25 fractions.317 In this heterogenous population with mixed performance status, no significant difference was noted in health-related quality of life or survival. Kramer et al. randomized 297 patients in the Netherlands to 16 Gy in 2 fractions or 30 Gy in 10 fractions and 7 thoracic symptoms were subsequently scored to create a composite total symptom score.318 Similar to the MRC study results in good-performance-status patients, prolonged survival was seen in the long-course arm (1-year OS, 11% vs. 20%). Although total symptom scores improved more quickly in the shortcourse arm, they were more durable with long-course radiotherapy. A meta-analysis of 13 random controlled trials has confirmed these relationships with dose, suggesting prolonged survival and palliation with higher BED regimens at the expense of increased esophageal toxicity.319 The optimal dose/fractionation for good-performance-status patients is unclear, but 30 to 39 Gy in 10 to 15 fractions is reasonable. Poor-performance-status patients should strongly be considered for short-course radiotherapy schedules, including 10 Gy in a single fraction, 17 Gy in 2 fractions, or 20 Gy in 5 fractions. Although radiation myelopathy is uncommon with these doses,320 strategies should be used to reduce this risk, including limiting the cord length in the field, adding an off-cord field, and/or administering a steroid regimen.

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While these studies inform how to deliver palliative thoracic radiotherapy, it is not clear when to best deliver it. In patients with minimal thoracic symptoms, a randomized multicenter study including 230 patients found no survival or quality-of-life benefit to immediate versus delayed palliative thoracic radiotherapy.321 In a subset of asymptomatic patients treated in a Dutch study with immediate thoracic radiotherapy, quality of life was impaired for several months following treatment and did not necessarily prevent later disease-related symptoms.322 Collectively, these results support a wait-and-see policy for palliative thoracic radiotherapy, reserving its use for the symptomatic patient. This is particularly true in the patient who will go on to receive systemic therapy, which can also lead to quality-of-life improvements and symptom palliation. In patients with very poor performance who may not survive long enough to realize the benefits of palliative radiotherapy, supportive care alone should be considered.323 Central airway obstruction presents a unique therapeutic dilemma. Even in the absence of significant symptoms, there is potential to develop recurrent pneumonias and sepsis in the setting of neutropenia from cytotoxic chemotherapy. Airway patency can be restored through conventional radiotherapy alone or by a variety of interventional techniques, including direct tumor bebulking via bronchoscopy, photodynamic therapy, endobronchial brachytherapy (EBB), and/or airway stenting. External radiotherapy can improve symptomatic and radiographic airway obstruction in approximately 70% and 80% of patients, respectively.324 This appears to be more likely with doses of at least 30 Gy in 10 fractions. Airway stenting can immediately restore patency, but risks of the procedure are not trivial, including bleeding, infection risk, and stent migration. The complication rate of stent placement is reported to be approximately 30%.325 Additional treatment is often necessary following a stent to maintain airway patency, with one institutional report showing prolonged survival in patients treated with radiation following stent placement.326 EBB is a technique that allows for focal radiation delivery from the bronchial lumen, permitting high doses at the tumor surface with steep dose fall off. This is accomplished using a flexible bronchoscope in conjunction with a remote afterloading device and a high-dose-rate brachytherapy source. Dose/fractionation schemes vary, including 10 to 15 Gy in a single fraction and 12 to 16 Gy in 2 fractions, typically prescribed at 1 cm depth. Several small trials have investigated the role of EBB in combination with EBRT. A systematic review concluded that there was not a significant benefit of routinely adding EBB to EBRT, but EBB may be a useful approach in the patient with refractory symptoms who has previously received EBRT.327 A major limitation of EBB is the inability to deliver adequate dose deeper into the lung parenchyma. The most common sites of metastases of NSCLC are bone, lung, and brain.298 Specific management of these problems is discussed elsewhere, but several points pertinent to brain metastases in NSCLC are worth mentioning here. Brain metastases in this disease are common, with an overall incidence of approximately 20%.64 Numerous prognostic factors for NSCLC brain metastases have been incorporated into the diagnosis-specific graded prognostic assessment reported by Sperduto et al., including age, performance status, presence of extracranial metastases, and the number of brain metastases.328 For the latter, distinctions are made between a single brain metastasis, 2 to 3, and greater than 3 metastases. Overall prognosis is poor, with a median survival of 7 months. Patients with limited brain metastases and a good performance status, however, warrant aggressive management. Patients with a solitary brain metastasis can experience long-term survival following surgery and/or SRS, especially if they have limited thoracic disease and no other metastases.329 RTOG 9508 was a randomized controlled trial investigating the addition of stereotactic radiosurgery (SRS) to whole-brain radiotherapy (WBRT) in patients with 1 to 3 brain metastases, two-thirds

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of which were from NSCLC. Adding SRS resulted in a higher rate of stable to improved performance status and in the subsets with a single brain metastasis and/or NSCLC histology, SRS improved OS.330 In similar patients with limited brain metastases, SRS with or without WBRT has been investigated in several trials. Conclusions from the individual trials were that WBRT reduces distant brain failures but does not improve survival and increases neurotoxicity.331-334 SRS alone is now the preferred strategy in this population, with a recent subset analysis of the N0574 Alliance trial showing no detriment in OS in patients with NSCLC who were treated with SRS alone compared with SRS + WBRT.335 For patients with more than 4 brain metastases, SRS may still be an appropriate option if overall tumor burden is low.336 Patients with multiple adverse prognostic factors may not require any cranial irradiation. In the randomized QUARTZ trial, investigators uncertain of the benefit of WBRT in poor-prognosis NSCLC randomized patients to best supportive care alone or WBRT. Although the supportive care alone did not meet their predefined noninferiority margin, no clinically meaningful differences in quality of life or survival were apparent.337 In the current era of routine staging with brain MRI, it is relatively common to identify small asymptomatic brain metastases. Whether these should be treated prior to systemic therapy remains controversial and needs to be individualized for the patient. One randomized controlled trial addressed this issue in patients with asymptomatic oligometastatic brain metastases in which patients were randomized to upfront SRS or initial cytotoxic chemotherapy. Although there was a trend for prolonged intracranial PFS with upfront SRS (median, 9.4 vs. 6.6 months), there was no difference in OS.338 The intracranial response rate to upfront cytotoxic chemotherapy was 37% in this trial. Intracranial control of immune checkpoint inhibition is still under evaluation. Results of a single-institution Phase II trial of previously untreated brain metastases showed a 33% response rate with pembrolizumab, with most of these responses being durable.339 Molecular information, specifically EGFR and ALK mutation status, has demonstrated substantial prognostic significance in brain metastases and is now incorporated into a molecular prognostic assessment tool.340,341 High intracranial response rates have been reported in patients with EGFR mutations treated with targeted TKI, with one series demonstrating an intracranial response rate of 74% with erlotinib or gefitinib.342 Osimertinib appears to have even better CNS penetration than the first-generation EGFR TKIs, as noted in a recent randomized trial.287 Crizotinib for patients with ALKrearranged NSCLC brain metastases has an approximate 50% response rate, but subsequent intracranial progression is common.343 In comparison with crizotinib, alectinib has significantly higher intracranial response rates (81% vs. 50%) and reduces intracranial progression at 12 months (9.4% vs. 41.4%).293 High response rates with the recent generations of targeted TKI have questioned the need for cranial irradiation. A Phase III trial of immediate EGFR TKI with icotinib was compared with WBRT with or without concurrent/sequential cytotoxic chemotherapy in EGFRmutant NSCLC and at least 3 brain metastases. This study found improved median intracranial PFS with icotinib versus WBRT (10 vs. 4.8 months),344 but conclusions are limited by the study design, in which EGFR-directed therapy after cranial irradiation would be standard as opposed to no systemic therapy or cytotoxic chemotherapy. There are no randomized trials of upfront SRS versus TKI, but one retrospective multi-institutional analysis suggests inferior survival when radiotherapy is deferred for upfront first-generation EGFR TKI.345 Prospective data is needed to determine the optimal sequencing of local and systemic therapy in this clinical scenario. In patients with numerous but asymptomatic brain metastases that would otherwise require WBRT, a reasonable approach may be upfront TKI with close surveillance. Efforts to combine systemic therapy with radiation have failed to improve

outcomes. RTOG 0302 specifically addressed the question of WBRT + SRS alone or the same treatment in combination with either temozolomide or erlotinib (patients were unselected for EGFR-activating mutations) for patients with 1 to 3 brain metastases. The addition of systemic therapy resulted in a trend for inferior survival at the cost of increased grade 3+ toxicity.346

CONTROVERSIES Decades of experience and clinical trials have set the current standards of care for NSCLC. However, rapidly evolving imaging and treatment technology, as well as effective targeted and immunotherapies, are changing the disease landscape. Modern clinical trials will be critical in adapting to these changes and in shaping future practice. Controversies for specific clinical situations relevant to the radiation oncologist are as follows: 1. With the advent of SBRT, what is the most appropriate therapy for medically operable NSCLC? While the current standard of care remains surgical resection, the results of the VALOR and STABLEMATES trials are awaited. 2. For patients with resectable N2 disease, what is the role of surgery and which patient groups benefit the most from trimodality therapy? Collectively, no survival benefit has been seen with the addition of surgery, but appropriately selected patients with minimal mediastinal involvement may have improved outcomes. 3. Prospective evidence and subgroup analyses about the benefit of PORT in patients with completely resected N2 disease are conflicting, with older studies suggesting increased noncancer death in those who received PORT. With modern radiation planning techniques having improved the therapeutic ratio, the Lung ART trial will clarify the role of PORT in this patient population. 4. The PACIFIC trial has changed the paradigm for definitive chemoradiation. Considering the potential for interaction between immune stimulation and radiotherapy, how should radiation, chemotherapy, and immunotherapy be combined to optimize efficacy? 5. In patients with advanced disease unfit for definitive chemoradiation, what is the optimal treatment approach? Studies are underway investigating the role of hypofractionated radiotherapy compared to conventional fractionation. Such treatment given in a sequential manner with systemic therapy matched to mutational or PD-L1 status may best balance treatment efficacy with toxicity. 6. In patients with oligometastatic NSCLC, how is radiation best integrated into the systemic therapy paradigm? Small Phase II studies have shown a benefit to consolidation radiotherapy in patients with stable or responding disease to cytotoxic therapy. This will be further tested in the large Phase III trial NRG LU002. Radiotherapy may also play a role in oligoprogressive disease. When and in what circumstances radiotherapy should be used in patients treated with targeted therapies and immune checkpoint inhibition will need further study.

CONCLUSIONS NSCLC is a challenging disease and will remain so for the foreseeable future. However, progress is evident in multiple respects. The rates of tobacco consumption have been declining in the United States, as are incidence rates of lung cancer. With more routine implementation of low-dose CT screening programs, one would reasonably expect higher rates of early-stage disease. Staging is more accurate with the use of FDG-PET and brain MRI, which better matches the stage of the patient to the appropriate therapy. Advances in radiation delivery in the form of SBRT, SRS, IMRT, motion management, and image guidance have

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CHAPTER 51 improved the therapeutic ratio of treatment in a variety of clinical situations. Systemic regimens for metastatic disease, including targeted agents and immune checkpoint inhibition, have clearly improved clinical endpoints with less toxicity. It is imperative that the field of Radiation Oncology adapt to this rapidly changing landscape and partner with our multidisciplinary colleagues to optimize care for these patients.

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A complete reference list can be found online at ExpertConsult.com.

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CHAPTER 51

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Non–Small Cell Lung Cancer

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110. Martin JT, Durbin EB, Chen L, et al. Nodal upstaging during lung cancer resection is associated with surgical approach. Ann Thorac Surg. 2016;101:238–244, discussion 244–235. 111. Boffa DJ, Kosinski AS, Furnary AP, et al. Minimally invasive lung cancer surgery performed by thoracic surgeons as effective as thoracotomy. J Clin Oncol. 2018;36:2378–2385. 112. Fernandez FG, Kosinski AS, Burfeind W, et al. The society of thoracic surgeons lung cancer resection risk model: higher quality data and superior outcomes. Ann Thorac Surg. 2016;102:370–377. 113. Yamato Y, Tsuchida M, Watanabe T, et al. Early results of a prospective study of limited resection for bronchioloalveolar adenocarcinoma of the lung. Ann Thorac Surg. 2001;71:971–974. 114. Landreneau RJ, Normolle DP, Christie NA, et al. Recurrence and survival outcomes after anatomic segmentectomy versus lobectomy for clinical stage I non-small-cell lung cancer: a propensity-matched analysis. J Clin Oncol. 2014;32:2449–2455. 115. El-Sherif A, Gooding WE, Santos R, et al. Outcomes of sublobar resection versus lobectomy for stage I non-small cell lung cancer: a 13-year analysis. Ann Thorac Surg. 2006;82:408–415, discussion 415–406. 116. Kodama K, Doi O, Higashiyama M, Yokouchi H. Intentional limited resection for selected patients with T1 N0 M0 non-small-cell lung cancer: a single-institution study. J Thorac Cardiovasc Surg. 1997;114:347–353. 117. Boffa DJ, Allen MS, Grab JD, et al. Data from The Society of Thoracic Surgeons General Thoracic Surgery database: the surgical management of primary lung tumors. J Thorac Cardiovasc Surg. 2008;135:247–254. 118. Balduyck B, Hendriks J, Lauwers P, Van Schil P. Quality of life after lung cancer surgery: a prospective pilot study comparing bronchial sleeve lobectomy with pneumonectomy. J Thorac Oncol. 2008;3:604–608. 119. Darling GE, Allen MS, Decker PA, et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg. 2011;141:662–670. 120. Raz DJ, Zell JA, Ou SH, et al. Natural history of stage I non-small cell lung cancer: implications for early detection. Chest. 2007;132:193–199. 121. Fang LC, Komaki R, Allen P, et al. Comparison of outcomes for patients with medically inoperable Stage I non-small-cell lung cancer treated with two-dimensional vs. three-dimensional radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:108–116. 122. Krol AD, Aussems P, Noordijk EM, et al. Local irradiation alone for peripheral stage I lung cancer: could we omit the elective regional nodal irradiation? Int J Radiat Oncol Biol Phys. 1996;34:297–302. 123. Sibley GS, Jamieson TA, Marks LB, et al. Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys. 1998;40:149–154. 124. Bradley J, Thorstad WL, Mutic S, et al. Impact of FDG-PET on radiation therapy volume delineation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;59:78–86. 125. Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2005;61:318–328. 126. Bogart JA, Hodgson L, Seagren SL, et al. Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904. J Clin Oncol. 2010;28:202–206. 127. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest. 2003;124:1946–1955. 128. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006;24:4833–4839. 129. Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys. 2009;75:677–682.

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Disease Sites

130. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303:1070–1076. 131. Timmerman RD, Hu C, Michalski J, et al. Long-term results of RTOG 0236: a phase II trial of stereotactic body radiation therapy (SBRT) in the treatment of patients with medically inoperable stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;90:S30. 132. Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys. 2005;63:1427–1431. 133. Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol. 2009;27:3290–3296. 134. Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer. 2004;101:1623–1631. 135. Senthi S, Lagerwaard FJ, Haasbeek CJ, et al. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol. 2012;13:802–809. 136. Videtic GM, Hu C, Singh AK, et al. A randomized phase 2 study comparing 2 stereotactic body radiation therapy schedules for medically inoperable patients with stage I peripheral non-small cell lung cancer: NRG oncology RTOG 0915 (NCCTG N0927). Int J Radiat Oncol Biol Phys. 2015;93:757–764. 137. Videtic GM, Gomez Suescun JA, Stephans KL, et al. A phase 2 randomized study of 2 stereotactic body radiation therapy (SBRT) regimens for medically inoperable patients with node-negative, peripheral non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2016;96:S8–S9. 138. Stephans KL, Woody NM, Reddy CA, et al. Tumor control and toxicity for common stereotactic body radiation therapy dose-fractionation regimens in stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2018;100:462–469. 139. Bongers EM, Haasbeek CJ, Lagerwaard FJ, et al. Incidence and risk factors for chest wall toxicity after risk-adapted stereotactic radiotherapy for early-stage lung cancer. J Thorac Oncol. 2011;6:2052–2057. 140. Dunlap NE, Cai J, Biedermann GB, et al. Chest wall volume receiving >30 Gy predicts risk of severe pain and/or rib fracture after lung stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2010;76:796–801. 141. Corradetti MN, Haas AR, Rengan R. Central-airway necrosis after stereotactic body-radiation therapy. N Engl J Med. 2012;366:2327–2329. 142. Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol. 2011;6:2036–2043. 143. Senthi S, Haasbeek CJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol. 2013;106:276–282. 144. Chang JY, Li QQ, Xu QY, et al. Stereotactic ablative radiation therapy for centrally located early stage or isolated parenchymal recurrences of non-small cell lung cancer: how to fly in a “no fly zone”. Int J Radiat Oncol Biol Phys. 2014;88:1120–1128. 145. Milano MT, Chen Y, Katz AW, et al. Central thoracic lesions treated with hypofractionated stereotactic body radiotherapy. Radiother Oncol. 2009;91:301–306. 146. Tekatli H, Haasbeek N, Dahele M, et al. Outcomes of hypofractionated high-dose radiotherapy in poor-risk patients with “ultracentral” non-small cell lung cancer. J Thorac Oncol. 2016;11:1081–1089. 147. Nyman J, Hallqvist A, Lund JS, et al. SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC. Radiother Oncol. 2016. 148. Ball DL, Mai T, Vinod S, et al. A randomized trial of SABR vs conventional radiotherapy for inoperable stage I non-small cell lung cancer: TROG 09.02 (CHISEL). International Association for the Study

of Lung Cancer 18th World Conference on Lung Cancer. Yokohama, Japan, 2017. 149. Dupuy DE, Fernando HC, Hillman S, et al. Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. Cancer. 2015;121:3491–3498. 150. Bi N, Shedden K, Zheng X, Kong FS. Comparison of the effectiveness of radiofrequency ablation with stereotactic body radiation therapy in inoperable stage I non-small cell lung cancer: a systemic review and pooled analysis. Int J Radiat Oncol Biol Phys. 2016;95:1378–1390. 151. Grills IS, Mangona VS, Welsh R, et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer. J Clin Oncol. 2010;28:928–935. 152. Timmerman RD, Paulus R, Pass HI, et al. Stereotactic body radiation therapy for operable early-stage lung cancer: findings from the NRG oncology RTOG 0618 trial. JAMA Oncol. 2018;4:1263–1266. 153. Nagata Y, Hiraoka M, Shibata T, et al. Prospective trial of stereotactic body radiation therapy for both operable and inoperable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group study JCOG0403. Int J Radiat Oncol Biol Phys. 2015;93:989–996. 154. Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015;16:630–637. 155. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552–3559. 156. Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008;26:5043–5051. 157. Kris MG, Gaspar LE, Chaft JE, et al. Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non-small-cell lung cancers: American Society of Clinical Oncology/ Cancer Care Ontario clinical practice guideline update. J Clin Oncol. 2017;35:2960–2974. 158. Chen HY, Yu SL, Chen CH, et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med. 2007;356:11–20. 159. Lau SK, Boutros PC, Pintilie M, et al. Three-gene prognostic classifier for early-stage non small-cell lung cancer. J Clin Oncol. 2007;25:5562–5569. 160. Kratz JR, He J, Van Den Eeden SK, et al. A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies. Lancet. 2012;379:823–832. 161. Wakelee HA, Dahlberg SE, Keller SM, et al. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017;18:1610–1623. 162. Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol. 2015;33:4007–4014. 163. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet. 1998;352:257–263. 164. Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol. 2006;24:2998–3006. 165. Douillard JY, Rosell R, De Lena M, et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys. 2008;72:695–701. 166. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst. 2007;99:442–450.

