The Washington Manual of Oncology [4 ed.] 1975153456, 9781975153458

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Dedicated to our colleagues in the Division of Oncology at the Washington University School of Medicine

Contributors Douglas Adkins, MD Professor Department of Medicine Washington University Attending Physician Barnes-Jewish Hospital St. Louis, Missouri

Rebecca L. Aft, MD, PhD Jeffrey Moley Professor of Surgery Department of Surgery Washington University School of Medicine Barnes-Jewish Hospital John Cochran Veterans Hospital St. Louis, Missouri

Manik Amin Assistant Professor Division of Oncology Department of Medicine Washington University School of Medicine St. Louis, Missouri

George Ansstas, MD Associate Professor Division of Oncology Department of Medicine Washington University School of Medicine St. Louis, Missouri

Olivia Aranha, MD, PhD Assistant Professor of Medicine Division of Oncology Department of Medicine Washington University School of Medicine Faculty Division of Oncology Department of Medicine Siteman Cancer Center, Barnes-Jewish Hospital St. Louis, Missouri

Vivek K. Arora, MD, PhD Assistant Professor Division of Oncology Department of Internal Medicine Washington University School of Medicine

St. Louis, Missouri

Shahed Nicolas Badiyan, MD Assistant Professor Department of Radiation Oncology Washington University St. Louis, Missouri

Dhruv Bansal, MD, MBA Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

David G. Brauer, MD, MPHS Clinical Fellow Department of Surgery Memorial Sloan Kettering Cancer Center New York, New York

Randall Brenneman, MD, PhD Chief Resident Physician (PGY-5) Department of Radiation Oncology Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Omar Hameed Butt, MD, PhD Fellow Department of Neurology Washington University St. Louis, Missouri

Jian Li Campian, MD, PhD Associate Professor of Medicine Department of Internal Medicine— Medical Oncology Washington University Barnes-Jewish Hospital St. Louis, Missouri

Amanda F. Cashen, MD Professor Department of Medicine Washington University St. Louis, Missouri

David Y. Chen, MD, PhD

Instructor in Medicine Division of Dermatology Department of Medicine Washington University School of Medicine St. Louis, Missouri

Katherine Clifton, MD Assistant Professor Department of Internal Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Lynn A. Cornelius, MD Professor Chief of Dermatology Washington University School of Medicine St. Louis, Missouri

Zachary D. Crees, MD Hematology/Oncology Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Mackenzie D. Daly, MD Assistant Professor Department of Radiation Oncology Washington University School of Medicine Barnes-Jewish Hospital St. Louis, Missouri

Maria Dans, MD Associate Professor Department of Medicine Division of Hospice and Palliative Medicine Washington University in St. Louis Clinical Director Palliative Care Services Barnes-Jewish Hospital St. Louis, Missouri

Siddhartha Devarakonda, MD Assistant Professor Division of Medical Oncology Department of Medicine Washington University St. Louis, Missouri

Haley Ellis, MD Resident Physician Department of Medicine Washington University Barnes-Jewish Hospital St. Louis, Missouri

Vanessa A. Eulo, MD Oncology Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Mary Ellen Flanagan, NP-C, MSN, OCN Nurse Practitioner Division of Medical Oncology Alvin J. Siteman Cancer Center Washington University School of Medicine St. Louis, Missouri

Feng Gao, PhD Associate Professor Division of Public Health Sciences Department of Surgery Washington University School of Medicine St. Louis, Missouri

Armin Ghobadi, MD Associate Professor Clinical Director Center for Gene and Cellular Immunotherapy (CGCI) Department of Medicine Washington University School of Medicine St. Louis, Missouri

Scott R. Goldsmith, MD Clinical Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Sasha Haarberg, PharmD, BCOP Clinical Oncology Pharmacist Department of Medicine/Division of Medical Oncology

Washington University School of Medicine St. Louis, Missouri

Jennifer Hedgecorth, PharmD, BCPS Oncology Clinical Pharmacist Washington University School of Medicine Siteman Cancer Center St. Louis, Missouri

Whitney Hensing, MD, MSCR Clinical Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Leonel Hernandez-Aya, MD Assistant Professor Division of Oncology Department of Medicine Washington University School of Medicine St. Louis, Missouri

Brett H. Herzog, MD, PhD Fellow Department of Medicine Barnes-Jewish Hospital/Washington University in St. Louis St. Louis, Missouri

Lindsay M. Hladnik, PharmD, BCOP Clinical Oncology Pharmacist Department of Medicine/Division of Medical Oncology Washington University School of Medicine St. Louis, Missouri

James J. Hsieh, MD, PhD Professor Department of Medicine Washington University St. Louis, Missouri

Jennifer J. Huang, MD, PhD Resident Department of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Jiayi Huang, MD Associate Professor Department of Radiation Oncology Washington University School of Medicine St. Louis, Missouri

Michael Dela Iglesia, MD, PhD Clinical Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Shu Jiang, MSc, PhD Assistant Professor Division of Public Health Sciences Department of Surgery Washington University in St. Louis St. Louis, Missouri

Ramon V. Jin, MD, PhD Clinical Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Tanner Michael Johanns, MD, PhD Assistant Professor Division of Oncology Department of Medicine Washington University School of Medicine St. Louis, Missouri

Brad S. Kahl, MD Professor of Medicine Director of Lymphoma Program Department of Medical Oncology Washington University School of Medicine St. Louis, Missouri

Karam Khaddour, MD Research Fellow Division of Oncology Department of Medicine School of Medicine

Washington University in St. Louis St. Louis, Missouri

Jessica Ley, BS Clinical Research Specialist Division of Medical Oncology Department of Internal Medicine Washington University St. Louis, Missouri

Joshua Loesche, PharmD, BCOP Clinical Oncology Pharmacist Department of Medicine/Division of Medical Oncology Washington University School of Medicine St. Louis, Missouri

Cynthia X. Ma, MD, PhD Professor Division of Oncology Department of Medicine Washington University School of Medicine Attending Physician Department of Medicine Barnes-Jewish Hospital St. Louis, Missouri

Mary-Kate Malecek, MD Clinical Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Janelle E. Mann, PharmD, BCOP Clinical Oncology Pharmacist Manager of Clinical Pharmacy Services Department of Medicine/Division of Medical Oncology Washington University School of Medicine St. Louis, Missouri

Neha Mehta-Shah, MD, MSCI Assistant Professor of Medicine Division of Oncology Department of Internal Medicine Washington University School of Medicine Barnes-Jewish Hospital St. Louis, Missouri

Basia M. Michalski, MD

Resident Physician Division of Dermatology Department of Medicine Washington University in St. Louis St. Louis, Missouri

J. Philip Miller, AB Professor Division of Biostatistics Department of Medicine Washington University St. Louis, Missouri

Daniel Morgensztern, MD Professor of Medicine Clinical Director of Thoracic Oncology Division of Oncology Alvin J. Siteman Cancer Center at Washington University School of Medicine St. Louis, Missouri

Ashley Morton, RN, MSN, ANP-BC Oncology Nurse Practitioner Division of Medical Oncology Department of Internal Medicine Washington University School of Medicine Medical Oncology Nurse Practitioner Division of Medical Oncology/Department of Internal Medicine Barnes-Jewish Hospital St. Louis, Missouri

David G. Mutch, MD Ira C and Judith Gall Professor Division of Gyn Oncology Department of Ob/Gyn Washington University School of Medicine Vice Chairman of Ob/Gyn Department of Ob/Gyn/Division of Gyn Oncology Barnes-Jewish Hospital St. Louis, Missouri

Sasa Mutic, PhD Professor Department of Radiation Oncology Barnes-Jewish Hospital St. Louis, Missouri

Katherine Navo, FNP Division of Medical Oncology Department of Internal Medicine Washington University School of Medicine

St. Louis, Missouri

Gradon Nielsen, MD Clinical Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Peter Oppelt, MD Assistant Professor of Medicine Department of Internal Medicine Washington University in St. Louis Siteman Cancer Center St. Louis, Missouri

Russell K. Pachynski, MD Assistant Professor Division of Oncology Department of Medicine Washington University School of Medicine St. Louis, Missouri

Kevin T. Palka, MD Assistant Professor Division of Oncology Department of Medicine Washington University School of Medicine Christian Hospital St. Louis, Missouri

Haeseong Park, MD, MPH Assistant Professor of Medicine Division of Oncology Department of Internal Medicine Washington University School of Medicine Assistant Professor of Medicine Internal Medicine, Division of Oncology Barnes-Jewish Hospital St. Louis, Missouri

Lindsay Peterson, MD, MSCR Assistant Professor Division of Oncology Department of Medicine Washington University School of Medicine St. Louis, Missouri

Patrik Pipkorn, MD, MSCI

Assistant Professor Department of Otolaryngology, Head and Neck Surgery Washington University in St. Louis St. Louis, Missouri

Matthew Allen Powell, MD Professor & Chief, Division of Gynecologic Oncology Department of Obstetrics & Gynecology Washington University School of Medicine St. Louis, Missouri

Valerie Prashad, PharmD, BCPS Clinical Oncology Pharmacist Division of Medical Oncology Washington University School of Medicine St. Louis, Missouri

Lesley Rao, MD Program Director Pain Medicine Fellowship Associate Professor of Anesthesiology Washington University School of Medicine St. Louis, Missouri

Lee Ratner, MD, PhD Professor Department of Medicine Washington University School of Medicine St. Louis, Missouri

Melissa A. Reimers, MD Assistant Professor of Medicine Division of Oncology Department of Internal Medicine Washington University in St. Louis St. Louis, Missouri

Clifford G. Robinson, MD Professor Department of Radiation Oncology Washington University in St. Louis Chief, Thoracic Radiation Oncology and Stereotactic Body Radiotherapy Barnes-Jewish Hospital St. Louis, Missouri

Anna Roshal, MD Assistant Professor Division of Oncology Department of Medicine Washington University School of Medicine St. Louis, Missouri

Kristen Sanfilippo, MD, MPHS Assistant Professor Division of Hematology Department of Medicine Washington University School of Medicine Staff Physician Hematology/Oncology, Department of Medicine John Cochran VA Medical Center St. Louis, Missouri

Rajiv K. Shah, MD Assistant Professor of Anesthesiology Washington University School of Medicine St. Louis, Missouri

Lauren Kelly Shea, MD, MS Clinical Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Keith Stockerl-Goldstein, MD Professor of Medicine Division of Oncology Department of Medicine Washington University School of Medicine Barnes-Jewish Hospital St. Louis, Missouri

Seth Strope, MD, MPH Associate Professor Urologic Surgery Division of Surgery Washington University School of Medicine St. Louis, Missouri

Robert A. Swarm, MD Professor Chief of Pain Management Division Department of Anesthesiology Washington University School of Medicine St. Louis, Missouri

Benjamin R. Tan, Jr., MD Associate Professor of Medicine Attending Physician

Division of Oncology Section of Medical Oncology Department of Medicine Washington University of Medicine Barnes-Jewish Hospital St. Louis, Missouri

Brian A. Van Tine, MD, PhD Associate Professor of Medicine Sarcoma Program Director Division of Medical Oncology Department of Medicine Washington University in St. Louis Barnes-Jewish Hospital/Siteman Cancer Center St. Louis, Missouri

Michael D. Toboni, MD, MPH Clinical Fellow Division of Gynecologic Oncology Department of Ob/Gyn Washington University Barnes-Jewish Hospital St. Louis, Missouri

Nikolaos A. Trikalinos, MD, MS Assistant Professor Department of Medical Oncology Washington University in St. Louis St. Louis, Missouri

Danielle Turlington, PharmD, BCOP Clinical Oncology Pharmacist Department of Medicine/Division of Medical Oncology Washington University School of Medicine St. Louis, Missouri

Jacob A. Varney, MD Assistant Professor Department of Internal Medicine Southern Illinois University School of Medicine Springfield, Illinois

Ramakrishna Venkatesh, MD, FRCS (Urol.) Professor Department of Urology/Surgery Washington University School of Medicine Urologist Department of Urology/Surgery Barnes-Jewish Hospital St. Louis, Missouri

Ravi Vij, MD, MBA Professor of Medicine Division of Medical Oncology Washington University School of Medicine Physician Department of Internal Medicine Barnes-Jewish Hospital St. Louis, Missouri

Fei Wan, PhD Assistant Professor Division of Public Health Science Department of Surgery Washington University in St. Louis St. Louis, Missouri

Tzu-Fei Wang, MD, MPH Associate Professor Department of Medicine University of Ottawa Staff Physician Department of Medicine The Ottawa Hospital Ottawa, Ontario, Canada

Andrea Wang-Gillam, MD, PhD Associate Professor Division of Oncology Department of Internal Medicine Washington University in St. Louis St. Louis, Missouri

Saiama Naheed Waqar, MBBS, MSCI Associate Professor of Medicine Division of Oncology Department of Medicine Washington University School of Medicine St. Louis, Missouri

Madison Weg, MD Resident Department of Medicine Washington University Barnes-Jewish Hospital St. Louis, Missouri

Tanya M. Wildes, MD, MSCI Associate Professor of Medicine and Anesthesiology Department of Medicine Washington University School of Medicine

Attending Physician Department of Medicine Barnes-Jewish Hospital St. Louis, Missouri

Jing Xi, MD, MPH Clinical Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Alice Yao Zhou, MD, PhD Hematology Oncology Fellow Division of Oncology Department of Medicine School of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Amy W. Zhou, MD Assistant Professor Division of Hematology Department of Medicine Washington University in St. Louis Barnes-Jewish Hospital St. Louis, Missouri

Preface It has been nearly 18 years since we launched the first edition of The Washington Manual of Oncology. We continue to see enormous progress in oncology with a better understanding of molecular alterations in cancer and advances in treatment. Although much work remains to be done, cancer care has become complicated and daunting. We have incorporated recent advances in diagnosis and therapy in this edition. Almost all the chapters have been extensively revised or rewritten. As before, this manual is written keeping the trainees in mind while also providing a quick update for oncology practitioners. We hope that you, the reader, find this manual practical, useful, and stimulating. As always, we will be very grateful to you for pointing out any inadvertent errors that have slipped all our editorial review process. Please feel free to e-mail us with your suggestions, feedback, and comments. Daniel Morgensztern, MD Armin Ghobadi, MD Ramaswamy Govindan, MD

Preface to the First Edition These are exciting times in oncology. The novel imaging techniques, improved supportive care, and the availability of several new agents that have novel mechanisms of action hold considerable promise in improving the outcomes of cancer patients. In this era of information overload, it is critically important to have a practical manual that is helpful to physicians taking care of patients with cancer. The chapters are arranged in a logical order beginning with evaluation of symptoms and proceeding in an orderly fashion through the workup, staging, and stage-directed therapy, finally ending with discussion on epidemiology and current focus of research. We have embarked on this first edition of The Washington Manual of Oncology to provide a very practical manual that is helpful to medical residents, fellows in training, nurse practitioners, and other practitioners of clinical oncology. Our plan is to publish this book in a timely fashion every 2 years to keep the information current and up-todate. Ramaswamy Govindan, MD

Acknowledgments First and foremost, we are delighted to welcome our dear colleague and a well-known expert in cellular therapy and hematologic malignancies, Dr. Armin Ghobadi. RG wants to gratefully acknowledge the contributions made by Dr. Daniel Morgensztern over the years. He was a coeditor for the third edition of this manual and now has assumed the key role of editing the book. His boundless enthusiasm, encyclopedic knowledge, and diligence in editing have been instrumental in producing this manual. We want to thank the individual contributors, who are all our dear and well-respected colleagues, for their efforts. As we have found over the years, several individuals work behind the scenes to produce a book. At Wolters Kluwer, Nicole Dernoski, acquisitions editor, and Sean McGuire, senior product development editor, were instrumental in keeping the project moving and persistent with follow-up. They were kind enough to accommodate our busy schedules and have been remarkably patient with our delays, edition after edition. I am very grateful for their insight, wisdom, and patience. We all owe a particular debt of gratitude to the leadership and inspiration provided by the chief of the Division of Oncology, John F. DiPersio, MD, PhD. We are blessed with wonderful children and adorable spouses and are immensely grateful for their support. Daniel Morgensztern, MD Armin Ghobadi, MD Ramaswamy Govindan, MD I thank my parents Silvia and Felipe Morgensztern; my lovely three children Alan, David, and Michael; and my beautiful wife Marcela. Daniel Morgensztern, MD I thank my wonderful wife Mojdeh and my amazing children Kevin and Bruce for bringing so much joy into my life every day. Armin Ghobadi, MD I am grateful to my lovely wife Prabha and our two adorable children Ashwin and Akshay for all their support. Ramaswamy Govindan, MD

Contents Contributors Preface Preface to the First Edition Acknowledgments

Cancer Biology and Molecular Diagnosis 1 Brett H. Herzog and Siddhartha Devarakonda 2 Principles and Practice of Surgery in Cancer Therapy David G. Brauer and Rebecca L. Aft

Principles and Practice of Radiation Oncology 3 Randall Brenneman, Sasa Mutic, and Clifford G. Robinson 4 Principles of Systemic Cancer Therapy: Cytotoxic Chemotherapy Janelle E. Mann and Valerie Prashad

5 Principles of Systemic Cancer Therapy: Molecularly Targeted Therapy Lindsay M. Hladnik, Joshua Loesche, and Janelle E. Mann

Cancer Immunotherapy 6 Michael Dela Iglesia and Tanner Michael Johanns 7 Principles of Gene and Cellular Immunotherapy for Cancer Zachary D. Crees and Armin Ghobadi

Biostatistics 101 as Applied to Oncology 8 Fei Wan, Shu Jiang, Feng Gao, and J. Philip Miller Neuro-oncology 9 Omar Hameed Butt, Alice Yao Zhou, Jiayi Huang, and Jian Li Campian Head and Neck Cancer

Peter Oppelt, Kevin T. Palka, Mackenzie D. Daly, Patrik Pipkorn, Jessica Ley, and Douglas Adkins

10 Small Cell Lung Cancer 11 Haley Ellis, Shahed Nicolas Badiyan, and Siddhartha Devarakonda Non–Small Cell Lung Cancer 12 Brett H. Herzog, Daniel Morgensztern, and Saiama Naheed Waqar Breast Cancer 13 Jing Xi, Cynthia X. Ma, and Katherine Clifton Thymoma and Mesothelioma 14 Vanessa A. Eulo, Mary Ellen Flanagan, and Daniel Morgensztern Esophageal and Gastric Cancer 15 Ramon V. Jin, Katherine Navo, and Haeseong Park 16

Colorectal Cancer Ashley Morton and Benjamin R. Tan

Hepatobiliary Cancers 17 Katherine Navo, Ashley Morton, and Manik Amin 18

Pancreatic Cancer Andrea Wang-Gillam

Kidney Cancer 19 Jennifer J. Huang and James J. Hsieh Bladder Cancer 20 Vivek K. Arora Prostate Cancer 21 Russell K. Pachynski, Ramakrishna Venkatesh, and Seth Strope Testicular Cancer and Germ Cell Tumors 22 Melissa A. Reimers Ovarian Cancer 23 Michael D. Toboni and Matthew Allen Powell Uterine, Cervical, Vulvar, and Vaginal Cancers 24 Michael D. Toboni and David G. Mutch

25

Sarcoma Brian A. Van Tine

26 Malignant Melanoma and Nonmelanoma Skin Cancer Basia M. Michalski, David Y. Chen, Lynn A. Cornelius, and Leonel Hernandez-Aya

Endocrine and Neuroendocrine Malignancies 27 Nikolaos A. Trikalinos Cancer of Unknown Primary Site 28 Zachary D. Crees and Daniel Morgensztern 29

Principles of Hematopoietic Cell Transplantation Mary-Kate Malecek and Amanda F. Cashen

Hodgkin Lymphoma 30 Mary-Kate Malecek and Neha Mehta-Shah 31 32 33

Non-Hodgkin Lymphoma Brad S. Kahl and Neha Mehta-Shah

Acute Leukemias and Myelodysplastic Syndromes Dhruv Bansal and Armin Ghobadi

Chronic Leukemias Lauren Kelly Shea and Keith Stockerl-Goldstein

Plasma Cell Dyscrasias 34 Scott R. Goldsmith and Ravi Vij HIV-Associated Malignancies 35 Lee Ratner Care of the Older Adult with Cancer 36 Gradon Nielsen and Tanya M. Wildes Cancer and Thrombosis 37 Kristen Sanfilippo and Tzu-Fei Wang 38 Oncologic Emergencies

Karam Khaddour and George Ansstas

39

Growth Factor Support in Oncology Madison Weg and Amy W. Zhou

Pain Management 40 Robert A. Swarm, Rajiv K. Shah, and Lesley Rao Palliative Care in Oncology 41 Jacob A. Varney, Anna Roshal, and Maria Dans 42 Management of Antineoplastic-Induced Nausea and Vomiting Sasha Haarberg and Jennifer Hedgecorth

43

Cancer Survivorship Whitney Hensing and Lindsay Peterson

Smoking Cessation and Counseling 44 Olivia Aranha Appendix Index

I.

THE HALLMARKS OF CANCER According to the clonal model of carcinogenesis, a malignant tumor arises from a single cell. This founder cell acquires an initial mutation that provides its progeny with a selective growth advantage, and from within this expanded population, another single cell acquires a second mutation that provides an additional growth advantage, and so on, until a fully transformed malignant cell emerges. Sustained proliferative signaling, evasion of growth suppressors, resistance of cell death, immortality, angiogenesis, invasion, and metastasis are all “Hallmarks of Cancer” that are critical in the development of a malignant tumor. These “Hallmarks of Cancer” have been updated over the past two decades to include novel findings related to the developing malignancy (genomic instability and mutation) and the tumor microenvironment (deregulating cellular energetics, tumor-promoting inflammation, and evading immune destruction) (Cell 2011;144:646) (Table 1-1). However, the ability of cancer cells to adapt to their environment and the selection pressures imposed by their unique microenvironments relies heavily on their ability to gain specific genomic and epigenomic alterations that lead to increased fitness.

TABLE 1-1

Summary of the Key Molecular and Genomic Changes Associated with Malignant Transformation (the Hallmarks of Cancer)

Hallmark

Cancer Cell Behavior

Genome instability and mutation

Obtain genomic alterations as well as driver mutations.

Resistance of cell death

Apoptosis is diminished, leading to increased proliferation, progression, and treatment resistance.

Evasion of growth

Dampening of suppressive signals from extrinsic and intrinsic sources

suppressors Sustained proliferative signaling

External and internal signaling pathways from growth receptors

Immortality

Telomerase production maintains telomeres.

Deregulating cellular energetics

Adaptive metabolism

Angiogenesis

Vascular endothelial growth factor (VEGF) expression and release induces neovascularization to supply nutrients.

Tumor-promoting inflammation

Inflammation results in altered cell proliferation, survival, and angiogenesis.

Evading immune destruction

Hijacking immune modulation signals to avoid immune-mediated death

Invasion and metastasis

Invasion of local tissues and eventual distant spread

II. GENOMIC ALTERATIONS IN CANCER Mutations, or alterations in DNA, occur via a variety of sources, including extrinsic and intrinsic cellular mechanisms, and lead to changes in protein expression or function. Exogenous insults to a cell, or to a mutagen, may be chemical, biologic, or radiation related. Failure of DNA replication or repair mechanisms are cell-intrinsic mechanisms of mutagenesis. One way to differentiate the source of mutation is to define the cell in which the mutation occurs. For instance, some cancer-causing mutations can occur in reproductive cells (germline mutations) and are associated with heritable cancer syndromes (Table 1-2). By contrast, most cancers arise from individual cells in a particular organ that obtain a DNA alteration, and these alterations cannot be passed on to an individual’s offspring (somatic mutations). Although not all mutations lead to disease (silent mutations), understanding how some of these mutations lead to hallmark changes in cancer is of critical importance for the identification and treatment of cancer. TABLE 1-2

Genetic Alterations Associated with Commonly Encountered Hereditary Cancer Syndromes

Syndrome

Cancers

Gene

Cowden syndrome

Breast, thyroid

PTEN

Familial melanoma

Melanoma, pancreatic cancer

CDKN2A (p16)

Familial adenomatous polyposis

Colon, duodenum

APC

Gorlin syndrome

Basal cell carcinomas

PTCH

Hereditary breast and ovarian cancer

Breast, ovarian, prostate, pancreatic cancer, melonoma

BRCA1/2

HNPCC

Colon, endometrial, stomach, biliary tract, ovarian

MLH1, MSH2, MSH6

Li–Fraumeni syndrome

Sarcoma, breast, CNS, adrenocortical, others

TP53

Multiple endocrine neoplasia type 1

Parathyroid adenoma, pancreatic islet, pituitary adenoma

MEN1

Multiple endocrine neoplasia type 2A and 2B

Parathyroid adenoma, medullary thyroid, pheochromocytoma

RET

Neurofibromatosis I

Neurofibrosarcoma, pheochromocytoma, optic gliomas

NF1

Retinoblastoma

Retinoblastoma, osteosarcoma

RB1

Peutz–Jeghers syndrome

Breast, gastrointestinal, pancreatic, ovarian

STK11/LKB1

Von Hippel–Lindau syndrome

Hemangioblastoma of the retina and CNS, renal cell carcinoma, pheochromocytoma

VHL

CNS, central nervous system; HNPCC, hereditary nonpolyposis colorectal cancer.