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CHAPTER 51 167. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379–386. 168. Eberhardt WE, Pottgen C, Gauler TC, et al. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol. 2015;33:4194–4201. 169. Martins RG, D’Amico TA, Loo BW Jr, et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement. J Natl Compr Canc Netw. 2012;10:599–613. 170. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014;383:1561–1571. 171. Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol. 2010;28:3138–3145. 172. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994;330:153–158. 173. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994;86:673–680. 174. Thomas M, Rube C, Hoffknecht P, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol. 2008;9:636–648. 175. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/ N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386:1049–1056. 176. Suntharalingam M, Paulus R, Edelman MJ, et al. Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys. 2012;84:456–463. 177. Shimada Y, Suzuki K, Okada M, et al. Feasibility and efficacy of salvage lung resection after definitive chemoradiation therapy for Stage III non-small-cell lung cancer. Interact Cardiovasc Thorac Surg. 2016;23:895–901. 178. Schreiner W, Dudek W, Lettmaier S, et al. Long-term survival after salvage surgery for local failure after definitive chemoradiation therapy for locally advanced non-small cell lung cancer. Thorac Cardiovasc Surg. 2018;66:135–141. 179. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg. 2001;121:472–483. 180. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol. 2007;25:313–318. 181. Kunitoh H, Kato H, Tsuboi M, et al. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol. 2008;26:644–649. 182. Buderi SI, Shackcloth M, Woolley S. Does induction chemoradiotherapy increase survival in patients with Pancoast tumour? Interact Cardiovasc Thorac Surg. 2016;23:821–825. 183. Feng W, Fu XL, Cai XW, et al. Patterns of local-regional failure in completely resected stage IIIA(N2) non-small cell lung cancer cases: implications for postoperative radiation therapy clinical target volume design. Int J Radiat Oncol Biol Phys. 2014;88:1100–1107. 184. Lally BE, Detterbeck FC, Geiger AM, et al. The risk of death from heart disease in patients with nonsmall cell lung cancer who receive

Non–Small Cell Lung Cancer

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postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database. Cancer. 2007;110:911–917. 185. Machtay M, Lee JH, Shrager JB, et al. Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma. J Clin Oncol. 2001;19:3912–3917. 186. Miles EF, Kelsey CR, Kirkpatrick JP, Marks LB. Estimating the magnitude and field-size dependence of radiotherapy-induced mortality and tumor control after postoperative radiotherapy for non-small-cell lung cancer: calculations from clinical trials. Int J Radiat Oncol Biol Phys. 2007;68:1047–1052. 187. Corso CD, Rutter CE, Wilson LD, et al. Re-evaluation of the role of postoperative radiotherapy and the impact of radiation dose for non-small-cell lung cancer using the National Cancer Database. J Thorac Oncol. 2015;10:148–155. 188. Bradley JD, Paulus R, Graham MV, et al. Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group–RTOG 9705. J Clin Oncol. 2005;23:3480–3487. 189. Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med. 2000;343:1217–1222. 190. Wang EH, Corso CD, Rutter CE, et al. Postoperative radiation therapy is associated with improved overall survival in incompletely resected stage II and III non-small-cell lung cancer. J Clin Oncol. 2015;33: 2727–2734. 191. Lad T. The comparison of CAP chemotherapy and radiotherapy to radiotherapy alone for resected lung cancer with positive margin or involved highest sampled paratracheal node (stage IIIA). LCSG 791. Chest. 1994;106:302S–306S. 192. Francis S, Orton A, Stoddard G, et al. Sequencing of postoperative radiotherapy and chemotherapy for locally advanced or incompletely resected non-small-cell lung cancer. J Clin Oncol. 2018;36:333–341. 193. Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer. 1987;59:1874–1881. 194. Cox JD, Azarnia N, Byhardt RW, et al. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11. J Clin Oncol. 1990;8:1543–1555. 195. Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995;87:198–205. 196. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionatedaccelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol. 2011;100:76–85. 197. Mauguen A, Le Pechoux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol. 2012;30:2788–2797. 198. Dillman RO, Herndon J, Seagren SL, et al. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996;88:1210–1215. 199. Sause W, Kolesar P, Taylor SI, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000;117:358–364. 200. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999;17:2692–2699.

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SECTION III

Disease Sites

201. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452–1460. 202. Auperin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181–2190. 203. Santana-Davila R, Devisetty K, Szabo A, et al. Cisplatin and etoposide versus carboplatin and paclitaxel with concurrent radiotherapy for stage III non-small-cell lung cancer: an analysis of Veterans Health Administration data. J Clin Oncol. 2015;33:567–574. 204. Liang J, Bi N, Wu S, et al. Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial. Ann Oncol. 2017;28:777–783. 205. de Castria TB, da Silva EM, Gois AF, Riera R. Cisplatin versus carboplatin in combination with third-generation drugs for advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2013;(8):CD009256. 206. Senan S, Brade A, Wang LH, et al. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016;34:953–962. 207. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-smallcell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005;23:5883–5891. 208. Vokes EE, Herndon JE 2nd, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: cancer and Leukemia Group B. J Clin Oncol. 2007;25:1698–1704. 209. Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol. 2003;21:2004–2010. 210. Davies AM, Chansky K, Lau DH, et al. Phase II study of consolidation paclitaxel after concurrent chemoradiation in poor-risk stage III non-small-cell lung cancer: SWOG S9712. J Clin Oncol. 2006;24:5242–5246. 211. Jalal SI, Riggs HD, Melnyk A, et al. Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology. Ann Oncol. 2012;23:1730–1738. 212. Ahn JS, Ahn YC, Kim JH, et al. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol. 2015;33:2660–2666. 213. Chang XJ, Wang ZT, Yang L. Consolidation chwemotherapy after concurrent chemoradiotherapy vs. chemoradiotherapy alone for locally advanced unresectable stage III non-small-cell lung cancer: a metaanalysis. Mol Clin Oncol. 2016;5:271–278. 214. Machtay M, Bae K, Movsas B, et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 2012;82:425–434. 215. Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol. 2008;26:2457–2463. 216. Schild SE, Hillman SL, Tan AD, et al. Long-term results of a trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small cell lung cancer: NCCTG N0028 (Alliance). J Thorac Oncol. 2017;12:697–703.

217. Bradley JD, Bae K, Graham MV, et al. Primary analysis of the phase II component of a phase I/II dose intensification study using threedimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J Clin Oncol. 2010;28:2475–2480. 218. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-bytwo factorial phase 3 study. Lancet Oncol. 2015;16:187–199. 219. Belderbos J, Uitterhoeve L, van Zandwijk N, et al. Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973). Eur J Cancer. 2007;43:114–121. 220. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377:1919–1929. 221. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;0:null. 222. Stinchcombe TE, Zhang Y, Vokes EE, et al. Pooled analysis of individual patient data on concurrent chemoradiotherapy for stage III non-smallcell lung cancer in elderly patients compared with younger patients who participated in US National Cancer Institute cooperative group studies. J Clin Oncol. 2017;35:2885–2892. 223. Langer CJ, Hsu C, Curran W, et al. Do elderly patients (pts) with locally advanced non-small cell lung cancer (NSCLC) benefit from combined modality therapy? a secondary analysis of RTOG 94-10. Int J Radiat Oncol Biol Phys. 2001;51:20–21. 224. Lilenbaum R, Samuels M, Wang X, et al. A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor-risk stage III non-small-cell lung cancer: results of CALGB 30605 (Alliance)/RTOG 0972 (NRG). J Thorac Oncol. 2015;10:143–147. 225. Westover KD, Loo BW Jr, Gerber DE, et al. Precision hypofractionated radiation therapy in poor performing patients with non-small cell lung cancer: phase 1 dose escalation trial. Int J Radiat Oncol Biol Phys. 2015;93:72–81. 226. Iyengar P, Westover KD, Court LE, et al. A phase III randomized study of image guided conventional (60 Gy/30 fx) versus accelerated, hypofractionated (60 Gy/15 fx) radiation for poor performance status stage II and III NSCLC Patients–An interim analysis. Int J Radiat Oncol Biol Phys. 2016;96:E451. 227. Giraud P, Morvan E, Claude L, et al. Respiratory gating techniques for optimization of lung cancer radiotherapy. J Thorac Oncol. 2011;6:2058–2068. 228. Underberg RW, Lagerwaard FJ, Cuijpers JP, et al. Four-dimensional CT scans for treatment planning in stereotactic radiotherapy for stage I lung cancer. Int J Radiat Oncol Biol Phys. 2004;60:1283–1290. 229. Underberg RW, Lagerwaard FJ, Slotman BJ, et al. Use of maximum intensity projections (MIP) for target volume generation in 4DCT scans for lung cancer. Int J Radiat Oncol Biol Phys. 2005;63:253–260. 230. Chan R, He Y, Haque A, Zwischenberger J. Computed tomographicpathologic correlation of gross tumor volume and clinical target volume in non-small cell lung cancer: a pilot experience. Arch Pathol Lab Med. 2001;125:1469–1472. 231. Bradley J, Bae K, Choi N, et al. A phase II comparative study of gross tumor volume definition with or without PET/CT fusion in dosimetric planning for non-small-cell lung cancer (NSCLC): primary analysis of Radiation Therapy Oncology Group (RTOG) 0515. Int J Radiat Oncol Biol Phys. 2012;82:435–441, e431. 232. Giraud P, Antoine M, Larrouy A, et al. Evaluation of microscopic tumor extension in non-small-cell lung cancer for three-dimensional conformal radiotherapy planning. Int J Radiat Oncol Biol Phys. 2000;48:1015–1024. 233. van Loon J, Siedschlag C, Stroom J, et al. Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features. Int J Radiat Oncol Biol Phys. 2012;82:448–456. 234. Yuan S, Meng X, Yu J, et al. Determining optimal clinical target volume margins on the basis of microscopic extracapsular extension of

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CHAPTER 51 metastatic nodes in patients with non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2007;67:727–734. 235. Rosenzweig KE, Sura S, Jackson A, Yorke E. Involved-field radiation therapy for inoperable non small-cell lung cancer. J Clin Oncol. 2007;25:5557–5561. 236. Yuan S, Sun X, Li M, et al. A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J Clin Oncol. 2007;30:239–244. 237. Bentel GC, Marks LB, Krishnamurthy R. Impact of cradle immobilization on setup reproducibility during external beam radiation therapy for lung cancer. Int J Radiat Oncol Biol Phys. 1997;38: 527–531. 238. Jan N, Balik S, Hugo GD, et al. Interfraction displacement of primary tumor and involved lymph nodes relative to anatomic landmarks in image guided radiation therapy of locally advanced lung cancer. Int J Radiat Oncol Biol Phys. 2014;88:210–215. 239. Kwint M, Conijn S, Schaake E, et al. Intra thoracic anatomical changes in lung cancer patients during the course of radiotherapy. Radiother Oncol. 2014;113:392–397. 240. Shumway D, Corbin K, Salgia R, et al. Pathologic response rates following definitive dose image-guided chemoradiotherapy and resection for locally advanced non-small cell lung cancer. Lung Cancer. 2011;74:446–450. 241. Kilburn JM, Soike MH, Lucas JT, et al. Image guided radiation therapy may result in improved local control in locally advanced lung cancer patients. Pract Radiat Oncol. 2016;6:e73–e80. 242. Chun SG, Hu C, Choy H, et al. Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial. J Clin Oncol. 2017;35:56–62. 243. Chang JY, Jabbour SK, De Ruysscher D, et al. Consensus statement on proton therapy in early-stage and locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2016;95:505–516. 244. Chang JY, Verma V, Li M, et al. Proton beam radiotherapy and concurrent chemotherapy for unresectable stage III non-small cell lung cancer: final results of a phase 2 study. JAMA Oncol. 2017;3:e172032. 245. Liao Z, Lee JJ, Komaki R, et al. Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer. J Clin Oncol. 2018;JCO2017740720. 246. Singh AK, Lockett MA, Bradley JD. Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2003;55:337–341. 247. Byhardt RW, Scott C, Sause WT, et al. Response, toxicity, failure patterns, and survival in five Radiation Therapy Oncology Group (RTOG) trials of sequential and/or concurrent chemotherapy and radiotherapy for locally advanced non-small-cell carcinoma of the lung. Int J Radiat Oncol Biol Phys. 1998;42:469–478. 248. Palma DA, Senan S, Oberije C, et al. Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2013;87:690–696. 249. Boyle J, Ackerson B, Gu L, Kelsey CR. Dosimetric advantages of intensity modulated radiation therapy in locally advanced lung cancer. Adv Radiat Oncol. 2017;2:6–11. 250. Al-Halabi H, Paetzold P, Sharp GC, et al. A contralateral esophagussparing technique to limit severe esophagitis associated with concurrent high-dose radiation and chemotherapy in patients with thoracic malignancies. Int J Radiat Oncol Biol Phys. 2015;92:803–810. 251. Machtay M, Hsu C, Komaki R, et al. Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non-small-cell lung carcinoma: analysis of the Radiation Therapy Oncology Group (RTOG) experience. Int J Radiat Oncol Biol Phys. 2005;63:667–671. 252. Movsas B, Scott C, Langer C, et al. Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving

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Disease Sites

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CHAPTER 51 308. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2018;4:e173501. 309. Lewis SL, Porceddu S, Nakamura N, et al. Definitive stereotactic body radiotherapy (SBRT) for extracranial oligometastases: an international survey of >1000 radiation oncologists. Am J Clin Oncol. 2017;40:418–422. 310. Sheu T, Heymach JV, Swisher SG, et al. Propensity score-matched analysis of comprehensive local therapy for oligometastatic non-small cell lung cancer that did not progress after front-line chemotherapy. Int J Radiat Oncol Biol Phys. 2014;90:850–857. 311. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18:895–903. 312. Gan GN, Weickhardt AJ, Scheier B, et al. Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Int J Radiat Oncol Biol Phys. 2014;88:892–898. 313. Ranck MC, Golden DW, Corbin KS, et al. Stereotactic body radiotherapy for the treatment of oligometastatic renal cell carcinoma. Am J Clin Oncol. 2013;36:589–595. 314. Inoperable non-small-cell lung cancer (NSCLC): a Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer. 1991;63:265–270. 315. A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Medical Research Council Lung Cancer Working Party. Br J Cancer. 1992;65:934–941. 316. Macbeth FR, Bolger JJ, Hopwood P, et al. Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol). 1996;8:167–175. 317. Sundstrom S, Bremnes R, Aasebo U, et al. Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol. 2004;22:801–810. 318. Kramer GW, Wanders SL, Noordijk EM, et al. Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol. 2005;23:2962–2970. 319. Fairchild A, Harris K, Barnes E, et al. Palliative thoracic radiotherapy for lung cancer: a systematic review. J Clin Oncol. 2008;26:4001–4011. 320. Macbeth FR, Wheldon TE, Girling DJ, et al. Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol). 1996;8:176–181. 321. Falk SJ, Girling DJ, White RJ, et al. Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial. BMJ. 2002;325:465. 322. Sundstrom S, Bremnes R, Brunsvig P, et al. Immediate or delayed radiotherapy in advanced non-small cell lung cancer (NSCLC)? Data from a prospective randomised study. Radiother Oncol. 2005;75:141–148. 323. Walasek T, Sas-Korczynska B, Dabrowski T, et al. Palliative thoracic radiotherapy for patients with advanced non-small cell lung cancer and poor performance status. Lung Cancer. 2015;87:130–135. 324. Lee JW, Lee JH, Kim HK, et al. The efficacy of external beam radiotherapy for airway obstruction in lung cancer patients. Cancer Res Treat. 2015;47:189–196. 325. Murgu SD, Egressy K, Laxmanan B, et al. Central airway obstruction: benign strictures, tracheobronchomalacia, and malignancy-related obstruction. Chest. 2016;150:426–441.

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326. Lemaire A, Burfeind WR, Toloza E, et al. Outcomes of tracheobronchial stents in patients with malignant airway disease. Ann Thorac Surg. 2005;80:434–437, discussion 437–438. 327. Cardona AF, Reveiz L, Ospina EG, et al. Palliative endobronchial brachytherapy for non-small cell lung cancer. Cochrane Database Syst Rev. 2008;(2):CD004284. 328. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77:655–661. 329. Hu C, Chang EL, Hassenbusch SJ 3rd, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer. 2006;106:1998–2004. 330. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004;363:1665–1672. 331. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295:2483–2491. 332. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10:1037–1044. 333. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29:134–141. 334. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316:401–409. 335. Churilla TM, Ballman KV, Brown PD, et al. Stereotactic radiosurgery with or without whole-brain radiation therapy for limited brain metastases: a secondary analysis of the North Central Cancer Treatment Group N0574 (Alliance) randomized controlled trial. Int J Radiat Oncol Biol Phys. 2017;99:1173–1178. 336. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multiinstitutional prospective observational study. Lancet Oncol. 2014;15:387–395. 337. Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388:2004–2014. 338. Lim SH, Lee JY, Lee MY, et al. A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer. Ann Oncol. 2015;26:762–768. 339. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17:976–983. 340. Sperduto PW, Yang TJ, Beal K, et al. The Effect of Gene Alterations and Tyrosine Kinase Inhibition on Survival and Cause of Death in Patients With Adenocarcinoma of the Lung and Brain Metastases. Int J Radiat Oncol Biol Phys. 2016;96:406–413. 341. Sperduto PW, Yang TJ, Beal K, et al. Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (lung-molGPA). JAMA Oncol. 2017;3:827–831. 342. Kim JE, Lee DH, Choi Y, et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer. 2009;65:351–354.

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343. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33:1881–1888. 344. Yang JJ, Zhou C, Huang Y, et al. Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial. Lancet Respir Med. 2017;5:707–716. 345. Magnuson WJ, Lester-Coll NH, Wu AJ, et al. Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor

receptor-mutant non-small-cell lung cancer: a retrospective multiinstitutional analysis. J Clin Oncol. 2017;35:1070–1077. 346. Sperduto PW, Wang M, Robins HI, et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys. 2013;85:1312–1318.

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52 Uncommon Thoracic Tumors Vivek Verma, Stephen G. Chun, and Charles R. Thomas Jr

KEY POINTS Incidence Three distinct neoplasms are discussed in this chapter: thymoma, bronchopulmonary carcinoid, and malignant pleural mesothelioma. The overall incidence of thymoma in the United States is 0.15 cases per 100,000 persons.1 Thymoma is the most common tumor of the anterior mediastinum, accounting for 30% of anterior mediastinal lesions and 20% of all mediastinal tumors in adults. The rate for bronchopulmonary carcinoids is 0.6 per 100,000 persons,2 which represent roughly 30% of neuroendocrine tumors.3 There are 10 cases per million people with malignant pleural mesothelioma (MPM) annually; it is classically linked to asbestos exposure.4 Rates of MPM are expected to peak in the United States in 2025. Biologic Characteristics Most thymomas are slow-growing tumors with an indolent natural history and are associated with myasthenia gravis. More aggressive thymomas are capable of locoregional invasion and progression. Pulmonary carcinoids generally are nonfunctional, but can sometimes cause paraneoplastic carcinoid syndrome. Negative prognostic factors include histologic atypia, nodal involvement, and the presence of intrathoracic symptoms at presentation. MPM is aggressive, and local progression by direct extension in the pleura is the primary cause of symptoms and death. Staging Evaluation Patients suspected of having thymoma or pulmonary carcinoid require routine physical examination, standard blood work, evaluation for paraneoplastic syndromes, and chest imaging. Attempts to obtain an affirmative tissue diagnosis should be pursued, when feasible, to prior to resection.5 Patients with suspected mesothelioma should be screened for a history of asbestos exposure; undergo imaging of the chest, abdomen, and pelvis; and be assessed for surgical candidacy. Although thoracentesis, percutaneous fine-needle aspiration, or ultrasound-guided core biopsy may yield an affirmative tissue diagnosis, the most accurate method is video-assisted thoracoscopic biopsy.

Primary Therapy Complete en bloc surgical resection should be attempted for resectable nonmetastatic thymomas. Curative resection of localized primary lung carcinoids is the treatment of choice. Endoscopic laser ablation may be used to palliate tumor obstruction, improve atelectasis, and reduce inflammation before resection. Extrapleural pneumonectomy (EPP) and pleurectomy are extensive surgical procedures for mesothelioma; patients require careful assessment to ensure that the operation will be tolerated physiologically. Adjuvant Therapy Encapsulated, noninvasive, stage I thymomas do not require adjuvant radiation therapy. It is controversial whether all stage II thymomas benefit from adjuvant radiotherapy (RT).6–8 Adjuvant RT should be considered for stage III–IV thymomas, positive margins, or recurrent disease. Typical carcinoids with negative margins do not require adjuvant therapy after resection. Adjuvant RT can be considered with high-risk features, such as size (> 3 cm), positive nodes, positive margins, and histologic atypia. Symptoms related to carcinoid syndrome, including flushing, can be relieved by pharmacologic agents such as octreotide.9 For mesothelioma, postoperative RT is controversial but can potentially reduce ipsilateral thoracic failures. Postoperative irradiation should include the entire volume immediately adjacent to the pleural space. Locally Advanced Disease Preoperative RT and definitive RT plus or minus concurrent chemotherapy are effective in patients with nonresectable thymoma or pulmonary carcinoid. Radiation for nonresectable mesothelioma is generally palliative in nature by virtue of adjacent normal tissue constraints. Palliation Thymomas, carcinoids, and mesothelioma are responsive to radiation and RT provides effective palliation for incurable symptomatic disease.

THYMIC TUMORS

degenerated keratinized epithelial cells (Hassall corpuscles), myoid cells, thymic lymphocytes (“thymocytes”), and B lymphocytes, which form rare germinal centers.10 Although various tumors and cysts can arise in the thymus, tumors of the thymus are uncommon. Most thymic tumors arise from the epithelial cells and they account for roughly 50% of anterior mediastinal masses.11,12 The most common thymic tumors are thymomas, thymic carcinomas, and thymic carcinoids. Ninety percent of thymomas are found in the anterosuperior mediastinum, and are the most common

The thymus gland is a bilobed lymphoepithelial organ located in the anterior mediastinum, behind the sternum and in front of the great vessels. In early life, the thymus functions in T-lymphocyte differentiation and maturation and releases T lymphocytes into the circulation. It weighs 12 to 15 g at birth and 40 g at puberty; during adulthood, it slowly involutes and is largely replaced by adipose tissue. The thymus is composed of an outer cortex consisting primarily of epithelial cells,

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CHAPTER 52 tumor found in the anterior mediastinum.12,13 Thymomas are associated with an exuberant lymphoid component composed of immature cortical thymocytes. Although they appear benign histologically, they may exhibit invasive clinical behavior. Thymic carcinomas (type C thymomas) also arise in the thymic epithelium, but are highly invasive and can metastasize. The histologic subtypes include clear cell, sarcomatoid, and anaplastic carcinoma. Low-grade thymic carcinomas (well-differentiated squamous cell carcinomas, basaloid carcinomas, and mucoepidermoid carcinomas) are characterized by a relatively more favorable clinical course, with a lower incidence of local recurrence and metastasis.14,15 Neuroendocrine tumors of the thymus are rare and likely fall into the spectrum of small cell carcinoma and neuroblastoma. These neuroendocrine carcinomas account for less than 5% of all neoplasms of the anterior mediastinum, and the presence of a small cell carcinoma should be ruled out prior to surgical resection. Unlike carcinoids in other locations, most thymic carcinoids behave aggressively, often invade locally, and commonly metastasize to regional lymph nodes.16–18 Approximately 50% of patients may develop endocrine abnormalities.19

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World Health Organization Classification of Thymic Epithelial Tumors

TABLE 52.1 Type A

Pathologic Classification Medullary thymoma Spindle cell thymoma

AB

Mixed thymoma

B1

Lymphocyte-rich thymoma Lymphocytic thymoma Predominately cortical thymoma Organoid thymoma

B2

Cortical thymoma

B3

Epithelial thymoma Atypical thymoma Squamoid thymoma Well-differentiated thymic carcinoma

C

Thymic carcinoma

Prognosis Benign clinical course

Moderately malignant clinical course

Highly malignant clinical course

Etiology and Epidemiology Thymomas are rare in the United States and data from the Surveillance, Epidemiology, and End Results (SEER) program estimate a thymoma incidence of 0.13 to 0.15 per 100,000 people.1 The typical age of onset of thymoma is between 40 and 60 years with a median age of 52 years and equal gender distribution.20–23 Thymomas are even more rare in children, accounting for approximately 15% of anterior mediastinal masses.20–23 Thymic carcinomas are distinct from invasive thymomas, both pathologically and clinically.24 They account for 5% to 36% of all thymic neoplasms, the wide range in incidences reflecting differences and changes in the pathologic classification of this rare tumor.25–28 Patients with thymic carcinoma are typically middle-aged or elderly, and there is a slight male predominance. Thymic carcinoids represent less than 5% of anterior mediastinum lesions29,30 and typically affect middle-aged men.15 A number of hypotheses surround the genesis of thymic tumors. There is a reported association between Epstein-Barr virus (EBV) infection and tumors of the thymus. As such, thymic diseases are more common in the far East, where the endemic EBV infection rates are high.31,32 Defective viral genomes have been isolated in patients with lymphoepithelioma-like thymic carcinoma lending further evidence of a role of viral infection in carcinogenesis.31,33–35 Childhood thymus irradiation has been linked to the development of thymic tumors,36 and familial cases have been reported, suggesting a possible relationship with cytogenetic anomalies.37,38 In an analysis of secondary or concomitant neoplasms in 1495 patients with acute lymphoblastic leukemia enrolled in two consecutive multicenter protocols, an increased risk of solid tumors was identified.39 Although the histologic characteristics of these second malignant tumors varied, thymoma was among the solid tumors identified in adult survivors of acute lymphoblastic leukemia. Among patients with primary thymic carcinoid tumors, up to 30% had multiple endocrine neoplasia type 1 or 2.40,41 Chromosomal abnormalities and loss of heterozygosity may also play a key role in thymic neoplasia. A distinctive chromosome abnormality involving translocation of fragments of chromosomes 15 and 19 [t(15:19) (q15:p13)] have been identified in children and young adults with thymic carcinoma.42–44 Deletion of the short arm of chromosome 6 is also associated with benign thymomas,45 suggesting that putative tumor suppressor genes involving chromosome 6 may contribute to the pathogenesis.46 In a small study of 37 cases, most World Health Organization (WHO) type A thymomas (Table 52.1) did not show any chromosomal

aberrations, whereas type B3 thymomas and thymic carcinoma (i.e., type C thymoma) shared some genetic aberrations, including the loss of chromosome 6 and the gain of chromosome 1q.47 The loss of chromosome 6, on which the human leukocyte antigen locus and some of the tumor suppressor genes have been identified, and the gain of chromosome 1q, to which growth promoter genes have been mapped,47–49 may play a role in tumorigenesis and pathogenesis of the paraneoplastic autoimmunity characteristics of thymoma.

Biologic Characteristics and Molecular Biology Patients with thymoma may have dysregulation of the lymphocyte selection process, associated with abnormal proliferation, autoimmunity, and immunodeficiency. Thymoma-associated autoimmune disease involves an alteration in circulating T-cell subsets.50–52 Factors influencing the different biologic behaviors of thymoma subtypes are poorly understood, although the increase in molecular profiling going forward may provide arguably better links to prognosis than stage alone.53–55 Altered TP53 expression may be implicated in the initial stages of tumorigenesis, and increased expression of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) may play a role in thymomagenesis.56 A decreased overall survival (OS) time is predicted by Src tyrosine kinase and TP53 coexpression.57 It has also been proposed that a deficiency in the autoimmune regulator (AIRE) gene has an oncogenic effect on thymomas. AIRE expression is lacking in approximately 95% of thymomas; therefore, loss of AIRE expression may provide a potential mechanistic link for the well-recognized association of autoimmunity with thymoma58,59 along with aneuploidy and expression of muscle autoantigens.60 Thymic carcinomas possess overt features of malignancy, similar to those of carcinoma arising in any other organ, with a higher propensity for capsular invasion and metastases than invasive thymomas. Paraneoplastic syndromes occasionally exist with well-differentiated lesions.61,62 Most variants of thymic carcinoma are highly lethal, producing frequent metastases to regional lymph nodes, bone, liver, and lung.63–65 Thymic carcinoma has been associated with increased expression of epithelial membrane antigen and cytokeratin subtypes.66–71 Markers for thymic carcinomas (as compared with thymomas) include somatic KIT gene mutations, CD70, CD5, and CD99, along with negative thyroid transcription factor-167 and a distinct cytokeratin profile.72–78 There may also be aberrant epigenetic regulation in these neoplasms, such as that

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mediated by the TET2 gene.79 Thymic carcinomas can be distinguished from lung carcinomas by a negative expression of TTF-1, and radiologic typing may provide further genomic/radiomic-based differentiation of thymomas.80,81

Histopathology In 1999, the WHO published a classification including six subtypes of thymic tumor, based on the relative proportion of epithelial and lymphocytic cells (see Table 52.1). This is the most widely accepted histologic classification system, and the WHO cell type is an independent prognostic factor.82–86 However, there is no direct correlation between the histopathology of thymomas and their malignant potential.20,87,88 The histologic diagnosis of thymoma can be difficult, and a variety of systems have been proposed to do so. The WHO classification, developed in 1999 and revised in 2004, is the one most widely accepted. Tumors with true malignant cytologic characteristics are considered to be thymic carcinomas rather than thymomas. Invasive thymomas invade the capsule macroscopically or microscopically, with typically “bland” cytologic characteristics of thymic epithelial cells admixed with mature lymphocytes. The term invasive thymoma should be used instead of malignant thymoma to denote the tumor’s predilection for capsular invasion. Grossly, thymomas are nodular, multilobulated, and firm. They may contain cystic spaces, calcification, or hemorrhage and may be neatly encapsulated, adherent to surrounding structures, or invasive. Thymomas generally have epithelial and lymphatic cells. They are classified as predominantly epithelial, predominantly lymphocytic, mixed lymphoepithelial, or spindle cell type. Morphologically, thymoma cells are rather large and may be round, oval, or spindle shaped with vesicular nuclei and small nucleoli. The cytoplasm is often eosinophilic or amphophilic. Thymic neoplasms arise from epithelial cells (Fig. 52.1). The lymphocytic component is mostly normal-appearing mature lymphocytes. Some of the other microscopic features that may be seen in thymomas include Hassall corpuscles, keratinizing squamous epithelium, rosettes, glands, cysts, papillary structures, and germinal centers. Immunohistochemistry is often helpful in making the diagnosis. Thymomas typically stain positive for thymic epithelial markers, including cytokeratin, thymosin β3 and α1, and epithelial membrane antigen. Thymic carcinomas exhibit malignant cytologic features, commonly with squamous differentiation. Other subtypes include lymphoepithelioma-like carcinomas, clear cell carcinomas, sarcomatoid carcinomas, adenosquamous carcinomas, mucoepidermoid carcinomas, adenocarcinomas, and basaloid squamous cell carcinomas.15,88 The histologic features of thymic carcinoids are identical to carcinoid tumors in other organs. Unlike thymomas, they are rarely encapsulated. Immunohistochemically, they may stain positively with CAM 5.2, low-molecular-weight cytokeratins, chromogranins, synaptophysin, and leucine-7.89

Clinical Features Most thymic tumors are discovered during myasthenia gravis work-up or incidentally on chest imaging. In fact, up to 70% of thymomas may be associated with paraneoplastic syndromes.27 Clinical symptoms vary greatly, depending on the size of the tumor and its effect on adjacent structures, but they are usually those of a mediastinal mass producing cough, chest pain, dyspnea, hoarseness, superior vena cava syndrome, and symptoms related to tumor hemorrhage.15,90,91 Patients may also have dysphagia, fever, weight loss, and anorexia. Some thymomas present with symptomatic paraneoplastic syndromes; the most common is myasthenia gravis, which is seen in approximately 45% of patients.92,93 Box 52.1 lists other syndromes.13,92,94–96 Thymic carcinoids may also be associated with Cushing syndrome, Eaton-Lambert

A

B Fig. 52.1 Lymphocyte-rich thymoma with dense lymphocytic cell population containing scattered larger epithelial cells with pale cytoplasm surrounding perivascular spaces. (A) Low power (×100). (B) High power (×400).

syndrome, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and hypercalcemia,19 but the classic carcinoid syndrome is rare. The causes of these syndromes remain obscure; autoantibodies have been demonstrated, albeit mostly in patients with thymoma.97–99 Myasthenia gravis is an autoimmune neuromuscular junction disorder characterized by the presence of antiacetylcholine receptor antibodies, which cause an acetylcholine receptor deficiency at the motor endplate. The disease is characterized by rapid exhaustion of voluntary muscular contractions, with a slow return to the normal state.96,100 Myasthenia gravis is common with thymoma, but rare in thymic carcinoma. Death in patients with thymoma and myasthenia gravis is commonly caused by complications of myasthenia gravis, whereas in patients without myasthenia gravis, death often is attributed to local progression of tumor.101 Older series reported a poor prognosis associated with myasthenia gravis,21,22,102 but several modern series have failed to confirm this observation.103–108 Myasthenia gravis may even confer a survival advantage because neuromuscular symptoms may lead to earlier discovery of localized disease.109–111 After thymectomy, patients with myasthenia gravis have attenuation of symptomatic severity over time, but not necessarily complete resolution.112–114

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CHAPTER 52

Paraneoplastic Diseases Associated With Thymoma BOX 52.1

Addisons disease Carcinoid syndrome Chronic mucocutaneous candidiasis Cushing syndrome DiGeorge syndrome Erythroid and neutrophil hypoplasia Hashimoto thyroiditis Hyperparathyroidism Hyperthyroidism Hypertrophic osteoarthropathy Hypogammaglobulinemia Lambert-Eaton syndrome Lupus erythematosus Myasthenia gravis Myocarditis polyarthropathy Myotonic dystrophy Myotonic dystrophy scleroderma Nephrotic syndrome Pancytopenia Panhypopituitarism Pemphigus Pernicious anemia Polymyositis Polyneuritis Red cell aplasia Rheumatoid arthritis Sarcoidosis Sjögren’ syndrome Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Ulcerative colitis Whipple disease

The predominant pattern of spread of thymomas is by direct invasion into adjacent organs. The degree of encapsulation and the invasion of adjacent tissues define prognosis for these tumors, rather than the histologic appearance.95 However, approximately 50% of cases in surgical series are noninvasive.12,20–22,101,115 Thymomas may metastasize as implants on pleural surfaces or pulmonary nodules, but rarely to extrathoracic areas.116 When thymomas disseminate, the most common site is the pleural cavity, where they form plaques, malignant pleural effusions, and diaphragmatic masses. Invasion into the superior vena cava, brachiocephalic vein, lung, and pericardium may also be observed.117 Thymic carcinomas invade locally and often involve the pleura and mediastinal nodes. Up to 30% of thymic carcinomas and carcinoids are metastatic to regional lymph nodes and distant sites at diagnosis.16,26,118 Thymic carcinomas have also been noted to spread to nonregional nodal regions, such as the neck and axilla.119 Distant metastases to the lungs, liver, and bone can also occur in 30% to 40% of cases,19 and they may be seen in up to 70% of patients within 8 years of initial diagnosis.120 Brain metastases are altogether rare, but have been documented.121

Prognosis The two most important prognostic factors for thymoma are invasiveness (stage) and completeness of surgical resection.21,23,103,104,122 Capsular invasion is commonly used as the basis for designation as benign or malignant. Tumor size and the presence of symptoms could also have

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prognostic value.118,123–126 Patients with complete or radical excision have significantly improved survival over those with subtotal resection or biopsy only.122,127 Although almost all noninvasive thymomas can be totally resected, the ability to achieve a complete resection in invasive cases varies from 58% to 73%.101,122,128 The 5-year and 10-year survival rates for well-encapsulated thymomas without invasion are more than 90%, and for invasive thymomas, the rates range from 30% to 70%.102,115,122,128 The 5-year survival rates according to Masaoka stage are 83% to 100% for stage I disease, 86% to 98% for stage II, 68% to 89% for stage III, and 50% to 71% for stage IV disease.16,122,129,130 The approximate 10-year survival rates are 80%, 78%, 47%, and 30%; the respective 15-year rates are 78%, 73%, 30%, and 8% for stages I to IV.130 Table 52.2 provides a summary of treatment results of the aforementioned thymoma studies, as well as additional investigations.131–143 A retrospective study of 324 patients found that patients with WHO types A, AB, and B1 had a 100% disease-specific survival rate without RT and therefore did not benefit from adjuvant RT.144 There was no survival difference for cell types B2 and B3 with or without adjuvant RT. Rieker et al.145 noted that survival rates of patients with types A, AB, B1, and B2 were better than for type B3, and that type C had the lowest OS. The prognostic value of the subtype of type B thymomas has been examined in one series that found no differences in recurrence or survival rates among the three subtypes of type B, but all patients who experienced recurrence had stage III disease, indicating an association with Masaoka stage.146 Although the degree of tumor invasiveness is strongly related to stage and prognosis, no data support the prognostic significance of the histologic findings, independent of tumor stage.106,147,148 The historical classification proposed by Marino and Muller-Hermelink categorized thymoma as cortical, mixed, and medullary types.149 Thymomas arising from the epithelial cells of the cortex were classified as cortical thymomas, and those arising from the medullary spindle cells were classified as medullary thymomas. Of note, thymic carcinomas were categorized as a separate entity. As with thymomas, total resection and stage at presentation are important prognostic factors for thymic carcinoma.16 Extensive lymph node dissection (> 10 nodes) is needed to accurately stage patients, and disease-free survival (DFS) can be as high as 90% in patients with N0 with extensive nodal dissection, whereas patients with node-positive disease can have DFS on the order of 33%.150,151 A nine-gene assay has been developed that dichotomizes thymomas into high- and low-risk of metastasis, with 10-year metastasis-free survival of 77% and 26%, respectively.152 This product is available commercially.153

Diagnostic Work-Up for Thymic Tumors The history and physical examination for a suspected thymoma should focus on signs and symptoms suggestive of myasthenia gravis, such as fatigue, diplopia, ptosis, and dysarthria. Constitutional symptoms such as fever, chills, and weight loss may suggest a mediastinal lymphoma. Routine screening blood work and chemistry testing may give clues to the presence of associated syndromes. In the case of suspected Cushing syndrome, a dexamethasone suppression test and urinary cortisol level should be obtained, although some carcinoids can be suppressed, which can make diagnosis difficult. The differential diagnosis, in addition to thymic lesions, includes germ cell tumors, lymphomas, and thyroid proliferative disorders. Serum alpha-fetoprotein and beta-human chorionic gonadotropin levels should be obtained in young men if a nonseminomatous germ cell tumor is suspected.154–156 Exclusion of metastases from extrathymic primary tumors is additionally important. The chest radiograph (Fig. 52.2) and CT scan with contrast defines the characteristics of a mediastinal lesion, as well as its relation to or