A. Sources of DNA damage. Both endogenous and exogenous processes can result in somatic mutations that, if left unresolved, can result in cancer development. Free radicals, spontaneous chemical reactions, and metal ion reactions are endogenous processes that can lead to DNA damage. Free radicals are by-products of normal cellular metabolism and play important roles in cell signaling and homeostasis. The − most common free radicals include OH , NO, and peroxides. Increased environmental stress may dramatically increase free radical production, resulting in DNA damage. Collectively, these changes are known as oxidative damage and include DNA sugar and base modifications, DNA–DNA and DNA–protein crosslinks, as well as DNA strand breaks. Of note, free radicals can also be generated by exogenous sources such as ionizing radiation, pollutants, and tobacco. Common spontaneous chemical changes that alter the structure of DNA such as deamination and depurination reactions can lead to DNA mutations. Furthermore, spontaneous hydrolysis, alkylation, and adduction reactions are all capable of inducing genomic damage; however, the mutagenic potential varies with each. DNA damage by endogenous metals such as iron, copper, nickel, chromium, magnesium, and cadmium have all been linked to human carcinogenesis. Metalcatalyzed reactions produce DNA adducts, resulting in a wide variety of organic metabolites. Metals such as arsenic, cadmium, lead, and nickel also directly inhibit DNA repair, which augments the mutagenic potential of the DNA damage they induce. Because they are more frequently discussed, many people are aware of the most

common exogenous sources of DNA damage, including chemical compounds, antineoplastic agents, and various types of radiation. Although a virtually infinite number of chemicals can damage DNA, a few families of environmental and therapeutic compounds illustrate the general mechanisms involved. Polycyclic aromatic hydrocarbons and related compounds are converted into reactive intermediate metabolites by the normal physiologic action of cytochrome P-450. These reactive intermediates cause DNA adducts, thereby damaging DNA. Many types of antineoplastic agents exert their therapeutic effect through DNA damage. Cell cycle–specific therapies include antimetabolites (i.e., 5-fluorouracil, 6mercaptopurine, and methotrexate) that interfere with nucleotide production as well as taxanes (i.e., docetaxel, paclitaxel) and vinca alkaloids that disrupt microtubule formation. Cell cycle–nonspecific drugs include cytotoxic alkylating agents (i.e., cyclophosphamide, busulfan, nitrogen mustard, and thiotepa) that result in DNA damage through the formation of covalent linkages, producing alkylated nucleotides, DNA–DNA cross-links, DNA–protein cross-links, and DNA strand breaks; anthracyclines (i.e., daunorubicin, doxorubicin) that inhibit topoisomerase II; and platinum-based therapies (i.e., carboplatin, cisplatin) that act primarily by causing intra- and interstrand cross-links. DNA damage caused by radiation can be classified into damage caused by ultraviolet radiation (UV light) or ionizing radiation. UV-B radiation produces cyclobutane pyrimidine dimers as well as pyrimidine (6-4) pyrimidone photoproducts; whereas UV-A radiation induces damage primarily via reactive oxygen species (ROS) production. Ionizing radiation induces a wide array of DNA damage, including single base alterations, cross-links, and single-strand breaks or double-strand breaks (DSBs). B. Types of DNA alterations. The classification of mutations typically depends on the amount of DNA that is affected. Small mutations or changes may only affect one gene, but large chromosomal alterations can change large swaths of the genome. 1. Single base-pair alterations. Single base-pair substitutions are among the most commonly observed mutations that occur in both coding and noncoding regions and may be a consequence of numerous processes, including errors in DNA replication, spontaneous chemical reactions, ROS damage, chemical mutagenesis, ionizing radiation, and failure of DNA repair mechanisms. A single base-pair substitution occurring within the coding sequence of a gene can lead to a significant change in the encoded amino acid, but does not cause a shift in the translational reading frame. These substitutions are classified into synonymous mutations and nonsynonymous mutations. Synonymous mutations are those in which a different codon still specifies the same amino acid, and the vast majority of these changes are neutral. There are two types of nonsynonymous mutations,

consisting of missense mutations (resulting in a codon that specifies a different amino acid) and nonsense mutations (production of a stop codon). The extent of disruption caused by missense mutations depends on the similarities or differences between the two amino acids, whereas nonsense mutations may lead to premature termination and reduced protein function. Substitutions that occur in the noncoding regions of genes, such as those in the 5′ regulatory region of a gene (a portion of the DNA that begins at the transcription start site and ends before the start codon for translation), can alter the pattern of gene expression. Noncoding regions of genes do not encode proteins; however, they perform several important gene regulatory functions, including modulating gene expression. Substitutions in introns, exons, or untranslated regions of a gene can also affect RNA processing. Genomic alterations such as single base-pair insertions or deletions (INDELs) lead to a shift in the translational reading frame; therefore, the amino acid being encoded is changed, leading to an altered protein structure and, presumably, function. These alterations frequently lead to either missense mutations or nonsense mutations depending on the altered codon. 2. Chromosomal alterations. Large chromosomal alterations are occasionally inherited, but many occur spontaneously or in the setting of environmental stressors such as certain carcinogens or radiation. They can be identified as deletions, inversions, duplications, or translocations. Deletions result when a segment of a chromosome, or the whole of it, is lost; whereas, an inversion is where a segment of the chromosome is detached and reattached in reverse order on the same chromosome. Duplication occurs when a segment of a chromosome is copied but is then inserted directly adjacent to the original either in tandem or in reverse orientation. When one part of a chromosome is transferred to a different part of either the same chromosome or a different chromosome, it is called a translocation. C. Targets of oncogenic mutations. Tumor suppressor genes and oncogenes are frequent targets of mutation in this multistep process of tumor evolution. 1. Tumor suppressor genes. Normal cellular functions of tumor suppressor gene products are highly diverse, including regulation of the cell cycle, cell differentiation, apoptosis, and maintenance of genomic integrity. Dozens of tumor suppressor genes have been identified, and numerous potential candidates have been described. Many of these genes were identified by virtue of the fact that they are mutated in the germline of persons who are affected by cancer syndromes. Nevertheless, for the vast majority of tumor suppressor genes, somatic mutations play a far more significant role in cancer development than do germline mutations. Genes, such as RB1, TP53, APC, NF1, NF2, WT1, MEN1, and VHL, regulate cell growth by inhibiting cell proliferation and promoting

apoptosis. These genes, and those like them, are considered rate limiting to cancer growth and typically require both alleles to be inactivated before tumor formation. When inactivated, genes involved in DNA repair and genomic maintenance, including MSH2, MLH1, PMS1, ATM, XPA through XPG, and FANCA, promote tumorigenesis via increased mutational rates within the cell. 2. Oncogenes. The normally functioning cellular counterparts, termed protooncogenes, are important regulators of many aspects of cell physiology, including cell growth and differentiation. Numerous proto-oncogenes have been identified, and their products include extracellular cytokines and growth factors (e.g., WNT and FGF3), transmembrane growth factor receptors (e.g., epidermal growth factor receptor [EGFR], human epidermal growth factor receptor 2 [HER2]), cytoplasmic kinases (e.g., BRAF), and nuclear proteins involved in the control of DNA replication (e.g., MYC and MYB). Oncogenes represent mutated forms of proto-oncogenes, resulting in neoplastic transformation. By inactivating growthinhibitory signals or by activating growth-promoting genes, growth factors, receptors, intracellular signaling pathways, or nuclear oncoproteins, these oncogenes often increase cellular proliferation. Some of the oncogenes rescue cells from senescence and apoptosis, leading to immortalization. Accumulated evidence from human malignancies and transgenic animal models indicates that mutation of a single oncogene is insufficient for acquisition of a fully transformed malignant phenotype and that oncogenesis is the process by which cells accumulate multiple mutations leading to overt malignancy over time. D. DNA repair. Although DNA replication is an incredibly precise and accurate process, mistakes do occur naturally. Cells are specially equipped with DNA repair mechanisms to prevent these DNA alterations from being catastrophic to the cell. Only rarely does DNA repair occur through simple chemical reversal of the damage; usually, it entails excision of altered DNA followed by resynthesis. However, many DNA alterations, including INDELs, duplications, inversions, and translocations, are not targets of DNA repair pathways and are therefore highly mutagenic. 1. Direct repair. Human cells produce very few enzymes capable of directly reversing DNA damage. One such enzyme is O6-alkyguanine DNA alkyltransferase, produced by the O6-methylguanine methyltransferase (MGMT) gene. It removes the naturally occurring mutagenic nonnative methyl group from O6-methylguanine, restoring the base to guanine. This dealkylation reaction is significant because the altered base incorrectly pairs with thymine and hence is highly mutagenic. More recently, a set of enzymes has been discovered to catalyze the oxidative demethylation of 1-methyladenine and 3-methycytosine. 2. Base excision repair (BER). A major source of DNA damage includes small chemical alterations. BER is responsible for repair of oxidized bases and

alkylated bases, and it is also responsible for correction of spontaneous depurination events, single-strand breaks, and some mismatched bases. Although these lesions do not typically impede transcription or DNA replication, they are especially prone to produce mutations, and BER plays a crucial role in maintaining the integrity of the genome. The most direct evidence linking the role of BER in cancer comes from germline mutations in the MYH gene, which produces a glycosylase responsible for removing adenine mispaired with 8oxoguanine or guanine. Mutations lead to recessive inheritance of multiple colorectal adenomas. 3. Nucleotide excision repair (NER). This is the most versatile DNA repair pathway, in which the damaged or incorrect portion of a DNA strand is excised and the resulting gap is filled by repair replication using the complementary strand as a template. Lesions repaired by NER typically serve as structural inhibitors to transcription and replication due to distortion of the helical conformation secondary to interference of normal base-pairing. At least four photosensitivity-related syndromes have been attributed to inborn errors in NER, including the autosomal recessive xeroderma pigmentosum, the brittle hair disorder trichothiodystrophy, ultraviolet sensitivity syndrome (UVSS), and a clinical disorder that combines features of both xeroderma pigmentosum and Cockayne syndrome. 4. Mismatch repair (MMR). The MMR system corrects nucleotides mispaired by DNA polymerases within an otherwise complementary paired DNA strand. This repair mechanism can also excise small INDEL loops of single-stranded DNA that result from polymerase slippage during replication of repetitive sequences or those that arise during recombination. The importance of this repair mechanism in maintaining genetic stability is illustrated by the observation that mismatch repair deficiency (dMMR) results in mutation rates up to 1,000 times higher than is normal, with a particular tendency for errors within microsatellites, which are short tandem repeats or homopolymeric stretches of DNA typically 1 to 10 nucleotides in length that are repeated up to 50 times (e.g., TATATATATATA). dMMR facilitates malignant transformation through the production of mutations in genes that harbor microsatellites in their coding regions, some of which have critical roles in the regulation of cell growth and apoptosis (e.g., the TGFBR2 gene, which encodes the transforming growth factor beta receptor II, and the BAX gene, which encodes a proapoptotic protein). Defects in MMR genes are responsible for hereditary nonpolyposis colorectal carcinoma (HNPCC). However, it is important to recognize that although microsatellite instability (MSI) can be demonstrated in a variety of malignancies, in most cases the phenotype is due to somatic rather than to germline mutations at MMR loci.

Clinically, it is important to note whether a tumor is due to dMMR or MSI because immunotherapies that target the interaction of programmed death (PD1) receptor and its ligand (PD-L1) axis are approved in patients with MSI-high or dMMR tumors. 5. Recombinatorial repair. Unrepaired DSBs are highly disruptive events that interfere with proper chromosome segregation during cell division and often induce various chromosomal aberrations including aneuploidy, deletions, and chromosomal translocations. The two main DSB repair mechanisms are homologous recombination and nonhomologous end joining. Both initiate a cascade of kinase reactions that not only recruit repair factors to the site of the break but also delay or terminate the cell cycle through DNA damage checkpoint control. The exact mechanism of cross-link repair in human cells remains unknown. Diseases associated with impaired DSB repair by homologous recombination include ataxia telangiectasia, ataxia telangiectasia–like disorder, Nijmegen breakage syndrome, Fanconi anemia, familial breast–ovarian cancer syndrome, Werner syndrome, Bloom syndrome, and Rothmund–Thomson syndrome. Prominent clinical features shared by these diseases include radiosensitivity, genomic instability, cancer susceptibility, and immunodeficiency. E. Epigenetic regulators. In addition to the genetic alterations in cancer cells, significant epigenetic alterations have been identified in nearly all human malignancies. Epigenetic changes tend to arise early in carcinogenesis, often preceding somatic mutations, and allow orchestration of activation and silencing pathways. 1. DNA methylation. DNA methylation is the addition of methyl groups to cytosine residues of CpG dinucleotides to form 5-methylcytosine and is catalyzed by DNA methyltransferases (DNMTs). Methylation typically occurs within CpG-rich regions (known as CpG islands) that are often distributed in the transcriptional start sites (TSS) of regulatory regions (i.e., promoter/enhancer regions) of genes. Hyper- and hypomethylation have been associated with tumorigenesis. For instance, gene expression defects linked to alterations in DNA methylation patterns involve the family of Tet methylcytosine dioxygenase proteins (TET1, TET2, and TET3) and isocitrate dehydrogenase proteins (IDH1 and IDH2). 2. Chromatin modifiers. Active chromatin remodeling is essential for development and maintenance of normal physiologic functions, but becomes pathologically altered in cancer, leading to widespread mitotically heritable aberrations in gene expression that are characteristic of oncogenesis. The chromatin modifiers include proteins that transfer or remove acetyl or methyl modifications from histone tails, alter the position of nucleosomes along the DNA, remove nucleosomes from DNA entirely, or change the histone composition of

nucleosomes in specific regions of the genome. Histone deacetylase (HDAC) inhibitors are now employed to treat several types of cancer, including multiple myeloma and some T-cell lymphomas. 3. RNA interference (RNAi). Several classes of double- or single-stranded RNA molecules also have a role in regulation of gene expression, including short interfering RNA (siRNA), micro-RNA (miRNA), small modulatory RNA (smRNA), and long noncoding RNA (lncRNA). Also referred to as RNAi, RNAmediated control of gene expression is abnormal in many malignancies. The genetic and epigenetic changes that occur within the developing tumor allow for great diversity among the cells. Progeny of the original cancer cell compete for nutrients and survival. Intratumoral competition in conjunction with the genetic and epigenetic flexibility results in “clonal heterogeneity,” where competing cells obtain different genetic and epigenetic alterations to survive in their local environment. This “flexibility” within the tumor cells leads to differential responses to therapies because some of these cells will be more or less susceptible to specific treatments, leading to persistence of subpopulations of cancer cells that lead to tumor recurrence. With implications for diagnosis, treatment choices, and patient survival, this is an extremely active area of scientific investigation. III. MOLECULAR TESTING Clinical application of insights derived from molecular genetic research has become increasingly important in patient care. Molecular analysis is useful for diagnosis, prognosis, or predicting response to various treatment options, monitoring minimal residual disease (treatment efficacy), identifying predisposition to disease, and detecting therapeutic targets in gene-specific therapy. Clinical molecular diagnostic methods have been integrated into many laboratory disciplines (Table 1-3), and published guidelines and recommendations from both professional societies and regulatory agencies have been developed to assist in the development and performance of clinical molecular pathology testing. TABLE 1-3

Summary of Major Methodologies for Molecular Diagnostics in Clinical Use Today

CML, chronic myebid leukemia, CNV, copy-number variant, INDELs, insertions/deletions; FISH, fluorescence in situ hybridization; LOH, loss of heterozygosity; MEN, multiple endocrine neoplasia; Mod, Moderate; MRD, minimal residual disease; PCR, polymerase chain reaction; RT-PCR real-time polymerase chain reaction; SNV, single-nucleotide variant; SV, structural variant.

Molecular testing has been practiced for several decades in surgical pathology in the form of immunohistochemistry and flow cytometry, in which antibodies are used to detect and quantify the expression of specific proteins of diagnostic, prognostic, or therapeutic importance. This continues to be utilized, particularly in determining hormone receptor status in breast cancer and PD-L1 expression status in a large number of solid tumors. However, in recent years, molecular diagnostics primarily refers to the analysis of changes in nucleic acids, either DNA or RNA, and most frequently implies direct mutation testing. Genetic testing can be designed to detect germline or somatic DNA alterations. At the interface of genetic disorders and acquired mutations in sporadic cancers are familial cancer syndromes. Familial cancer syndromes are inherited disorders that place patients at increased risk for particular types of tumors. Tumors resulting from a predisposition syndrome differ from their sporadic counterparts in several respects: earlier age of onset, bilateral or multifocal tumors, occurrence in multiple family members, and occurrence in more than one generation of a family. The carriers of the increased risk inherit a genetic predisposition for tumor formation as an autosomal dominant trait; this risk factor is a gene-specific germline mutation that may be screened for in DNA isolated from circulating lymphocytes (or other non-tumor tissue) of affected individuals rather than from tumor tissue. The characterization of the specific genes underlying familial cancer syndromes has provided important insights into the nature of

many tumor suppressor genes and oncogenes. Several molecular techniques, described later in more detail, are commonly used in oncology. A. Traditional karyotype analysis. Metaphase chromosome analysis can be performed on many different cell types, although different sampling and handling procedures may be required. Inappropriate handling, as well as delay between specimen collection and culture initiation, can markedly decrease the likelihood that the sample will grow in vitro. Communication and coordination with the cytogenetics laboratory are essential. Traditional karyotype analysis begins with a period of in vitro cell culture of the tissue sample and may be aided by the presence of mitogens to stimulate cell division. After a period of time in culture, cells undergo a process known as harvesting to produce a cell preparation suitable for downstream analysis. During the harvest, cells are exposed to a hypotonic solution, which causes cell swelling and assists in aiding proper chromosome spreading, followed by fixation using a methanol–acetic acid mixture. At times, a mitotic inhibitor may be used during harvest to arrest cells in metaphase. Slides are prepared by dropping the fixed cell suspension onto a glass microscope slide, followed by staining to allow for visualization. The most widely used staining technique is termed G-banding and relies on an enzymatic digestion (often with trypsin) followed by treatment with Giemsa or Wright stain to band the chromosomes. Chromosome resolution and quality are variable (dependent on the cell type, as well as on the mode of preparation), but karyotype analysis is most often performed with a resolution of 400 to 600 bands per haploid set of chromosomes. Analysis is performed at a band-for-band level to identify structural and numeric chromosome abnormalities. Routine chromosome analysis of oncology specimens (bone marrow, involved peripheral blood, and tissue) requires band-for-band analysis of 20 metaphase cells. During analysis, a karyogram is generated and serves as the representative image of the chromosomal complement of the cell displayed in a standard format. A standard clinical cytogenetics report will include information about the study performed, including banding technique, number of cells counted and analyzed, and banding resolution, as well as providing an interpretation, and a karyotype described according to the International System for Cytogenetic Nomenclature (ISCN). B. Fluorescence in situ hybridization (FISH). Use of nucleic acid probes labeled with fluorochromes and visualized through fluorescence microscopy has revolutionized in situ hybridization for detection of abnormalities in chromosome number and chromosome structure. FISH probes may be categorically described as unique sequence probes, repetitive sequence probes, or whole-chromosome probes. The most commonly used probe type is that which hybridizes to a unique sequence in the

genome. Unique sequence probes may be used to detect changes in the copy number of a specific locus (e.g., TP53), or to assay for rearrangements involving a specific locus (such as BCR-ABL or PML-RARA). Repetitive sequence probes hybridize to sequences that are present in hundreds to thousands of copies, and so produce strong signals; the most widely used probes of this type bind to alpha-satellite sequences of centromeres. Beta-satellite sequences, Y-chromosome satellite sequences, and telomeric repeat sequences may also serve as FISH probe targets. Repetitive sequence probes are most useful for the detection of chromosome aneuploidy. Whole-chromosome probes, also known as chromosome painting probes, consist of thousands of overlapping probes that recognize unique and moderately repetitive sequences along the entire length of individual chromosomes. Probes of this type are used to confirm the interpretation of aberrations identified by traditional karyotype analysis, or to establish the chromosomal origin of structural rearrangements that are difficult to evaluate by other approaches. The most commonly utilized form of FISH is metaphase FISH, which analyzes cells in active division to determine chromosomal rearrangements because the specific probes are able to be visualized relative to chromosome position. C. Polymerase chain reaction (PCR). PCR makes it possible to detect a broad range of chromosomal abnormalities, from gross structural alterations such as translocations and deletions to single base-pair mutations, in individual genes. PCR can be performed on areas of tumor (or even individual cells) macro- or microdissected from routinely prepared tissue or cytology slides, or separated by flow cytometry. This is an advantage in that PCR methods enable correlation between tissue morphology and genetic abnormalities of specific regions of tumor, specific cell populations, or even individual cells. The clinical utility of PCR is due to the wide range of template DNA that can be amplified, the technique’s intrinsic extreme sensitivity, and the wide range of variations of the basic method that can be performed. D. Next-generation sequencing (NGS). NGS methods have revolutionized the life sciences by dramatically increasing the throughput of DNA sequencing. Many of the currently available NGS techniques have been described as cyclic array sequencing platforms, because they involve dispersal of target sequences across the surface of a two-dimensional array, followed by sequencing of those targets. The resulting short sequence reads can be reassembled de novo or, much more commonly in clinical applications, aligned to a reference genome. The Illumina (Illumina Inc., San Diego, CA), Ion Torrent (Thermo Fisher Scientific, Waltham, MA), and Roche 454 (Roche Diagnostics, Indianapolis, IN) platforms are the most widely used at present. NGS has several attributes that are attractive in cancer testing. Because each library fragment is individually sequenced, the resulting data can resolve intratumor

sequence heterogeneity, revealing the clonal structure of the tumor. NGS has the potential to detect all four of the major classes of genetic variation: single-nucleotide variants, INDELs, structural variants, and copy-number variants. The technique can be performed on DNA extracted from formalin-fixed, paraffin-embedded tissue, a commonly available specimen type. Finally, although these tests are currently not inexpensive, the cost per nucleotide sequenced is extremely low, and the cost of the test increases less than linearly with the size of the region analyzed. Although NGS was initially developed as a research technique, it has found several prominent roles in clinical testing. NGS has also been adopted as a platform for simultaneous sequencing of multiple genes for constitutional disorders, including familial cancer syndromes. However, the most prominent application of NGS is in clinical oncology, where it is used to identify novel or potentially targetable mutations. E. Quantitative PCR. Also referred to as real-time polymerase chain reaction (RTPCR), this method permits more reliable quantification of the amount of input DNA than is possible by traditional endpoint measurement of the DNA product. Because the PCR product is quantified as the reaction progresses (i.e., in real time) rather than after PCR completion, it avoids the potential artifacts of amplification efficiency. Quantitative PCR often provides more precise measurements of DNA or mRNA than can be achieved by filer hybridization or microarray-based methods. When mRNA is the substrate, quantitative RT-PCR can be used to correlate changes in gene expression with the clinical features of a disease or a specific tumor type. One example in current use is the Oncotype DX breast cancer assay (Genomic Health, Inc., Redwood City, CA), which measures the expression of 21 genes by RTPCR and applies a formula to calculate a recurrence score. F. Flow cytometry. Flow cytometry utilizes fluorescently labeled antibodies to detect cell surface or intracellular proteins, helping to characterize populations of cells. It can be used on cells isolated from blood, bone marrow, or tissue, which are then incubated with the fluorescently labeled antibodies of interest and analyzed on a flow cytometer, which measures the fluorescence emitted per cell. Depending on the cytometer used to analyze the data, large numbers of proteins can be analyzed, and because of this specificity and sensitivity, it is used in several types of cancer to further characterize cells, such as in lymphoma, or determine whether an abnormal cell is present at very low levels, such as in minimal residual disease testing. G. Microarray-based gene expression profiling. The morphologic features of disease are essentially reflections of altered gene expression within diseased cells. Characterization of disease-specific alterations in gene expression is therefore an area of intense interest. Given the limitations of Northern blot hybridization, a variety of new methodologies have been developed to identify differentially expressed genes,

of which microarray technology is the most widely used. Microarray technology is based on the principle of nucleic acid hybridization. Fundamentally, a DNA microarray (or gene chip) employs multiple sets of DNAs or oligonucleotides complementary to the thousands of genes to be investigated, each attached at a known location on a glass or nylon membrane substrate the size of a computer chip. When RNA extracted from the clinical sample is used as the input, microarrays make it possible to rapidly measure the expression of thousands of genes in parallel. Fluorophore-labeled test (or target) RNA derived from the specimen is hybridized to the chip, and emitted light produced by laser scanning allows for quantitation of gene expression of even low-abundance transcripts. One such assay that has entered clinical use is MammaPrint (Agendia, Inc., Irvine, CA), which was approved by the U.S. Food and Drug Administration (FDA) for use in patients with breast cancer. The test measures expression of 70 genes on a microarray platform to classify patients into a low-risk or high-risk group. H. Emerging techniques 1. Circulating-tumor DNA (ctDNA). Improved NGS sensitivity has enabled the detection of DNA in the blood that comes from tumor cells (ctDNA). Using ctDNA has led to detection of mutations at diagnosis and relapse that have shown the potential to impact therapeutic considerations. 2. Neoepitope prediction. Targeting specific mutations with antibody-directed therapies is a rapidly evolving field. To appropriately gauge which new epitopes might be expressed on the cell surface and a potential target for anticancer therapies, prediction algorithms have been employed on the basis of the potential binding of the putative neo-antigen to major histocompatibility complex (MHC) class I and II molecules. 3. Molecularly targeted imaging. With the introduction of more targeted or immune-directed therapies, identifying imaging techniques that predict for either response to therapy or are able to better monitor changes in the immune microenvironment are being actively developed. 4. Pharmacogenetics. In addition to tumor-specific genetic abnormalities, genetic variation has been estimated to account for 20% to 95% of variability in the metabolism, disposition, and effect of the drugs used to treat patients with cancer. Pharmacogenetics offers the opportunity not only to optimize the efficacy of therapy but also to minimize toxicity. Many centers are now using prospective genotyping of a few targeted genes to guide antineoplastic treatment and dosing choices. These include thiopurine methyltransferase (TPMT) point mutations in mercaptopurine therapy for acute leukemia, thymidylate synthase enhancer region (TSER) polymorphisms in 5-fluorouracil therapy for colorectal cancer, and uridine 5′-diphospho (UDP)-glucuronosyl transferase (UGT1A1) promoter

region variants in irinotecan therapy for metastatic colorectal cancer. Genomewide analysis of the role of genetic variation in predicting an individual patient’s response to treatment with a specific drug is known as pharmacogenomics. 5. Analysis of epigenetic modifications. Techniques for quantitative detection of the methylation status of every human gene individually have been developed. Given the effect of epigenetic changes on gene expression, it is reasonable to anticipate that the pattern of methylation at defined sets of loci may eventually become a component of the pathologic evaluation of individual tumors. At present, no test based on methylation is associated with clear clinical benefit. 6. Proteomics. This technique is focused on the analysis of patterns of protein expression rather than on the analysis of nucleic acids. Methods for highsensitivity, high-throughput evaluation of protein expression profiles have been developed—methods that make it possible to identify patterns that correlate with specific malignancies, underlying mutations, epigenetic changes, transcriptional profiles, response to drug therapy, and so on. 7. Analysis of RNAi. It has recently become clear that several classes of short single-stranded or double-stranded RNA molecules that are responsible for RNAi have a profound role in the regulation of gene expression. The demonstration that the profile of miRNAs (one class of small RNAs that mediate RNAi) is different in normal and neoplastic tissue, that alterations in miRNA are oncogenic, and that RNAi-based approaches can have therapeutic benefit all suggest that analysis of specific small RNA molecules, either individually or on a genome-wide basis, may in the future have an important role in the molecular evaluation of tumors. ACKNOWLEDGMENT The authors thank Drs. John Pfeifer and Elizabeth Chastain, authors of the previous edition of this chapter. SUGGESTED READINGS Bozic I, Antal T, Ohtsuki H, et al. Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci USA 2010;107:18545–18550. Cottrell CE, Al-Kateb H, Bredemeyer AJ, et al. Validation of a next-generation sequencing assay for clinical molecular oncology. J Mol Diagn 2014;16:89–105. Gersen SL. The Principles of Clinical Cytogenetics. New York, NY: Springer, 2012. Hanahan D, Weinberg R. Hallmarks of cancer: the next generation. Cell 2011;144:646–674. International HapMap Consortium. A haplotype map of the human genome. Nature 2005;437:1299–1320. Ladanyi M, Gerald WL. Expression Profiling of Human Tumors: Diagnostic and Research Applications. Totowa, NJ: Humana Press, 2003. Laird PW. Principles and challenges of genome wide DNA methylation analysis. Nat Rev Genet 2010;11:191–203. López CA, Cleary JD, Pearson CE. Repeat instability and the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol 2010;11:165–170. Misek DE, Imafuku Y, Hanash SM. Application of proteomic technologies to tumor analysis. Pharmacogenomics

2004;5:1129–1137. Pfeifer JD. DNA damage, mutations, and repair. In: Molecular Genetic Testing in Surgical Pathology. Philadelphia, PA: Lippincott Williams & Wilkins, 2006:29–57. Pritchard CC, Salipante SJ, Koehler K, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. J Mol Diagn 2014;16:56–67. Vogelstein B, Kinzler KW. The Genetic Basis of Human Cancer, 2nd ed. New York, NY: McGraw-Hill, 2002. Weinberg RA. Biology of Cancer. 2nd ed. New York, NY: Garland Science Publishers, 2013.