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TABLE 52.2

Selected Studies of Adjuvant Therapy for Thymoma

Study

No. Patients (Stage)

Irradiation Regimen

Radiation Dose

Local Control Rate (%)

5-Year Survival

2004

43 (III) 20 (IVA)

Preoperative/ postoperative ± chemotherapy

24 Gy-30 Gy preoperative 45 Gy–55 Gy postoperative

—

Median PFS 59% (III) 21% (IVA)

Preoperative radiation therapy improved resection rate

Cowen et al.132

1995

13 (I) 46 (II) 58 (III) 32 (IVA)

Preoperative/ postoperative ± chemotherapy

22 Gy–50 Gy preoperative 30 Gy–70 Gy postoperative (median, 40 Gy–55 Gy)

78.5% (overall rate) 100% (I) 98% (II) 69% (III) 59% (IVA)

59.5% (DFS) (49.5% at 10 yr)

Stage and extent of resection influenced local control and survival rates

Curran et al.115

1988

43 (I) 21 (II) 36 (III) 3 (IV)

Postoperative for stages II-IV

32 Gy–60 Gy

100% (II-III, total resection) 79% (II-III, subtotal resection or biopsy)

100% (I) (DFS) 58% (II) 53% (III)

No recurrence for stage I after surgery only; radiation therapy improved local control rates for stages II-III

Haniuda et al.133

1992

70 (II/III)

Postoperative

40 Gy-50 Gy

100% (IIp1)a 70% (III)

74% (II) 69% (III)

Radiation therapy benefited patients with pleural adhesion, without microinvasion

Jackson and Ball230

1991

28 (II/III)

Postoperative (after biopsy or subtotal resection)

32 Gy–60 Gy (mean, 42 Gy)

61%

53% (OS) (44% at 10 years)

High rate of radiation therapy complications (11%), with two deaths

Kondo and Monden16

2003

522 (I) 247 (II) 201 (III) 101 (IV)

Postoperative ± chemotherapy

— 43.7 Gy ± 7.7 Gy (II) 45.4 Gy ± 8.4 Gy (III)

99.1% (I) 95.9% (II) 71.6% (III) 65.7% (IV)

100% (I) 98% (II) 89% (III) 71% (IV)

Largest study; no difference in recurrence rates ± radiation therapy in stages II and III patients; high complete resection rates

Latz et al.292

1997

10 (II) 14 (III) 19 (IV)

Postoperative ± chemotherapy

10 Gy–72 Gy (median, 50 Gy)

81%

90% (II) 67% (III) 30% (IV)

Uncertain radiation therapy benefit for completely resected stage II tumors

Mornex et al.134

1995

21 (IIIA) 37 (IIIB) 32 (IVA)

Preoperative and postoperative ± chemotherapy

30 Gy–70 Gy (median, 50 Gy)

86% (IIIA) 59% (IIIB-IVA)

64% (IIIA) 39% (IIIB)

Great impact of radiation therapy on local control rates; > 50 Gy recommended for incompletely resected tumors

Nakahara et al.128

1988

45 (I) 33 (II) 48 (III) 12 (IVA) 3 (IVB)

Postoperative (73% received radiation therapy)

30 Gy–50 Gy

—

100% (I) 91.5% (II) 87.8% (III) 46.6% (IV) 97.6% (complete resection) 68.2% (subtotal) 25% (biopsy)

Complete resection plus radiation therapy resulted in best survival rates

Ogawa et al.135

2002

13 (I) 61 (II) 25 (III)

Postoperative

30 Gy–61 Gy (median, 40 Gy)

RFS 100% (I) 90% (II) 56% (III)

100% (I) 90% (II) 48% (III)

8% mediastinal failure in involved-field group versus 0 for mediastinal field; however, pleural failure is dominant in both

Pollack et al.127

1992

11 (I) 8 (II) 10 (III) 7 (IV)

Postoperative; primary RT (22 patients)

50 Gy (median)

59% (OS)

74% (I) 71% (II) 50% (III) 29% (IV)

Patients with incomplete resections did worse; multimodality treatment recommended for these patients

Singhal et al.6

2003

30 (I) 40 (II)

Postoperative vs. surgery alone

45 Gy–54 Gy

98.6% (OS)

94% (I) 90% (II)

One recurrence each in the surgery-alone and postoperative RT groups

Bretti et al.

Year 131

Comments

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CHAPTER 52

Uncommon Thoracic Tumors

873

TABLE 52.2

Selected Studies of Adjuvant Therapy for Thymoma—cont’d

Study Urgesi et al.104

Year 1990

No. Patients (Stage) 59 (III) 18 (IVA)

Irradiation Regimen Preoperative and postoperative

Radiation Dose 39.6 Gy–60 Gy

Local Control Rate (%) 85% to 90%

5-Year Survival 78% (III) (58% at 10 years)

Zhu et al.136

2004

47 (I) 41 (II) 41 (III) 32 (IVA) 9 (IVB)

Postoperative and definitive

50 Gy–55 Gy 60 Gy–65 Gy

96% (II) 56% (III) 43% (IVA) 22% (IVB)

86.4% (OS) 96% (II) 78% (III) 57% (IVA) 36% (IVB)

No local control or survival benefit for extended-field versus involved-field radiation therapy

Shen et al.137

2013

21 (I) 30 (II) 15 (III) 6 (IV)

Postoperative

45 Gy–64 Gy

94% WHO Type A + AB 87% WHO Type B1-3

Adjuvant RT showed no obvious survival benefit

Safieddine et al.138

2014

66 (I), 123 (II), 45 (III), 11 (IV), remainder unknown

Postoperative, preoperative

-

-

95%

Radiotherapy not independently associated with survival

Omasa et al.139

2015

895 (II), 370 (III)

Postoperative

-

-

91% (with RT), 87% (without)

No impact of RT on RFS or OS

Modh et al.140

2016

5 (I-II) 110 (III-IVA)

Postoperative, definitive

54 Gy (median)

-

81%

No direct assessment of RT alone

Yan et al.141

2016

33 (I), 22 (II), 18 (III), 15 (IV)

Postoperative, definitive

Median 50.4 Gy (range, 45 Gy–70 Gy)

-

For stages II/III, 73% (surgery alone), 88% (surgery + RT)

No PFS or OS benefit to addition of RT

Rimner et al.142

2016

870 (II), 393 (III)

Postoperative

90% without adjuvant radiotherapy, 95% with

Adjuvant radiotherapy associated with increased survival, but not recurrence-free survival

Carillo et al.143

2017

88 (II)

Postoperative

96%

High survival with surgery and adjuvant RT

40 Gy–55 Gy

94%

Comments Most relapses were out of radiation therapy fields

a

Fibrous adhesion to the mediastinal pleura without microscopic invasion. DFS, Disease-free survival rate; Gy, gray; OS, overall survival rate; PFS, progression-free survival rate; RFS, recurrence-free survival rate; ±, with or without.

A B Fig. 52.2 (A) Anteroposterior chest radiograph demonstrates a mass (arrow) projecting over the left mediastinum and hilum. (B) Lateral chest radiograph confirms the location of the mass in the anterior mediastinum.

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874

SECTION III

Disease Sites

A

B Fig. 52.3 Computed tomography (CT) demonstrates a mass (arrow) with calcification in the anterior mediastinum. (A) Axial view. (B) Coronal view.

Points

0

10

20

30

40

Infiltration of surrounding fat

Total points

60

70

80

90

100

"7 cm

Tumor size before chemotherapy !7 cm

Roundness

50

Lobulated Round Yes No

0

40

Probability of stage III/IV

80

120 0.2

160 0.4

200 0.6

240 0.8

0.1 0.3 0.5 0.7 Fig. 52.4 Nomogram to Predict Stages III/IV Thymoma Using Computed Tomography Findings at Presentation. (Used with permission from Marom EM, Milito MA, Moran CA, et al: Computed tomography findings predicting invasiveness of thymoma. J Thorac Oncol. 2011;6(7):1274–81.)

invasion of other mediastinal structures.157–159 Thymic tumors are usually homogeneous, well-demarcated lesions with a round or lobulated shape, and occasionally have calcifications (Fig. 52.3).160,161 The presence of fat planes between the tumor and adjacent structures suggests localized disease. Pleural involvement may be seen in advanced disease. The radiographic presence of both an anterior compartment mass as well as “drop” metastases to the pleura is highly suggestive of the diagnosis. Thymic carcinomas often contain calcifications, cysts, or necrosis on imaging.162 A nomogram has been developed by Marom et al.163 using CT characteristics to predict the Masaoka stage (Fig. 52.4), which can also be utilized to predict tumoral response to neoadjuvant therapy.164 In the absence of symptoms and signs, extensive radiographic imaging is unnecessary. Magnetic resonance imaging (MRI) has not been shown superior to CT scanning.165,166 The role of positron-emission tomography (PET) has not been well established, as FDG (fluorodeoxyglucose) uptake in thymomas is variable.

However, PET/CT can help distinguish thymomas from thymic carcinomas, although conflicting data exist regarding the capacity to predict WHO grade.167–171 A report of 51 patients found that FDG uptake was higher in patients with thymic carcinoma than thymoma, and type B3 thymomas had higher uptake than lower histologies (A through B2).169 Similar results were seen in 47 patients from Italy, where maximum standardized uptake value (SUVmax) and ratio of SUVmax to tumor size correlated with WHO grade and Masaoka stage.170 However, a series of 58 patients from Japan found that, although SUVmax can differentiate between thymic carcinoma and thymoma, there was no difference between the low- and high-risk thymoma groups.167 High uptake of FDG also appears to correlate with the degree of tumor invasiveness,172–174 and may be helpful in identifying nodal and distant metastasis.168 Depending on the particular institution, patients presenting with a thymic mass may need histologic diagnosis before definitive therapy. CT- or ultrasound-guided fine-needle aspiration biopsy can establish

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CHAPTER 52

TABLE 52.3

Thymoma

Masaoka Staging System for

Uncommon Thoracic Tumors

TABLE 52.4

Malignancies

875

TNM Staging of Thymic

Stage

Description

I

Macroscopically completely encapsulated with no microscopic detectable capsular invasion

TX

Primary tumor cannot be assessed

Macroscopic invasion into surrounding mediastinal fatty tissue or mediastinal pleura or microscopic invasion into the capsule

T0

No evidence of primary tumor

T1

Localized tumor limited to pleural involvement

T1a

Encapsulated or unencapsulated, with or without extension into mediastinal fat

T1b

Extension to mediastinal pleura

T2

Extension to/involvement of the pericardium

T3

Extension to/involvement of the lung, brachiocephalic vein, superior vena cava, chest wall, phrenic nerve, extrapericardial vessels

T4

Extension to/involvement of the great vessels, myocardium, trachea, or esophagus

II

PRIMARY TUMOR (T)

III

Macroscopic invasion into surrounding organs (e.g., pericardium, great vessels, lung) or intrathoracic metastases, or both

IVA

Pleural or pericardial implants or dissemination

IVB

Lymphogenous or hematogenous metastases

Adapted from Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981;48:2485–92.

REGIONAL LYMPH NODES (N) 175

the diagnosis preoperatively with a sensitivity and specificity of 87% to 90% and 88% to 100%, respectively.176 When larger tumor samples are required to distinguish between lymphoma and lymphoidpredominant thymoma, core-needle biopsy provides sufficient specimens with an overall sensitivity of 96% and specificity of 100%.176 Bronchoscopy, video-assisted thoracoscopic surgery, mediastinoscopy, or anterior thoracoscopy may help yield the diagnosis before resection, especially if enlarged lymph nodes are present.154,177,178 The potential risk of capsule rupture, leading to spillage and seeding of tumor cells during biopsy, has been debated and remains unsettled.102,179,180

Staging

NX

Regional nodes cannot be assessed

N0

No lymph node metastasis

N1

Anterior (perithymic) node(s)

N2

Deep intrathoracic, pericardial, or distant node(s) DISTANT METASTASIS (M)

MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1a

Separate pleural or pericardial nodule(s)

M1b

Metastasis in pulmonary parenchymal or other distant organ(s)

181

Bergh et al. introduced the first clinical staging system for thymoma in 1978. Their staging system was subsequently modified by Masaoka et al.122 in 1981 and is the most widely accepted (Table 52.3). It is largely based on pathologic findings at time of surgery. A separate, simplified staging paradigm was proposed by Suster and Moran.182 Stage I lesions are localized and encapsulated; stage II lesions are locally invasive; and stage III lesions have nodal, visceral, or distant metastasis. Although a tumor-node-metastasis (TNM) staging system was proposed by Tsuchiya et al.,183 there were no TNM classifications for thymic neoplasms until the AJCC 8th edition (Table 52.4).184 This recent framework may better help to predict and stratify outcomes.185

STAGE GROUPINGS I

T1 N0 M0

II

T2 N0 M0

IIIA

T3 N0 M0

IIIB

T4 N0 M0

IVA

Any T N1 M0 Any T N0-1 M1a

IVB

Any T N2 M0-1a Any T Any N M1b

Surgery for Thymoma

From Amin MB, Edge SB, Greene FL, et al., editors, for the American Joint Committee on Cancer: AJCC Cancer Staging Manual, ed 8. New York, Springer, 2016.

Surgical resection is the primary therapy for thymomas. Supporting retrospective data, randomized evidence now indicates that patients who present with symptoms of myasthenia gravis benefit from a thymectomy, although the risk of myasthenic events may not entirely dissipate after surgery.103,186–191 Consequently, surgical resection alone for stage II thymomas is a reasonable approach.6,7 In general, surgical resection for thymoma carries low risks of morbidity and mortality; most surgical deaths can be attributed to a myasthenia gravis crisis, but the risk can be minimized with appropriate perioperative management, including plasmapheresis, in selected situations.101,192 After an encapsulated thymoma without associated myasthenia gravis is removed without disturbing the integrity of the capsule, recurrences are rare.21,193–195 Successful surgical treatment of locally invasive thymoma depends on the completeness of resection.196 Consequently, the surgeon should remove as much of the lesion as possible, including surrounding mediastinal fat, thus possibly converting to an extended thymectomy.197 However, resection of an involved phrenic nerve is controversial,

and surgeons advocate debulking alone, leaving both phrenic nerves intact if there is phrenic nerve involvement because of the respiratory morbidity from resection. When complete resection is not possible, although definitive radiation therapy is a consideration, a debulking operation can be considered, because good long-term results can be achieved when such surgery is followed by postoperative radiation therapy.101 For stage IVA cases, one-fourth of which are resectable,59 surgical approaches have varied from discrete resection of pleural metastases to en bloc mediastinal dissection with extrapleural pneumonectomy (EPP).92 A few small single-institution series have suggested that EPP may improve local control rates for large-volume disease.198–200 The conventional surgical approach for thymoma resection uses an open sternotomy; however, there has been recent interest in using limited or minimally invasive techniques, with encouraging results, especially for

Treatment

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876

SECTION III

Disease Sites

smaller and noncystic tumors.201–206 The surgeon should delineate the extent of the tumor, specify the areas of invasion, and identify the areas of positive or questionable margins and residual disease with metallic clips to assist future radiation therapy planning.

Radiation Therapy for Thymoma Although the role of adjuvant irradiation for invasive thymomas has never been tested in a randomized fashion, RT is an effective adjuvant therapy for invasive thymomas,207,208 and most retrospective studies have reported improvements in local tumor control and survival rates after adjuvant irradiation, along with a corresponding shift in patterns of failure.96,111,113,124,127,209,210 Patients with completely resected stage I thymoma should not routinely receive postoperative RT as the recurrence rate is approximately 0 to 2%.89,96,199–201 Controversy exists regarding whether adjuvant RT should be used for completely resected stage II thymomas. The rationale for offering adjuvant RT is that local recurrence rates may approach 30% in certain series and that RT can spare patients from repeat thoracotomy to salvage recurrence.115,118,144,211 Kondo and Monden16 reported a multi-institutional retrospective study of 1320 patients with stage II or III thymic epithelial tumors and found no significant difference in recurrence rates with surgery alone versus adjuvant RT. This observation may reflect the fact that most patients underwent complete resection (100% with stage II disease and 85% with stage III disease); as has been pointed out by the study authors, the recurrence rates they found were lower than in previous reports. On the other hand, a recent analysis from the International Thymic Malignancies Interest Group (n = 1263) showed an increase in both 5- and 10-year overall survival with the addition of adjuvant radiotherapy for both stage II and III disease.142 Additional “meta-analyses” and database reviews have provided conflicting results as to the value of adjuvant radiotherapy for stage II thymoma.212 Two reviews limited to completely resected stage II thymoma found no reduction in recurrence after adjuvant RT,213,214 whereas other studies (albeit with mixed stages included) suggest RT may improve survival.215,216 A SEER study of 901 patients showed a 10% absolute improvement in 5-year OS rates, but no statistical difference in causespecific survival rates in patients with stages II to III disease.211 Two studies from national Japanese databases demonstrated no differences in outcomes with stages II and/or III disease, yet two investigations from the United States National Cancer Database demonstrated increased OS with adjuvant RT for stage II/III cases.217,218 Although the impact of adjuvant radiotherapy on late toxicity has not been extensively studied, a SEER database analysis of 1334 patients treated between 1973 and 2005 did not find an increase in long-term cardiac mortality rates or rates of secondary malignant tumors for patients treated with RT compared with patients treated with surgery alone.219 Patients with gross fibrous adhesions of the tumor to the pleura at the time of surgery may be at particularly high risk for local failure following surgery alone. Haniuda et al.133,220 found that patients with fibrous adhesions to the mediastinal pleura without microscopic invasion benefited most from postoperative RT. Although postoperative RT may decrease local recurrence, as expected, it does not decrease the incidence of subsequent pleural dissemination that may occur outside of the radiation field, which is the most common site of failure after radiation.214

Locally Advanced Thymoma For patients with stage III to IV disease, there is greater consensus regarding the use of adjuvant RT. Urgesi et al.104 reported no in-field recurrences in a study of 33 patients with completely resected stage III thymoma treated with postoperative irradiation. Curran et al.115 reported

a 53% 5-year actuarial mediastinal relapse rate in patients with stages II/III disease after surgery alone, compared with 0 after total resection and irradiation and 21% after subtotal resection or biopsy and irradiation. Similarly, in a study of 70 patients with Masaoka stages III to IV thymoma, the relapse rate for patients receiving postoperative radiation therapy was reduced from 50% to 20%, and most disease (80%) recurred outside of the irradiated field.221 Neoadjuvant RT has been advocated for nonresectable or marginally resectable thymomas.21,222–224 Several small studies assessing preoperative RT for extensive disease found a decrease in tumor burden at the time of surgery, with response rates as high as 80%, and described a theoretical decrease in the potential for tumor seeding during surgery.101,115,132,225 Onuki et al.225 found that a dose of 12 Gy to 20 Gy given to 21 patients with stage III thymomas resulted in a 76% response rate, with more aggressive WHO histologic subtypes having a less robust volume reduction. Preoperative chemoradiation has also been tested in locally advanced thymic tumors with favorable results. Korst et al.226 found that in a group of 22 patients with 71% Masaoka stage III/IV disease with aggressive histology (62% B3 thymoma or thymic carcinoma), two cycles of cisplatin and etoposide concurrent with 45 Gy led to a 77% R0 resection rate and 14% R1 resection rate.226 These series demonstrated that preoperative irradiation facilitated total or subtotal resection of the invasive thymoma mass by reducing the tumor volume.222 Definitive RT has been used in nonsurgical candidates or patients with nonresectable advanced disease.227,228 Overall, definitive RT achieves 65% local control and 5-year survival rates of 40% to 50%.229–231 In a report by Marks et al.,232 tumor was controlled in all nine cases treated with RT with a median follow-up of 5.5 years. Another report observed tumor control in 8 of 11 patients with malignant thymoma with a minimal follow-up of 2 years.233 Five-year survival rates of 53% to 87% and 10-year survival rates of 44% have been reported for these patients. Urgesi et al.234 reported the use of radiation therapy alone in 21 patients with intrathoracic recurrences of thymoma. The 7-year survival rate of 70% was similar between those treated with definitive RT and surgery with adjuvant therapy. However, the retrospective nature of these studies, small number of patients, differing amounts of clinical disease, and variations in radiation doses and techniques are significant confounding variables.