Alongside major advances in medical, immunologic, and radiologic interventions in the care of the patient with cancer, the field of surgical oncology has similarly undergone many significant changes in recent years. These include the acceptance of sentinel lymph node biopsy (SLNB) over lymphadenectomy, the integration of new imaging modalities and pharmaceuticals for intraoperative identification of tumors, and the growing interest in and success of minimally invasive approaches. With so many advances across multidisciplinary oncologic care, deciding when to involve a surgeon can be a challenging and constantly changing target. Historically, surgery was the sole treatment modality for solid tumors. Excisions offered the potential for cure but were often morbid, requiring aggressive margins of normal tissue surrounding a lesion and complete resection of draining lymph node basins. Radiation and systemic medical therapies have paved the way for a more conservative surgical approach. The extent and subsequent morbidity of any necessary surgery can be affected by either neoadjuvant regimens, which can decrease tumor size and the potential for locoregional spread, or adjuvant regimens, which can treat residual disease or decrease the likelihood of locoregional recurrence. Once a diagnosis of cancer is suspected, the surgical oncologist may be the first point of contact within a larger multidisciplinary team. The surgeon may have an active role in establishing a diagnosis and, once a diagnosis is made, must draw on a comprehensive knowledge of multidisciplinary oncologic care to communicate these findings with the patient, plan additional staging procedures, decide whether a patient is likely to ever be a candidate for resection, and determine what types of nonsurgical therapies should be included in a treatment plan and in what sequence these should be delivered. The surgical oncologist can offer the patient with cancer a broad spectrum of possible procedures for diagnosis, local control, cure, and palliation. To aid in multidisciplinary

collaboration, this chapter reviews procedures with which we encourage multidisciplinary oncology team members to become familiar, with the goal of clarifying when and how to involve surgeons in the care of the patient with cancer. I.

DIAGNOSTIC PROCEDURES Once a lesion has been identified, the surgical oncologist can be one of many specialists to obtain a tissue biopsy for definitive diagnosis. In general, when requesting biopsies, two decisions must be made regarding (1) how much tissue is necessary for the pathologist to make a definitive diagnosis and (2) choosing a biopsy approach that balances a high diagnostic yield with low procedural morbidity. A referral to a proceduralist for a biopsy should include a description and location of the lesion of concern and details for delivering the tissue to the pathologists (fresh or fixed). Including a differential diagnosis can also be helpful. In general, it is preferable to biopsy the periphery of a lesion. The central core of many solid tumors may be necrotic and, therefore, nondiagnostic if biopsied. In contrast, at the periphery, viable tumor is found and the interface of tumor against or invading into normal tissue can be informative for the pathologist. For all biopsy approaches, the risk of bleeding and the periprocedural management of anticoagulants or hematologic disorders affecting coagulation must be carefully considered. A. Fine-needle aspiration (FNA) is performed using a small (22- or 25-gauge) needle to obtain passes through tissue, which is then sent for cytologic evaluation. Imaging guidance is often used in both percutaneous and endoscopic (e.g., endoscopic ultrasound [EUS] or endobronchial ultrasound [EBUS]) approaches. Advantages of FNA include the relative speed of the procedure, minimal setup, and, if done percutaneously, the ability to perform this procedure using only local (topical) anesthesia. Disadvantages include the potential for inadequate sample size, bleeding after multiple passes limiting further yield, and numerous drawbacks of analyzing a tumor at the cellular level rather than obtaining whole pieces of tissue. Finally, the risk of seeding the needle track with malignant cells is difficult to quantify, but it must be acknowledged when choosing any biopsy approach. B. Core-needle biopsy utilizes a larger needle (frequently up to 14-gauge) to obtain a larger fragment of tissue, allowing for evaluation of tumor architecture. Similar to FNA, imaging is often used to guide core-needle biopsies unless a lesion is superficial and easily palpable. For certain core-needle techniques such as stereotactic breast biopsies, a metallic or similar radiopaque marker can be left at the site of the biopsy for future reference. The main advantage of core-needle biopsy is the ability to obtain sufficient tissue for architectural analysis without making an incision. Disadvantages include pain, bleeding, and sampling error (missing the tissue of interest), and careful consideration must be given to the approach with

regard to whether structures are possibly at risk in the path of the needle, which is particularly relevant for intrathoracic or intra-abdominal biopsies. C. Surgical biopsy may be most appropriate for lesions requiring large amounts of tissue for diagnosis and lesions not amenable to needle biopsy because of either their anatomic locations or the potential for sampling error. Most surgical biopsies can be performed on an outpatient basis. Depending on the surgeon’s practice patterns or his or her relationship with the consulting clinician, a clinic visit may be necessary before proceeding with the biopsy, particularly if sedation or general anesthesia will be required; surgical biopsies of lesions in the abdominal cavity or thoracic cavity require general anesthesia. In the clinic, a physical examination is performed to determine where the incision should be made, informed consent is obtained, and a risk assessment relevant to receiving anesthesia should be reviewed. 1. Incisional biopsy removes only a piece of the lesion. Some tumors have a propensity for seeding the biopsy cavity and incision, so the incision should be planned in such a way that it can be incorporated and completely excised in any future surgery (e.g., making a longitudinal incision for biopsy of an extremity sarcoma and later incorporating that incision into a larger definitive excision). 2. Excisional biopsy removes the entire lesion. Indications for complete excision include instances where upfront surgery is the definitive treatment of choice for all possible diagnoses in the differential or where the gross architecture of the lesion impacts the diagnosis (e.g., obtaining whole lymph nodes for the diagnosis and subtyping of lymphoma). Where relevant, specimens should be oriented for accurate pathologic margin assessment, which can be useful should re-excision be necessary if the surgical margins were positive or unacceptably close. D. Cutaneous biopsies. There are various ways to biopsy topical lesions that can be performed in an office setting with minimal morbidity. These can be done with or without local anesthesia. Shave biopsies provide ample tissue for diagnosis and do not require suture closure, but they risk missing critical information such as depth of invasion, which is particularly relevant in the management of cutaneous malignancies. Punch biopsies obtain a cylindrical core of tissue using a 2- to 6-mm circular surgical blade. The procedure is easy to perform and provides a fullthickness specimen, but the defect may require a simple suture closure. II. STAGING: DETERMINING THE EXTENT OF DISEASE AND RESECTABILITY When disease extent needs to be evaluated, imaging is often sufficient for staging. However, if pathologic rather than clinical imaging-based staging is desired, surgical procedures and pathologic analysis for staging are much more sensitive than is imaging and can significantly inform patient management. There are a number of possible staging procedures, some of which are done before proceeding with definitive therapy and

surgery, whereas others are done at the same time as definitive surgery. A. SLNB is based on the anatomic and pathologic understanding that organs, and therefore tumors, have lymphatic drainage in predictable and hierarchic patterns where a tumor “drains” to the first draining lymph node (the sentinel node) and then to additional nodes in that regional lymphatic basin. Numerous studies have demonstrated that localized malignancies metastasize to a sentinel node before involving other nodes in the basin. Therefore, the presence of disease in the sentinel node predicts the status of the entire regional lymphatic basin without requiring completion lymphadenectomy of that basin and the associated morbidity of a completion lymphadenectomy. SLNB is currently used most frequently for staging the axilla in breast cancer and regional nodal basins in melanoma. The utility of SLNB is an ongoing point of discussion for many other malignancies. Disadvantages of SLNB are related to the skill of the operator and the quality of the preoperative lymph node mapping, which may result in a significant false-negative rate. Lymphatic mapping for surgery is performed in one of two ways. The first technique involves the injection of a radiolabeled colloid around the lesion, which is detected in lymph nodes using a gamma probe intraoperatively. The second technique employs injection of dye (isosulfan blue or methylene blue), which is injected around the tumor in the operating room immediately before making an incision; the dye is then allowed time to be taken up by the lymphatic system and is eventually directly observed in lymph nodes. If the site of nodal drainage is uncertain or more than one nodal basin is potentially involved (e.g., melanoma of the skin of the back in the midline), then lymphoscintigraphy may be done immediately before surgery to image the draining nodal basins that should be targeted in surgery. B. Lymphadenectomy may be indicated on the basis of the primary pathology and the documented involvement of lymph nodes in a particular nodal basin. The benefit of lymphadenectomy varies from malignancy to malignancy and is heavily influenced by the effectiveness of adjuvant treatment modalities for the cancer in question. The benefit must also be weighed heavily against the morbidity of lymphadenectomy. Lymphedema is rare after SLNB for breast cancer (5%), but is much more common after lymphadenectomy (15% or more), although adjuvant radiation appears to have an impact on the incidence of lymphedema (Ann Surg Oncol 2017;24:2972). Additional risks associated with lymphadenectomy over SLNB include nerve and vascular injury. Therefore, SLNB has come to replace lymphadenectomy as a staging modality, and lymphadenectomy is reserved for instances where the likelihood of complications from nodal disease, local recurrence, or metastases is high. In some cases, such as in gastric adenocarcinoma, the ideal extent of regional lymphadenectomy is the subject of ongoing study and controversy. C. Laparoscopy for staging has supplanted laparotomy because of the obvious

advantages of decreased pain without sacrificing diagnostic yield. It is often done under general anesthesia on an outpatient basis. Diagnostic laparoscopy can also be performed as the first step of planned definitive surgical excision; if distant or unresectable disease is discovered with laparoscopy, then the definitive resection is aborted to avoid a surgery that is no longer indicated and proceed straight to systemic therapy. Biopsies of solid organs, lymph nodes, and suspicious lesions can be obtained, as can peritoneal washings for cytology. When laparoscopy is combined with intraoperative ultrasonography, lesions deep in the parenchyma of an organ can be identified and relationships with adjacent structures such as major blood vessels can be defined; intraoperative ultrasound is perhaps the most sensitive imaging technique for the detection of liver metastases. Disadvantages of diagnostic laparoscopy are specific to the location and number of incisions as well as what tissue is biopsied. Port-site metastases are rare; the likelihood can be reduced through careful tissue handling and the routine use of ports and/or specimen extraction bags that reduce or eliminate contact between the specimen being extracted and the normal tissue of the peritoneum and abdominal wall. D. Mediastinoscopy and Video-Assisted Thoracoscopic Surgery (VATS) are two modalities used for evaluation of mediastinal adenopathy, including the preoperative staging of lung cancer. Although these procedures are highly accurate, they have associated morbidity and require general anesthesia; as such, they may be unnecessary staging modalities if adequate tissue samples can be obtained through less-invasive methods such as EBUS. III. SURGICAL PERSPECTIVES ON NEOADJUVANT THERAPY Neoadjuvant treatment protocols are used for many cancers as a possible bridge to a potentially curative surgery. The primary goal of neoadjuvant treatment in this setting is to reduce the burden of disease and, thereby, reduce the extent of resection necessary to gain locoregional control of tumors. For certain cancers, particularly if a pathologic complete response is possible, the tumor location can be marked with metallic clips before the initiation of neoadjuvant therapy so that the site of treated tumor can be known at the time of surgery. Preoperative radiation may be used alone or in combination with chemotherapy to reduce tumor size before resection. In some cancers, such as rectal cancer, radiation is associated with decreased rates of local recurrence and improved survival when given preoperatively (N Engl J Med 1997;336:980). Surgical advantages of preoperative radiation include (1) reducing tumor size and thereby reducing the extent of resection and (2) reducing potential seeding of tumor cells when manipulated during surgery. Disadvantages of preoperative radiation include the resulting tissue fibrosis, which may obscure natural tissue planes and resection margins and increase the difficulty and

•

•

•

morbidity of the surgery. Preoperative radiation can cause a degree of tissue ischemia that may negatively impact wound healing and may alter decision-making regarding the types of reconstruction that can be performed. In addition to treating potential occult metastatic disease, a secondary goal of neoadjuvant treatment is patient selection: Patients may progress on neoadjuvant treatment and are no longer surgical candidates because of systemic disease or locally advanced and unresectable disease. Aggressive tumor biology, including nonresponse to treatment, suggests that these patients would not have benefited from upfront surgery because they were likely to experience early postoperative recurrence or metastatic progression. Patients not well enough to tolerate certain chemotherapy or immunotherapy regimens may not be well enough to tolerate surgery. Physical frailty and malnutrition can be worsened by neoadjuvant therapy and are associated with a greater incidence of complications after surgery. In addition, these patients may not benefit from surgery for their cancer if they are unlikely to tolerate adjuvant therapy based on their intolerance to neoadjuvant therapy. Alternatively, lack of response to or intolerance of neoadjuvant therapy may be an indication that surgery is the best and perhaps the only available treatment modality for a patient. Such cases should be reviewed at multidisciplinary tumor boards before surgical intervention to ensure there is some expectation of benefit from surgery.

IV. PROCEEDING WITH DEFINITIVE SURGERY Complete removal of the tumors has many favorable effects including minimizing the burden of disease and eliminating poorly vascularized stroma that provides some degree of resistance to chemotherapy or radiation. Surgical planning involves consideration of variables related to (1) the underlying pathology and (2) the patient. A. Pathology-specific variables largely dictate the extent of resection necessary. The goal of any oncologic operation should be complete resection of local disease. A secondary goal, where appropriate, should be obtaining tissue for staging and regional control. 1. Tumor stage is the most important variable in determining the extent of resection. This information can be obtained from cross-sectional imaging, preoperative biopsies, or other tests such as EUS. The depth of invasion and the expected risk and pattern of malignant spread, hematogenously or along mucosa, fascial planes, and nerves, dictate the margins of normal tissue that should be resected around a lesion (Table 2-1). The comorbidity necessary to complete a resection must be considered, including the proximity and potential for resection of other organs (blood vessels, bowel requiring resection and/or diversion, and any necessary reconstruction), and the resultant duration of a procedure. The

extent or completion of resection is verified by the pathologist using the residual tumor (R) classification system. The R categories are defined by the American Joint Committee on Cancer (AJCC) as TABLE 2-1

Adequate Tissue Margins for Primary Malignancy Treated with Surgery Alone

Tissue

Margin

Rationale or Comment

Basal cell carcinoma

2 mm

Very localized malignant area

Squamous cell carcinoma of head/neck

4–6 mm

May be limited by adjacent structures

0.5–1 cm 1 cm 1–2 cm 2 cm

Increasing lesion depth is associated with higher risk of incomplete resection and/or local recurrence

Sarcoma

Negative margins

High risk of incomplete resection and/or local recurrence

Breast, invasive

No ink on tumor, or >1 mm

High potential for multifocality; consider combination with radiation therapy if breast-conserving therapy (lumpectomy)

Colon

5 cm

Potential for submucosal spread not identifiable at the time of surgery

Rectal

2 cm distal margin

Difficult to obtain any additional distal margin while preserving functional outcome

Esophagus

10 cm

High potential for extensive submucosal spread

Lung

Anatomic lobectomy

Ongoing trials; segmentectomy or wedge resection may show equal survival in early-stage or low-risk pathologies

Pancreas

1–5 mm

Controversy exists as to whether positive pancreatic duct margins are associated with overall survival

Liver

1 cm

Anatomic resection is not superior to wedge resection

Stomach

4 cm

High potential for extensive submucosal spread

Melanoma In situ 2.0 mm

a. R0. Complete resection, margins histologically negative, no residual tumor left after resection b. R1. Incomplete resection, margins histologically involved, microscopic tumor remains after resection of gross disease c. R2. Incomplete resection, margins macroscopically involved or gross disease remains after resection If margins are positive after resection (R1 or R2), options include further

surgery for re-excision, adjuvant therapy such as radiation to the site of resection, or careful follow-up. Adjuvant radiation may reduce the likelihood of local disease progression, but risks wound complications and poor cosmetic results, particularly with high doses. 2. Nodal stage. Tumor biology and the expected routes of regional or metastatic spread dictate the need for resection of additional tissue, often lymph nodes, for pathologic staging. The specific tumor pathology dictates the approach to and the extent of nodal sampling necessary. Organizations like the AJCC set forth minimum numbers of lymph nodes necessary for appropriate staging for each cancer type. Although these recommendations are not always evidence based, they serve as quality measures, and lymph node yield should be reported on all pathology reports. Controversy exists as to whether patients benefit from lymph node sampling or lymphadenectomy due to control of locoregional disease, more accurate staging through adequate tissue sampling, or both. 3. Minimally invasive approaches. The decision to proceed with a minimally invasive approach—be it endoscopic, thoracoscopic, laparoscopic, robotic, etc.— is often made at the time of surgical consultation. Minimally invasive surgeries are accepted as standard of care for most urologic and gynecologic procedures involving tumors without significant local invasion, and minimally invasive approaches are becoming more common in many other subspecialties of surgical oncology. In general, minimally invasive procedures result in shorter hospital stay, less intraoperative blood loss, decreased requirement for analgesics, and earlier return to normal activities. The decision to proceed with a minimally invasive approach is a complex interaction of patient-specific variables (e.g., age, ability to tolerate insufflation, ability to tolerate potentially longer operating room times), surgeon-specific variables (e.g., number of minimally invasive procedures performed, comfort with the management of intraoperative complications), and tumor-specific variables (e.g., size, position, and invasion of critical structures). Concerns have been raised that minimally invasive approaches compromise the ability to achieve wide margins and en bloc resection of draining nodal basins; studies examining these issues for multiple cancers have reported no significant differences in margins, lymph node yield, or survival. 4. Reconstruction. Reconstructive surgery is a growing field of surgical oncology and is regularly performed by surgeons trained in plastic surgery techniques. Common techniques include skin grafts and flaps, either rotational (moving a piece of muscle and/or tissue into a different site by rotating it on its original preserved blood supply) or free (placing a piece of muscle and/or soft tissue it into a different area of the body by recreating the blood supply). Advantages of reconstruction include the closure of soft-tissue defects that otherwise may

require chronic wound management or return trips to the operating room, improved quality of life through enhanced functional and cosmetic outcomes, and bringing well-perfused tissue into a wound bed. Disadvantages of reconstruction include the possibility for wound complications at the donor site and increased operative time. Plans for adjuvant therapy, particularly radiation, should be made clear preoperatively, because these may influence the reconstructive options (e.g., if high-dose radiation is planned, free flaps may not be suitable, because the vascular anastomosis may respond poorly to radiation). 5. Premalignant lesions and prophylactic surgery. Surgery is indicated for a number of premalignant lesions or as prophylaxis for a number of inherited or acquired disorders (Table 2-2). TABLE 2-2

Prophylactic Surgery

Diagnosis

Cancer Risk

Surgery

FAP

100% risk of colon cancer

Proctocolectomy, or colectomy with ileorectal anastomosis and ongoing rectal surveillance

Ulcerative colitis

With dysplasia, >50% risk of colon cancer

Proctocolectomy, or colectomy with ileorectal anastomosis and ongoing rectal surveillance

Multiple endocrine neoplasia II

100% risk of medullary thyroid carcinoma

Total thyroidectomy

BRCA1 or 2

>40% risk of breast cancer; >20% risk of ovarian cancer

Bilateral mastectomy; consider bilateral salpingooophorectomy

FAP, familial adenomatous polyposis.

6. Surgery for local recurrence. Local recurrence of cancer can result from incomplete excision at the initial surgery, the presence of residual cancer cells distant from the primary lesion, or metachronous primary tumors that develop in residual normal tissue. Similar surgical principles apply for the resection of recurrent disease, although surgery can be more complex because of altered tissue planes and scar tissue from prior surgeries. 7. Metastasectomy—surgery for metastatic disease. Patients with evidence of disseminated cancer are not often considered to be candidates for surgical resection. However, certain patients with isolated metastases that are amenable to complete surgical resection may benefit from resection; common sites include liver metastases or solitary pulmonary metastases. Before being considered for surgery, the patients, particularly those with more aggressive primary pathologies, often undergo a prolonged period of nonsurgical therapy and observation to ensure adequate response to treatment and a sufficient time

interval without disease progression. Alternatively, patients with symptomatic metastases that cannot be treated by other means may require palliative resection to improve quality of life (e.g., head and neck cancers, melanoma, or breast cancer). B. Patient-specific variables 1. Performance status. First and foremost in assessing a patient’s candidacy for surgery is an overall assessment of the patient’s functional status. This is used as a general marker for the surgeon and the anesthesia team to (1) assess the patient’s surgical risk by estimating his or her burden of comorbidities and (2) offer a baseline assessment that can be used to discuss the patient’s expected postoperative recovery and functional status. Examples of preoperative assessment grading systems include the American Society of Anesthesiologist’s (ASA) Physical Status Classification System and the Eastern Cooperative Oncology Group (ECOG) Performance Status. There is a growing body of literature to support perioperative risk reduction through prehabilitation, defined as enhancement of functional capacity in anticipation of an upcoming physiologic stressor such as surgery and general anesthesia. Prehabilitation exercise interventions have been associated with decreased complications and length of stay after elective surgery including cancer surgery (Surgery 2016;160:1189). 2. Comorbidities. A patient’s overall performance status is highly dependent on the number, type, and severity of a patient’s comorbid conditions. With increased use of quality measurement and quality improvement tools, the impact of certain comorbidities on outcomes—both medical and functional—can be measured. One example of a tool used to predict outcomes for specific procedures based on comorbidity is the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Risk Calculator (riskcalculator.facs.org). Tools such as this one can be incorporated into a discussion of the risks and expected outcomes of surgery. Comorbidities strongly associated with worse postoperative outcomes include age, performance status, cardiopulmonary conditions, hepatic function, and renal function. a. Cardiac and pulmonary workup may be necessary preoperatively. Tests to consider include echocardiograms, stress tests, and pulmonary function tests, particularly for patients with chronic cardiopulmonary comorbidities or those who have received neoadjuvant therapies with cardiac or pulmonary toxicities. Appropriate extent of workup should be discussed and reviewed by a team including surgeons, anesthesiologists, and, as appropriate, other specialists such as cardiologists or pulmonologists. 3. Medications. Patients with cancer may be on a number of medicines of

importance to the surgeon. Medications in the following categories should be carefully reviewed by the surgeon in collaboration with the prescribing provider, be it the oncologist, primary care physician, or another specialist such as a cardiologist. Attention must be given to the route of administration and duration of action, and alternate routes of administration or replacement medications must be considered in advance of surgery depending on the planned surgery and reconstruction, including any anticipated limitations to enteral feeding access. a. Chemotherapy is routinely stopped preoperatively to diminish perioperative immunosuppression and to improve the patient’s nutritional status and potential for wound healing. Although stopping chemotherapy 4 weeks before any planned surgery is common, the specific timing is dependent on a number of factors including the specific chemotherapy regimen and the extent of planned surgery. b. Corticosteroids and immunosuppression similarly should be stopped before surgery to diminish the detrimental effect on wound healing. Certain immunosuppressants, particularly those for long-term prevention of rejection after transplant, should not be stopped but may have to be adjusted. c. Anticoagulation for cardiac conditions (e.g., therapeutic anticoagulation for atrial fibrillation or antiplatelet therapy for coronary artery disease) or venous thrombosis is common. Patients may need approval from specialists to hold these medications or may need to be admitted before surgery for bridging protocols. d. Immunotherapy is a rapidly growing field of medicine. As such, knowledge of the risks of long-term administration of these medicines may be insufficient to fully understand their impact on operative outcomes and recovery. 4. Goals of care are critical, but they are often overlooked preoperative variables regardless of the underlying tumor biology. With regard to setting goals of care for surgical management of cancer, the oncologist and the surgeon are both in unique positions where information sharing is essential. The oncologist may already be familiar with the patient longitudinally and may have insight to the patient’s goals of care. In addition, the oncologist may have expectations for adjuvant treatment. On the other hand, the surgeon may not share the same knowledge about the patient’s expectations or plans for adjuvant treatment but can offer an in-depth discussion about surgery that may not be possible in an oncologist’s office. Such a discussion should include the risks, benefits, and alternatives to any procedure and must include the expected recovery, including the risks of diminished quality of life as a result of prolonged recovery due to pain, malnutrition, or reconstruction, as well as the possibility of loss of

independence including discharge to a non-home setting (i.e., skilled nursing facility or rehabilitation facility). If not done already, documentation of goals of care through advanced directives and appointing a durable power attorney for health care should be done before undergoing surgical evaluation. Involving a palliative care specialist even in the absence of a terminal diagnosis should be encouraged. In a randomized trial, early involvement of palliative care was associated with improved quality of life and longer survival for patients with non–small-cell lung cancer (N Engl J Med 2010;363:733). C. Intraoperative considerations. Intraoperatively, successful resection requires adequate exposure of the tumor and adjacent structures, excision of previous biopsy sites, maintaining a bloodless surgical field to visualize the extent of tumor spread, and en bloc resection of the tumor and an appropriate margin of surrounding normal tissue. Principles to consider in decreasing the likelihood of local recurrence or wound seeding include minimizing manipulation of the tumor, confining dissection to normal tissue, and early ligation of major feeding vessels at their origin. If a second area of the body requires surgery at the time of tumor excision, new gloves, gowns, sheets, and instruments are regularly used to prevent seeding of tumor cells from one site to another. D. Postoperative care 1. Recovery is dictated by the extent and success of surgery and the patient-specific variables affecting the development of complications and the return to preoperative levels of functioning. Expected recovery should be discussed in preoperative consultation and can be modeled using risk calculators such as the one previously mentioned from ACS-NSQIP. In turn, the success and speed of recovery dictates a patient’s return to intended oncologic therapy (RIOT), should that be appropriate. The resumption of preoperative medications, including anticoagulants or chemotherapy, should be cleared by the surgeon in conjunction with the rest of the multidisciplinary oncology team. 2. Follow-up and surveillance after surgery is shared between the surgeon and the rest of the multidisciplinary oncology team. Surgeons regularly have patients return to clinic 2 to 4 weeks after surgery for wound checks and to ensure that a patient is meeting milestones for recovery and can increase his or her physical activity without restrictions. Depending on the cancer and the structure of a surgeon’s practice and collaborative arrangements with oncologists, ongoing follow-up and surveillance can be shared with or alternated between the surgeon and oncologist, or handed off entirely to a single clinician. V. OTHER PROCEDURES A. Vascular access