Palliation For incurable disease requiring palliation for intrathoracic or other symptoms, thymic radiation is an effective treatment. Thymic neoplasms are generally responsive to radiation therapy235 and a short course of palliative radiation therapy over 1 to 2 weeks is likely to improve symptoms from tumor burden.236

Chemotherapy for Thymoma In general, thymomas are chemosensitive tumors, but chemotherapy is mostly reserved for locally advanced or metastatic disease. No randomized trials have compared different chemotherapeutic agents.229 Anthracycline- and/or platinum-based regimens have commonly been used, with response rates of more than 50% with the application of cisplatin-based combination chemotherapy.230,237 Commonly employed combinations include cisplatin, doxorubicin, and cyclophosphamide (PAC), with reported overall responses in excess of 70%,235,238,239 along with cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC) with response rates approximating 90% in one study with a 43% complete response rate.240,241 Similar results with combination PAC have been reported in Taiwan; all responders had overexpression of the topoisomerase 2α gene, but patients with no detectable expression progressed with treatment.242

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CHAPTER 52 Trials of cis/carboplatin with amirubicin243 or paclitaxel244,245 have also been reported, with noted efficacy in thymic carcinomas.

Targeted Agents for Thymoma Because thymic tumors harbor a number of molecular aberrations, this has encouraged the exploration of targeted biologic agents.246,247 Although EGFR overexpression is common in thymic tumors,248 complete and durable responses to EGFR-directed therapies are uncommon.249,250 Although patients with thymic carcinomas also have higher serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) than controls,251 low response rates have been observed with bevacizumab and erlotinib.250 Similarly, KIT overexpression led to testing imatinib, which showed no substantial activity.252,253 A Phase II trial of sunitinib in thymic neoplasms that progressed on prior chemotherapy displayed disease control in 91% of patients with thymic carcinoma and 81% of those with thymoma.254,255 Inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus, have been shown in a Phase II study to have a disease control rate of 78% in thymic carcinomas and 94% in thymomas.256 Epigenetic modulation has also shown activity in thymic neoplasia in a phase I/II study of the histone deacetylase inhibitor belinostat and the anti-IGF-1 antibody cixutumumab for recurrent/refractory disease have also shown antineoplastic activity.257

Combined Modality Therapy for Thymoma The role of chemotherapy after resection is controversial and has not been well established, but some evidence indicates that it can be effective with acceptable toxicity in selected cases.258–261 Typically the same drugs used for nonresectable or advanced disease are employed. There is also a suggestion that neoadjuvant chemotherapy is feasible and may improve the resectability of locally advanced thymomas.226,261,262 A Phase II study of 22 patients with nonresectable thymoma treated with induction PAC resection, adjuvant irradiation, and consolidative chemotherapy found a 77% response rate, a 95% 5-year OS rate, and a 79% 7-year OS rate.239 A trial from the Japanese Clinical Oncology Group reported on 23 patients with nonresectable stage III thymoma treated with weekly dose-dense cisplatin, vincristine, doxorubicin, and etoposide and found no deaths from toxicity, but only 57% were able to complete chemotherapy as planned.263 Thirteen of the patients were able to undergo resection, with nine R0 resections. With a 62% response rate, efficacy of the dose-dense regimen was no better than with conventional chemotherapy.235,239 Additional small studies suggest neoadjuvant chemotherapy may improve resectability of locally advanced invasive thymoma.259,260,264 Chemotherapy followed by radiotherapy has also been studied without surgery in locally advanced disease with a median survival of 93 months in one trial using PAC chemotherapy.235

Treatment of Thymic Carcinoma Although the optimal treatment of thymic carcinoma is unclear, surgical extirpation remains the cornerstone of therapy and, in most published studies, surgery has been followed by adjuvant RT.14,118,265–267 Because many series are gathered over decades, it has been difficult or impossible to control for the changes in pretreatment tumor imaging, surgical techniques, and RT planning/delivery, all of which may contribute to the inconsistent results in the literature. A prescriptive dose range has yet to be identified, with most studies using 40 Gy to 70 Gy at 1.8 Gy to 2 Gy per fraction; in general, doses of 45 Gy to 55 Gy are used in the adjuvant setting. It is generally recommended not to exceed definitive doses of 60 Gy. In a series of 26 patients treated with surgery and adjuvant irradiation, Hsu et al.266 observed a 77% 5-year OS rate, with respective 82% and 66% survival rates for completely resected and subtotally resected cohorts.

Uncommon Thoracic Tumors

877

With a median dose of 60 Gy (range, 40 Gy to70 Gy), an excellent 5-year local control rate of 91% was observed. For a cohort of 40 patients receiving definitive or adjuvant RT, Ogawa et al.14 reported an absence of local recurrence for those with complete resection and radiation doses greater than 50 Gy. Kondo and Monden16 reported the largest retrospective comparative study and found no statistically significant survival benefit from the addition of adjuvant RT to surgical resection, although no definitive conclusions could be made owing to subgroup sample size limitations and the retrospective nature of the study. Although local control rates are increased with irradiation, a survival benefit remains to be demonstrated. For patients with any question of clinical resectability, neoadjuvant platinum-based chemotherapy is a reasonable treatment consideration.268 For patients with early stage cancer with completed resected disease, there is some thought that adjuvant radiation is not indicated.269 Table 52.5 summarizes some of the treatment results of thymic carcinoma, including publications not discussed in the text.270–280

Treatment of Thymic Carcinoid Complete surgical resection is the preferred method of treatment, although recurrence and distant metastases are common.16,281,282 A SEER analysis of 160 patients found that the median survival time was 79 months in patients who had surgical resection compared with 26 months in those who did not have surgery.282 Patients who received RT had a worse OS rate, but these patients were also more likely to have advanced disease. In a study of 40 patients, the recurrence rate was 64%, even though 35 of the 40 patients had a complete resection,16 and the 5-year survival rate was 84%. Despite a lack of conclusive evidence, incomplete resections followed by irradiation or chemotherapy (or both) may improve local control rates.30,120,282,283 However, distant metastases occur in approximately 30% of patients.284 The long-term prognosis is poor, with an overall 5-year survival rate of less than 30%.281,285

Techniques of Irradiation For optimal radiation treatment planning, a 4D CT scan with intravenous contrast should be performed to account for respiratory motion.286 Clips placed at the time of surgery denoting the extent of resection in completely resected tumors or outlining regions of residual disease and preoperative imaging are crucial to delineate the postoperative radiation volume. Preoperative imaging should be fused with the 4D CT scan used for radiation planning to aid with contouring the preoperative gross tumor volume (GTV).287 An internal clinical target volume (iCTV) should be generated encompassing the tumor bed and areas of suspected subclinical disease based on the maximal intensity projection and typically, the iCTV will extend 1 to 2 cm from the preoperative GTV. Prophylactic nodal irradiation of regions, such as the uninvolved mediastinal and supraclavicular nodal, is not warranted.288,289 The margin for the planning target volume (PTV) for setup error depends on institution, but generally is a 0.5 to 1 cm expansion from the iCTV when using daily image guidance. Historically, 2D- and 3D-conformal radiation therapy has been used for the treatment of thymic neoplasms. Conventional port arrangements using a number of field arrangements such as two opposed anteroposterior (AP/PA) ports (weighted 2 : 1 or 3 : 2), wedged-pairs, and AP/PA with a posterior off-cord oblique have been used. However, 2D and 3D techniques expose large amounts of uninvolved normal tissues, such as the heart and lungs, to high doses of radiation. As many patients with thymic malignancies are expected to be cured, every effort should be made to employ advances in technology to achieve conformity to reduce the likelihood of late radiation complications. Intensity-modulated radiation (IMRT) with motion management should be considered to improve conformity and allow better sparing

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878

SECTION III

TABLE 52.5

Disease Sites

Selected Studies of Thymic Carcinoma No. Patients 43

Treatment TR/SR ± Ch/RT

Local Control Rate (%) 52 (CR)

16

TR/SR/BX ± Ch/RT

186

TR/ST/BX ± Ch/RT

Study Blumberg et al.118

Year 1998

5-Year OS 65% (35% at 10 years) 68% (TR) 62% (SR)

Comments Masaoka stage was not prognostic, but invasion of innominate vessel was prognostic

Chang et al.265

1992

Kondo and Monden16

2003

77

31% (median, 30 mo)

Better survival rate was seen with squamous type

49 (TR)

50.5% (OS) 66.9% (TR) 30.1% (SR) 24.2% (BX) Subgroups: 72.2% (TR alone) 73.6% (TR + RT) 46.6% (TR + Ch/RT) 81.5% (TR + Ch)

Largest number of patients gathered from multiple institutions in Japan; total resection was the most important factor in survival rate; RT did not improve results for completely resected tumors

Liu et al.270

2002

38

TR/SR/BX ± Ch/RT

27% (MS, 24 mo)

Grade, stage, and resectability were predictors of survival rates

Lucchi et al.268

2001

13

TR/SR ± Ch/RT

46 (OS)

61% (MS, 38 mo)

100% objective tumor response with induction chemotherapy, but small study

Nakamura et al.270a

2000

10

BX + Ch ± RT

0

0% (MS, 11 mo)

Poor survival rate for nonresectable disease; median chemotherapy response was only 6 mo

Ogawa et al.14

2002

40

TR/SR/BX ± Ch/RT

100 (TR + RT)

38% (28% at 10 years)

Long-term study; better survival and local control rates with complete resection + RT (12 of 16 patients versus 1 of 24 patients)

Shen et al.137

2013

43

TR/SR ± Ch/RT

61% at 7 years

Thymic carcinomas are more likely to present with advanced Masaoka stage than thymoma

Roden et al.270b

2013

29

TR/SR/BX ± Ch/RT

36%

Weight loss is associated with worse survival

Okereke et al.198

2012

16

TR/SR ± Ch/RT

63% (MS, 57 mo)

Long-term survival can be achieved with R0 resection

De Montpreville et al.271

2013

37

TR/SR/BX ± Ch/RT

67% at 3 years (MS, 94 mo)

Lymph node dissection should be systematic when resection is performed

Wang et al.272

2014

58

TR/SR/BX ± Ch/RT

-

43%

Stage and degree of resection most important prognostic factors

Ruffini et al.273

2014

229

TR/SR/BX ± Ch/RT

72% (all)

79% (stage I/II), 60% (stage III), 24% (stage IV)

Improved survival to radiotherapy in all patients

Litvak et al.274

2014

121

TR/SR/BX ± Ch/RT

80% (stage I/II), 33% (stage III/ IV)

100% (stage I), 81% (stage II), 51% EPP (stage III), 17-24% (stage IV)

Improved survival with stage IV disease limited to lymph nodes as compared with distant metastasis

Yen et al.275

2014

54

TR ± Ch/RT

-

79% (nonrecurrent disease)

Included both recurrent and nonrecurrent disease; higher PFS with surgery for recurrences

Ahmad et al.276

2015

1042

TR/SR/BX ± Ch/RT

85% (stage I/II), 65% (stage III), 55% (stage IV) at 5 years

60%

Radiotherapy associated with improved recurrence-free and overall survival on multivariable analysis

Fu et al.277

2016

329

TR/SR ± RT

-

67%

Postoperative radiotherapy associated with improved survival

Hishida et al.278

2016

306

TR/SR/BX ± Ch/RT

-

61%

Radiotherapy associated with improved RFS, especially for R0 resection

Tseng et al.279

2016

78

TR/SR/BX ± Ch/RT

-

42% (R0), 33% (R1), 20% (R2), 15% (BX only)

Adjuvant radiotherapy associated with improved survival

Zhai et al.280

2017

135

TR/SR/BX ± Ch/RT

81% at 5 years

42%

Radiotherapy associated with increased locoregional control, especially in advanced stages

88

BX, Biopsy only or nonresectable; Ch, chemotherapy; CR, complete response; DSS, disease-specific survival; EPP, extrapleural pneumonectomy; MS, median survival; OS, overall survival; RT, radiation therapy; SR, subtotal resection or debulking; TR, total or complete resection; ±, with or without. Adapted from Eng TY, Fuller CD, Jagirdar J, et al. Thymic carcinoma. State of the art review. Int J Radiat Oncol Biol Phys. 2004;59:654–64. Downloaded for [email protected] upr07 ([email protected]) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on April 23, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

CHAPTER 52

Uncommon Thoracic Tumors

879

A

B

C Fig. 52.5 Axial (A), coronal (B), and sagittal (C) views for intensity-modulated radiation therapy (IMRT). Isodose lines are closely conformal to the shape of the planning target volume (red).

of normal critical structures.290 Fig. 52.5 shows an IMRT plan, compared with other modalities and techniques in Fig. 52.6. Adjuvant doses of 45 Gy to 55 Gy given by conventional fractionation have been used effectively in most cases.104,109,135,229,291,292 For patients with microscopic or gross residual disease, definitive doses of 60 Gy are likely required to achieve tumor control.134,228,293 With the increasing availability of proton radiation therapy, there is a potential for an improved therapeutic ratio in radiation therapy for thymomas by taking advantage of the proton dose distribution. Multiple studies have displayed the dosimetric superiority of proton therapy over intensitymodulated radiotherapy in decreasing doses to the lungs and heart, which may be correlated with cardiac events and risk of secondary malignancy.294–298 Respecting normal tissue tolerances is paramount to minimizing risk of acute and late radiation toxicity. The maximal dose to the spinal cord should be less than 45 Gy. Complex beam arrangements and arc therapy should be encouraged to maximize degrees of freedom to reduce high and intermediate dose delivered to the heart, lungs, and esophagus. The lung V20 should be kept below 30% to 35%, the heart V40 less than 30%, and maximum esophageal dose less than 60 Gy when using IMRT.

Treatment Algorithm and Controversies The initial treatment for thymic tumors is surgery if the disease is resectable. Adjuvant irradiation should be considered for patients with features at high risk for recurrence. Definitive radiation can be considered for a nonresectable or inoperable tumor. The following guidelines should be considered:

not receive adjuvant therapy after a complete thymectomy (R0 resection, negative margins) with close interval surveillance imaging. B2, B3) with less than a complete thymectomy may benefit from adjuvant RT. Doses of 50 Gy to 60 Gy are generally recommended in this setting. and can be treated with adjuvant radiation after R0 resection to doses of 50 Gy to 54 Gy. B1, B2, B3, C) are recommended adjuvant radiation therapy after a complete thymectomy. neoplasms is controversial. They can be treated with induction chemotherapy plus or minus neoadjuvant chemoradiation followed by resection. Alternatively, nononcologic thymectomy with postoperative thoracic irradiation plus or minus consolidation chemotherapy can be considered.

PULMONARY CARCINOID TUMORS Neuroendocrine lung tumors fall along a spectrum of aggressiveness ranging from paragangliomas (discussed elsewhere), typical carcinoids, atypical carcinoids, large-cell neuroendocrine tumors, and small-cell lung carcinomas (discussed elsewhere).299,300 The term carcinoid was originally defined as a carcinoma-like lesion without invasive characteristics by Oberndorfer in 1907.301 Pulmonary carcinoids used to be

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880

SECTION III

Disease Sites

A

B Fig. 52.6 Sample dose distributions for a volumetric modulated arc therapy (VMAT) plan (A) and passive scattered proton beam therapy (PBT) (B).

known as bronchial adenomas because they were believed to be benign, but have since been demonstrated to have malignant potential. Pulmonary or bronchial carcinoid tumors are typically low-grade malignant neoplasms that are embryonic neuroectoderm derivatives and are part of the amine precursor uptake and decarboxylation system. These cells are the Kulchitsky (enterochromaffin) cells, which are located in the basal layer of bronchial epithelium.302,303 Approximately 25% of carcinoids are located in the respiratory tract, which is the second-most common site after the gastrointestinal tract. Pulmonary carcinoids are frequently centrally located and confined to the main or lobar bronchi.304 These tumors are rare, and their biologic behavior mostly depends on their histologic characteristics.