1. Central venous catheters and ports. Many patients with cancer require frequent venous catheterization for phlebotomy and infusions. Peripheral venous sites can become quickly exhausted because of the trauma of repeated use, venotoxic effects of cytotoxic agents, and the undesirability of accessing veins in limbs with compromised outflow such as those after proximal lymphadenectomy. Central venous catheters are designed for repeated venous access and are available in tunneled externalized types (e.g., Hickman or Broviac (Bard Peripheral Vascular, Inc.; Tempe, AZ)) or implantable types (e.g., Port-A-Cath (Smiths Medical; Dublin, OH), Infusaport). They are placed on an outpatient basis under local anesthesia with or without sedation. The choice of catheter type and placement location will depend on a number of factors including the expected duration of therapy requiring venous access, the anticipated infection risk to the patient, any history of prior central lines or central vein thrombosis, and the number of lumens needed. It is important to discuss these factors beforehand with the proceduralist who will be performing the procedure. a. Although complication rates are low, they include pneumothorax, hemothorax, air embolism, cardiac arrhythmia, and venous or arterial injury. Long-term complications can include vein thrombosis, embolism, and infections including bacteremia. Infections and symptomatic catheterassociated thrombosis are indications for catheter removal. Relative contraindications to placement include uncorrected thrombocytopenia or coagulopathy and previous irradiation to the head or neck, which can result in scarring or fibrosis of the veins intended to be used for central access. For these latter patients or patients with a known history of central vein thrombosis, an ultrasonography or venous angiography before the procedure may be useful to document venous patency. Patients who are hypercoagulable from their cancers may benefit from low-dose anticoagulation to prevent venous or catheter-associated thrombosis. 2. Arterial catheters: hepatic artery infusion catheters. Hepatic artery infusion pumps (HAIPs) are an option for treating patients with hepatic metastases. A catheter is inserted into the gastroduodenal artery and is connected to a subcutaneous port through which chemotherapy can be instilled and continuously infused into the hepatic artery, taking advantage of the fact that liver metastases commonly derive blood supply from the hepatic arterial circulation, in contrast to normal liver, which derives the majority of its blood supply from the portal circulation. This method allows for the delivery of higher doses of local chemotherapy without risking systemic toxicity, because the chemotherapeutic quickly undergoes first pass metabolism in the liver. Studies of HAIPs for the treatment of colorectal liver metastases have demonstrated greater response rates

and survival advantages, although such results are limited to institutions regularly implementing this into their protocols. B. Enteral access. Malnutrition is common in the patient with cancer and proceduralists may be asked to provide enteral access to combat anorexia and weight loss from a multitude of sources including tumor burden, side effects of treatment, and anxiety or depression. Pre- or postoperative nutritional supplementation has been associated with improved outcomes after surgery and should be considered in most high-risk patients undergoing complex surgeries. In addition, many surgical patients may require surgical enteral access depending on reconstruction either temporarily or permanently excluding or bypassing the alimentary tract. The most common morbidities associated with enteral alimentation are abdominal distension, nausea, or diarrhea; these symptoms can be addressed through changes to the formula or rate of administration of the supplement. The route of administration of nutritional support is selected on the basis of length of anticipated need, intestinal tract function, degree of malnutrition, and the safety of access for administration. In patients with adequate gastrointestinal (GI) function, enteral alimentation is preferred over the parenteral route: Enteral alimentation is less expensive, does not require venous access and the related infectious risk, and perpetuates normal mucosal health and associated immune benefits. 1. Gastrostomy tubes (G-tubes) are commonly placed percutaneously (percutaneous endoscopic gastrostomy tube, or PEG tube) using endoscopic or fluoroscopic guidance. Contraindications to PEG tubes include ascites or prior gastric or upper abdominal surgery. Patients with altered anatomy should be considered for a G-tube placed under direct visualization using laparoscopy or laparotomy. These tubes can serve dual functions of (1) providing a conduit for feeding and (2) palliative intestinal decompression in the event of a bowel obstruction, although decompression can be limited by the diameter of the tube, the consistency of a patient’s enteral intake, and the physical location of the tube in relation to the stomach body. Advantages of G-tubes include the ability to rely on the reservoir function of the stomach to allow for bolus rather than for continuous feeds, and the relative ease of replacing dislodged tubes through the resultant gastrocutaneous fistula. Disadvantages include risk of aspiration in patients with lower esophageal sphincter dysfunction or with compromised ability to protect their airway. 2. Jejunostomy tubes. Jejunostomy tubes (J-tubes) are small-caliber feeding tubes placed distal to the ligament of Treitz. These can be placed percutaneously, but are more commonly done via laparotomy or laparoscopy. Advantages of J-tubes include the ability to bypass upper GI obstructions as well as a theoretical

reduction in the risk of aspiration compared to G-tubes, although this reduction is not regularly demonstrated in the literature. Disadvantages include the need for continuous infusions of low osmolar loads to reduce the likelihood of diarrhea and, once dislodged, these tubes are not as easily replaced. In addition, they are often much smaller in caliber than are G-tubes and, therefore, may become easily clogged, particularly if crushed pills are administered. For this reason, crushed pills should not be administered via most standard J-tubes. Medications in liquid form are appropriate and ongoing care must be given to flush these tubes when not in continuous use. C. Other interventions and procedures. Surgeons may perform one of a number of other interventions for targeted treatment of tumors. Many of these are incorporated into multimodal treatment of hepatic malignancies, although some of these techniques and technologies have been applied to other pathologies. For patients with hepatic malignancies, these may be the only procedural option, because the presence of cirrhosis or chemotherapy-induced liver injury may preclude them from having sufficient functional liver remnant to survive a major hepatic resection. Generally, the evidence suggests that ablation confers a survival benefit over untreated disease or chemotherapy alone in patients ineligible for resection. In some studies, the overall survival rate may approach that of surgical resection. However, the local recurrence rate is generally inferior to that for surgical resection, and multiple treatments may be needed to achieve local control. Many of these can be performed surgically, often laparoscopically or percutaneously, on lesions less than 4 cm in diameter on an outpatient basis. 1. Radiofrequency ablation (RFA) is currently the most widely used and studied ablative therapy. Probes are inserted into a tumor under image guidance and radiofrequency (RF) energy is emitted from the electrode, generating heat leading to coagulation necrosis of the treated tissue. This technique relies on the ability of the tissue to conduct current, so it is less reliable for certain tissue types including lung or bone. Large blood vessels adjacent to the tumor can result in a “heat sink” effect, preferentially conducting current away from the lesion and thereby reducing the effectiveness of treatment. 2. Microwave ablation. Microwave ablation is similar to RFA in that it generates heat within the target tissue. Unlike RFA, microwave ablation is not as influenced by the ability of the tissue to conduct electricity, making it a better choice for tissues with higher impedance. It is also less vulnerable to “heat sink” effect and can treat large tumor volumes more reliably than does RFA. 3. Cryotherapy freezes tumor, resulting in ice formation in the intracellular and extracellular spaces leading to tumor destruction. A number of tumors, in addition to liver tumors, are treated with cryotherapy, including kidney cancer,

prostate cancer, and cutaneous malignancies. 4. Irreversible electroporation (IRE) does not induce thermal injury. Instead, pulsed current is implemented to disrupt the cell membrane and form pores, resulting in apoptosis. This technique is not subject to heat sink and does not yield thermal injury to nearby tissues, making it a reasonable approach for tumors in high-risk areas such as pancreatic tumors or liver tumors near major vessels. Although it has promising advantages, its use is limited to a few centers with significant experience. VI. SURGICAL EMERGENCIES AND PALLIATION Surgeons are often consulted regarding the management of complications that are a result of tumor progression or antineoplastic therapy. Any involvement of a surgeon in the care of the patient with cancer is an instance in which information sharing between the surgeon and oncologist is essential. The surgeon should be consulted to review the case and discuss short-term risks of surgery and the expected recovery, but the oncologist and patient should communicate a clear understanding of the overall prognosis and the patient’s goals of care. Too frequently, these discussions take place in the context of the emergency itself, when the patient may be too ill and the family is unable to take sufficient time to weigh the risks and benefits of surgery against the patient’s goals of care. Hence, we encourage documentation of a patient’s wishes at the time of diagnosis and revisiting these throughout the duration of therapy, hopefully well in advance of the development of complications or emergencies. Many of these can be managed with procedures that may not require surgery and the risks of general anesthesia, although the prognosis, severity of illness, and the patient’s wishes for care regularly dictate the best treatment option (Table 2-3). TABLE 2-3

Palliative Procedures for Emergencies

Presentation

Procedure

Malignant pleural effusion

• Thoracostomy tube • Pleurodesis/sclerosis

Pericardiac effusion

• Bedside pericardiocentesis • Surgical pericardial window

Biliary obstruction

• ERCP for biliary stent • PTC and stent/drain • Surgical choledochojejunostomy or cholecystojejunostomy

Bowel obstruction, large

• Endoscopic stent • Surgical diverting colostomy or ileostomy with mucous fistula

Bowel obstruction, small

• Endoscopic stent • Surgical resection or bypass • Palliative gastrostomy tube

Esophageal obstruction

• Endoscopic stent • Palliative gastrostomy tube (more likely to have to be performed surgically, if unable to pass endoscope)

Locally advanced breast cancer

• Salvage mastectomy

ERCP, endoscopic retrograde cholangiopancreatography; PTC, percutaneous transhepatic cholangiography.

A. Bowel perforation. Perforation of the GI tract in patients with cancer carries a high morbidity and mortality. Although most perforations are from benign causes (diverticulitis, appendicitis, and peptic ulcer disease), they can also occur as a result of chemotherapy or radiation therapy or as primary presentation of a malignancy. Examples include full-thickness colon cancers perforating through the colon wall, obstructing colon cancers resulting in upstream dilation and eventual perforation, or the treatment response of some malignancies such as GI lymphomas resulting in full regression and necrosis of the bowel wall. Patients undergoing cancer therapy are often immunosuppressed and malnourished, which can limit the inflammatory response and thereby blunt the traditional clinical signs of perforation (peritonitis, leukocytosis, fever, and tachycardia). Mortality rates can be quite high, particularly for patients with sepsis and those who are actively on treatment or otherwise immunosuppressed; comfort care and nonsurgical treatments should be discussed in patients with an overall poor prognosis. B. Bowel obstruction. Intestinal obstruction is common in patients with cancer presenting with nausea, vomiting, abdominal distension, and obstipation. Benign sources of obstruction such as adhesions from previous surgery and radiation enteritis account for approximately one-third of cases in these patients. Primary (ovarian, colonic, and stomach) malignancies or metastatic disease (lung, breast, and melanoma) are the cause of intestinal obstruction in two-thirds of cases. In a small percentage of patients with cancer, functional obstruction can occur as a result of electrolyte abnormalities, radiation therapy, malnutrition, narcotic analgesics, and prolonged immobility. In these patients, correction of the underlying cause and bowel decompression are the cornerstones of treatment. The approach to the diagnosis and treatment of obstruction in patients with cancer should be similar to that for patients with benign disease. Diagnosis is most frequently made by computed tomography (CT) scan, although additional studies using oral or rectal contrast may be diagnostic and/or therapeutic in some cases. Intravenous (IV) contrast can be particularly helpful in determining the perfusion of the bowel wall and in distinguishing tumor from bowel. All patients should be

initially resuscitated with IV fluids, have electrolyte abnormalities corrected, be decompressed with a nasogastric tube, and have their urine output monitored. Signs of compromised bowel viability or perforation (abdominal tenderness, leukocytosis, fever, persistent tachycardia, and free intra-abdominal air) should prompt immediate bedside surgical consultation. Patients with a complete bowel obstruction rarely respond to medical management, but upward of 50% of patients with a partial small bowel obstruction will resolve their obstruction with nonoperative measures. Endoscopic stenting may be an option for palliation of a bowel obstruction. Upper GI or colonic obstructions can be stented by advanced endoscopists if they are able to pass a wire through the obstruction. If not, and the patient wishes to proceed with further care, surgical intervention will be necessary. Surgery for a malignant bowel obstruction is associated with significant 30-day postoperative morbidity (30%) and mortality (10%), and, even with successful surgery, patients may not experience resolution of abdominal pain, nausea, or vomiting. Patients who are not candidates for surgery may be offered a palliative G-tube for decompression in place of a nasogastric tube. C. Neutropenic enterocolitis (typhlitis) often occurs in patients who are undergoing chemotherapy and are neutropenic for more than 7 days. Symptoms include febrile neutropenia, diarrhea, abdominal distension, and right lower quadrant pain. Radiologic findings are often nonspecific or may demonstrate thickening of the cecum. Initially, the presentation can be very similar to that of appendicitis and may prompt immediate surgical consultation, although the decision to proceed with surgery should be made in collaboration with the oncology team. Most episodes will resolve with nonoperative management including bowel rest, IV fluid resuscitation, nasogastric decompression, and broad-spectrum antibiotics. However, if patients develop perforation, uncontrolled hemorrhage, become septic, or symptoms continue to worsen despite medical therapy, surgery should be performed promptly. A right hemicolectomy is the surgery of choice and may require a temporary or permanent diverting ostomy. D. Biliary obstruction. The prognosis for patients with biliary obstruction from metastatic disease is poor, with 2-month mortality rates approaching 70%. Treatment should be aimed at preventing cholangitis and palliating jaundice and associated pruritus. Although surgical bypass can be performed, less-invasive techniques including endoscopic retrograde cholangiopancreatography (ERCP) with stent placement or percutaneous transhepatic cholangiography (PTC) for drainage should be considered initially. E. Hemorrhage. Patients with malignancies who develop bleeding should undergo the same workup as do those without malignant disease. Resuscitation, correction of coagulopathies, and a workup to define the bleeding site should be initiated

immediately. If the patient is stable, angiography, tagged red blood cell scan, embolization, or endoscopic interventions can be used to diagnose and treat hemorrhage. F. Pericardial tamponade. Metastatic disease leading to malignant obstruction of the pericardial lymphatics is the most common cause of pericardial tamponade in patients with cancer. Lung cancer, breast cancer, lymphoma, leukemia, melanoma, and primary neoplasms of the heart are most commonly implicated in tamponade. Patients often present with vague symptoms of chest pain, dyspnea, and anxiety. On examination, decreased heart sounds, tachycardia, pulsus paradoxus, and jugular venous distension can be found. Echocardiography is the best test to assess pericardial fluid and its effect on cardiac function. Operative pericardotomy and pericardial window are quick procedures, but there is significant risk associated with inducing general anesthesia in a patient with compromised cardiac output. Pericardiocentesis can be performed quickly at the bedside and may be lifesaving in a patient in tamponade and shock. G. Superior vena cava syndrome (SVCS) results from an impedance to outflow from the superior vena cava due to external compression by malignancy, fibrosis, or thrombosis. In most cases, SVCS develops gradually with symptoms including dyspnea and facial edema or fullness. Unless SVCS causes impedance of the airway from laryngeal edema (an emergency treated with intubation, tracheostomy, or emergent radiation therapy), a thorough workup can be conducted. Chest radiography, cross-sectional imaging, and biopsies can be useful in determining the etiology and appropriate treatment of superior vena cava (SVC) obstruction. Treatment can include diuretics, elevation of the head, steroids, and chemotherapy and/or radiation therapy directed at the underlying cause. Surgical treatment, through bypass of the innominate vein to the right atrium, is a highly morbid procedure and should be considered as a last resort. H. Spinal cord compression. Spinal cord compression is an acute emergency. The severity of neurologic impairment at presentation dictates the potential reversibility of symptoms. Early recognition is essential in preventing progressive or irreversible neurologic deterioration that can lead to paralysis and loss of sphincter control. Extradural metastatic lesions of the vertebral body or neural arch are the most common cause of spinal cord compression in patients with malignancies. Metastatic lesions from the lung, breast, prostate cancers, and multiple myeloma are the most common lesions responsible for spinal cord compression. Of these, 10% occur in the cervical vertebrae, 70% in the thoracic vertebrae, and 20% in the lumbosacral vertebrae. The majority of patients will present with localized back pain that usually precedes the onset of neurologic deterioration by weeks to months. As tumors expand, they often impinge on the anterior aspect of the spinal cord, resulting in

motor weakness and loss followed by sensory loss. The onset of urinary retention, constipation, and/or loss of bowel or bladder control is a late and ominous manifestation. Magnetic resonance imaging (MRI) is the study of choice for evaluating patients with suspected spinal cord compression. The patient should be immediately started on steroids, and treatment options include radiation therapy, surgery, chemotherapy, or a combination of all three. Laminectomy is effective in managing patients with epidural masses, and in select cases, surgical resection of the mass may be possible. SUGGESTED READINGS Cedermark B, Dahlberg M, Glimelius B, et al. Improve survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336(14):980–987. Moran J, Guinan E, McCormick P, et al. The ability of prehabilitation to influence postoperative outcome after intraabdominal operation: a systematic review and meta-analysis. Surgery 2016;160(5):1189–1201. Nguyen TT, Hoskin TL, Habermann EB, et al. Breast cancer-related lymphedema risk is related to multidisciplinary treatment and not surgery alone: results from a large cohort study. Ann Surg Oncol 2017;24(10):2972–2980. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363(8):733–742.

I.

INTRODUCTION Optimal care of patients diagnosed with cancer is a multidisciplinary effort, often combining two or more of the classic disciplines: surgery, radiotherapy (RT), and systemic therapy (i.e., chemotherapy). Standard-of-care cancer therapy requires an accurate diagnosis, achieved by the coordinated effort of pathologists, radiologists, and clinical laboratory physicians. Many professionals are intimately involved in the coordinated care of patients with cancer, including, but not limited to, physicians, nursing staff, physicists, psychologists, and social workers. Radiation oncology is a clinical and scientific discipline devoted to caring for patients with cancer and other diseases using ionizing radiation, conducting basic science and clinical studies regarding the mechanisms of the biologic efficacy and physical basis underlying RT, and in trainee education. The goal of RT is to administer a precisely measured dose of radiation to a defined target volume in an accurate and reproducible manner while minimizing damage to surrounding healthy tissue. For cancer therapy, the goal of RT is to eliminate tumor cells in the target volume while maintaining patient quality of life and prolonging survival in a cost-competitive manner. RT eradicates tumor cells by causing damage to their genetic material (i.e., DNA) through double-stranded DNA (dsDNA) breaks to a level sufficient to induce cell death during mitosis. RT is also effective in reducing cancer-associated pain, restoring luminal patency, maintaining skeletal integrity, and preserving organ function, with minimal morbidity and efficient treatment times. Patients under consideration for RT are assessed by the radiation oncologist in the context of their competing medical comorbidities, treatment goals, potential prior RT courses, and estimated life expectancy. Evaluation may also include requesting additional staging studies and determining the most appropriate therapeutic strategy for the patient in collaboration with other providers. RT should not be provided

to a patient with cancer unless there is a reasonable expectation of short- or long-term patient benefit. II. TYPES OF RADIATION USED IN RT Many types of radiation are used for treating both benign and malignant diseases. The most common form of radiation employed clinically is external beam radiotherapy (EBRT) using photons or electrons. Photons are x-ray or gamma-rays that may be considered as bundles of energy that deposit dose as molecular ionizations in matter. The term x-ray describes radiation produced by machines, whereas gamma-rays refer to radiation emitted by decay of radioactive isotopes (i.e., atoms with the same number of protons but varying neutrons). Typical RT units used in modern x-ray therapy are linear accelerators that produce x-ray energies ranging from 4 to 25 million volts or MV. Linear accelerators produce x-rays by generating electrons and accelerating them toward a tungsten target. Upon impact, x-rays, or quanta of energy, are released as radiation proportional to the energy lost by the electron upon target impact in a process termed bremsstrahlung, or braking radiation. The most common source of gamma-rays for EBRT (i.e., teletherapy) has been cobalt, 60Co, a manmade isotope of cobalt generated by irradiating a stable cobalt isotope (59Co) with neutrons in a nuclear reactor. Most RT facilities no longer use gamma-rays because of their low energy, unfavorable dose distribution, and need for regular dose recalculation and source replacement. One exception is the Gamma Knife unit used for intracranial stereotactic radiosurgery (SRS) that houses greater than or equal to 192 60Co sources that deliver high radiation doses to intracranial targets via triangulation of multiple source beamlets. Electrons or β particles are also used for RT. Similar to the distinction between x-rays and gamma-rays, the term electron describes machine-generated electrons, whereas β particle describes electrons emitted by decay of radioactive material. Electrons deposit their maximal energy slightly deep to the skin surface and have a sharp dose falloff beyond their range. Electron therapy is used mainly for treating skin or superficial tumors a few centimeters deep to the skin, with a small but detectable radiation dose that continues beyond the target. Other sources of external beam radiation are protons (i.e., hydrogen ions, or hydrogen atoms without an electron), carbon ions (i.e., carbon atom with loss of six electrons), and neutrons. Protons and carbon ions are positively charged particles that deposit dose at a constant rate over most of their beam path, with most of the dose deposited at the end of their range as they decelerate in tissue, and virtually no radiation dose beyond this maximum. Hadron therapy refers to the therapeutic use of charged particles larger than electrons, and typically refers to therapy using protons or carbon ion beams; the term protons is used here to refer to hadron therapy because protons are currently the most clinically employed hadron. Charged particle dose deposition is

inversely proportional to the square of their velocity, reaching a maximum, or Bragg peak, as the particle comes to rest. Beyond the Bragg peak, the dose delivered is negligible, representing a major potential advantage of protons over photons, because proton therapy can greatly limit dose to normal tissues beyond the target, and the total amount of radiation (i.e., integral dose) delivered to the patient. Similar to photons, protons induce cell death via ionizations that damage cellular DNA. Proton dosedeposition characteristics can limit dose to surrounding organs at risk (OARs); and because of this physical property, protons may be useful for repeat irradiation where normal structures beyond the target have already received the maximum tolerated radiation dose. Protons are also used commonly for treating pediatric cancers because they can limit irradiation of developing organs and bones, and potentially decrease the risk of radiation-associated malignancies by lowering the delivered integral dose compared to x-rays. Proton therapy is also being investigated in other cancer sites, such as the esophagus and lung, where improved reduction in dose to multiple uninvolved adjacent OARs (e.g., the lung, heart, esophagus, circulating lymphocytes) may be beneficial compared to x-rays. Most RT centers in the United States do not offer protons because of the high initial capital investment for the required equipment; however, this list continues to expand with the advent of more cost-effective single-room gantry systems (https://www.ptcog.ch/index.php/facilities-in-operation). Neutrons are uncharged nuclear particles that can be produced similarly to protons and used for RT. Neutrons deposit large amounts of energy as ionizations close to their initial interaction sites with the nuclei of atoms in tissue. Experience with neutrons is limited to a few centers because of the cost of producing and maintaining neutron RT units. Currently, the only center in the United States offering neutron therapy is at the University of Washington, where neutrons are effectively used to treat salivary gland cancers. A diagram comparing standard depth–dose characteristics for photons, electrons, protons, carbon ions, and neutrons is shown in Figure 3-1.

FIGURE 3-1 Depth–dose curves for photons (x-rays), electrons, protons, and neutrons at energies used in radiation therapy.