Etiology and Epidemiology No clear causative or environmental risk factors have been identified for carcinoids. Carcinogens that are associated with lung cancer have not been consistently associated with pulmonary carcinoids,305 although a few studies revealed a higher frequency of smokers with atypical carcinoids and these may lie on the spectrum of small-cell carcinomas.306–308 The annual incidence of carcinoid tumors is 1 to 2 cases per 100,000 people in the United States.2,305 For bronchopulmonary carcinoids, improved diagnostic tools have led to an increase in incidence from 0.6 to 1.35 per 100,000 people/year.3,309 Carcinoid tumor of the lung represents about 3% of all lung malignant tumors, with an equal frequency in men and women,3,305 approximately 3500 new cases were reported in 2004.310,311 Bronchial carcinoids are the most common primary lung tumor in children, typically presenting in late adolescence. Typical carcinoids are about four times more common than atypical carcinoids. Data from the SEER program of the National Cancer Institute has shown a trend for increasing incidence of pulmonary carcinoids.305,309

Biologic Characteristics and Molecular Biology Carcinoid tumors, which occur sporadically, are believed to arise from multipotent neural crest cells that are derived from embryonic neuroectoderm. The WHO classification of lung neuroendocrine tumors describes two different subtypes of carcinoids, typical and atypical, with distinctive clinical behaviors and different prognoses.300,311,312 Although most pulmonary carcinoids are nonfunctional, some secrete a variety of physiologically active substances, leading to paraneoplastic syndromes, including carcinoid syndrome, Cushing syndrome, and acromegaly.302 Serotonin (5-hydroxytryptamine [5-HT]) is a frequently encountered vasoactive substance released by carcinoid tumors. Other substances, including corticotropin, histamine, dopamine, substance P, neurotensin, prostaglandins, and kallikrein, have been reported.313–318 Some neoplastic cells express mutant retinoblastoma (RB1) or mutant TP53 gene products, and they show occasional loss of heterozygosity, especially in atypical carcinoids.319 In atypical carcinoids, there is also a high frequency of molecular alterations and inactivation of tumor suppressor genes, such as the TP53, RB1, CDKN2A (previously designated p16), and CDKN2D (previously designated p19) genes. There is also evidence for mutations in several genes normally involved in chromatin remodeling as an associative agent in these tumors.320 Most familial pulmonary carcinoids have been reported in patients with multiple endocrine neoplasia type 1. In cases of atypical and typical lung carcinoids, there is a characteristic allelic loss within the region of 11q13, which harbors the MEN1 tumor suppressor gene.321–325 Other frequently detected genetic alterations in lung carcinoids, especially atypical carcinoids, include losses of 3p, 5p, 9p, 10q, and 13q.322,325 Ki-67 expression in more than 5% of nucleoli is a poor prognostic factor for survival.326

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CHAPTER 52

Uncommon Thoracic Tumors

881

Pathology and Pathways of Spread Carcinoids, which are thought to be derived from different embryonic divisions of the gut, are classified accordingly. Foregut carcinoids are often found in the lungs, bronchi, and stomach, and midgut and hindgut tumors are seen in the small and large intestines. Histologically, they may stain positive with silver or Grimelius stains, cytokeratin 7 and 11, neuron-specific enolase, synaptophysin, carcinoembryonic antigen, and chromogranin; there is no marker exclusive to carcinoids, however.327–329 Microscopically, they are characterized by small uniform cells and the presence of numerous membrane-bound, neurosecretory eosinophilic granules containing a variety of hormones and biogenic amines in the cytoplasm. Most pulmonary carcinoids (70% to 90%) are typical carcinoids or well-differentiated neuroendocrine tumors, which are characterized by small cells with well-rounded nuclei; atypical carcinoids (10% to 30%), or poorly differentiated neuroendocrine tumors, have malignant histologic features of increased nuclear atypia with high mitotic activity (more than two mitoses per 10 high-power fields), lymphovascular invasion, nuclear pleomorphism, and areas of necrosis.300,329–332 It is sometimes difficult to establish the specific diagnosis of carcinoid tumors because of small biopsy samples or to differentiate atypical carcinoid from small-cell lung carcinoma without immunohistochemical tests.300,333–335 Well-differentiated carcinoids are often indolent, with a relatively low risk of nodal or distant metastasis (3% to 15%).310,332,336–338 Atypical carcinoid may have an aggressive clinical course, with frequent organ metastases.319,339,340 The risk of nodal metastasis, frequently to mediastinal lymph nodes, is 30% to 57%.310,341,342 Distant metastases occur in more than 20% of patients.310 The most common sites of distant metastasis include liver, bone, adrenal glands, brain, skin, and soft tissue.311,343–346 The biologic behavior of these tumors varies depending on the histologic characteristics. Typical carcinoid tumors of the lung have a better prognosis than other primary lung cancers, with a 5-year survival rate greater than 90%. For atypical carcinoids, 5-year survival rates range from 25% to 75%.343,347–351 A population-based study of more than 1400 patients from Europe showed a 5-year OS rate of 78% for pulmonary carcinoids as a whole.352 Although typical carcinoids have an indolent clinical course, atypical carcinoids behave more aggressively, with nodal involvement in 20% to 60% of cases and a higher rate of distant metastases. Fig. 52.7 shows a right-sided hilar atypical carcinoid tumor with associated mediastinal adenopathy. The recurrence rates and stage at presentation are higher than for typical carcinoids. The proliferation rates, as assessed by MIB-1 and Ki-67, are also higher than for typical carcinoids.311,352,353 These figures may be associated with increased propensity to metastasize.354

Clinical Manifestations, Patient Evaluation, and Staging Carcinoids are detected like other space-occupying tumors. The most common findings on a chest radiograph include a mediastinal/hilar mass with occasional atelectasis. Functioning carcinoids are suspected on the basis of the signs and symptoms; the diagnosis is confirmed by demonstrating increased urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). TTF-1 is expressed in 80% of metastatic pulmonary carcinoids, but not in intestinal carcinoids, which may be of value in the workup and diagnosis of pulmonary carcinoids.327,355 The median age at diagnosis for pulmonary carcinoid tumors is around 64 years.3 Carcinoids in children are rare.356 Between 70% and 80% of these tumors are located centrally near the hilum within the tracheobronchial tree and may produce a variety of clinical symptoms and neuroendocrine manifestations.357,358 About 25% of patients present with symptoms such as recurrent pneumonia, cough, hemoptysis, or chest pain. Carcinoids are vascular tumors and can also

Enlarged paratracheal node

A

Right hilar mass

B Fig. 52.7 Atypical Carcinoid. (A) The preoperative computed tomography (CT) scan shows a right hilar mass. (B) There was also right paratracheal adenopathy. Lymph node involvement is seen more commonly in atypical carcinoid than in typical carcinoid.

bleed secondary to bronchial irritation. Hyperparathyroidism may also be seen. At least 50% of pulmonary atypical carcinoid tumors present in the periphery of the lung, with diagnosis of asymptomatic, incidental lesions.351,359,360 Carcinoids may produce various amines and polypeptides with corresponding signs and symptoms, often precipitated by emotional upset, food ingestion, or alcohol. The serotonin metabolite 5-HIAA, which is excreted in urine, acts on smooth muscle to produce bronchoconstriction or diarrhea, colic, and malabsorption. Histamine and bradykinin, through their vasodilator effects, cause flushing. The release of such vasoactive substances into the systemic circulation can cause the carcinoid syndrome, characterized by episodic flushing, typically of the head and neck; asthmatic wheezing; abdominal cramps with recurrent diarrhea resulting in malabsorption syndrome; and valvular heart disease, including right-sided endocardial fibrosis, leading to pulmonary stenosis and tricuspid regurgitation.361 Bronchial carcinoids generally have low serotonin content because the tumor cells lack the aromatic amino acid decarboxylase enzyme and cannot make serotonin and its metabolites. Hence, the secretion of 5-hydroxytryptamine (5-HTP) is increased and 5-HIAA urinary excretion is normal. Lesions of the left side of the heart, which have been reported with bronchial carcinoids, are rare because serotonin is destroyed during passage through the lung. Some patients complain of decreased libido and impotence. However, the incidence of carcinoid syndrome or other paraneoplastic syndromes,

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882

SECTION III

TABLE 52.6

Disease Sites

Presenting Symptoms in Patients With Pulmonary Carcinoids Schrevens et al.357 (n = 67)

Kaplan et al.339 (n = 144/62)a

Fink et al.310 (n = 142)

Machuca et al.364 (n = 126)

Cough

—

39%/45%

35%

24%

Dyspnea, wheezes

—

17%/25%

41%b

—

Chest pain

7%

9%/18%

—

12% 30%

Symptoms

Infection, fever

42%

—

—

Weight loss

—

11%/20%

15%c

—

Hemoptysis

21%

16%/12%

23%

—

Paraneoplastic syndromes

0%

1%/3%

5 cm) or metastatic disease.362 Paraneoplastic syndromes in the absence of lymph node or distant metastases do not affect the prognosis.360,363 Levels of human chorionic gonadotropin and pancreatic polypeptide are occasionally elevated. Patients with a suspected lung mass require a thorough history and physical examination. Routine blood tests and chemistry tests may give clues to the presence of associated syndromes (Table 52.6).310,339,357,364 The differential diagnosis, in addition to bronchopulmonary carcinoid, includes lung carcinoma and metastasis from an extra-pulmonary primary tumor. CT and bronchoscopy are two of the most valuable diagnostic procedures. Up to 80% of carcinoids manifest with type 2 somatostatin receptors, and the receptors can be targeted by radioactive octreotide or pentetreotide. Somatostatin receptor scintigraphy with indium-111–radiolabeled octreotide (111In-octreotide) has demonstrated reliable uptake in primary tumors and been used to detect early recurrence.365–367 FDG-PET scans are often normal.306,368–370 Transbronchial biopsy or CT- or ultrasound-guided fine-needle aspiration biopsy may establish the diagnosis. Bronchoscopy, videoassisted thoracoscopic surgery, or mediastinoscopy may also help yield a diagnosis before resection, especially if enlarged lymph nodes are present. Prognostic factors include atypical histologic findings, staging, and the presence of symptoms at the time of presentation.356–358,365,368 A high mitotic rate, size larger than 3.5 cm, and female gender have also been implicated as prognostic factors for patients with atypical pulmonary carcinoids.307 There is no specific staging system for pulmonary carcinoids, but the AJCC lung cancer staging system (TNM) is commonly used. In an analysis of 513 carcinoid tumors from the International Association for the Study of Lung Cancer (IASLC) and 1619 cases from the SEER database, TNM staging was found to correlate with survival.371

Treatment

Primary Therapy Curative resection is the primary treatment for pulmonary carcinoids when possible.311,345,346,372–374 After complete resection, the long-term results are generally excellent.310,345,357,372 Conservative surgical resection, consisting of wedge or segmental resection, is the preferred therapy for localized pulmonary carcinoids.375,376 Patients with central lesions may require bronchial sleeve resection or sleeve lobectomy.373 Endoscopic laser ablation is not considered curative, but may be used to alleviate tumor obstruction, improve atelectasis, and reduce inflammation before

resection.337 Intraoperative nodal evaluation should be performed and, if the results are positive, complete nodal dissection is indicated. Because of higher rates of local recurrence in patients with atypical carcinoids, a more extensive surgical procedure, such as lobectomy or pneumonectomy with nodal dissection, should be considered.311,345,346,375 Patients may present with metastatic or nonresectable disease, however, and curative resection may not be obtainable. Debulking and other cytoreduction procedures may be of benefit in gastrointestinal carcinoids,377,378 but these procedures are of uncertain benefit for patients with pulmonary carcinoids.

Medical Management Certain symptoms, including flushing, can be relieved by pharmacologic agents. Ondansetron, one of the specific 5-hydroxytryptamine-3 (5-HT3) antagonists, provides sustained symptomatic relief in patients with carcinoid syndrome.379 Somatostatin analogs are potent inhibitors of neuropeptide release and gut exocrine or endocrine function. These analogs are effective in relieving symptoms by binding to somatostatin receptors (mainly, receptor 2),380 which are present in approximately 80% of carcinoids, leading to inhibition of hormone secretion.381,382 Octreotide and lanreotide, long-acting analogs of somatostatin, are the drugs of choice. The response rate is about 70% for symptomatic improvement, and there is a more than 50% reduction in urinary 5-HIAA secretion, with a median duration of response of 12 months. Data suggest that these somatostatin analogs may have a direct antitumoral effect, with stabilization of tumor growth and reduction of tumor size in patients with carcinoids of various sites.379,380 More recently, peptide receptor radionuclide therapy with radiolabeled somatostatin analogs have shown promise in clinical trials. 90Y-DOTATOC (90Y-edotreotide) has an yttrium-90 (90Y) atom with high binding affinity for somatostatin receptors.382 Two trials with 39 and 90 patients with progressive/metastatic neuroendocrine tumors have shown symptom improvement in 63% to 74% of patients, although it is unclear what the response rate would be in pure bronchial carcinoid.383,384 177LuDOTATATE (177Luoctreotate) can be given therapeutically, but also can be used for imaging and dosimetry after therapy.

Radiation Therapy No prospective trials have addressed the use of RT for patients with bronchopulmonary carcinoids. In general, typical carcinoids do not routinely require adjuvant RT or chemotherapy after R0 resection.310,345,357,372,385 A retrospective series of 25 patients (12 typical and 13 atypical tumors) with node-positive bronchial carcinoids treated at the Memorial Sloan

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CHAPTER 52 Kettering Cancer Center (MSKCC) found no survival benefit from routine postoperative RT.304 However, adjuvant radiation therapy has been used in patients at high risk for locoregional recurrence, including those with large tumor size (> 3 cm), positive nodes, positive margins, atypical histologic findings, residual disease, and inoperable.332,339,386,387 There has also been anecdotal experience on stereotactic radiotherapy for pulmonary carcinoids.388 Neuroendocrine tumors are classically radioresponsive and palliative RT can yield dramatic improvements in tumor symptoms. For patients with locally advanced or metastatic disease, surgery is generally limited to those whose metastases are confined to one site amenable to local resection.377 RT has been used successfully to palliate symptoms in patients with locally advanced or metastatic disease.389 Local control and symptomatic relief can be achieved in most patients with 40 Gy to 50 Gy. Endoscopic resection and laser photoablation have been used for palliation of symptoms.337 Somatostatin analogs alone or in combination with chemotherapy or interferon-alpha may be considered for symptomatic treatment or tumor stabilization.390

Chemotherapy Unlike chemotherapy for small-cell lung cancer, systemic chemotherapy has produced only limited success in patients with metastatic carcinoid tumors.387,391 No effective chemotherapeutic regimen has been established, but aggressive chemotherapy is recommended in high-risk patients with nonresectable progressive or metastatic disease.341,392 Several trials have shown response rates of 21% to 33% with various combinations of doxorubicin, streptozotocin, cyclophosphamide, etoposide, oxaliplatin, and fluorouracil in patients with metastatic carcinoids.341,393–397 Patients with atypical carcinoids treated with cisplatin and etoposide appear to have a higher response rate than patients treated with other regimens.

Targeted Agents A number of genetic mutations have been identified in these tumors that may be targetable by biologics. Mutations involving the mammalian target of rapamycin (mTOR) occur in about 15% of pancreatic neuroendocrine tumors.398 The mTOR inhibitor everolimus is approved for use in advanced pancreas neuroendocrine tumors.399 Although subgroup analyses of randomized data have found a progression-free

TABLE 52.7

883

Uncommon Thoracic Tumors

survival benefit to everolimus over placebo, direct Phase III trials have observed no OS differences in adding everolimus to octreotide, potentially owing to the heterogeneity in patients between the aforementioned investigations.400,401 Next, because neuroendocrine tumors exhibit angiogenesis and increased vascularity,402 bevacizumab and sunitinib have been tested in advanced neuroendocrine tumors, with bevacizumab exhibiting a more favorable toxicity profile.403–406 Although Phase II data have been encouraging, Phase III data are pending.403,407 There is also prospective evidence for adding pasireotide to everolimus.408 Tumor-targeted irradiation with radioactive somatostatin analogs (111In-octreotide or 131I-metaiodobenzylguanidine [131I-MIBG]) has been used, often as second- or third-line therapy.387,409,410

Results of Therapy Patients with typical carcinoid tumors treated with surgery alone have a good outcome. However, patients with atypical pulmonary carcinoid tumors and regional lymph node metastases are at high risk for recurrent disease and have worse survival rates when they are treated with resection alone.340 The 5-year OS rate ranges from 78% to 100% for all resected pulmonary carcinoids, 90% to 100% for typical carcinoids, 25% to 69% for atypical carcinoids, and 18% to 38% for metastatic carcinoids.336–338,340,342,346 Ten-year rates are 10% to 20% lower than those at 5 years. Several additional larger studies are summarized in Table 52.7.411–422 Despite a lack of clinical data,423 the National Comprehensive Cancer Network (NCCN) recommends considering adjuvant chemotherapy and/or RT for stage IIIA atypical carcinoids.424

Irradiation Techniques The same general principles of thoracic irradiation apply to irradiation of pulmonary carcinoids. As in treating other tumors, surgical clips denoting the extent of resection or outlining regions of residual disease are useful in guiding postoperative CTV similar to those discussed with thymoma or non–small-cell lung cancer. There are no consistent guidelines regarding dose and fractionation regimens. Postoperative doses of 45 Gy to 58 Gy delivered in daily 1.8-2 Gy fractions have been reported (see Table 52.7). For patients with gross residual or nonresectable disease, definitive doses as high as 60 Gy may be justified.

Treatment Results of Large Studies for Pulmonary Carcinoids Local Control Rate (%)

Survival Time/Rate

Comments

4 Ch + RT 14 Ch (no surgery)

22% (OS)

20 mo MS

4 of 18 responded to Ch ± RT without surgery (inoperable patients).

106 atypical

Surgery ± RT/Ch

—

61% OS at 5 years 35% OS at 10 years 28% OS at 15 years

Higher mitotic rate, size ≤ 3.5 cm, female gender, presence of rosettes are independent variables (multivariate analysis) for worse survival rates.

2004

19 atypical

15 surgery 3 surgery + RT/Ch 1 Ch + RT

89%

79% OS at 3 years 41 mo MS 74% DSS at 3 years

Adjuvant RT may improve rates in those with positive margins or positive nodes.

2001

128 typical 14 atypical

All surgery (four inoperable or refusal)

—

89% at 5 years 82% at 10 years 75% at 5 years 56% at 10 years

Long-term results are excellent with typical carcinoids.

Study

Year

No. Patients

Treatment

Wirth et al.385a

2004

8 typical 10 atypical (advanced or metastatic)

Beasley et al.307

2000

Choi et al.344 Fink et al.310

Continued

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884

SECTION III

TABLE 52.7

Disease Sites

Treatment Results of Large Studies for Pulmonary Carcinoids—cont’d

Study Kaplan et al.339

Year 2003

No. Patients 144 typical 62 atypical

Treatment 129 surgery 12 surgery + RT/Ch 2 Ch + RT 35 surgery 19 surgery + RT/Ch 9 Ch + RT

Han et al.386a

2013

12 atypical

6 surgery 2 surgery + RT 3 surgery + Ch 1 surgery + RT/Ch

Carretta et al.386

2000

36 typical 3 atypical 5 LCNEC

Schrevens et al.357

2004

Fink et al.310

Local Control Rate (%) 92% at 5 years (surgery, stage I) 77% at 5 years (surgery, stage I)

Survival Time/Rate 79% DSS at 5 years 63% DSS at 10 years 39% DSS at 20 years 60% DSS at 5 years 37% DSS at 10 years 28% DSS at 20 years

Comments Poor prognostic factors: male gender, high stage, symptoms at presentation, and age ≤ 60 years; 56 of 206 had second malignant tumors; atypical carcinoids had worse outcome.

92%

37 mo MS

Although only 1 patient developed a local recurrence, 5 of 12 patients developed distant metastasis.

Surgery ± RT/Ch

—

93% AS at 5 years 70% AS at 5 years

Patients with nodal metastases had worse outcome.

59 typical 8 atypical

All surgery

—

92% at 5 years 67% at 5 years (92% OS at 5 years, 84% OS at 10 years)

Independent prognostic factors were nodal status and pathologic type; size of primary tumor did not correlate with nodal metastasis.

2001

128 typical 14 atypical

All surgery (four inoperable or refusal)

—

89% at 5 years 82% at 10 years 75% at 5 years 56% at 10 years

Long-term results are excellent with typical carcinoids.

Ferguson et al.411

2000

109 typical 26 atypical

All surgery

—

90% at 5 years 70% at 5 years

Early-stage tumors did well regardless of histologic type.

Zhong et al.412

2012

106 typical 25 atypical

All surgery

—

96% at 3 years 87% at 5 years 71% at 10 years

Nodal status and histology were independent prognostic factors on multivariate analysis.

Canizares et al.413

2014

127 (all atypical)

Surgery ± RT/Ch

92% at last follow-up

80% at 5 years

Sublobar resection independently associated with locoregional recurrence.

Steuer et al.414

2015

441 (unspecified type)

Surgery (78%) ± RT (Ch unknown)

-

69-85% at 3 years if nonmetastatic

Delivery of radiation not independently linked with survival.

Filosso et al.415

2015

126 (all atypical)

Surgery with any adjuvant therapy in < 20%

94% at 5 years

77% at 5 years

Sublobar resection is poor prognostic factor.

Mezzetti et al.389

2003

10 atypical

—

—

71% OS at 5 years 60% OS at 10 years

Stolz et al.416

2015

95 typical 42 atypical

Surgery ± RT/Ch

-

At 5 years, 97% (typical), 71% (atypical)

Nodal involvement most correlated with prognosis

Okereke et al.417

2016

96 typical 21 atypical

Surgery

-

At 5 years, 96% (typical), 87% (atypical)

Nodal involvement not correlated with prognosis

Hobbins et al.418

2016

1,341 (unspecified type)

Surgery (77%) with any adjuvant therapy in < 10%

-

85% at 3 years

Included metastatic disease (~20% of cohort)

Cattoni et al.419

2017

240

Surgery

-

94% at 5 years

Construction of novel prognostic model better indicative of outcomes over TNM staging

Cusumano et al.420

2017

159 typical 36 atypical

Surgery ± RT/Ch

-

At 5 years, 97% (typical), 78% (atypical)

Nodal status correlated with survival

Ramirez et al.421

2017

113 typical 46 atypical 10 unknown

Surgery (72%)

-

At 5 years, 90% (typical), 81% (atypical)

Included metastatic patients; nodal status associated with survival

Sadowski et al.422

2018

83 typical 14 atypical 16 unknown

Surgery (86%) with adjuvant Ch in < 5%

-

Mean 86 months (typical), 48 months (atypical)

No difference in disease-free interval between typical and atypical histology

AS, Actuarial survival rate; Ch, chemotherapy; DSS, disease-specific survival rate; LCNEC, large cell neuroendocrine carcinoma; MS, median survival rate; OS, overall survival rate; RT, radiation therapy.

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CHAPTER 52

Treatment Algorithm and Controversies Surgery is the primary treatment for typical and atypical pulmonary carcinoids. Although conservative resection has resulted in low recurrence rates and excellent long-term survival rates for patients with well-differentiated pulmonary carcinoids, the adequacy of such resection in patients with atypical carcinoids has not been settled. More extensive surgical procedures, with higher treatment-related morbidity rates, have been advocated by some investigators.341,425 Palliative irradiation should be considered for those with symptomatic disease.

Uncommon Thoracic Tumors

885

Clinicians should also be attuned to the possibility of hereditary cancer predisposition syndromes in patients without risk factors for asbestos exposure. The BRCA1-associated protein 1 (BAP1) is involved with the homologous recombination pathway of DNA repair and the germline mutations of BAP1 predispose MPM in absence of antecedent asbestos exposure.435–437 Wild-type BAP1 functions as a tumor suppressor and deubiquitinase that complexes with BRCA1. In patients with MPM where the BAP1 hereditary cancer predisposition syndrome is suspected, referral to genetic counseling should be considered, especially because of the risk of other malignancies such as renal carcinoma and uveal melanoma.438

Biologic Characteristics and Molecular Biology

MESOTHELIOMA Malignant pleural mesothelioma (MPM) is an aggressive pleural malignancy that is associated with asbestos exposure. MPM continues to have disappointing oncologic outcomes with dismal survival because it has a high propensity for local failure and metastatic spread even after aggressive locoregional therapy. MPM spreads by direct extension and seeding throughout the pleural space, including fissures, diaphragmatic and pericardial surfaces, and through the chest wall and into the mediastinum, peritoneum, and lymph nodes. Whereas combination cisplatin and pemetrexed chemotherapy has been shown be crucial to prolong survival in MPM, long-term survival outcomes remain dismal and optimizing effective locoregional therapy remains a daunting challenge. Surgical resection carries substantial perioperative morbidity and mortality and seldom achieves oncologic margins. Even in carefully selected patients with early-stage disease, patients have 2-year survival rates of 10% to 33%.426–428 For this reason, hemithoracic radiation therapy has been explored to improve local control, but it is controversial,428–430 especially because local recurrence is still the most common site of relapse and the absence of randomized evidence that supports the use of radiation.431 Treating the hemithorax with radiation is clinically challenging because of the large treatment volume and the presence of multiple organs at risk, such as the heart, kidneys, liver, remaining lung, and spinal cord, that limit the dose that can safely be delivered. These physical factors dramatically limit the ability to use radiation therapy for MPM without risking severe radiation toxicity. Given these challenges in the treatment of MPM, efforts to integrate technological advances in radiation and to translate basic science discoveries to the clinic will be paramount to improve survival for these patients.

Etiology and Epidemiology Asbestos exposure is the major causative factor responsible for most MPM. The Center for Lung Cancer and Related Disorders estimates a peak incidence of approximately 4000 cases in the United States expected in 2025. As a result of the latency period between initial asbestos exposure and development of MPM, the median age of diagnosis in typically in the sixth decade of life. Approximately 90% of mesothelioma cases can be attributed to prior asbestos exposure, usually related to an occupational exposure. Although its use has been abandoned in the United States, historically asbestos has been used in construction for insulation, automobile parts, and shipbuilding, which explains the male predominance of MPM. The asbestos-like compound erionite has also emerged as an environmental hazard in Turkey, Australia, and the United States that is now recognized to predispose MPM.432,433 Although there is no direct association between mesothelioma and tobacco abuse, smoking amplifies the risk for carcinogenesis when there is concurrent asbestos exposure.434

Malignant pleural mesothelioma carcinogenesis is a prolonged and complex process spanning over decades from initial carcinogenic insult to progression and metastasis. Inciting transforming agents, such as asbestos and erionite, are believed to create a chronic inflammatory microenvironment that activates proinflammatory signaling cascades such as NF-kB.439,440 Activation of the canonical NF-kB pathway has been clearly linked to malignant transformation and progression of MPM.440 Consistent with the immunoinflammatory dysregulation present in MPM carcinogenesis, up-regulation of PD-1 and PD-L1 have been detected in MPM and targeting of this pathway may hold promise to improve outcomes in MPM.441,442 Mutations have also been identified in DNA repair proteins, such as the gatekeeper TP53, and the homologous recombination protein BAP1. Roughly 50% of MPM have been found to have mutations in the cytoskeletal scaffolding protein NF2 that is thought to facilitate local spread. Epigenetic dysregulation has also been identified in MPM as manifested by mutations in the histone methyltransferease SETD2. Dysregulation of a number of cell cycle signaling pathways, such as p16INK4A, p14ARF, PI3K, IL-1, TNF-α, and AKT, have been shown to promote growth and survival of MPM. Recently, the high-mobility group box-1 (HMGB1) protein has been implicated in MPM progression and also as a potential biomarker for early detection.443,444 It is hoped that identification and characterization of these key cell-signaling pathways, MPM may yield opportunities to improve oncologic outcomes for this population by improving diagnosis and treatment.

Clinicopathologic Features and Prognostic Factors The pathologic diagnosis of mesothelioma can be challenging in MPM owing to challenges in obtaining sufficient tissue and cytologic similarity to alternative histologies. Immunohistochemistry for markers such as WT-1, CK5/6, and calretinin can be particularly helpful in establishing a MPM diagnosis. The histologic subtype of MPM has long been associated with prognosis. The most common (50% to 67%) histological subtype is epithelioid, which is associated with the best prognosis; this is followed by mixed (20% to 40%) and sarcomatoid (5% to 15%) disease, the latter of which has the poorest prognosis (Fig. 52.8). Metastases to any thoracic regional nodal station are associated with worse outcomes. In contrast to primary lung malignancies, it is not clear that mediastinal metastases reflect a worse prognosis in comparison to hilar or intrapulmonary nodal metastases. Although oncologic margins are inherently difficult to achieve in MPM, the completeness of resection has also been shown to have prognostic value with R1 or R2 resections having worse outcome in some series in comparison to those who achieve R0 resection.445 Thrombocytosis and high levels of platelet-derived growth factor may also predict a worse outcome. Several reports suggest that serum levels of mesothelin are elevated in most patients at diagnosis and that they fall after surgery. Serum mesothelin may be a potential

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886

SECTION III

Disease Sites

B

A

C

Fig. 52.8 Histologic Subtypes of Malignant Pleural Mesothelioma. (A) Epithelioid. (B) Biphasic (insert shows epithelioid with a sarcomatoid component). (C) Sarcomatoid.

biomarker marker for detecting tumor recurrence,446 and clinical trials have evaluated antibodies to this molecule.447 Other positive prognostic factors include young age, early-stage disease, good performance status, lack of chest pain, and presence of symptoms for longer than 6 months.448

Clinical Evaluation and Staging Dyspnea, chest pain, cough, and weight loss are common presenting symptoms of MPM. All patients should be asked about their history of asbestos exposure. Pulmonary function tests demonstrate a restrictive pattern resulting from “trapping” of the lung or of chest wall involvement. MPM has a tendency to grow along tracks of previous chest tubes and all sites of previous instrumentation should be identified and examined for evidence of tumor seeding. Such chest wall progression may manifest as pain, a nodule, or an ulcer. Particularly when transthoracic extension is identified, the axillary and supraclavicular lymph nodes should also be assessed for involvement.

Imaging Following initial chest radiography, contrast-enhanced CT scan of the chest is standard for radiographic staging. Circumferential pleural thickening, an irregular pleural contour, or contraction of the ipsilateral hemithorax are common findings. Invasion of the diaphragm or chest wall is difficult to detect in early cases, so CT imaging may underestimate the true extent of the disease. Miliary disease can be present on the undersurface of the diaphragm or peritoneum and remain undetected by imaging. Pleural-based irregular masses are common, particularly in dependent regions. The interlobar fissures are often involved. MPM can invade adjacent structures, such as the chest wall, mediastinum, great vessels, vertebral body, or heart. Mediastinal and hilar lymph nodes can be involved with tumor, but the pattern of spread often differs from that of non–small-cell lung cancers. MPM spreads to the lower paraesophageal nodes (station 8), pulmonary ligament nodes (station 9), and diaphragmatic nodes much more commonly than lung cancers. Pericardial effusions and ascites can also be seen on CT, and they should be evaluated pathologically before any attempt at curative resection. The anteromedial extent of tumor, particularly extension across the midline, should be determined before surgery. Because surgery obliterates the costomediastinal space, the anterior pleural reflection cannot be accurately delineated on postoperative studies. The utility of MRI in the staging of mesothelioma is controversial. MRI may slightly be more accurate in predicting the extent of invasion

into the chest wall, diaphragm, and great vessels. The finding of chest wall invasion should not preclude surgery, however, as long as the region of invasion can be removed with a limited chest wall resection. Invasion to the peritoneal surface of the diaphragm cannot always be appreciated without invasive staging. PET/CT scanning has been applied to mesotheliomas owing to avid FDG uptake. Sensitivity and specificity of 90% or more has been reported and is helpful in distinguishing between benign pleural thickening and MPM.449–451 Furthermore, PET/CT, when compared with CT, in a series of 35 patients, upstages tumors and therefore prevents unnecessary surgery in up to 40% of patients.452

Invasive Staging Thoracentesis is often the first procedure performed to obtain tissue diagnosis, but it only has a diagnostic sensitivity of 32%.453 Percutaneous fine-needle aspiration biopsy similarly has low diagnostic sensitivity, although ultrasound-guided core-needle biopsy has been reported to improve accuracy.454 Before commencing multimodality treatment, accurate preoperative staging is necessary. Historically, an open pleural biopsy has been the gold standard.455 More recent data have shown that less invasive thoracoscopic biopsy should be the preferred method for obtaining tissue for diagnosis.456–458 Diagnostic thoracentesis is an alternative, although it has a lower yield than video-assisted thoracoscopic surgery.459 Because of the proclivity to track along sites of chest wall violation, limiting the number of port sites at the time of video-assisted thoracoscopic surgery and placing port sites where they are easily excised help to reduce local chest wall recurrence. When it is difficult to establish entrance into the pleural space, it is preferable to perform a limited open biopsy of the parietal pleura by extending the port site incision slightly, rather than to perform a formal thoracotomy. A thoracotomy performed for diagnosis significantly compromises potentially curative surgery. Some experienced clinicians obtain pretreatment laparoscopy with peritoneal lavage and cervical mediastinoscopy in all patients considered for resection. This is because CT, PET, and MRI are less successful in determining tumor involvement at two critical sites: contralateral mediastinal nodal involvement and tumor invasion through the diaphragm (involvement at either site negates resection). At the MD Anderson Cancer Center, of 118 patients with MPM who were clinically and radiographically determined to have resectable disease, laparoscopy and peritoneal lavage revealed transdiaphragmatic or peritoneal involvement in 12 (11%) of 109 patients and mediastinoscopy identified positive

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CHAPTER 52

TABLE 52.8

Uncommon Thoracic Tumors

887

TNM Staging of Mesothelioma PRIMARY TUMOR (T)

REGIONAL LYMPH NODES (N)

TX

Primary tumor cannot be assessed

NX

Regional nodes cannot be assessed

T0

No evidence of primary tumor

N0

No regional lymph node metastasis

T1

Tumor limited to the ipsilateral parietal pleura, with or without mediastinal pleura and with or without diaphragmatic pleural involvement

N1

T1a

No involvement of the visceral pleura

Metastases in the ipsilateral bronchopulmonary or hilar lymph node(s) and/or in the subcarinal or ipsilateral mediastinal lymph nodes (including ipsilateral internal mammary and peridiaphragmatic nodes)

T1b

Tumor also involving the visceral pleura

N2

T2

Tumor involves each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following: 1. Involvement of diaphragmatic muscle 2. Extension of tumor from visceral pleura into underlying pulmonary parenchyma

Metastases in the subcarinal or ipsilateral mediastinal lymph nodes (including ipsilateral internal mammary and peridiaphragmatic nodes)

N2

Metastases in the contralateral mediastinal, internal mammary, or hilar lymph node(s) or the ipsilateral or contralateral supraclavicular or scalene lymph node(s)

T3

T4

Locally advanced, but potentially resectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following: 1. Invasion of the endothoracic fascia 2. Invasion into mediastinal fat 3. Solitary completely resectable focus of tumor invading the soft tissues of the chest wall 4. Nontransmural involvement of the pericardium Locally advanced, technically nonresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following: 1. Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction 2. Direct transdiaphragmatic extension to the peritoneum 3. Direct extension to mediastinal organs 4. Direct extension to the contralateral pleura 5. Direct extension into the spine 6. Extension to the internal surface of the pericardium with or without a pericardial effusion or tumor involving the myocardium

DISTANT METASTASIS (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis STAGE GROUPINGS

I

T1N0M0

IA

T1a N0 M0

IB

T2-3 N0 M0

II

T1-2 N1 M0

IIIA

T3 N1 M0

IIIB

T4 N0-1 M0 T1-4 N2 M0

IV

Any T; any N M1 RESIDUAL TUMOR (R)

RX

Presence of residual tumor cannot be assessed

R0

No residual tumor

R1

Microscopic residual tumor

R2

Macroscopic residual tumor

From Amin MB, Edge SB, Greene FL, et al., editors, for the American Joint Committee on Cancer: AJCC Cancer Staging Manual, ed 8. New York, Springer, 2016.

contralateral nodes in 4 (4%) of 111 patients. Overall, 15 (13%) patients were identified with occult advanced disease and spared unnecessary EPP.

Staging The AJCC 8th edition staging system for mesothelioma is shown in Table 52.8. The staging systems are useful only after surgical staging, and no clinical staging system has been developed.

Treatment Surgery

Extrapleural pneumonectomy. Extrapleural pneumonectomy consists most commonly of an en bloc resection of the entire ipsilateral lung, including parietal/visceral pleura, as well as the ipsilateral pericardium and hemidiphragm. Historically, EPP has been the most utilized

surgical technique for MPM, because it achieves the greatest460 degree of cytoreduction and may allow for safer delivery of adjuvant therapy compared with pleurectomy. A review of 34 studies of EPP found a perioperative mortality rate of up to 11.8% and a median OS of 9.4 to 27.5 months. Without adjunctive therapy, however, EPP has been associated with recurrence rates as high as 80%. Studies including EPP as part of multimodality therapy have reported local recurrence rates between 40% and 50%, with local recurrence as low as 13% (7 of 55 patients) in one study using 54 Gy hemithoracic irradiation after EPP.461 An EPP is an extensive surgical procedure, removing the ipsilateral lung along with the parietal pleura, pericardium, and most of the hemidiaphragm, so patients require careful preoperative assessment to exclude the presence of locally advanced or distant disease (which would preclude resection) and meticulous cardiopulmonary screening

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888

SECTION III

Disease Sites

to ensure that the operation can be tolerated physiologically. Surgical staging of the mediastinum and abdomen (with washings) should be performed when assessing patients for EPP. In general, patients should have adequate cardiac function (i.e., ejection fraction > 40% and no reversible ischemia on radionuclide imaging) and have an estimated postoperative forced expiratory volume in 1 second (FEV1) value greater than 0.8 L/min or 30% of predicted. The ideal surgical candidate has good performance status, with epithelioid histology without lymph node involvement to avoid futile thoracotomy. Even in centers with extensive experience with carefully selected patients, EPP has a high rate of complications.462,463 Because of the extremely poor prognosis of the sarcomatoid subtype, some have advocated against EPP, which carries with it substantial morbidity in the face of unlikely curative resection.464 Even after EPP, the diffuse nature of most malignant mesotheliomas and the manipulation of the exposed tumor during surgery put the entire ipsilateral chest cavity, diaphragm insertion, pericardium, mediastinum, and bronchial stump at high risk for local recurrence. The hemithorax and mediastinum have an irregular shape and are adjacent to critical structures, such as the spinal cord, liver, kidneys, esophagus, heart, and contralateral lung. These are important to consider when planning adjuvant management following EPP. Pleurectomy. Pleurectomy for MPM is not necessarily a curativeintent surgery for MPM, with a lack of standardized consensus definitions for this procedure, but may be useful for select patients.465 A (partial) pleurectomy in itself is a palliative/diagnostic procedure, where partial resection of parietal and/or visceral pleura is performed without intent to achieve oncologic margins. Pleurectomy with decortication completely strips the parietal/visceral pleura with an intent to remove known gross disease. Extended pleurectomy/decortication adds the additional step of resecting the diaphragm and/or pericardium. Although cytoreduction is theoretically not as complete with pleurectomy compared with that achieved with EPP, pleurectomy allows for ipsilateral lung sparing and potential improvement in postoperative morbidities and/or mortality. Pleurectomy is effective in allowing expansion of the trapped lung and reduces the likelihood of recurrent pleural effusion. It is often accompanied by decortication, a procedure that strips the pleura from the lung, and is thus an equally technically cumbersome procedure as EPP, if not greater. There is evidence that pleurectomy/decortication is significantly more commonly utilized in contemporary time periods, and when performed with multidisciplinary approaches at high-volume centers, can lead to improved outcomes.466,467 Several retrospective studies have evaluated survival following pleurectomy versus EPP, with multiple displaying equipoise,466,468 and others showing increased survival with pleurectomy.469 Although pleurectomy has been associated with less morbidity as compared to EPP, it is challenging to interpret these retrospective data with modern improvements in staging, perioperative care, and surgical technique.470,471

Chemotherapy The combination of cisplatin plus the antifolate pemetrexed has a well-defined role in patients with advanced mesothelioma based on the landmark randomized clinical trial by Vogelzang et al.472 In this study, the median survival time was 12.1 months for the pemetrexed plus cisplatin arm and 9.3 months for the cisplatin alone arm (p = 0.020). Time to progression was improved from 3.9 months to 5.7 months by the addition of pemetrexed (p = 0.001). The response rate was 17% for cisplatin alone compared with 41% for combined treatment. Combination cisplatin and pemetrexed has also been studied as part of multimodality therapy in localized disease. Krug et al.473 reported

the results of a multicenter Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by EPP and RT, with a promising median survival time of 29.1 months and a 2-year survival rate of 61.2%. For patients who cannot tolerate cisplatin, carboplatin plus pemetrexed is moderately active and has an acceptable toxicity profile.474–476 Historically, a multitude of cytotoxic chemotherapeutics have been explored for MPM.477–479 Reported response rates of roughly 25% have been obtained with methotrexate (37%),480 gemcitabine plus cisplatin (48%),481 pemetrexed plus carboplatin (25%),474 pemetrexed plus cisplatin (38%),482 mitomycin plus cisplatin (26%),483 raltitrexed plus oxaliplatin (26%),484 and doxorubicin plus cisplatin (28%).485 Trials of targeted agents and immunotherapy in MPM are accruing, which may provide further insights going forward. A notable Phase III trial has displayed improved overall survival when adding bevacizumab to cisplatin/pemetrexed in nonresectable disease.486 There have also been prospective reports of the tyrosine kinase inhibitors nintendanib and dovitinib,487,488 the VEGF receptor inhibitor cediranib,489 the WT1-analog peptide vaccine galinpepmut-S,490 microRNA minicells,491 the CTLA-4 antibody tremelimumab,492 pegylated arginine deaminase,493 CD40-activating antibody,494 the histone deacetylase inhibitor vorinostat,495 and everolimus.496 Additionally, MPM displays expression of PD-L1, which may be an important therapeutic target in a subset of patients with MPM having a worse prognosis; clinical trials testing such agents are underway.441,497 In part owing to encouraging results from prospective studies, such as IFCT-1501/MAPS-2 and KEYNOTE-028,441 NCCN guidelines now include consideration for pembrolizumab or nivolumab with or without ipilimumab for previously treated cases.