Brachytherapy (BT), derived from the Greek brachy for “short,” involves RT using temporary or permanent placement of radioactive source(s) in close proximity to the target tissue. BT can be performed using either encapsulated (i.e., radioactive material covered with an inert material such as platinum) or unsealed (i.e., radioactive material in liquid or pill form) sources. The absorbed dose of radiation falls off rapidly with increasing distance from the BT source (1/radius2 for a point source and 1/radius for a line source); thus, higher doses can be safely delivered to the target tissue with reduced dose to the surrounding normal tissue. Prescribed BT doses are generally delivered over days to weeks for low-dose rate (LDR, 12 Gy/hour) approaches, with LDR doses dependent on the initial activity of the material implanted, and HDR dependent on the time the source is within the patient. BT sources can be placed temporarily, as in the use of iridium-192 (192Ir) for HDR applications where a sealed radioactive source is remotely introduced by a machine called an afterloader through catheters to the tumor target, or permanently, as in implantation of individual metal-coated seeds containing iodine-125 (125I) into target tissue or immobilizer, usually in the operating room. Some common applications of sealed BT include treatment of prostate (HDR or LDR) cancer, early-stage breast cancer (mainly HDR), soft-tissue sarcoma (HDR), and cervical cancer (HDR and LDR). In select cases, sealed BT sources may be used within a

lumen in the palliative setting to relieve malignant obstruction in a previously irradiated field, such as obstructing esophageal and endobronchial tumors, where an HDR BT source is temporarily placed in close proximity to the target via an endoscopic approach using catheters. Unsealed sources are soluble radioactive substances administered via ingestion or injection. Examples include iodine-131 (131I) ingested to treat thyroid cancers, yttrium90 (90Y)-embedded resin or glass microspheres injected to occlude hepatic tumor vasculature to treat metastatic or primary liver malignancies, radium-223 (223Ra, Xofigo) delivered intravenously to treat osseous lesions in metastatic castrate-resistant prostate cancer, or targeting ligands conjugated to radioactive isotopes such as Lutathera (177Lu, lutetium-177-dotatate) to treat neuroendocrine tumors, and Zevalin (ibritumomab tiuxetan anti-CD20 monoclonal antibody [mAb], conjugated to 90Y) for treatment of refractory low-grade or follicular non-Hodgkin lymphoma. III. GOALS OF RADIATION THERAPY The clinical use of radiation involves the coordinated effort of many professionals with a variety of interrelated functions. The goal of any proposed RT should be defined before initiating the RT treatment process, and can be divided into two main categories: A. Curative. The patient has a probability of long-term survival after adequate therapy sufficient to eradicate local disease after accounting for acute/late side effects of treatment. B. Palliative. The patient has a low probability of extended survival beyond weeks/months. Treatment is designed to address symptoms affecting a patient’s quality of life such as pain from tumor mass effect, neurologic changes, or bleeding from tortuous tumor vasculature. In curative RT, some side effects may be deemed acceptable by the treating physician and patient after shared discussion. However, in palliative RT, no major side effects should be seen. In palliation of epithelial solid tumors causing complications due to mass effect or pain, relatively high doses of RT (sometimes 75% to 80% of curative dose) are required to provide adequate tumor control over the patient’s remaining life expectancy. There are some exceptions to high-dose palliative RT, including patients with lymphoma or multiple myeloma, or for treatment of bleeding (e.g., patients with cervical or endobronchial cancers). Some cancers, such as low-grade lymphoma, are long-standing and incurable. Incurable cancers also fall into the palliative category because long-term tumor control may be sacrificed to avoid RT-related complications. Recent advances in multimodal cancer therapy have extended the natural history of many cancers, increasing the frequency of patients with controlled primary tumors and limited metastatic disease. Although patients with metastases are currently considered incurable, those with one to five sites of metastases and controlled primary tumors have oligometastatic disease and

may derive improved overall survival from local ablative RT (Lancet 2019;393:2051– 2058). The role of ablative RT in oligometastatic patients appears promising but warrants further investigation. IV. BASIS FOR PRESCRIPTION OF RT A. Tissue diagnosis of malignancy and molecular characterization obtained if possible (e.g., p16 status for head and neck cancer, programmed death ligand [PD-L1] status for non–small cell lung cancer [NSCLC], isocitrate dehydrogenase 1 [IDH1] proteins for glioblastoma) B. Staging studies performed to evaluate tumor extent and define RT target volume (e.g., computed tomography [CT], magnetic resonance imaging [MRI], or functional imaging with positron emission tomography [PET]) and other studies C. Goal of therapy (i.e., curative vs. palliative) defined after staging/evaluation/discussion with patient D. Consideration and order of multimodality therapy (i.e., RT alone or following surgery, or treatment combining RT with neoadjuvant/concurrent/adjuvant chemotherapy or surgery) E. Select the optimal RT dose, modality, site, and volume to be treated depending on anatomic location, histology, stage, lymph node involvement, and adjacent OARs for the RT target. F. Assess treatment tolerance by evaluating the patient’s performance status, prior RT and other therapy, and comorbidities that could increase the risk of RT-induced side effects. In addition to coordinating the patient’s care in a multidisciplinary manner, radiation oncologists work closely with medical physicists who calibrate RT machines, evaluate RT dose calculations, and innovate, commission, and optimize new RT machines, radiation dosimetrists who design RT plans, and radiation therapists who carry out approved RT plans to ensure delivery of safe, accurate, and cost-effective RT. The ultimate responsibility for treatment decisions and executing approved RT plans always resides with the radiation oncologist. V. RADIOBIOLOGIC PRINCIPLES A. Probability of tumor control. RT elicits the death of cancer cells by causing dsDNA breaks, through either direct or indirect ionization of the molecular bonds forming the DNA double helix. It is axiomatic in RT that higher radiation doses elicit better tumor control, based on a wealth of published in vitro and in vivo experimental models demonstrating dose-dependence cell killing by single and multiple repeateddose RT. For every increment of radiation dose, a certain fraction of cells is killed. Therefore, the total number of surviving tumor cells is proportional to the initial

number of tumor cells present minus the number killed by each fraction. As such, various total RT doses yield different probabilities of tumor control, depending on lesion extent (i.e., number of clonogenic cells present), inherent clone radiosensitivity, and number of clones remaining after RT. Additional factors affecting the RT efficacy include DNA repair following RT, intratumoral oxygen tension, number of cells in radiosensitive phases of the cell cycle (e.g., G2 and M), and rate of tumor cell repopulation. B. Subclinical disease refers to tumor cell deposits too small for clinical detection that, if left untreated, may evolve into clinically apparent tumors. For subclinical disease in treating squamous cell carcinoma of the upper respiratory tract or for adenocarcinoma of the breast, doses of 45 to 50 Gy using conventional fractionation result in disease control in more than 90% of patients. Microscopic tumor, as at the surgical margin, should not be regarded as subclinical disease; cell aggregates of 106/cc or greater are required for detection. Such volumes need higher RT doses ranging from 60 to 65 Gy over 6 to 7 weeks for epithelial tumors. For clinically palpable tumors, doses of 60 (for T1) to 75 to 80 Gy or higher (for T4 tumors) are required (2 Gy/day, five fractions weekly). This dose range and tumor control probability (TCP) has been documented for squamous cell carcinoma and adenocarcinoma (Fletcher GH. Textbook of Radiotherapy. Philadelphia, PA: Lea & Febiger, 1980). Ideally, such high RT doses could be delivered; however, they often exceed normal tissue tolerance, and can result in unacceptable debilitating or lifethreatening complications. C. Effects of radiation on tissues and the linear–quadratic equation. RT can result in three broad categories of DNA damage based on cell lethality. Lethal damage is an extent of dsDNA damage that overwhelms cellular DNA repair mechanisms. Sublethal damage (SLD) is DNA damage that is repairable when a single dose of xrays is divided into two or more fractions. Potentially lethal damage (PLD) is damage that ranges from repairable to lethal damage, depending on growth conditions (i.e., cell cycle progression) during or after a dose of x-rays. Sublethal damage repair (SLDR) and potentially lethal damage repair (PLDR) are important concepts in considering normal tissue repair. Normal tissues have substantial capacity to recover from SLD or PLD induced by radiation (at tolerable dose levels). Injury to normal tissues may be caused by the RT effect on the microvasculature or stem cells of the supporting stroma. Ionizing radiation induces a variety of changes in tissues, depending on the total dose, fractionation schedule (i.e., daily dose and time), and volume treated. For many tissues, OAR toxicity is inversely related to the dose received by the volume of the organ (i.e., a lower dose to a larger organ volume and higher dose to a smaller target volume may be equitoxic). A useful principle for normal tissue toxicity is to

determine whether an organ functions in a serial or parallel manner. Serial organs, such as the spinal cord, central nervous system (CNS), or gastrointestinal (GI) tract, are those whose function is impaired if a single functional subunit of that organ is damaged. Parallel organs, such as the liver, kidney, or lung, lose clinically relevant functionality only when a certain volume of the parallel units is damaged. Chronologically, RT effects can be subdivided into acute (i.e., first 6 months), subacute (i.e., second 6 months), or late, depending on when effects are observed. The gross manifestations of RT damage depend on the kinetic properties of the tissue-resident stem cells (i.e., slow or rapid renewal) and RT dose. A correlation has been established between the incidence and severity of acute reactions and late effects for some disease sites (Radiother Oncol 2001;61:223–31; Radiother Oncol 1999;53:37-44). Formulations based on dose–survival models have been proposed to describe the dependence of cell killing on RT dose and fractionation. These models are useful in evaluating the biologic equivalence of various doses and fractionation schedules, with assumptions based on a linear–quadratic survival curve represented by the equation lnS = αD + βD2 for a single dose or lnS = α(nd) + β (nd)d  (4.1) for a fractionated dose, where n is the number of fractions, d dose/fraction, and nd total dose. In this equation, α represents the linear (i.e., first-order dosedependent) component of cell killing, and β represents the quadratic (i.e., secondorder dose-dependent) component of cell killing. Thus, α represents the less reparable component of lethal radiation damage, that is, damage like a dsDNA break for which the lethality is not reduced by fractionating the radiation dose. Conversely, β represents damage that can be repaired (i.e., its lethality is reduced such as a singlestranded DNA break) when the radiation dose is fractionated. At low doses, the α (linear) component of cell killing predominates. At high doses, the β (quadratic) component of cell killing predominates. The dose at which the two components of cell killing are equal constitutes the α/β ratio. In general, tissues with a high mitotic rate, such as the skin and mucosa, respond acutely to RT and have a high α/β ratio (between 8 and 15 Gy), whereas low or postmitotic tissues such as the brain and spinal cord have a low α/β ratio (1–5 Gy) and display delayed or late RT effects. Therefore, the severity of late effects changes more rapidly with varying the RT dose per fraction when a total dose is selected to yield equivalent acute effects. With decreasing RT dose per fraction, the total dose required to achieve a certain isoeffect increases more for late-responding tissues than that for immediately responding tissues. Therefore, in hyperfractionated regimens (1.2–1.4 Gy/fraction), the tolerable RT dose increases more for late effects than for

early effects. Conversely, if large doses per fraction are used, the total dose required to achieve isoeffects in late-responding tissues is reduced more for late effects than for early effects. A biologically equivalent dose (BED) can be obtained using the following equations, derived from the equation for cell survival after a fractionated dose: BED = −ln S/α = nd[1 + d/(α/β )] = D[1 + d/(α/β )]  (4.2) To compare two treatment regimens (with some reservations), the following formula can be used: Dx = Dr[(α/β + dx)/(α/β + dr)]  (4.3) in which Dr is the known total dose (reference dose), Dx is the new total dose (with different fractionation schedule), dr is the known dose per fraction (reference), and dx is the new dose per fraction. The following is an example using this formula: Suppose 50 Gy in 25 fractions is delivered to yield a given biologic effect. If one assumes that the subcutaneous tissue is the limiting parameter (late reaction), it is desirable to know what the total dose to be administered will be, using 4-Gy fractions. Assume α/β = 5 Gy. Using the earlier equation Dx = 50 Gy(5 + 2)/(5 + 4) = 39 Gy  (4.4) Answer: A dose of 50 Gy in 25 fractions provides the same BED as 39 Gy in 4Gy fractions. As the total dose to a particular tumor and surrounding normal tissues increases, both TCP and normal tissue complication probability (NTCP) increase. Both TCP and NTCP are sigmoidal in shape. The farther these two curves diverge, the more favorable the therapeutic ratio (Fig. 3-2). When the curves are close together, increases in RT dose will lead to exponential increases in NTCP. The TCP and NTCP curves can be separated by the use of biologic modifiers, radioprotectors, and improved RT delivery methods (e.g., daily imaging for treatment localization, intensity-modulated radiation therapy [IMRT], proton therapy). For example, IMRT for locally advanced NSCLC significantly reduces posttreatment radiation pneumonitis compared to three-dimensional conformal RT (3D-CRT) for the same RT dose, despite larger treatment volumes, and is now considered, with some exceptions, to be standard of care due to lower rates of serious lung toxicity with IMRT (J Clin Oncol 2017;35:56).

FIGURE 3-2 The therapeutic ratio represents the relationship between two sigmoidal curves; the tumor control probability (TCP) and the normal tissue complication probability (NTCP) curves. The further the two curves are separated, the higher the TCP and the lower the NTCP.

When the TCP and NTCP curves are well separated, higher doses of RT can be safely delivered. Chemotherapy also modifies TCP and NTCP curves, often shifting both leftward. Therefore, with chemoradiation (CRT), lower doses of RT are required to produce a given TCP/NTCP. Biologic factors also contribute to the TCP and NTCP. Defects in DNA repair will lower the dose for both curves unless the defect is unique to the clonal cells comprising the tumor. In contrast, defective apoptotic pathways tend to increase radiation resistance. An acceptable complication rate for severe injury is 5% to 10% in most curative clinical situations. Moderate sequelae are noted in varying proportions depending on the dose and fractionation of radiation given and the volume irradiated of the specific organ at risk. In 2010, a seminal series of articles that provides clinicians with evidence-based dosimetric tools to guide radiation treatment planning to minimize normal tissue complications was published. This QUantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) is an evaluable source describing dose and volume parameters shown to be associated with organ-specific radiation toxicity. Table 3-1 is a QUANTEC summary of dose, volume, and outcome data for OARs treated with conventional fractionation (1.8–2 Gy/fraction) (Int J Radiat Oncol Biol Phys 2010;76:S10). Recent updates to QUANTEC are organ-site specific, with an

increasing emphasis on patient-reported outcomes and defined clinical functional endpoints (Int J Radiat Oncol Biol Phys 2018;100:391). TABLE 3-1

QUANTEC Summary of Dose, Volume, and Outcome Data for OAR Treated with Conventional Fractionation (1.8–2 Gy per Fraction)a

aAll data are estimated from the literature summarized in the QUANTEC reviews unless otherwise noted.

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. aAll at standard fractionation (i.e., 1.8–2.0 Gy per daily fraction) unless otherwise noted. V is the volume of the x organ receiving ≥× Gy. Dmax = Maximum radiation dose. aNon-TBI. aWith combined chemotherapy. aD = minimum dose received by the “hottest” ×% (or × cc’s) of the organ. x aSevere xerostomia is related to additional factors including the doses to the submandibular glands. aEstimated by Dr. Eisbruch. a

aClassic radiation-induced liver disease (RILD) involves anicteric hepatomegaly and ascites, typically occurring

between 2 weeks and 3 months after therapy. Classic RILD also involves elevated alkaline phosphatase (more than twice the upper limit of normal or baseline value). aFor optic nerve, the cases of neuropathy in the 55–60 Gy range received ≈59 Gy (see optic nerve paper for details). Excludes patients with pituitary tumors where the tolerance may be reduced. 3D-CRT, 3-dimensional conformal radiotherapy; BED, biologically effective dose; RILD, radiation-induced liver disease; RTOG, radiation therapy oncology group; SBRT, stereotactic body radiotherapy; SRS, stereotactic radiosurgery. From Marks LB, Yorke ED, Jackson A, et al. Use of NTCP models in the clinic. Int J Radiat Oncol Biol Phys 2010;76(3):S10.

Combining RT with surgery or systemic therapy frequently modifies the tolerance of normal tissues and/or tumor response to a given dose of radiation by affecting cell turnover, which may necessitate adjustments in RT planning and dose. For example, in definitive CRT for esophageal cancer, concurrent chemotherapy consisting of 5-fluorouracil (5-FU) and cisplatin and RT to 50.4 Gy improves local tumor control and similar esophagitis rates versus RT alone using 64 Gy (J Clin Oncol 2002;20:1167). There is increasing evidence that combining immunotherapy and RT using stereotactic body radiation therapy (SBRT) can be safely combined for solid cancers; however, larger randomized studies are required (J Clin Oncol 2018;36:1611). D. Dose–time factors. Dose–time considerations constitute a complex function expressing the interdependence of total RT dose, time, and fraction number to produce a biologic effect. Short overall treatment times are required for rapidly proliferating tumors; more slowly proliferating tumors can be treated with longer overall treatment times. With regard to fractionation, five fractions/week with conventional RT doses, for example, are preferable to three fractions/week because the latter schedule may elicit 10-fold less cell killing per week. In general, RT dose fractionation spares acute tissue reactions (e.g., skin and mucosa) because of compensatory accelerated epithelial proliferation and repair of SLD. Therefore, a prolonged RT course with smaller daily RT fractions will decrease early/acute reactions. However, serious late damage to normal tissue will not be reduced because such effects are not proliferation dependent. Worse, extensively prolonging treatment time allows growth of rapidly proliferating tumors, making prolonged treatment schedules undesirable. RT may be delivered by conventional fractionation, hypofractionation, hyperfractionation, or accelerated fractionation schedules. In the United States, conventional fractionation is defined as a daily fraction size of 1.8 to 2.0 Gy, and in the nonpalliative setting, it is typically delivered 5 days/week over 5 to 8 weeks to a total dose of 45 to 80 Gy. The other fractionation schedules are defined by RT doses and durations as compared to conventional fractionation.

Hypofractionation refers to fraction sizes larger than conventionally fractionated radiation therapy and are delivered once daily. Typically, a lower total dose is delivered and designed to achieve the same TCP as does conventional fractionation. Common examples of hypofractionation in the United States are palliative therapy regimens of 30 Gy in 10 once-daily fractions, 20 Gy in 5 once-daily fractions, or 8 Gy in a single fraction. The difficulty with hypofractionation is the effect of the larger dose per fraction on normal tissues, specifically negating the normal tissuesparing effects of fractionation. As a consequence, this leads to lower total dose threshold tolerances for toxicity in normal tissues compared with conventional fractionation, and thus, historically, reluctance to increase the total dose delivered to tumors that may be adjacent to sensitive structures (e.g., spinal cord). Recent technologic advancements in patient immobilization and image-guided radiation therapy (IGRT) have allowed for safe delivery of large cumulative doses of highly hypofractionated radiation (e.g., 10–18 Gy/fraction) with subcentimeter accuracy and excellent clinical outcomes. Reported results of hypofractionated SBRT, defined as five or fewer treatments, have shown local–regional control rates, metastatic disease control rates, and cancer-specific survival similar to surgical management, with minimal normal tissue toxicity for medically inoperable (JAMA 2010;303:1070) and, more recently, operable early-stage NSCLC patients; however, results from the ongoing VALOR trial comparing SBRT to surgery are awaited (JAMA Oncol 2018;4:1263). The basic rationale of hyperfractionation is that using smaller doses per fraction of 1.1 to 1.2 Gy in two to three fractions/day allows higher cumulative doses to be delivered over the same treatment duration compared to conventional fractionation, but within the tolerance of late-responding tissues. Late-responding tissues such as the bowel, spinal cord, kidney, lung, and bladder have the same probability of complications with hyperfractionation. However, the patient may experience more acute reactions as a result of the larger total dose. The typical period between daily fractions is 6 hours to allow late tissue repair. An example of hyperfractionation is 69.6 Gy total dose delivered over a 6-week period in twice-daily fractions of 1.2 Gy for NSCLC. Hyperfractionation may offer overall survival benefit of 3.9% compared to conventional fractionation at 10 years for squamous cell carcinomas of the head and neck based on an updated meta-analysis of 33 trials including over 11,000 patients (Lancet Oncol 2017;18:1221). The rationale for accelerated fractionation is to decrease tumor cell repopulation, or increase in total cell number to replace a fraction of those killed by RT during treatment, by treating more frequently over a shorter time period; this increases the TCP for a given total dose. Therefore, RT fraction size and treatment duration are decreased when compared to conventional fractionation. An example of

accelerated fractionation is treatment of limited-stage small cell lung cancer: 45 Gy in 30 twice-daily fractions of 1.5 Gy with concurrent cisplatin/etoposide (N Engl J Med. 1999;340:265). E. Prolongation of overall treatment time, tumor control, and morbidity. Treatment interruptions lower the TCP for the same RT. The RT dose to yield for a given TCP must increase when fractionation is prolonged because of tumor cell repopulation. It is estimated that greater than 1 Gy must be added to the cumulative dose for each treatment day over 28 days for patients with head and neck cancer (Radiother Oncol 1990;17:95). Tumor cell repopulation may negate an estimated 0.38 Gy/day of RT after 12 days of treatment for NSCLC. Overall, prolonging treatment time for conventional RT through planned or avoidable interruptions in daily scheduled treatments negatively affects outcomes and should be avoided when possible. VI. RADIATION TREATMENT PLANNING A. Introduction to treatment planning. The International Commission on Radiation Units and Measurements (ICRU) Report No. 50 and, more recently No. 62, define the volumes of interest in treatment planning (ICRU 50. Prescribing, Recording, Reporting, Photon Beam Therapy. Washington, DC: International Commission on Radiation Units and Measurements, 1994; ICRU 62. Prescribing, Recording, Reporting, Photon Beam Therapy (Supplement to ICRU Report 50). Bethesda, MD: International Commission on Radiation Units and Measurements, 1999). Defining tumor and target volumes is a crucial step in RT planning. Gross tumor volume (GTV) is defined as all known gross disease, including involved regional lymph nodes, and is determined by physical examination and imaging (i.e., such as CT, MRI, and/or PET). Clinical target volume (CTV) encompasses the GTV plus surrounding potential microscopic disease. The internal margin (IM) accounts for variations in CTV size, shape, and position due to physiologic processes such as tumor movement during inspiration/expiration, bladder filling/emptying, and bowel peristalsis, and is added to the CTV to create the internal target volume (ITV). The setup margin (SM) accounts for uncertainties in patient positioning with each daily fraction and beam alignment during treatment planning. The actual treated target is called the planning target volume (PTV), and consists of the SM added to the ITV. In shorthand, PTV = (CTV + IM) + SM = ITV + SM. In addition, OARs that surround the PTV, especially those in a previously irradiated field, play a critical role in planning evaluation of an RT treatment plan. The organ at risk volume (PRV) is the OAR volume plus a margin, similar to the PTV, and is defined as PRV = OAR + IM + SM. Thus, final RT volumes incorporate uncertainties as to the total extent of tumor, daily tumor position during treatment, and setup volumes, to reduce the probability that a defined target is underdosed for a given RT plan and to ensure that

OARs are not overdosed. B. Simulation is the process of accurately identifying the tumor volume(s) and OAR(s) to determine the optimal configuration of radiation beams necessary to treat the tumor and avoid OARs. Modern RT treatment planning systems use CT imaging for simulation, in which patients are placed in either supine or prone positions optimized for patient comfort and reproducibility, assisted by various immobilization devices such as customized thermoplastic masks for CNS cancer treatments, or expanded polystyrene molds conforming to a patient’s body for immobilization for abdominal or pelvic treatments. Individual CT slices can be imaged several times during CT simulation to capture GTV and OAR movement due to respiratory excursion and other physiologic processes (also known as 4D-simulation). CT scan slices are obtained of the region(s) of interest, and contours delineated (GTV, CTV, ITV, PTV, OAR, and PRV) by the radiation oncologist on the CT images, often assisted by registration and fusion to other diagnostic imaging such as MRI (i.e., T1/T2, multiparametric, thin slice), PET/CT scans, or CT myelograms. The conventional simulator had previously been the workhorse of simulation, consisting of a table, gantry with 360 degrees of rotation, as well as fluoroscopy and diagnostic x-ray capability, but has been replaced by CT simulation in the vast majority of treatment centers. The goal of RT treatment planning is to adequately irradiate the PTV(s) while minimizing RT dose to surrounding OARs and noncontoured normal tissue to reduce the probability of acute and late toxicity. Treatment toxicity may be reduced in many ways: by identifying the optimal treatment position, reducing the ITV via patient deep-inspiration breath hold or tumor tracking with gating, daily alignment to fiducial markers, daily imaging to reduce setup uncertainty, and RT delivery techniques to decrease OAR dose and to increase PTV dose conformity. The overall goal of RT planning is to generate a delivery approach tailored to the patient’s anatomy that utilizes the most reproducible patient position that maximizes PTV dose and minimizes OAR dose to augment the therapeutic ratio of RT. C. 3D treatment planning and IMRT. CT simulation allows definition of tumor volume and OAR structures, 3D treatment planning to optimize dose distribution, and radiographic verification of volume treated (Int J Radiat Oncol Biol Phys 1994;30:887). Modern computer technology facilitates accurate and timely calculation of RT dose in 3D, as well as dose–volume histograms (DVHs) that graphically depict the RT dose a given structure volume receives. These tools form the basis for sophisticated 3D treatment-planning systems that yield relevant information in evaluating tumor extent, distinguishing target volume(s) and normal tissues, virtually simulating therapy, generating digitally reconstructed radiographs (DRRs), designing treatment portals and aids (e.g., compensators, blocks),

calculating 3D dose distributions and dose optimization, and evaluating final treatment plans in the primary treatment and reirradiation settings. In addition, DVHs are extremely useful as a means of dose display, particularly in comparing multiple treatment plan dose distributions to identify the optimal plan. They provide a graphic summary of the entire 3D dose matrix, and facilitate determination of whether a target volume or critical structure receives radiation in excess of what is recommended or desired, often referred to as a dose constraint. Because DVHs do not provide spatial dose information, they cannot replace the other methods of dose display such as room-view displays. For example, a DVH may show the %PTV receiving the prescribed RT dose, but cannot identify under- or overdosed regions within the volume or target of interest. Treatment verification is another area in which 3D treatment-planning systems play an important role. Data from sequential CT simulation slices can be used to create DRRs from CT slices that recreate diagnostic x-rays. DRRs can provide a “beam’s eye view” that shows how the patient appears to the linear accelerator head where the radiation beam enters from CT slices, and this information can be useful to verify treatment geometry, localization of the radiation treatment port, and beam blocks. IMRT is an advanced form of 3D treatment planning and conformal therapy that optimizes RT to irregularly shaped volumes through a process of complex inverse treatment planning and dynamic RT delivery that modulates photon beam fluence (i.e., intensity). By varying photon fluence across multiple distinct treatment fields/ports, the radiation dose can be modulated to conform to irregular shapes (i.e., concave) and to design a heterogeneous dose distribution. Several IMRT hardware and software packages are commercially available, including rotational slice-byslice, dynamic multileaf, static (step and shoot) multileaf, milled compensator, helical tomotherapy, and arc delivery systems (e.g., volumetric modulated arc therapy [VMAT], RapidArc). Central to IMRT are multileaf collimators (MLCs) and the concept of inverse treatment planning. MLCs are a set of shielding vanes measuring 0.5 to 1 cm wide located in linear accelerator heads that sculpt the RT portal. Each vane is controlled independently and can remain stationary (static MLC) or move across the treatment field during “beam-on” time (dynamic MLC). To understand inverse treatment planning, one must first understand traditional forward treatment planning. In forward treatment planning, the radiation oncologist draws the radiation portals, considers the dose distribution generated, and adjusts the portals accordingly to achieve the desired dose distribution. Forward planning is cumbersome. Inverse planning reverses that order. The radiation oncologist contours, or defines, the desired target volumes and critical structures to avoid on the CT simulation slices electronically and prescribes an ideal dose distribution to meet