Rationale for Irradiation Although technical challenges remain for clinical radiation delivery, several lines of evidence suggest that RT can be effective in treating mesothelioma.498,499 Mesothelioma cell lines have radiosensitivities similar to those of non–small-cell lung cancer.500,501 Consistent with this radiobiologic data, some evidence has suggested a dose-response relationship for symptom palliation (the subject of the ongoing SYSTEMS-2 trial), such as doses greater than 40 Gy.502,503 This dose-response relationship suggests that clinically significant cell killing results from modest radiation doses. Radiation has also been observed to reduce the local failure rate at thoracotomy or other instrumentation sites. Thus, postoperative irradiation may be effective in reducing locoregional recurrence and potentially improve survival rates. These lines of evidence have provided impetus for further exploration of radiation for MPM in the curative setting.

Curative Radiation Therapy Radiation therapy alone. Definitive doses of RT alone cannot be achieved in the hemithorax for MPM owing to the large RT volume and proximity to normal structures such as the spinal cord. Because of the anatomic limitations, RT without surgery is, at best, considered palliative. Radiation therapy combined with surgery. Several groups have reported promising outcomes for patients with MPM treated with surgery and irradiation, with or without chemotherapy.

Radiation Therapy After Extrapleural Pneumonectomy The only randomized trial to date evaluating adjuvant RT was the SAKK 17/04 study, which was composed of 151 patients receiving neoadjuvant cisplatin/pemetrexed, 113 of whom underwent EPP, and 54 of whom were randomized (1 : 1) to RT versus lack thereof.504 The median total RT dose was 55.9 Gy. The median locoregional recurrence-free survival in the respective arms were 9.4 versus 7.6 months, which was not

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CHAPTER 52 statistically significant. It is likely that a lack of statistical power played a role in the findings of that trial, and thus the results must be interpreted with caution. Reports have been conflicting regarding the impact of aggressive adjuvant therapy on patterns of failure after EPP. A study from the Dana Farber Cancer Institute included 49 patients treated with EPP and 35 patients who received radiotherapy, 30.6 Gy to the “hemithorax” followed by a boost to about 50 Gy, following four to six cycles of chemotherapy.431 The most common site of first recurrence was local (35% of patients), whereas abdominal and contralateral thorax relapse was also common.

Uncommon Thoracic Tumors

889

It is likely that abdominal recurrences were related to extension of local disease (Fig. 52.9). Isolated distant relapses were uncommon. On the other hand, a Phase II study from MSKCC evaluating adjuvant hemithoracic RT reported only 13% locoregional relapse (in the pleura or regional lymph nodes) in the subset of 55 patients treated with EPP.505 Distant organs were frequent sites of first recurrence, particularly in stage III disease. The treatment technique involved photon irradiation to a dose of 54 Gy in 30 fractions.506 A report of 86 patients treated with EPP followed by IMRT at the MD Anderson Cancer Center also supports the contention that high-dose RT may limit local tumor relapse.507 The target dose was

A

B Fig. 52.9 Extrapleural pleumonectomy (EPP) can abdominalize portions of the posterior costophrenic recess. (A) A preoperative radiograph shows that the diaphragm on the contralateral side (black arrow) is higher than the ipsilateral hemidiaphragm (white arrow). (B) After EPP, the posterior insertion of the reconstructed hemidiaphragm (white arrow) is well above the now flattened, remaining hemidiaphragm (black arrow). In this example, the posterior insertion of the diaphragm is about 15 cm higher than before surgery.

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890

SECTION III

Disease Sites

45 Gy to 50 Gy to the hemithorax, with 13 patients receiving a boost to 55 Gy to 60 Gy. All irradiation was completed in 25 fractions. Although most patients (77 of 86) had T3 or T4 disease, only 14 (16%) patients experienced a local recurrence, whereas 51 (59%) patients developed distant metastasis. Although encouraging, this must be contextualized with the short survival and/or follow-up times with which to detect local relapses. The results of multimodality EPP studies are difficult to interpret owing to patient selection as well as variable interpretation of whether a relapse should be categorized as local or distant. It is critical to distinguish marginal failures, which require better definition of the clinical target volume from in-field failures that may require higher dose. OS appears to correlate well with stage, with much worse outcomes reported for lymph node-positive disease. For example, median survival was 33.8 months for stage I/II disease compared with 10 months for stages III/ IV disease in the MSKCC experience. In a recent Canadian series of 60 patients treated with induction chemotherapy, EPP and hemithoracic RT (≤ 50 Gy),508 median survival was a provocative 59 months for N0 disease but dropped to fewer than 14 months in the remaining patients.

TABLE 52.9 Study

Large Studies of MPM Combining Surgery With Postoperative Radiotherapy Year Surgery

519

Multimodality therapy, including EPP, is reasonably well tolerated in select reports from experienced centers, but treatment is rigorous with potential for substantial toxicity and thus many patients do not complete planned therapy. The use of IMRT after EPP is controversial given initial reports of fatal radiation pneumonitis.505 More recent accumulating data suggest that severe pneumonitis may be avoided if stringent dose constraints for the remaining lung are used in IMRT planning.509,510 A summary of large trials for MPM is shown in Table 52.9.431,507,511–518 Although definitive conclusions cannot be reached, it appears that high-dose postoperative irradiation can dramatically reduce ipsilateral thoracic failures in patients undergoing EPP. Local relapse is more common with pleural decortication than after EPP, and the role of RT in these settings remains unclear. To get a true sense of the benefit of radiotherapy, accurate in-field failure needs to be well documented. Although postoperative irradiation may be well tolerated in experienced hands, the potential for severe toxicity must be considered. The impact of including chemotherapy is difficult to discern and further assessment of systemic therapy is of importance given the benefit in advanced disease.

No. Patients RT Dose

Local Failure (%)

Median Survival

Maasilta

1991

Pleurectomy

34

55 Gy–70 Gy

33% progression, but remainder with “stable” disease

12 mo median

Lee et al.519a

2002

Pleurectomy

24

41.4 Gy (median) 5 Gy–15 Gy IORT

“Most”

18 mo median

Gupta et al.511

2005

Pleurectomy

123

42.5 Gy 3DCRT (median) 54 of 123 patients IORT

56%

14 months

Rosenzweig et al.522

2012

Pleurectomy

20

46.8 Gy (median)

48% local failure at 1-year

26 mo median

Friedberg et al.527

2012

Pleurectomy + PDT

38

25 of 38

31.7 mo median

Baldini et al.431

1997

EPP

49

30.6 Gy 3DCRT, ≈20 Gy boost

43%

22 months

2003

EPP

28

45 Gy–50 Gy

0 2 marginal misses

Not yet reached (2-year OS 62%)

Yajnik et al.506

2003

EPP

35

54 Gy

13/35

Not reported

Gomez et al.507

2013

EPP

86

45 Gy–50 Gy 3DCRT, 15% boosted to 55 Gy–60 Gy

16%

15 months

Weder et al.479

2004

Chemotherapy + EPP

19

Selected volumes

8 of 13 (13 patients completed all therapy)

16.5 mo median

Minatel et al.512

2015

Pleurectomy (35 extended, 34 partial)

69

50 Gy (IMRT)

35%

65% (extended), 58% (partial) at 2 years

Kishan et al.513

2015

Pleurectomy

45

45 Gy (23 3DCRT, 22 tomotherapy)

87% 3DCRT, 50% tomotherapy

-

Bece et al.514

2015

EPP

49

45-50.4 Gy (3DCRT), 37% boosted to 50.4-54 Gy (IMRT)

31 months

Thieke et al.515

2015

EPP

62

48 Gy–54 Gy (IMRT)

40%

20 months

Rimner et al.516

2016

Pleurectomy

27

50.4 Gy (IMRT)

59%

24 months

Shaikh et al.517

2017

Pleurectomy

209

Unspecified range; 131 3DCRT, 78 IMRT

56%

20 months (IMRT), 12 months (3DCRT)

Kapeles et al.518

2018

EPP and pleurectomy

Median 54 Gy (unspecified techniques)

-

14 months

Ahamad et al.

535

78

EPP, Extrapleural pneumonectomy; Gy, gray; IORT, intraoperative radiation therapy; 3DCRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy.

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CHAPTER 52

Radiation Therapy After Pleurectomy A study performed between 1982 and 1988 in Helsinki reported high rates of pulmonary toxicity and pulmonary function deterioration in 34 patients (29 after partial pleurectomy) treated with high doses of adjuvant hemithorax 3DCRT (55 Gy to 70 Gy).519,520 A larger experience from MSKCC511,521,522 included 123 patients treated with pleurectomy or decortication from 1974 to 2003 with adjuvant external beam RT; 54 patients also received an intraoperatively placed 125I or 192Ir boost to gross disease, and a subset of patients received 32P. Radiation doses were 45 Gy to the pleural surface, but the dose to “most of the lung” was kept below 20 Gy by combining electron and photon fields. As in the Helsinki report, substantial toxicity was noted, including 25% grade-3 to grade-4 toxicity, 10% severe pulmonary symptoms, and two treatment-related mortalities within 1 month of treatment. Median survival time was 13.5 months, with 1-year actuarial local control of 42%. More recently, IMRT has been explored in the postpleurectomy setting. The highest level of evidence is from a Phase II trial of 27 patients receiving a median of 46.8 Gy.516 This treatment was tolerated well, with six and two cases of grades 2 and 3 radiation pneumonitis, respectively. The median survival was 24 months. Although outcomes of studies using radiotherapy adjuvant to pleurectomy/decortication suggest reduced locoregional failure rates compared with historical controls of surgery alone, local failure remains common. Toxicities may be ameliorated by modern, advanced RT techniques. Current NCCN guidelines are equivocal with respect to RT after pleurectomy. Given the low likelihood of curing MPM, it is of utmost importance that normal tissue constraints be strongly respected to avoid unnecessary radiation toxicity.523

Intrapleural Photodynamic Therapy Photodynamic therapy (PDT) uses light activation of sensitized tumor cells to achieve sterilization. It can be delivered intraoperatively immediately following pleurectomy or EPP with the goal of sterilizing microscopic disease throughout the thorax.469,524 One advantage of PDT is direct visualization of regions at risk for recurrence. The depth of penetration of the light is a few millimeters, which may limit potential pulmonary toxicity. A Phase I trial of Foscan-mediated PDT found that the maximal tolerated dose of photosensitizer was 0.1 mg/kg 6 days before surgery.525 Dose-limiting toxicity at the next dose level consisted of systemic capillary leak syndrome and led to death in two of three patients treated. Other PDT-related toxicities included wound burns and skin photosensitivity. Fourteen patients were treated at the maximal tolerated dose without significant complications. Photodynamic therapy can be used with other adjuvant therapies.526 One encouraging series was published from the University of Pennsylvania where 38 patients were treated with radical pleurectomy and PDT.527 Most patients (97%) had stage III/IV disease. Median survival was 31.7 months for all patients, but only 6.8 months for the 7 of 38 patients with nonepithelioid histology. Median progression-free survival was 9.6 months.

Palliative Radiation Therapy Pain control. Irradiation can provide effective palliation for patients with MPM. The highest level of evidence comes from a Phase II trial of 40 patients with MPM-related pain, and delivery of 20 Gy in 5 fractions. Of 30 patients alive to assess pain control at 5 weeks (the primary endpoint), nearly half reported reduction in pain.528 Whereas a number of palliative radiation schedules can be safe in MPM, because of the limited life expectancy and importance of systemic therapy in MPM, we advocate avoiding prolonged palliative courses and to limit palliative radiation to 1 to 2 weeks.

Uncommon Thoracic Tumors

891

Therapy for drain sites. Unlike most malignant tumors, MPM has a tendency to recur along tracks of previous chest wall instrumentation.529,530 One randomized trial (n = 40) has shown decreased local failures in patients receiving elective RT to drain sites (21 Gy in 3 fractions).529 Two other larger Phase III trials found no reductions in the incidence of tumor seeding in irradiated patients.524,531 Another randomized trial in Europe, the PIT study, is ongoing (NCT01604005).

Irradiation Techniques Patient immobilization and setup. Two basic techniques have been described for thoracic irradiation following EPP.506,532 A description of the IMRT techniques for the postoperative treatment of MPM has been described.507,532 This level of detail is required to ensure that the complex target volumes can be identified and reproducibly treated for 5 weeks. Computed tomography simulation. Radiopaque wires should be used to mark surgical incisions and tissue equivalent bolus can extend to 4 cm around wires. Patients should be immobilized supine on the CT simulator using a combination of a vacuum bag and an “extended wing board with T-bar handgrip” immobilization device used in conjunction with a headrest. The patient should be scanned from the middle neck to the anterior superior iliac spine. This low inferior border allows complete definition of both kidneys so that accurate dose-volume histograms can be constructed. Four-dimensional simulation with assessment of respiratory motion should be performed with consideration of motion management with respiratory gating or breath hold to minimize radiation treatment volumes. Target volume delineation. The ipsilateral mediastinum should be included in the target volume,533,534 even for patients who are nodenegative. The superior border should be placed at the thoracic inlet. The medial border includes the ipsilateral nodal regions, the trachea and subcarinal regions, or the vertebral body.506,532 The posterior mediastinal structures behind the heart need not be included, because no failures in this region have been reported despite their omission from the CTV.533 The anteromedial pleural reflection is a potential problem for target volume delineation. As shown in Fig. 52.10, A, the medial pleural space sometimes can cross the midline. This anatomic relationship can be lost after surgery (see Fig. 52.10, B). When possible, this region should be marked intraoperatively with radiopaque clips. Alternatively, the medial extent of the pleura could be identified on preoperative CT scans and then estimated on the treatment-planning CT scan. This has been the site of a marginal miss in our series (see Fig. 52.10, C, arrow). The inferior border should be the insertion of the diaphragm. The location of this is quite variable, ranging from vertebrae L1 to L4. Because of this variability, the diaphragm insertion should be marked by intraoperative placement of radiopaque clips535 or by suturing the neodiaphragm in this location.506 When the border of the intrathoracic contents and the abdominal contents are well marked, the target volume margins can be maximally reduced. Because there can be great difficulty in differentiating liver from thoracic fluid, the use of radiopaque Gore-Tex patches for diaphragm reconstructions is helpful. Another potential source of contouring error is the medial extent of the crus of the diaphragm, especially at its most inferior extent. The ipsilateral crus is usually difficult to identify after surgery without clips. The best way to individualize the inferior edge of the target volume is with intraoperative placement of radiopaque clips, with particular attention to the crus. When the entire region is extensively clipped, a pattern such as that seen in Fig. 52.11 emerges, with regions of potential pitfall highlighted. These potential problem areas include the anterior medial pleural

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892

SECTION III

Disease Sites

A

C

B Fig. 52.10 The costomediastinal sulcus can cross the midline. (A) Preoperatively, pleural thickening crosses the midline anteriorly (arrow). (B) This involvement is obliterated by the extrapleural pneumonectomy (EPP), and the medial edge of the clinical target volume (CTV) was placed at the insertion of the rib (arrow). (C) The tumor recurred immediately adjacent to the CTV (arrow) in a region that received less than 40 Gy.

reflection, the crus of the diaphragm, and the inferior aspect of the diaphragmatic insertion.

Treatment Planning

TABLE 52.10 Suggested Target Dosing and Dose Constraints for Mesothelioma Radiotherapy

Three-Dimensional Conformal Radiation Therapy

Target or Organ

Goal Dose or Constraint Dose

The 3D-CRT therapy approach has been described best in two reports from the MSKCC.505,506 The technique applies anteroposteriorposteroanterior beam geometry to the hemithorax using the volumes described previously as the CTV. For right-sided cases, an abdominal block is present throughout treatment and the region is boosted with electrons at 1.53 Gy per day, which accounts for scatter under the block. For left-sided cases, the kidney and heart are blocked. The kidney block is present throughout treatment and the heart block is added after 19.8 Gy. The spinal cord is shielded after 41.4 Gy in all cases. The goal dose to the target volume is 54 Gy in 30 fractions, with the dose calculated at the midplane with equally weighted beams. Patients were treated with arms akimbo. Treatment by this approach results in good coverage of most volumes at risk to the target dose of 54 Gy. Doses are homogeneous within the regions at risk, although regions such as the crus, the pericardium, and the neodiaphragm may be difficult to treat.

CTV

50 Gy in 25 fractions

bCTV

60 Gy in 25 fractions

Lung

< 20% to receive > 20 Gy and mean < 8.5 Gy

Liver

< 30% to receive > 30 Gy

Contralateral kidney

< 20% to receive > 15 Gy

Heart

< 50% to receive > 45 Gy

Spinal cord

< 10% to receive > 45 Gy No portion to receive > 50 Gy

Esophagus

< 30% to receive > 55 Gy

bCTV, Boost clinical target volume; CTV, clinical target volume; Gy, gray.

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A

Heart 19.8 Gy

Abdominal field

Abdominal field

Spinal cord 41.4 Gy

Spinal cord 41.4 Gy

Fig. 52.11 Potentially problematic areas for clinical target volume (CTV) determination. Three parts of the CTV are potentially difficult to discern without great care: the anteromedial pleural reflection of the sternopericardial recess (1), the inferior and medial extents of the crus of the diaphragm (2), and the inferior insertion of the diaphragm (3).

B Fig. 52.12 The total prescribed dose from the anteroposterior (A) and posteroanterior (B) photon fields and supplemental electron fields was 54 Gy in 1.8-Gy fractions. At the start of treatment, blocks were placed in the region of the abdomen. During treatment of the left hemithorax, an anterior heart block was placed at 19.8 Gy. Blocked areas were subsequently delivered 1.53 Gy daily through an en face electron field. At 41.4 Gy, anterior and posterior blocks were placed over the spinal cord. (Used with permission from Hill-Kayser CE, Avery S, Mesina CF, et al: Hemithoracic radiotherapy after extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma. A dosimetric comparison of two well-described techniques. J Thorac Oncol. 2009;4:1431–37.) Downloaded for [email protected] upr07 ([email protected]) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on April 23, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.

894

SECTION III

Disease Sites

50 Gy 30 Gy 10 Gy A

B

C Fig. 52.13 (A to C) The dose distributions for intensity-modulated radiation therapy (IMRT) demonstrate good coverage of the clinical target volume (CTV) and the high-dose gradients achievable with this technique. The goal was 50 Gy to the CTV. The 50-Gy, 40-Gy, 30-Gy, and 10-Gy isodose lines are shown in magenta, orange, green, and blue, respectively.

Intensity-Modulated Radiation Therapy The target doses and the dose-volume limits for the critical s