target coverage and OAR constraints. Inverse planning starts with the planning endpoint (i.e., ideal dose distribution) and finds, through mathematical optimization algorithms that consider various weighted parameters for the structures of interest and RT target defined by the radiation oncologist, the beam characteristics (i.e., fluence profiles), producing the best approximation of the ideal dose. IMRT is in widespread clinical use, and has clear advantages for treatment of many cancer sites such as locally advanced NSCLC with targets in close proximity to critical OARs such as the heart, esophagus, and spinal cord. D. IGRT and stereotactic radiation therapy. Increasingly sophisticated RT treatmentplanning and delivery systems require parallel precision in patient immobilization and daily verification of patient and tumor position. Treatment planning develops an RT plan from a snapshot of patient anatomy at the time of simulation; however, a patient’s anatomy may change during the days/weeks of treatment. One way to account for these potential variations is to use image guidance during RT in the form of IGRT. IGRT involves using various imaging modalities to assess tumor position before or during an RT course, sometimes with the assistance of bony anatomy, stationary organs, or external or internal fiducial markers such as radiopaque wires or coils, to reduce the random/systemic errors associated with daily patient setup. Examples of IGRT modalities used before treatment include ultrasonography, optical (light-based) devices, on-board kV fluoroscopy, x-ray, cone-beam computed tomographic (CBCT), and megavoltage computed tomographic (MVCT) imaging. Image guidance systems that can image during RT include the CyberKnife kV-x-ray tracking system, Calypso beacon localization system using radiofrequency from implanted fiducial markers, and, most recently, linear accelerators with on-board real-time magnetic resonance imaging to guide RT (MRgRT), such as ViewRay’s MRIdian and Elekta’s Unity systems, or CT guided systems such as Varian’s Halcyon, facilitating daily localization and adaptation of RT volumes to account for changes and motion during treatment. IGRT improves daily patient and tumor localization, allowing the radiation oncologist to decrease the size of the SM when creating a PTV. In consequence, the irradiated PTV size can be significantly reduced without sacrificing local tumor control; this also minimizes normal tissue toxicity by reducing the surrounding irradiated OAR volume (Int J Radiat Oncol Biol Phys 2012;84:125). In addition, combining IGRT and IMRT further reduces complications compared with more conventional, non-IGRT, 3D treatment techniques (Radiat Oncol 2014;9:44). IGRT also permits treatment gating, where the RT beam can be automatically turned off if the target moves outside of a prespecified tolerance window; precision can be achieved to less than 1 mm for intrafraction motion in prostate cancer (Int J Radiat Oncol Biol Phys 2016;94:1015). Gating may potentially further reduce PTV

volume(s), and is being assessed in prospective trials using online adaptive MRgRT. Continued improvements in the geometric accuracy of RT delivery, and development of advanced treatment techniques allowing for excellent coverage of irregularly shaped targets with surrounding steep dose gradients, have facilitated development of effective treatment strategies to safely deliver large RT doses to targets in close proximity to sensitive structures or previously irradiated fields. An excellent example is the ever-expanding use of hypofractionated SBRT in definitive and palliative RT for many different cancers. SBRT was initially developed to treat intracranial lesions with large single doses of radiation, known as SRS. The SRS system with the longest clinical experience involves the use of a frame rigidly attached to the patient’s head using surgical screws that define a 3D coordinate system. Lesion location is defined within this coordinate system with the frame in place using different diagnostic imaging tools such as CT or MRI. The patient is aligned on the treatment machine according to the lesion location as defined by the coordinate system relative to the rigid frame rather than to labile anatomic surrogates. Using MRI-based localization techniques, rigid stereotactic frame immobilization permits delivered RT to be accurate within 1 to 2 mm (Neurosurgery 2001;48:1092). SRS accuracy allows for the safe delivery of large doses of RT near critical structures such as the optic chiasm and optic nerves. SRS is used mainly for the treatment of brain metastases, but also for pituitary adenomas/carcinomas, meningiomas, and benign intracranial pathologies, such as arteriovenous malformations and trigeminal neuralgia. Examples of SRS delivery systems include linear accelerator–based cone or micro MLC systems, as well as the 60Co Gamma Knife radiosurgery system. Modern immobilization devices, such as the thermoplastic S-frame mask and the semirigid vacuum body fixation system, achieve geographic accuracies similar to SRS rigid frames, both for intra- and extracranial targets (Int J Radiat Oncol Biol Phys 2012;84:520). Patient positioning is further refined by addition of IGRT, which facilitates inter- and intrafraction localization of targets and daily OAR movement. Failing to account for this movement could result in a geographic miss during high-dose RT, and unexpected toxic irradiation of an adjacent sensitive structure. SBRT, also known as stereotactic ablative radiotherapy (SABR), applies SRS techniques to tumors or tumor surrogates in the body, but aligns the RT machines to the tumor or tumor surrogate using image guidance. Spine SBRT is an excellent example of a growing treatment modality using the aforementioned technologic advancements to deliver very high doses of RT to lesions only a few millimeters from the spinal cord—a relatively radiosensitive structure organized serially with low α/β ratio, for which damage can cause myelitis/paralysis. Recent studies indicate excellent pain and local control rates for spine SBRT for unresected bone metastases

greater than 80% at 1 year, with risk of vertebral body fracture related to the total fraction number (Adv Radiat Oncol 2018;3:245). Spine SBRT is also used for metastatic disease in the postsurgical setting, with local control rates appearing to be superior to that for conventional radiation, pending prospective evaluation (Int J Radiat Oncol Biol Phys 2016;95:1414). Evolving experience with using SABR for oligometastatic patients demonstrates increased overall survival for patients with limited metastatic disease (1-5 lesions) compared to standard of care palliative RT (Lancet 2019;393:2051–2058). It is imperative to understand that safe and effective SBRT/SABR delivery is a highly sophisticated and complex treatment technique requiring advanced technology merged with a coordinated effort from a team of radiation therapists, dosimetrists, physicists, and radiation oncologists. Such situations merging the necessary technology and qualified personnel may not be immediately available in all community settings. VII. COMBINATION OF THERAPEUTIC MODALITIES A. Irradiation and surgery. The rationale for preoperative RT relates to the ability of radiation to (1) eradicate subclinical or microscopic disease beyond the margins of standard surgical resection, (2) diminish tumor implantation by decreasing the number of viable cells within the operative field, (3) sterilize lymph node metastases outside the operative field, (4) decrease the potential for clonogenic tumor cells to seed distant metastases, and (5) to facilitate resection of borderline resectable lesions (e.g., pancreatic cancer). The main disadvantage of preoperative RT is that it may interfere with postoperative wound healing. This interference, however, is minimized when RT doses are less than 4 to 50 Gy over 5 weeks. The rationale for postoperative radiotherapy (PORT) is that RT can sterilize the postoperative surgical field of residual microscopic tumor cells, including lymph node metastases, through delivering lower RT compared to preoperative RT. The potential disadvantages of PORT are related to delaying RT until wound healing is completed. Theoretic and experimental evidence suggests that RT efficacy may be impaired by hypoxia in the surgical field caused by vascular disruption. B. Irradiation and systemic therapy. Chemotherapy and RT combine to obtain an additive or supra-additive effect. Enhancement describes any increase in effect greater than that for either therapy alone on the tumor or on normal tissues. Calculation of additivity, supra-additivity, or subadditivity is simple when in vitro dose–response curves are linear. When chemotherapeutic agents are used, the agents should not be cross-resistant, and each agent should be quantitatively equivalent to the other. Chemotherapy, alone or combined with RT, may be used in several settings. Primary chemotherapy is used as part of the primary lesion treatment

(even if later followed by other local therapy), and when primary tumor response is the key identifier of systemic effects. Adjuvant chemotherapy is used as an adjunct to other local modalities as part of the initial curative treatment. The term neoadjuvant chemotherapy describes chemotherapy as the initial treatment of patients with localized tumors, before surgery or RT. Administration of chemotherapy before RT produces some cell killing and reduces the number of cell clones to be killed by RT, such as for small cell lung cancer. Concurrent chemotherapy describes chemotherapy administered during RT, and has a strong rationale because it could augment RT efficacy, and could also affect subclinical disease early in treatment, with combination therapy possibly increasing normal tissue toxicity. Concurrent CRT is standard of care for locally advanced esophageal and lung cancer, gliomas, cervical cancer, and head and neck cancers. C. RT and immunotherapy. The emerging fourth pillar of cancer therapy, immunotherapy, involves treatment with agents that facilitate immune-mediated destruction of tumor cells. Currently, the most widely employed strategy for immunotherapy is the utilization of mAbs that either directly or indirectly inhibit signaling of the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 expressed on cytotoxic effector T cells, otherwise referred to as immune checkpoint blockade (ICB). Other strategies to enhance antitumor immune responses include systemic administration of cytokines such as interleukin (IL)-2, or chimeric antigen receptor (CAR)-modified autologous T cells; these strategies remain to be tested with concurrent RT. Several U.S. Food and Drug Administration (FDA)approved ICB agents are standard of care for first-line treatment of cancers in the metastatic setting including melanoma, breast, bladder, renal cell, and NSCLC. There is extensive preclinical data supporting the immunogenic effects of RT through activation of innate and adaptive immune mechanisms, and synergy with ICB. Maintenance ICB with durvalumab following definitive CRT is standard of care for NSCLC, and improves overall survival with no significant increase in adverse events or decrement in patient-reported quality of life (NEJM 2017;377:1919; NEJM 2018;379:2342). Immunotherapy is hypothesized to be augmented by RT-induced cell death, and indirect clinical evidence for this comes from patients with NSCLC who had a prior history of RT demonstrated improved progression-free survival after receiving ICB (Lancet Oncol 2017;18:895). In extraordinary circumstances, RT elicits regression of lesions outside of the treatment field in a process referred to as the abscopal effect (Br J Radiol 1953;26:234). There is much interest in determining how to increase the probability of abscopal responses using RT combined with immunotherapy to improve local control and reduce distant failures after definitive local tumor therapy (Nat Rev Cancer 2018;18:313). Experience regarding concurrent immunotherapy and RT continues to

accumulate, with retrospective evidence indicating the safety of combinatorial strategies, and data from prospective trials pending. D. Integrated multimodality cancer management. Combination therapy with the three classic modalities, or, more recently, immunotherapy and/or targeted molecular therapy using agents that inhibit driver mutations in genes like EGFR in NSCLC. Large primary tumors and lymph node metastases must be removed surgically or treated with definitive local therapy with RT. Regional microextensions are eliminated effectively by RT without the anatomic, and at times physiologic, deficit produced by equivalent surgical resection. Chemotherapy and targeted therapies are applied mainly to control disseminated subclinical disease, although they also have an effect on some larger tumors, and may elicit immunogenic cell death (Cancer Cell 2015;28:690). Organ preservation, as exemplified by equivalent outcomes for RT combined with local tumor excision compared to radical surgery, as in extremity soft-tissue sarcoma, early-stage breast cancer, and bladder preservation for muscleinvasive bladder cancer, is vigorously promoted to improve patient well-being, with equivalent local tumor control and overall survival. VIII.FOLLOW-UP Patients are evaluated once weekly while receiving RT to assess the physical and psychological responses to treatment. These on-treatment visits (OTVs) are essential to identify and act upon early complications of treatment through a combination of behavioral therapy, skin care, oral agents for pain control, rehydration, assessment for hemodynamic stability, and triaging for medical conditions requiring urgent assessment and intervention. Weekly OTVs are crucial to identify conditions that may be life threatening, negatively impact a patient’s quality of life, or impair the ability to complete RT as scheduled. IX. QUALITY ASSURANCE A comprehensive quality assurance program is critical in any radiation oncology center to ensure the best possible treatment and to establish and document all operating policies procedures. Quality assurance procedures in radiation therapy will vary, depending on whether a standard treatment or clinical trial is carried out at single or multiple institutions. Particularly in multi-institutional studies, clear instructions and standardized parameters are needed in dosimetry procedures, treatment techniques, and treatment planning to be carried out by all participants. Many reports of the National Cancer Institute’s Patterns of Care Study demonstrate a definite correlation between the quality of the radiation therapy delivered at various types of institutions and the outcome of therapy. The director of the department appoints the Quality Assurance Committee, which

meets regularly to review the following: results of review and audit process, physics quality assurance program report, outcome studies, mortality and morbidity conference, any case of “misadministration” or error in delivery of more than 10% of the intended dose, and any chart in which an incident report is filed. Quality Assurance programs are essential to determine if standard of care RT is being appropriately administered, as well as to help identify clinical situations where additional research is required to improve patient outcomes. Additional details can be obtained from the American College of Radiology. SUGGESTED READINGS Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:2342–2350. Brodin NP, Kabarriti R, Garg MK, et al. Systematic review of normal tissue complication models relevant to standard fractionation radiation therapy of the head and neck region published after the QUANTEC reports. Int J Radiat Oncol Biol Phys 2018;100:391–407. Bruynzeel AME, Tetar SU, Oei SS, et al. A prospective single-arm phase 2 study of stereotactic magnetic resonance guided adaptive radiation therapy for prostate cancer: early toxicity results. Int J Radiat Oncol Biol Phys 2019;115:1086–1094. Chun SG, Hu C, Choy H, et al. Impact of intensity-modulated radiation therapy technique for locally advanced non-smallcell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial. J Clin Oncol 2017;35:56–62. Dörr W, Hendry JH. Consequential late effects in normal tissues. Radiother Oncol. 2001;61(3):223–231. 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;18:1116–1125. Fowler JR. Fractionation and therapeutic gain. In: Steel GG, Adams GE, Peckham MJ, eds. Biological Basis of Radiotherapy. Amsterdam, the Netherlands: Elsevier Science, 1983:181–194. Galluzzi L, Buqué A, Kepp O, et al. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 2015;28:690–714. Halperin EC, Wazer DE, Perez CA, et al. Perez and Brady’s Principles and Practice of Radiation Oncology. Philadelphia, PA: Wolters Kluwer, 2019. Hui R, Özgüroğlu M, Villegas A, et al. Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study. Lancet Oncol 2019;1670– 1680. ICRU 50. Prescribing, Recording, Reporting, Photon Beam Therapy. Washington, DC: International Commission on Radiation Units and Measurements, 1994. ICRU 62. Prescribing, Recording, Reporting, Photon Beam Therapy (Supplement to ICRU Report 50). Bethesda, MD: International Commission on Radiation Units and Measurements, 1999. Keall PJ, Ng JA, Juneja P, et al. Real-time 3D image guidance using a standard LINAC: measured motion, accuracy, and precision of the first prospective clinical trial of kilovoltage intrafraction monitoring-guided gating for prostate cancer radiation therapy. Int J Radiat Oncol Biol Phys 2016;94:1015–1021. Lacas B, Bourhis J, Overgaard J, et al. Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis. Lancet Oncol 2017;18:1221–1237. Li W, Sahgal A, Foote M, et al. Impact of immobilization on intrafraction motion for spine stereotactic body radiotherapy using cone beam computed tomography. Int J Radiat Oncol Biol Phys 2012;84:520–526. 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;36:1611–1618. Marks LB, Yorke ED, Jackson A, et al. Use of NTCP models in the clinic. Int J Radiat Oncol Biol Phys 2010;76:S10. Mehta N, Zavitsanos PJ, Moldovan K, et al. Local failure and vertebral body fracture risk using multifraction stereotactic body radiation therapy for spine metastases. Adv Radiat Oncol 2018;3:245–251.

Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combinedmodality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20:1167– 1174. Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol 1953;26(305):234–241. Ngwa W, Irabor OC, Schoenfeld JD, et al. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer 2018;18:313– 322. Nix MG, Rowbottom CG, Vivekanandan S, et al. Chemoradiotherapy of locally-advanced non-small cell lung cancer: analysis of radiation dose-response, chemotherapy and survival-limiting toxicity effects indicates a low α/β ratio. Radiother Oncol 2020;143:58–65. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet 2019;393:2051– 2058. Perez CA, Purdy JA, Harms W, et al. Design of a fully integrated three-dimensional computed tomography simulator and preliminary clinical evaluation. Int J Radiat Oncol Biol Phys 1994;30:887–897. Redmond KJ, Lo SS, Fisher C, et al. Postoperative stereotactic body radiation therapy (SBRT) for spine metastases: a critical review to guide practice. Int J Radiat Oncol Biol Phys 2016;95:1414–1428. 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. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303:1070–1076. 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. Weiss E, Hirnle P, Arnold-Bofinger H, et al. Therapeutic outcome and relation of acute and late side effects in the adjuvant radiotherapy of endometrial carcinoma stage I and II. Radiother Oncol. 1999;53(1):37–44. Yu C, Apuzzo ML, Zee CS, et al. A phantom study of the geometric accuracy of computed tomographic and magnetic resonance imaging stereotactic localization with the Leksell stereotactic system. Neurosurgery 2001;48:1092–1098. Zelefsky MJ, Kollmeier M, Cox B, et al. Improved clinical outcomes with high-dose image guided radiotherapy compared with non-IGRT for the treatment of clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2012;84:125–129.

I.

INTRODUCTION A. General. Antineoplastic agents have a narrow therapeutic index and, as such, small changes in dose may result in unacceptable toxicity. Pretreatment characteristics including age, performance status, concurrent medications, renal and hepatic function, interpatient pharmacokinetic and pharmacodynamic variability, cachexia, obesity, and other comorbidities impact the efficacy and toxicity profile of many agents administered. In addition, many antineoplastic agents are extensively metabolized by cytochrome P-450 enzymes, resulting in the potential for drug–drug interactions and subsequent alterations in antineoplastic drug concentrations. The sequence of drug administration may also alter the antitumor effect or impact the severity of toxicities observed. Lastly, calculation and manipulation of the actual dose to be administered is based on a variety of factors, including the patient’s height and weight, commercially available antineoplastic vial size, previous response, tolerability, and treatment intent. Therefore, many factors should be considered when determining a patient’s antineoplastic dose.

II. CALCULATION OF DOSE A. General. The dose of antineoplastic agents may be based on a flat dose (e.g., pembrolizumab), on body weight (e.g., bevacizumab), or, more commonly, a standardized reference body surface area (BSA) to provide consistent exposure of drug across various body types. Utilization of BSA is thought to be ideal because of the known relationship between body size and physiologic functions, including blood volume, cardiac output, glomerular filtration rate (GFR), and liver blood flow. The rationale for calculating the dose on the basis of BSA is to reduce interpatient variability of systemic antineoplastic exposure and to limit the toxicity exerted by the

drug. B. Formulas 1. Dubois and Dubois. This formula is the most widely utilized, originally derived in 1916 by making molds of nine nonobese individuals who varied in age, size, and shape. By trial and error, this formula was created using height and weight alone to approximate BSA. However, caution should be used when applying this formula to infants and young adults. BSA (m2) = W0.425 × H0.725 × 0.007184 W = weight (kg) H = height (cm) 2. Gehan and George. In 1970, the DuBois and DuBois formula was validated by Gehan and George by directly measuring the skin surface area of 401 individuals, including a large number of children. However, it was found that the BSA was overestimated by 15% in approximately 15% of the cases. In an effort to simplify the task of calculating the surface area, the authors provided tables and charts to estimate BSA from height and weight. 3. Mosteller. By modifying the equation proposed by Gehan and George, Mosteller et al. provided an equation that is easy to remember and calculate, with a slight loss of accuracy of only 2%. Although the initial validation was only based on evaluations of adolescent and adult subjects, a subsequent study utilizing infants and children found it to be equally applicable BSA (m2) = √H1 (cm) × Wt (kg) / 3,600 4. Calvert. Early studies of carboplatin noted that a patient’s pretreatment renal function impacts the severity of thrombocytopenia observed. Approximately 70% of the drug is excreted unchanged via the urine within 24 hours, and pharmacokinetics suggests that the toxicity and efficacy of carboplatin is dictated primarily by pretreatment GFR. On the basis of these observations, Calvert et al. validated a simplified formula utilizing a targeted area under the curve (AUC) for carboplatin dose calculation and accounting for GFR in an effort to minimize the toxicity. Standard practice uses a maximum GFR of 125 mL/minute. Dose (mg) = AUC (GFR + 25) C. Manipulation of doses. The dose of an antineoplastic agent administered to a patient depends not only on patient factors and mathematical calculations but also on the recommended maximum dose or the treating physician’s practice of rounding or capping of the dose. It is not uncommon for a dose to be rounded if it is within 5% to 10% of the nearest commercially available vial size. The practice of rounding, in fact, is supported by a sizeable literature base and does confer a potential cost

D.

E.

F.

G.

savings to the health care system. Some antineoplastic medications have recommended maximum doses to limit toxicity. For example, doxorubicin has a maximum lifetime dose of 550 mg/m2, the carfilzomib dose should use a capped BSA of 2.2 m2, and in certain indications, mitomycin has a maximum flat dose of 14 to 20 mg. Overall, modification of the antineoplastic dose must be done cautiously to prevent a clinically significant change from the intended dose. Amputees. None of these equations included amputees in the patient sample leading to their validation. Furthermore, some of the formulas found a loss in accuracy in children and short and/or obese patients, thereby questioning the accuracy of applying these same equations to amputees. Although the formulas have not been validated, it is recommended to evaluate the data provided by Colangelo and colleagues, proposing two alternative equations for this patient population. Obesity. It was once believed that dosing obese patients on their actual body weight would result in increased toxicities secondary to the distribution of lipid-soluble drugs into adipose tissue. Therefore, ideal body weight, an adjusted body weight, or a capped BSA has historically been used to calculate the dose to be administered. Several reports have been published; however, assessing this practice and their results concluded that there was no increase in toxicity observed in obese patients with breast, colon, or small cell lung cancer who received antineoplastic doses based on actual body weight. Furthermore, manipulation of the dose downward in obese patients with breast cancer who received cyclophosphamide, doxorubicin, and 5fluorouracil negatively impacted overall survival in the cancer and leukemia group B study 8541 trial (J Clin Oncol 1996;14:3000). The American Society of Clinical Oncology released clinical practice guidelines on appropriate dosing for obese patients with cancer in 2012 (J Clin Oncol 2012;30:1553). The expert panel recommended that full weight–based antineoplastic doses be used to treat obese patients, particularly when the treatment goal is cure. Elderly. As a person ages, many physiologic changes that influence the effects of antineoplastic agents may take place. However, these changes do not take place at the same stage of life for each individual. There are no set guidelines addressing how to handle dose calculations in the elderly, but hypoalbuminemia, reduced hepatic and renal blood flow, cardiac dysfunction, and other comorbidities need to be considered when determining a treatment plan. In addition, this patient population is frequently taking medications that may interact with the efficacy and safety profile of any agent(s) administered. Hepatic dysfunction. Several antineoplastic agents undergo hepatic metabolism and any alteration in their clearance or the metabolic capacity of the liver may result in potential complications. Data are limited in this situation, and many take the simple approach of assessing liver function by evaluating the total bilirubin. Other

laboratory values such as the transaminases, serum alkaline phosphatase, and albumin may also impact systemic exposure and the ability of the liver to metabolize these medications. Therefore, all hepatic function tests may need to be taken into consideration before deciding the final dosage of an antineoplastic regimen. Although there is little data for combination regimens, there are some individual agents that are known to necessitate a dose adjustment based on hepatic function (see Appendix I). To further complicate the situation, one may find that the liver dysfunction is a result of the tumor and may need to determine whether dose alteration should be considered at all. Currently, there are no consensus recommendations for dosing antineoplastic drugs for tumor-related liver dysfunction. H. Renal dysfunction. Several antineoplastic agents are eliminated through the kidneys, and even minor alterations in renal function may impact their safety. Furthermore, the literature is limited to case reports and small case series with regard to end-stage renal disease and the dosing of antineoplastics in patients with cancer. The choice and dose of the agent need to be considered carefully, as well as the method and optimal timing of dialysis in patients with renal dysfunction to assure maximal drug exposure while minimizing toxicity (see Appendix I). SUGGESTED READINGS Arriagada R, Le Chevalier T, Pignon JP, et al. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 1993;329:1848–1852. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748–1756. Colangelo PM, Welch DW, Rich DS, et al. Two methods for estimating body surface area in adult amputees. Am J Hosp Pharm 1984;41:2650–2655. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:863–871. Eklund JW, Trifilio S, Mulcahy MF. Chemotherapy dosing in the setting of liver dysfunction. Oncology 2005;19:1057–1063. Eneman JD, Philips GK. Cancer management in patients with end-stage renal disease. Oncology 2005;19:1199–1212. Gehan EA, George SL. Estimation of human body surface area from height and weight. Cancer Chemother Rep 1970;54:225–235. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology Clinical Practice Guidelines. J Clin Oncol 2012;30:1553–1561. Meyerhardt JA, Catalano PJ, Haller DG, et al. Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 2003;98:484–495. Mosteller RD. More on simplified calculation of body surface area. N Engl J Med 1988;318:1130. Mosteller RD. Simplified calculation of body surface area. N Engl J Med 1987;317:1098. Rosner GL, Hargis JB, Hollis DR, et al. Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541. J Clin Oncol 1996;14:3000– 3008.

I.

BACKGROUND A. Traditional cytotoxic chemotherapy generally affects rapidly dividing normal and malignant cells. Advances in cancer biology, however, have led to the identification of numerous specific molecular targets for drug therapy. These molecular targets often play a key role in the signal transduction pathways that regulate tumor cell growth, proliferation, migration, angiogenesis, and apoptosis. Molecularly targeted therapy is a broad term encompassing several classes of agents, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs).

II. TYROSINE KINASE INHIBITORS A. Tyrosine kinases. Tyrosine kinases catalyze the transfer of gamma-phosphate from adenosine triphosphate (ATP) to tyrosine residues in protein targets. They play a key role in the transduction of signals within cellular signaling cascades that are ultimately responsible for the regulation of gene transcription within the nucleus. Tyrosine kinases are further classified into receptor and non–receptor tyrosine kinases. 1. Receptor tyrosine kinases. Receptor tyrosine kinases assist in the transmission of signals from extracellular ligands to the cell nucleus. They are composed of a ligand-binding extracellular domain, a lipophilic transmembrane domain, and an intracellular domain containing a catalytic site. Receptor tyrosine kinases are unphosphorylated, monomeric, and inactive without the presence of a ligand. Ligand binding to the extracellular domain induces dimerization of the

tyrosine kinase. This, in turn, leads to autophosphorylation of the intracellular domain, converting the tyrosine kinase to an active state. More specifically, when the intracellular domain undergoes autophosphorylation, binding sites for signaling proteins are formed. These signaling proteins are recruited to the membrane, and, subsequently, multiple downstream signaling cascades are activated. Signals are conveyed from the cell membrane to the nucleus, resulting in alterations in DNA synthesis and cell growth, proliferation, migration, angiogenesis, and apoptosis. Examples of receptor tyrosine kinases include epidermal growth factor receptor (EGFR)—ErbB/human epidermal growth factor receptor (HER)—family members, vascular endothelial growth factor receptors (VEGFRs), and platelet-derived growth factor receptors (PDGFRs) alpha and beta. 2. Non–receptor tyrosine kinases. Non–receptor tyrosine kinases play a role in the conveyance of intracellular signals. They lack the transmembrane domain and are primarily located intracellularly. More specifically, they are found on the inner surface of the plasma membrane, cytosol, and nucleus. Inhibitory proteins and lipids and intramolecular autoinhibitory mechanisms maintain the non–receptor tyrosine kinases in an inactive state. Activation may occur by intracellular signals causing dissociation of the inhibitory proteins and lipids, by other kinases causing phosphorylation, or by the recruitment of the tyrosine kinase to transmembrane receptors causing subsequent oligomerization and autophosphorylation of the tyrosine kinase. Similar to receptor tyrosine kinases, the non–receptor tyrosine kinases activate multiple signaling pathways. Examples of non–receptor tyrosine kinases include BCR-ABL, c-KIT, and c-Src. B. Functional alterations of tyrosine kinases in cancer. Within tumor cells, there is a loss of tyrosine kinase regulation. The dysregulation of tyrosine kinases within cancer cells may occur through numerous mechanisms. Proteins may be fused to tyrosine kinases, resulting in constant oligomerization, autophosphorylation, and activation. This typically occurs as the result of chromosomal translocations, with one of the most common examples being the formation of the BCR-ABL oncogene as a result of t(9;22) in chronic myeloid leukemia (CML). Other mechanisms described in the literature include mutations causing interruptions in the autoregulation of tyrosine kinases; abnormal expression of receptor tyrosine kinases, their associated ligands, or both; or a decrease in the processes that regulate tyrosine kinase activity, thereby causing an increase in tyrosine kinase activity. Through the action of TKIs, unregulated tyrosine kinases and, often, multiple signaling pathways are inactivated, leading to a decrease in tumor cell growth, proliferation, migration, angiogenesis, and/or apoptosis. III. MONOCLONAL ANTIBODIES

A. Background. mAbs are targeting agents that recognize cell surface proteins/receptors as antigens, particularly on the surface of tumor cells. There are three main classes of mAbs: unconjugated, conjugated, and radioimmunoconjugates. Unconjugated mAbs directly affect signaling pathways by inhibiting ligand–receptor interactions. These are mAbs against either the receptor or its ligand. They may also indirectly stimulate host defense mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) or complement-mediated lysis, causing antitumor activity. Examples of unconjugated mAbs include rituximab, daratumumab, obinutuzumab, trastuzumab, cetuximab, panitumumab, and bevacizumab. Conjugated mAbs, or antibody–drug conjugates (ADCs), are mAbs combined with protein toxins or cytotoxic agents. Examples of conjugated mAbs include brentuximab vedotin, inotuzumab ozogamicin, gemtuzumab ozogamicin, polatuzumab vedotin, and adotrastuzumab emtansine. Radioimmunoconjugates are mAbs in combination with radioisotopes intended to deliver radiation to the tumor, such as ibritumomab tiuxetan. Antibodies, or immunoglobulins (Igs), are Y-shaped molecules containing four chains (two identical light chains and two identical heavy chains). There is a fragment antigen binding (Fab) and a fragment crystalline (Fc) portion of the antibody. The Fab portion contains variable regions, including complementaritydetermining regions (CDRs), that enable the antibody to bind to a specific antigen. The Fc portion contains constant regions that are identical in all Igs of the same isotype (i.e., IgA, IgG, and IgM) and function as binding sites for leukocytes and complement. mAbs may be manufactured from multiple sources of B lymphocytes (i.e., murine, human, and primate). Murine mAbs are derived entirely from mice. Chimeric mAbs are composed of a murine variable region of the antibody with a constant region derived from humans, making approximately 65% to 90% of the agent of human origin. Humanized mAbs consist of variable and constant regions derived from humans with CDRs derived from mice, making approximately 95% of the agent of human origin. Primatized mAbs contain variable regions from monkeys and constant regions from humans. Human mAbs are derived entirely from humans. mAbs are often manufactured by genetic manipulation to produce a humanized agent. Humanization of the agent decreases the immunogenicity of the mAb, thereby decreasing the production of human antimouse antibodies (HAMAs). HAMAs have the potential to inactivate and eliminate pure murine mAbs after repeated administration, decreasing the half-life of the agent. But HAMAs may also contribute to allergic reactions after the formation of the antibody–HAMA complexes. Pure murine mAbs also ineffectively stimulate host defense mechanisms, such as ADCC and complement-mediated lysis, because of differences between murine and human immune systems.

The United States Adopted Names (USAN) Council has developed guidelines for the nomenclature of mAbs for standardization purposes and to enable identification of the mAb composition for patient safety intent because of the potential for the development of source-specific antibodies. In general, the product source identifiers precede the suffix -mab. Also incorporated into the product name is a code syllable for the target disease state of the agent. In addition, the U.S. Food and Drug Administration (FDA) guidance in 2017 outlined requirements for an FDAdesignated suffix for each originator biologic product, related biologic product, and biosimilar product. This suffix must be “devoid of meaning and composed of four lowercase letters” Examples of this nomenclature include polatuzumab vedotin-piiq, cemiplimab-rwlc, and trastuzumab-anns. Refer to Tables 5-1 and 5-2 for a list of product source identifiers and code syllables for the target disease states. Specific guidelines also exist for the nomenclature of radiolabeled and other conjugated mAbs. TABLE 5-1

Product Source Identifiers

Source

Identifier

Human

-u-

Mouse

-o-

Rat

-a-

Humanized

-zu-

Hamster

-e-

Primate

-i-

Chimera

-xi-

TABLE 5-2

Code Syllables for the Targeted Disease State of the Agent Disease

Tumor

Viral

-vir-

Colon

-col-

Bacterial

-bac-

Melanoma

-mel-

Immune

-lim-

Mammary

-mar-

Infectious Lesions

-les-

Testis

-got-

Cardiovascular

-cir-

Ovary

-gov-

Prostate

-pr(o)-

Miscellaneous

-tum-

Disclosures: Information for adult population only (pediatric information is not included). Drugs in each section are listed in alphabetical order. IV. MOLECULAR TARGETS IN ONCOLOGY BCR-ABL tyrosine kinase inhibition. The BCR-ABL tyrosine kinase is formed by the fusion of the BCR gene on chromosome 22 and the c-ABL tyrosine kinase gene on chromosome 9. This fusion protein forms as a result of the chromosomal t(9;22), or the Philadelphia chromosome, which has been implicated in approximately 95% of adult patients with CML, 15% to 20% of adult patients with acute lymphocytic leukemia (ALL), and 5% of adult patients with acute myeloid leukemia (AML). Subsequently, there is constitutive activation of the tyrosine kinase, leading to the activation of several transduction pathways, resulting in dysregulated cell proliferation and an inhibition of apoptosis. Imatinib inhibits the BCR-ABL tyrosine kinase, but also has inhibitory effects on other tyrosine kinases including c-KIT and PDGFR alpha and beta. As a result of this non–BCR-ABL kinase inhibition, imatinib has shown efficacy in the treatment of other malignancies, including gastrointestinal stromal tumors (GISTs), which have mutations in c-KIT or PDGFR alpha. Dasatinib also has inhibitory effects on BCR-ABL as well as on several other tyrosine kinases. This agent displays approximately 325-fold more potency than imatinib does against ABL and has activity against imatinib-resistant BCRABL mutations. A. Bosutinib (Bosulif) 1. FDA-approved indications. Philadelphia chromosome–positive CML (newly diagnosed in chronic phase or chronic, accelerated, or blast phase with resistance or intolerance to previous therapy) 2. Pharmacology. TKI a. Mechanism. Inhibits BCR-ABL tyrosine kinase, which blocks proliferation and causes apoptosis in BCR-ABL–positive cell lines; inhibits SRC family (including SRC, LYN, and HCK); has activity in many imatinib-resistant BCR-ABL mutations (exceptions T315I and V299L) b. Metabolism. Hepatic metabolism through CYP3A4 to primarily inactive metabolites. Eliminated primarily in the feces (91%), with minimal urinary excretion (3%) 3. Toxicity a. Common. Edema, fever, fatigue, headache, rash, diarrhea, nausea, vomiting, abdominal pain, decreased appetite, thrombocytopenia, anemia, increased transaminases, and cough 4. Administration a. FDA-approved dose. Newly diagnosed chronic-phase CML dose is 400 mg orally once daily. Chronic, accelerated, or blast-phase CML with resistance or

intolerance to prior therapy is 500 mg orally once daily. May be increased to 600 mg once daily if complete response not achieved B. Dasatinib (Sprycel) 1. FDA-approved indications. Philadelphia chromosome–positive CML in chronic, accelerated, or blast phase in patients resistant or intolerant to prior therapy including imatinib; Philadelphia chromosome–positive CML in patients newly diagnosed in chronic phase; Philadelphia chromosome–positive ALL with resistance or intolerance to prior therapy 2. Pharmacology. TKI a. Mechanism. Multitargeted TKI affecting BCR-ABL, the SRC family, c-KIT, EPHA2, and PDGFR beta kinases; binds to both active and inactive ABL kinase domains b. Metabolism. Extensive hepatic metabolism through CYP3A4. Primarily fecal elimination; 0.1% and 19% of the dose eliminated unchanged in the urine and feces, respectively 3. Toxicity a. Common. Myelosuppression, fluid retention/edema, nausea, diarrhea, headache, hemorrhage, fatigue, rash, musculoskeletal pain, and dyspnea 4. Administration a. FDA-approved dose. Chronic-phase CML: 100 mg orally once daily with optional dose escalation to 140 mg once daily. Accelerated or blast phase CML: 140 mg orally once daily. Philadelphia chromosome–positive ALL: 140 mg orally once daily C. Imatinib (Gleevec) 1. FDA-approved indications. Philadelphia chromosome–positive CML (newly diagnosed in chronic phase or in chronic, accelerated, or blast phase after failure of interferon alpha), relapsed or refractory Philadelphia chromosome–positive ALL; KIT (CD117)–positive unresectable and/or metastatic malignant GIST, adjuvant treatment following resection of KIT (CD117)–positive GIST, myelodysplastic syndrome/myeloproliferative disease (MDS/MPD) associated with PDGFR gene rearrangements, aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation or with c-KIT mutational status unknown, hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL), and dermatofibrosarcoma protuberans (DFSP) 2. Pharmacology. TKI a. Mechanism. Inhibits BCR-ABL tyrosine kinase, which blocks proliferation and causes apoptosis in BCR-ABL–positive cell lines; inhibits stem cell factor (SCF; c-KIT) receptor tyrosine kinases, which inhibit proliferation and

cause apoptosis in GIST cells that express c-KIT mutations; inhibits PDGFR alpha and beta tyrosine kinases b. Metabolism. Hepatic metabolism through CYP3A4 to active metabolite (Ndemethylated piperazine derivative). Eliminated primarily in the feces (68%), with some urinary excretion (13%) as metabolite and unchanged drug 3. Toxicity a. Common. Nausea, vomiting, diarrhea, rash, fluid retention/edema, fatigue, muscle cramps, musculoskeletal pain, and abdominal pain 4. Administration a. FDA-approved dose. Chronic-phase CML dose is 400 mg orally daily, may be increased to 600 mg daily. Accelerated phase or blast crisis dose is 600 mg once daily, may be increased to 800 mg daily (400 mg twice daily). Dosing for Philadelphia chromosome–positive ALL is 600 mg orally daily. Dosing for GIST is 400 to 800 mg daily. Dosing for ASM and HES/CEL is 100 to 400 mg daily. Dosing for DFSP is 800 mg daily (400 mg twice daily). MDS/MPD dose is 400 mg daily. D. Nilotinib (Tasigna) 1. FDA-approved indications. Newly diagnosed chronic-phase CML, CML in chronic or accelerated phase in patients resistant or intolerant to prior therapy including imatinib 2. Pharmacology. TKI a. Mechanism. Inhibits BCR-ABL tyrosine kinase, which blocks proliferation and causes apoptosis in BCR-ABL–positive cell lines; inhibits c-KIT and PDGFR b. Metabolism. Hepatic metabolism through CYP3A4 to inactive metabolites. Eliminated primarily in the feces (93%), with 69% being parent drug 3. Toxicity a. Common. Headache, fatigue, fever, night sweats, rash, pruritus, nausea, vomiting, diarrhea, constipation, neutropenia, thrombocytopenia, anemia, nasopharyngitis, arthralgia, and cough b. Black box warnings. QT prolongation and sudden deaths 4. Administration a. FDA-approved dose. Newly diagnosed chronic-phase CML: 300 mg orally twice daily. Chronic or accelerated phase in resistant or intolerant patients: 400 mg orally twice daily E. Ponatinib (Iclusig) 1. FDA-approved indications. CML or Philadelphia chromosome–positive ALL for whom no other TKI therapy is indicated or those who are T315I-positive

2. Pharmacology. TKI a. Mechanism. Pan-inhibitor of BCR-ABL tyrosine kinase including T315I, which blocks proliferation and causes apoptosis in BCR-ABL–positive cell lines; inhibits VEGFR, fibroblast growth factor receptor (FGFR), PDGFR, EPH, and SRC kinases and KIT, RET, TIE2, and Fms-like tyrosine kinase 3 (FLT3) b. Metabolism. Hepatic metabolism through CYP3A4, -2C8, -2D6, and -3A5. Eliminated primarily in the feces (87%), with some urinary excretion (5%) 3. Toxicity a. Common. Hypertension, arterial occlusion, fatigue, headache, fever, extremity pain, rash, dry skin, lipase increased, abdominal pain, constipation, nausea, diarrhea, vomiting, arthralgia, and myalgia b. Black box warnings. Arterial occlusion; venous thromboembolism; heart failure; hepatotoxicity, liver failure, and death 4. Administration a. FDA-approved dose. 45 mg orally once daily Anaplastic lymphoma kinase (ALK) fusion targeting. ALK is a membrane-associated tyrosine kinase receptor of the insulin receptor superfamily. ALK was first identified as a fusion protein in anaplastic large cell lymphoma cell lines. ALK chromosomal rearrangements have been discovered in anaplastic large cell lymphoma (50% to 60%), inflammatory myofibroblastic tumors (27%), and non–small cell lung cancers (NSCLCs; 4% to 7%). In NSCLC, the EML4-ALK fusion oncogene is the most commonly reported ALK mutation. This inversion on chromosome 2 leads to a fusion of the kinase domain of ALK and EML4 echinoderm microtubule–associated protein-like 4 region, inv(2) (p21p23). The EML4-ALK fusion mediates ligand-independent dimerization of the kinase, leading to the continuous downstream signaling of the PI3K-AKT, STAT3, and Ras Raf-ERK pathways and causing cell survival and proliferation. ALK inhibitors have a classical ATP-competitive mechanism of action with dose-dependent inhibition on the phosphorylation of ALK as well as c-MET, preventing cellular proliferation and inducing apoptosis. A. Alectinib (Alecensa) 1. FDA-approved indications. Advanced NSCLC with ALK-positive disease, as detected by an FDA-approved test 2. Pharmacology. TKI a. Mechanism. Potent inhibitor of ALK. The major metabolite, M4, shows activity against multiple mutant forms of the ALK enzyme, including mutations identified in patients who have progressed on crizotinib. b. Metabolism. Hepatic, primarily through CYP3A4, -M4 is also metabolized

by CYP3A4. Primarily excreted in feces (98%, 84% unchanged parent and 6% as M4), and 4 cm), T4a (moderately advanced), and T4b (very advanced). T can be further reclassified depending on involvement of specific structures or depth of invasion for oral cancer. N stage is subdivided into N0 (no regional lymph node involvement), N1 (single ipsilateral lymph node ≤3 cm), N2a (single ipsilateral lymph node >3 cm but ≤6 cm), N2b (multiple ipsilateral lymph nodes, none >6 cm), N2c (bilateral or contralateral lymph nodes, none >6 cm), and N3 (lymph node >6 cm). Nodal disease can be further categorized depending on absence or presence of clinical or pathologic

involvement of extracapsular spread. M stage is divided into M0 (no distant metastases) and M1 (distant metastases present). Given the diversity in the staging system, it is imperative to check guidelines for correct staging for each subsite. B. Management of early-stage cancers. Early-stage SCCHN is managed with either surgery or definitive radiation therapy. Both approaches have similar cure rates. Advantages of surgery include shorter treatment and recovery time and avoidance of radiation toxicity including mucositis, xerostomia, and dental caries. However, surgery can result in organ dysfunction including speech and/or swallowing problems, particularly with open techniques, and has limited applicability in patients with poor performance status and comorbidities. Radiation therapy is an alternative to a surgical procedure that would result in unacceptable cosmesis and/or organ function. However, radiation therapy is given over an extended interval, and resolution of acute toxicities often requires several months. Furthermore, chronic radiation toxicity (particularly xerostomia) is common, but can be somewhat mitigated with advanced techniques. Regional differences in the general approach to early-stage cancers exist, often hinging on advanced surgical or radiation expertise among members of the treatment team. The ultimate goal is a high cure rate with minimum morbidity. C. Management of locally advanced, nonmetastatic disease 1. Primary surgery. Surgery to remove all visible tumors may be used as the initial therapy for locally advanced cancers of the head and neck. Current approaches to surgery increasingly involve procedures such as transoral endoscopic CO2 laser or robotic resection and selective neck dissections. In contrast to open procedures and radical neck dissections, these more recent approaches to surgery lower the morbidity of the procedure and improve the likelihood of acceptable postoperative function. Following complete resection, adjuvant radiation-based therapy is usually recommended to most patients with locally advanced disease. In some patients, a biopsy of the primary tumor by the surgeon and fine-needle aspiration biopsy of suspicious regional nodes is performed for diagnosis, after which the patient is referred for definitive radiation-based therapy. Critical information regarding the delineation of tumor can be obtained with operativebased and sometimes with office endoscopy before proceeding with definitive nonsurgical therapies. 2. Adjuvant therapy. Following complete tumor resection, adjuvant therapy with postoperative radiation therapy (POART) or postoperative adjuvant radiation and concurrent chemotherapy (POACRT) is usually given to patients with locally advanced disease. Adjuvant therapy is recommended when there is involvement of one or more cervical lymph nodes, perineural involvement, lymphovascular invasion, and/or a positive surgical margin at the site of primary tumor resection.

The total radiation dose in the adjuvant setting is 60 to 66 Gy administered to the primary and involved lymph nodes, and 50 Gy to lower risk nodal stations in the neck. The duration of radiation therapy is 6 to 7 weeks, with treatment optimally starting 4 to 6 weeks postoperatively. The exact fractionation schema, portals, and use of boost-dose radiation are determined by site. POACRT is recommended for tumors with high-risk pathologic features: involved cervical lymph nodes with extranodal extension and/or positive surgical margins (N Engl J Med 2004;350:1937, N Engl J Med 2004;350:1945). Some also include the following as high-risk features: tumors with perineural and lymphovascular invasion, multiple positive cervical nodes, and/or large (T3 or T4) primary tumors. 3. Definitive chemoradiation. Concurrent chemotherapy and radiation therapy (CRT) is the standard of care for the nonsurgical management of locally advanced cancers of the head and neck in patients who are able to tolerate such therapy. The Meta-analysis of Chemotherapy in Head and Neck Cancer (MACHNC) meta-analysis of 93 randomized trials of 17,346 patients demonstrated a significant overall survival (OS) benefit with CRT compared with radiation therapy alone (Radiother Oncol 2009;92:4). The OS benefit is 6.5% at 5 years with CRT. However, the acute toxicity (particularly mucositis and renal dysfunction) of CRT is greater than that of radiation alone, which may partly explain why the OS benefit of CRT is greatest for patients younger than age 60 years and who have good performance status and few comorbidities. Several chemotherapy agents have been combined concurrently with radiation therapy; however, the most commonly used agent is cisplatin. The EGFR inhibitor cetuximab was also shown to improve OS when given concurrently with definitive radiation therapy. Cisplatin at 100 mg/m2 on days 1, 22, and 43 is widely recognized as the gold standard when given concurrently with radiation therapy in SCCHN; a lower weekly dose of cisplatin at 30 or 40 mg/m2 is also used. However, the lower dose intensity may result in poorer outcomes and local–regional control (J Clin Oncol 2018;36:1064). A randomized trial of cetuximab given concurrently with radiation therapy versus radiation alone for definitive treatment of locally advanced SCC of the oropharynx, larynx, and hypopharynx demonstrated an OS benefit with cetuximab. In the cetuximab arm of the trial, cetuximab (400 mg/m2) was given 1 week before initiation of radiation, followed by 250 mg/m2 weekly for the duration of the radiation (total of eight doses). Median OS increased from 29.3 months in the radiation-alone arm to 49 months in the cetuximab plus radiation arm (p = 0.006). Survival at 3 years favored the cetuximab and radiation arm

over the radiation-alone arm (55% vs. 45%, p = 0.05, respectively). The toxicities were similar between the two arms, with the exception of a greater risk of skin toxicities (acneiform rash and radiation dermatitis) and infusion reactions in the cetuximab arm. Surprisingly, the risk of mucositis with cetuximab and radiation was similar to that with radiation alone. An update of this trial confirmed that the OS benefit of cetuximab added to radiation persisted through 5 years of followup (Lancet Oncol 2010;11:21). Retrospective analysis confirmed that this benefit was seen in both HPV-related and HPV-unrelated disease. Thus, level I evidence supports the use of single-agent cisplatin or cetuximab in combination with radiation therapy. Retrospective analysis of Radiation Therapy Oncology Group (RTOG) trials found poorer disease control rates and OS when delivered doses of cisplatin were lower than the target doses were, supporting the importance of dose intensity. The benefit of adding 5-fluorouracil (5-FU) or taxanes to cisplatin with radiation is uncertain. 4. Salvage surgery following definitive chemoradiation. If a complete tumor response is not achieved following definitive CRT or if the cancer recurs locally or regionally after CRT, salvage surgical resection of the primary tumor site and/or the neck nodes may result in long-term survival in a fraction of patients. However, salvage surgery may be technically challenging following CRT, and the morbidity of the procedure may be significant. 5. Induction chemotherapy before definitive chemoradiation. Randomized trials of induction chemotherapy have shown mixed results. The MACH-NC metaanalysis of these trials found that a survival benefit was not consistently observed with induction chemotherapy except in the subset of patients given cisplatin and 5-FU (PF). The TAX 324 trial compared two different induction regimens consisting of PF or PF plus docetaxel (TPF) given before definitive CRT with weekly carboplatin (N Engl J Med 2007;357:1705). TPF (docetaxel 75 mg/m2 on day 1, cisplatin 100 mg/m2 on day 1, and 5-FU 1,000 mg/m2 continuous intravenous infusion (CIVI) daily on days 1 to 4 every 3 weeks) was compared with PF (cisplatin 100 mg/m2 on day 1 and 5-FU 1,000 mg/m2 CIVI daily on days 1 to 5 every 3 weeks) given for three cycles before definitive CRT. The median OS was significantly longer in the TPF arm compared with that in the PF arm (70.6 months vs. 30.1 months; p = 0.0058). The OS benefit of TPF over PF persisted at 6 years in an updated analysis (Lancet Oncol 2011;12:153). The TAX 323 trial was a randomized trial of similar design that compared TPF versus PF, except that all patients had unresectable disease and all were treated with definitive radiation therapy alone (N Engl J Med 2007;357:1695). This trial also showed an OS benefit in the TPF arm compared with that in the PF arm. The PARADIGM trial compared induction chemotherapy followed by

definitive CRT with CRT alone using TPF as the induction chemotherapy (Lancet Oncol 2013;14:257). There was no improvement in OS for induction chemotherapy, possibly related to the failure to accrue the target number of patients and unexpectedly high OS in both arms, perhaps due in part to the rising incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC), which carries a better prognosis. In another trial by the Spanish Head and Neck Cancer Cooperative Group (TTCC), induction chemotherapy failed to improve progression-free survival (PFS) or OS (Ann Oncol 2014;25:216). The DeCIDE trial randomized patients with heavy nodal burden (N2/N3 disease) to receive CRT alone (hydroxyurea, docetaxel, 5-FU given concurrently with radiation) versus TPF followed by CRT. Although this trial did demonstrate a nonstatistically significant decrease in the cumulative incidence of distant failures with induction TPF, there was no difference in OS (J Clin Oncol 2014;32:2735). Overall, data is lacking that induction chemotherapy improves outcomes compared to current standard-of-care definitive radiation combined with either high-dose bolus cisplatin or cetuximab. D. Management of locally and/or regionally recurrent disease. Patients with local or regional recurrence only should be evaluated for potential salvage surgery or radiation therapy. If salvage surgery is not possible, and radiation therapy has previously been administered, concurrent chemotherapy with repeat irradiation may be effective in some patients. However, tissue tolerance, the extent of earlier radiation, and significant toxicity limit routine recommendation for this approach. Patients who are not candidates for local therapies may be treated with palliative chemotherapy. E. Management of metastatic disease. Median OS of patients with metastatic SCCHN is approximately 10 to 12 months. Lung, bone, and liver are the most common sites of distant disease. HPV-related OPSCC may display unusual patterns of metastases, including delayed and multiorgan recurrences. Platinum-based chemotherapy has long been the standard front-line therapy for metastatic disease. In 2008, a randomized trial showed that the addition of cetuximab to platinum and 5-FU (the EXTREME regimen) significantly improved median OS (10.1 vs. 7.4 months, respectively) and PFS (5.6 vs. 3.3 months, respectively) (N Engl J Med 2008;359:1116). This trial was the first to demonstrate an OS benefit with a targeted agent in incurable SCCHN. However, the KEYNOTE-048 demonstrated an improvement with pembrolizumab, a programmed cell death 1 (PD-1) inhibitor– based therapy compared to the EXTREME regimen. For patients with tumors expressing programmed death ligand 1 (PDL-1), single-agent pembrolizumab demonstrated an improvement in OS (12.3 vs. 10.3 months). The combination of pembrolizumab, carboplatin, and 5-FU demonstrated an improvement in OS in the

total population, including in patients with no expression of PDL-1, with a median OS of 13 months versus 10.7 months for the EXTREME regimen (Lancet 2019;394:1915). Response rates for single-agent pembrolizumab were lower than it was the EXTREME regimen. However, for patients who did respond, the duration of response was markedly longer with pembrolizumab (23.4 months’ median duration of response compared to 4.5 months’ duration of response for EXTREME). For patients previously treated with a platinum-based therapy, both pembrolizumab and nivolumab (another PD-1 inhibitor) demonstrated improvement in OS compared to other single-agent treatments (docetaxel, cetuximab, methotrexate) with response rates of approximately 15%, with most of the benefit driven by patients with tumors expressing PDL-1. Several standard chemotherapeutic agents have activity against SCCHN and can provide palliation of symptoms. These include cisplatin, carboplatin, 5-FU, paclitaxel, docetaxel, methotrexate, pemetrexed, ifosfamide, and gemcitabine. The Eastern Cooperative Oncology Group (ECOG) 1395 study showed similar response rates, OS, and toxicity for the combinations of cisplatin and 5-FU or paclitaxel (J Clin Oncol 2005;23:3562). Furthermore, the ECOG 1393 showed no differences between high-dose (175 mg/m2) and low-dose (135 mg/m2) paclitaxel when combined with cisplatin (J Clin Oncol 2001;19:1088). In patients with platinumrefractory SCCHN, the tumor response rate of alternative standard chemotherapy is low. In platinum-refractory SCCHN, single-agent cetuximab resulted in a tumor response rate of 13% and a disease control rate of 46% (J Clin Oncol 2007;25:2171). However, median time to progression (TTP) and OS were only 70 and 178 days, respectively. F. Complications of disease 1. Aspiration with risk of pneumonia should be considered in the patient with fever or cough. Weight loss or risk of aspiration may require placement of feeding gastrostomy tubes. Some patients will minimize aspiration with certain postures (chin tuck maneuver) or dietary modification, and consultation with a speech pathologist is often helpful in rehabilitation. Shortness of breath should prompt evaluation of the airway and the potential need for tracheostomy. 2. Fungating tumors may ulcerate, bleed, and cause airway obstruction. Invasion of the carotid artery by tumor may be a terminal event and may be heralded by an episode of sentinel bleeding. 3. Pain control. Inability to swallow may limit narcotic analgesic choices. Transdermal fentanyl patches allow longer pain relief, with concentrated opiate elixirs for breakthrough pain. Opiate doses should be titrated to achieve pain control. Tumors invading nerves at the skull base may produce neuropathic pain

syndromes that are helped by coanalgesics such as amitriptyline or gabapentin. 4. Paraneoplastic syndromes may include hypercalcemia because of tumor secretion of parathyroid hormone–related protein (PTHrP) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH). G. Complications of treatment 1. Complications of surgery may affect cosmesis, speech, airway patency, and ability to swallow. Reconstructive flap techniques and prosthetics may minimize these problems. Neck dissection may result in shoulder weakness if resection or injury of the 11th cranial nerve occurs. After total laryngectomy, a tracheoesophageal puncture (TEP) may allow speech by diverting expired air into the esophagus to vibrate the remaining pharyngeal tissue or flap. An electrolarynx, a handheld device that serves as a vibratory source for phonation, may also be used to allow communication following laryngectomy. 2. Acute radiation toxicity may include severe painful mucositis, loss of taste sensation, and inability to swallow. Oral candidiasis complicating mucositis may be treated with topical agents (nystatin or clotrimazole) or systemic agents (fluconazole). A cocktail of equal volumes of diphenhydramine suspension, nystatin, viscous lidocaine, and aluminum hydroxide/magnesium hydroxide suspension may be used as a topical oral swish solution for mucositis. Some patients may prefer a solution of one teaspoon of baking soda and half a teaspoon of salt in a quart of water for milder mucositis. Opiates are indicated for more severe pain. Skin toxicity in the radiation port should be treated with emollients such as Aquaphor, Biafine, Silvadene and wound dressings, as appropriate. 3. Late radiation effects include xerostomia, which may be addressed by frequent oral hydration, pilocarpine, or cevimeline. Artificial saliva is available, but poorly accepted by most patients. Dental caries is a chronic toxicity that may lead to tooth loss. Good dental hygiene and use of fluoride preparations may minimize this complication. Osteoradionecrosis may be treated conservatively with the PENTOCLO protocol, a two-phase protocol combining Augmentin, ciprofloxacin, prednisone, nystatin, and omeprazole. After 4 to 6 weeks of this therapy, the patient will go on to receive pentoxifylline, vitamin E, and clodronate. Fibrosis of the neck tissues may result in trismus, lymphedema, and loss of range of motion. Exercises, deep tissue massage, and manual lymphatic drainage may be helpful to reduce these side effects. Patients may also benefit from a pneumonic pump to address both internal and external lymphedema. Impaired swallowing because of weakness of pharyngeal constrictor muscles and aspiration may occur. Patients should work closely with speech and language pathologists to maximize techniques to reduce risk of aspiration. Severe laryngeal edema, although rare, may require tracheostomy for management and should

prompt consideration of possible disease recurrence. 4. Chemotherapy toxicities vary according to the agents used. Chemotherapy given with radiation may increase the severity of mucositis. Cisplatin may cause nausea/vomiting, nephrotoxicity, peripheral neuropathy, ototoxicity, and myelosuppression. 5-FU may cause myelosuppression and mucositis. Taxanes may result in alopecia, myelosuppression, myalgias, and allergic reactions. Cetuximab is associated with acneiform rash, dry skin or skin fissuring, paronychial inflammation, and hypersensitivity infusion reactions. Minocycline may be helpful in managing the rash. PD-1 inhibitors are associated with a wide range of immune mediated toxicities. IV. LIP AND ORAL CAVITY A. Anatomy. Cancer of the lip and oral cavity is the most common site of malignancy in the head and neck, representing 30% of total cancers. Sites contained within this group are cancers originating from the lip, floor of mouth, anterior two-thirds of the tongue, buccal mucosa, gingiva, hard palate, and retromolar trigone. B. Presentation. Although this region is easily accessible, patients often present after a prolonged interval of symptoms and with advanced disease. Patients may present with symptoms such as nonhealing oral lesions, pain in the mouth or ear, trismus, and weight loss. A pertinent history should include assessment of tobacco use including chewing tobacco and alcohol consumption. Dental problems and a history of chronic mucosal irritation should also be noted. Determination of oral functional status (biting, chewing, swallowing, and speech) is essential. On physical examination, complete evaluation of the nares, oral cavity, oropharynx, hypopharynx, and larynx should be performed by clinical examination and fiberoptic endoscopy or mirror examination. Evaluation for trismus and tongue movement is also important. Fixation of the tongue (ankyloglossia) and trismus suggest an advanced lesion. Palpation with a gloved finger should be used to inspect the lips, buccal mucosa, oral tongue, retromolar trigone, and floor of mouth. The state of the patient’s dentition should also be noted. Cranial nerve evaluation should also be performed. The neck should be evaluated for lymphadenopathy. Level 1 neck nodes are located in the submandibular–submental region, level 2 nodes along the proximal third of the sternocleidomastoid muscle at the angle of the mandible, level 3 nodes along the middle third of the sternocleidomastoid muscle, level 4 nodes along the distal third of the sternocleidomastoid muscle, and level 5 nodes in the posterior triangle. Cancers of the lip and oral cavity tend to metastasize to level 1 and level 2 nodes first. C. Staging. In addition to the history and physical examination, the staging evaluation should include an examination under anesthesia (EUA) and radiographic imaging.

Computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck is necessary to obtain a better anatomic understanding of the extent of the cancer. A CT scan shows details of bone involvement, whereas an MRI gives a better view of soft-tissue involvement. Often, these techniques are complementary. A panorex may also be helpful in examining for mandibular bony involvement. CT scan of the chest should be performed to rule out pulmonary metastasis. Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT is widely used in staging of patients with advanced disease and may aid in developing radiation ports. D. Pathology. SCC is the leading histology of lip and oral cancers. Adverse pathologic features include depth of invasion, infiltrative borders, poorly differentiated tumors, and perineural and lymphovascular invasion. Sarcomatoid, spindle cell, and basaloid features may also portend a worse prognosis. Less common histologies include adenoid cystic carcinoma and mucoepidermoid cancer of the minor salivary glands. These are discussed in more detail later in this chapter. E. Natural history of disease. SCC of the lip and oral cavity presents most commonly as local or local–regional disease with relatively late spread to distant sites. 1. Field cancerization is an important concept in the natural history of head and neck cancer, especially with oral cavity tumors. Because the exposure of the mucosa to carcinogens in tobacco is diffuse across the aerodigestive tract, invasive cancer may be surrounded by areas of dysplasia or carcinoma in situ. Patients with head and neck cancer are at an increased risk of developing second primary cancers in the head and neck, lung, and esophagus. The risk is approximately 3% to 4% per year and generally tapers at a lifelong risk of 20% to 25% in survivors of the first treated head and neck SCC. 2. Leukoplakia and erythroleukoplakia are premalignant lesions of the oral mucosa, related to the epithelial injury because of tobacco and ethanol. Leukoplakia is a white patch of mucosa that cannot be scraped off. Erythroleukoplakia may appear red and velvety and more commonly demonstrates dysplasia or carcinoma in situ on biopsy. The risk of malignant transformation increases with duration of these lesions and is higher with erythroleukoplakia compared with leukoplakia. Treatment may include close observation or surgical resection, particularly if high-grade dysplasia is present. Early studies of retinoids such as isotretinoin (13 cis-retinoic acid) showed promising results in the treatment of leukoplakia. Isotretinoin (1.5 mg/kg/day by mouth for 3 months followed by 0.5 mg/kg/day) produced a response rate of 55%, with most patients maintaining their response over the course of 1 year. However, a large randomized trial failed to show a reduction in the risk of second cancers or recurrence of the primary cancer with

isotretinoin in patients who had been treated with definitive radiation therapy for stages I and II SCCHN (J Natl Cancer Inst 2006;98:441). This trial did show that smoking cessation after radiation treatment of the SCCHN was associated with a significantly lower risk of second cancers and improved OS compared with continued smoking. F. Treatment of lip and oral cavity SCC 1. Early stage. Most patients are treated by surgery alone. Neck dissections are performed in patients with thick (>3 to 5 mm) or larger tumors. Radiation is an alternative to surgery in patients who decline surgery or are not surgical candidates. 2. Locally advanced. Most patients are treated by surgery followed by adjuvant therapy based on pathologic features. CRT is an alternative to surgery in patients who decline surgery or are not surgical candidates. V. OROPHARYNX A. Anatomy. Cancer of the oropharynx includes sites in the soft palate, palatine tonsils, posterior and lateral oropharyngeal walls, and the base of tongue. Its borders include the junction of the hard and soft palate, the tonsillar arch, and the circumvallate papillae on the tongue. B. Presentation. Many of the features described earlier for cancers of the oral cavity also apply to cancers of the oropharynx. The vast majority of these cancers (>70%) are associated with chronic human papillomavirus (HPV) infection, with high-risk HPV-16 being the most common serotype in OPSCC. 1. Pertinent history should include an assessment of tobacco and alcohol use and comorbid disease. Odynophagia, dysphagia, neck mass, otalgia, trismus, and weight loss should also be noted. HPV is considered to be a sexually transmitted virus, and a thorough sexual history should be obtained in HPV-associated tumors. 2. The physical examination includes an assessment of performance status and a complete evaluation of the nares, oral cavity, oropharynx, hypopharynx and larynx, cervical lymph nodes, and cranial nerves. An evaluation for trismus, status of dentition, and tongue movement and atrophy should be performed, along with palpation of the tongue, tonsils, and soft palate. Lymph nodes in the neck should be examined with measurement of palpable nodes, noting their size, level, and whether they are fixed to underlying tissue. OPSCC tends to metastasize to level 2 and level 3 lymph nodes. 3. HPV-related OPSCC often presents with small primary tumors and large necrotic neck lymph nodes. Typically, these patients are younger Caucasian males with little or no prior smoking history.

C. Staging. Along with history and physical examination, the staging evaluation of patients with oropharynx cancer includes diagnostic imaging, EUA with biopsy of the primary lesion, and evaluation for distant metastases and synchronous primaries. CT or MRI of the primary site and neck and CT of the chest can be performed, although FDG-PET/CT is often preferred for staging purposes. 1. HPV-positive OPSCC. Owing to the improved prognosis seen with HPV-related OPSCC, a revised TNM staging system for these cancers has been adopted: stage I (composed of T1/T2 and N0/N1 tumors), stage II (comprising T3 and N2 tumors), stage III (composed of T4 and N3 tumors), and stage IV (reserved for distant metastatic disease). 2. HPV-negative OPSCC. Similar to other SCCHNs, staging of HPV-negative OPSCC is defined by the size and extent of the primary tumor, extent of nodal disease, and presence or absence of distant metastases. Of note, T4 and N2/N3 tumors are still classified as stage IV disease. D. Pathology. SCC is the histology found in more than 90% of cancers in the oropharynx. Less common pathologies include lymphomas involving Waldeyer ring (palatine and lingual tonsils, and adenoids), mucosal melanomas, and minor salivary gland tumors, including adenocarcinomas, adenoid cystic carcinomas, and mucoepidermoid carcinomas. Distinction should be made between welldifferentiated and poorly differentiated SCCs. Adverse pathologic factors include depth of invasion, infiltrative borders, poorly differentiated tumors, and perineural and lymphovascular invasion. Sarcomatoid differentiation or basaloid features may also portend a worse prognosis. 1. All OPSCCs should be evaluated for HPV infection. HPV-associated OPSCC is typically nonkeratinizing, with strong expression of p16 (a surrogate marker) by immunohistochemistry. HPV DNA polymerase chain reaction (PCR) or in situ hybridization can be used as confirmatory tests, although these tests are not routinely done, and various studies have reported that 8% to 33% of p16-positive OPSCCs lack HPV DNA. E. Natural history of disease. OPSCC generally presents with locally advanced disease. HPV-associated OPSCC carries a much better prognosis than does HPVnegative OPSCC. Five-year survival for patients with HPV-positive disease is 75% to 85%, compared to under 50% for similarly staged HPV-negative patients. A significant portion of patients who present with level 2 or 3 neck masses and an SCC of unknown primary are found on EUA with an operating room microscopy and with directed biopsies to have HPV-related OPSCC. In smoking-related OPSCC, the effects of tobacco and alcohol on the mucosa cause a field cancerization effect, leading to an increased risk of second primary cancers. F. Treatment of OPSCC

1. HPV-positive disease. Utilizing the standard treatment approaches for HNSCC, the cure rate approaches 80% for these patients. De-escalation of treatment can reduce acute and chronic toxicities and improve quality of life. De-escalation, either by reducing the amount of chemotherapy or radiation treatments, remains investigational, and numerous de-escalation clinical trials are currently under way. Two randomized phase III trials (RTOG 1016 and the De-ESCALaTE trial) investigated cisplatin versus cetuximab given concurrently with definitive radiation for locally advanced HPV-related oropharyngeal cancers in patients with limited/no smoking history and each demonstrated an OS benefit for cisplatin over cetuximab. OS in the RTOG study demonstrated estimated 5-year OS of 84.6% with cisplatin compared to 77.9% in the cetuximab group; median follow-up in the De-ESCALaTE trial was shorter (median follow-up 25.9 months), but likewise demonstrated improved OS at 2 years for cisplatin over cetuximab (97.5% vs. 89.4%). Taken together, cisplatin should be considered the standard systemic agent given with radiation for HPV-related oropharyngeal carcinoma (Lancet 2019;393:40, Lancet 2019;393:51). 2. HPV negative, stages I and II. Patients may be treated with surgery that includes resection of the primary tumor and at-risk neck lymph nodes. Radiation provides clinical equipoise with surgery and is an alternative in patients who decline surgery or are not surgical candidates. 3. HPV negative, stages III and IV. Patients may be treated with surgery that includes resection of the primary tumor and grossly involved and at-risk neck lymph nodes. Adjuvant therapy (radiation or CRT) is offered depending on pathologic features. CRT, or induction chemotherapy followed by CRT, can be offered if surgery is not a feasible option. VI. LARYNX AND HYPOPHARYNX A. Anatomy. Cancers of the larynx and hypopharynx represent challenges in treatment because of their key involvement with speech and swallowing. As such, these sites have been associated with the most research on organ preservation (attempts to avoid total laryngectomy), while maintaining the best chance for cure. The boundaries of the hypopharynx are the level of the hyoid bone superiorly and the lower border of the cricoid inferiorly. Tumors in this area may be divided into those arising from the pyriform sinuses, the posterior wall of the hypopharynx, and the postcricoid area. Tumors of the larynx may be divided into those located predominantly above the true vocal cords (supraglottic), those arising from the true vocal cords (glottic), or those below the true vocal cords (subglottic). Cancers of the larynx are far more common than are cancers of the hypopharynx. B. Presentation. The presentation of cancers of the larynx and hypopharynx varies

greatly with their primary site. Tumors of the supraglottic larynx or the pyriform sinus are often diagnosed only after cervical metastasis appears because of their greater access to lymphatics and vague symptoms of dysphagia or odynophagia. Conversely, glottic cancers present with hoarseness, often despite a small tumor size, and the tumors may remain localized to the primary site until thyroid cartilage invasion occurs. Cancers of the larynx and hypopharynx may cause airway obstruction, resulting in stridor and requirement for immediate tracheostomy. Weight loss is also frequent at presentation. 1. Pertinent history should include an assessment of tobacco and alcohol use, the existence of comorbid diseases, and symptoms of dysphagia, odynophagia, weight loss, dyspnea, and hoarseness. Unilateral paralysis of a vocal cord may result in speech that deteriorates with longer use of the voice and improves with rest. Patients may also become dyspneic with speech. Symptoms of aspiration should be sought. A history of gastroesophageal reflux should be noted. 2. Physical examination includes assessment of performance status, complete evaluation of the oral cavity, oropharynx, hypopharynx, and larynx with indirect examination or fiberoptic laryngoscopy, testing of cranial nerves, and palpation of the neck. Palpation and visualization of the base of tongue should be done to note whether there is superior extension of the tumor to this site. Pooling of saliva in the hypopharynx may interfere with the office examination and requires better visualization at the time of EUA and biopsy. Fixation of the true vocal cord should be noted, because this affects staging, and diagramming the extent of the lesion is helpful. C. Staging. The staging of cancers in the larynx and hypopharynx requires EUA with biopsy to determine the extent of the lesion and search for synchronous primary cancers. CT or MRI imaging is performed to define the extent of the primary disease and involved neck nodes. Chest CT and/or fluorodeoxyglucose (FDG)-PET/CT are used to assess for distant metastases and second primary cancers. The tendency of the thyroid cartilage to display irregular calcification should be noted, because it may result in overestimating cartilage invasion on staging. In addition to size of the primary tumor, the staging criteria for the primary (T stage) include whether adjacent subsites of the hypopharynx (pyriform sinus, pharyngeal wall, and postcricoid region) or supraglottic larynx (suprahyoid epiglottis, infrahyoid epiglottis, aryepiglottic folds, arytenoids, and false vocal cords) are involved. D. Pathology. SCC, or one of its variants, is the histologic description of more than 95% of tumors arising in the larynx and hypopharynx. Tumors of minor salivary gland histology (adenoid cystic, adenocarcinoma, and mucoepidermoid carcinoma) occur infrequently. The supraglottic larynx may be the site of neuroendocrine small cell carcinomas and should be recognized because of their tendency for distant

spread and sensitivity to CRT. E. Stage-directed approach to therapy 1. Early stage. Early-stage disease is most likely to be encountered in glottic carcinomas owing to early symptoms of hoarseness. The primary approach may consist of surgical resection or radiation therapy with similar cure rates. In most cases, a larynx-conservation surgery approach is feasible, including a transoral endoscopic laser resection, open supraglottic, or open vertical hemilaryngectomy. These approaches permit preservation of speech but may be limited (particularly with the open approaches) by problems with aspiration, which can be problematic in patients with chronic pulmonary disease. Posttreatment voice quality is usually excellent with transoral surgery and radiation therapy, but may be less satisfactory with open approaches. 2. Locally advanced. The traditional approach to locally advanced tumors of the larynx and hypopharynx has been surgical resection with total laryngectomy or laryngopharyngectomy and adjuvant radiation therapy. However, CRT is also effective and allows preservation of speech and swallowing in the majority of patients. Interest in larynx preservation led to trials of CRT in an attempt to avoid total laryngectomy and preserve anatomy and function. The Veterans Administration (VA) larynx trial compared laryngectomy and postoperative adjuvant radiation with induction chemotherapy followed by definitive radiation therapy for those patients whose tumors responded favorably to induction chemotherapy and total laryngectomy and adjuvant radiation for those patients whose tumors did not respond favorably to induction chemotherapy (N Engl J Med 1991;324:1685). Cisplatin and 5-FU were administered every 3 weeks, with primary tumor response assessment after the second cycle. Patients with tumors that responded favorably received an additional cycle of chemotherapy followed by definitive radiation, whereas patients whose tumors did not respond favorably underwent total laryngectomy followed by adjuvant radiation therapy. Salvage total laryngectomy was performed in patients with persistent or locally recurrent disease after radiation therapy. This treatment approach resulted in equivalent OS with induction CRT as compared with total laryngectomy and adjuvant radiation therapy and permitted 64% of the surviving patients in the nonsurgical treatment arm to retain their larynx. A European Organization for the Research and Treatment of Cancer (EORTC) trial in cancers of the pyriform sinus compared the results of surgical resection and adjuvant radiation therapy with a similar induction CRT strategy (N Engl J Med 2003;349:2091). Patients were randomized to surgery and adjuvant radiation therapy or induction chemotherapy with cisplatin and 5-FU followed by

definitive radiation therapy. Patients with chemosensitive tumors as assessed after cycle 1 received a total of three cycles of chemotherapy followed by definitive radiation therapy with salvage surgery for nonresponders to chemotherapy or in those patients with persistent or recurrent disease following definitive radiation. As in the VA larynx trial, OS was equivalent between these two treatment approaches, and functional larynx preservation at 3 years was achieved in 42% (95% CI, 31% to 53%) of patients on the induction chemotherapy arm. RTOG 91-11 was an intergroup, three-arm randomized trial that compared induction chemotherapy followed by definitive radiation therapy (as given in the VA trial) to CRT to radiation therapy alone. The CRT arm received three cycles of high-dose (100 mg/m2) bolus cisplatin given every 21 days concurrent with radiation therapy. Eligible patients included those with stage III to IV laryngeal cancer who would require total laryngectomy as surgical management. Patients with T4 primaries were excluded if they had more than minimal thyroid cartilage invasion or more than 1-cm tumor extension onto the base of the tongue. The larynx preservation rate was significantly higher with CRT compared to induction chemotherapy followed by radiotherapy therapy and to radiation therapy only (83.6% vs. 70.5% vs. 65.7%, respectively). The 5-year OS was similar in the three arms (55%). Long-term (10-year) follow-up of the RTOG 91-11 trial showed that induction chemotherapy followed by radiation therapy and CRT had similar laryngeal-free survival, whereas deaths not because of larynx cancer or treatment were higher with CRT (30.8% vs. 20.8% with induction chemotherapy vs. 16.9% with radiation therapy alone) (J Clin Oncol 2013;31:845). Together, these trials demonstrate the feasibility of organ preservation in most cases of locally advanced cancers of the larynx and hypopharynx without adversely affecting survival. F. Natural history of disease. Local–regional control is a major challenge in the treatment of patients with cancer of the larynx and hypopharynx. The lack of symptoms in early pyriform sinus cancers can be contrasted with the frequent development of symptoms (hoarseness) with early glottic cancer. The effect of anatomy with confinement of many laryngeal cancers to the primary site because of surrounding thyroid cartilage contrasts with the advanced disease typically seen in hypopharynx cancers, which typically have submucosal spread and local lymphovascular spread. Although most recurrences of laryngeal and hypopharyngeal cancers occur within the first 3 years of treatment, continued vigilance is warranted for the development of metachronous primary head and neck cancers. All patients should be repeatedly counseled about the benefits of smoking cessation. Also, patients with cancers of the larynx and hypopharynx are at significant risk for subsequent development of lung cancer.

VII. NASOPHARYNGEAL CANCER A. Anatomy. The borders of the nasopharynx include the choanae (anterior), the soft palate (inferior), and lateral walls, including the fossae of Rosenmuller and the Eustachian tube orifices. Its sloping roof along the skull base (superior and posterior) lies in close proximity to the foramen lacerum and the carotid artery as it enters the cavernous sinus. Tumors may extend through the foramen ovale to access the middle cranial fossa and the cavernous sinus with access to the oculomotor (CN III), trochlear (CN IV), trigeminal (CN V), and abducens (CN VI) nerves. Optic nerve (CN II) and orbital invasion is possible in advanced cases. There is a rich lymphatic supply with retropharyngeal nodes, including the lateral retropharyngeal nodes (of Rouvière), representing an important route of spread. B. Presentation. The presentation of nasopharyngeal cancer has many unique features. Symptoms at diagnosis may be related to the primary site, disease in the neck, or distant metastases. The epidemiology of this cancer is different from that of other head and neck sites. Causes of nasopharyngeal cancer include EBV infection, HPV infection, and smoking. 1. Pertinent history may include geographic, genetic, and environmental factors. The highest incidence of nasopharyngeal cancers is found in southern China and Southeast Asia. Genetic factors related to host response to EBV infection may explain the increased risk among people of Asian ancestry. Other risk factors have been implicated, including diet (consumption of salted fish and low intake of fresh fruits and vegetables) and smoking. Symptoms may include a painless neck mass, nasal obstruction, epistaxis, headache, persistent sinusitis symptoms, dysphagia, odynophagia, Eustachian tube dysfunction with sterile middle ear effusion, or cranial neuropathies (particularly the abducens and trigeminal nerves). Trismus may indicate invasion of the pterygoid region. 2. Physical examination includes assessment of performance status, complete evaluation of the nares and oral cavity, and a thorough evaluation of the cranial nerves. Proptosis may indicate orbital invasion. Evaluation of the nasopharynx with fiberoptic endoscopy or EUA with biopsy is appropriate. The status of dentition should be noted, because any needed restoration or extractions should precede the initiation of radiation therapy. Lymph nodes in the neck should be palpated and palpable nodes measured. C. Staging. Along with history and physical examination, the staging evaluation of patients with nasopharynx cancers includes diagnostic imaging, including MRI and CT from the base of the skull to the clavicles, EUA, and chest CT or FDG-PET/CT to look for distant metastases. MRI and CT are complementary and helpful for delineating disease extent because of early skull base involvement. The neck nodal staging system is different for nasopharyngeal carcinoma as compared with other

mucosal sites of head and neck cancers. The staging for nasopharyngeal cancer is distinct from the other head and neck sites. T stage is subdivided into T0 (no evidence of primary tumor), T1 (no parapharyngeal extension), T2 (parapharyngeal extension), T3 (involvement of skull base of paranasal sinuses), and T4 (involvement of cranial nerves, hypopharynx, orbit, infratemporal fossa, or intracranial extension). The lymph node staging includes N0 (no regional lymph node metastasis), N1 (unilateral metastasis in cervical lymph nodes ≤6 cm above the supraclavicular fossa and/or unilateral or bilateral retropharyngeal lymph nodes ≤6 cm), N2 (bilateral cervical lymph nodes ≤6 cm), and N3 (lymph nodes >6 cm or extension to the supraclavicular fossa). Stage I is defined as T1N0M0, stage II as T1N1M0 or T2N01M0, and stage III as T1-2N2M0 or T3N0-2M0. Stage IV is subdivided into IVA (T4N0-2M0), IVB (T0-4, N3M0), and IVC (any T and N plus M1). D. Pathology. Carcinomas represent 85% of nasopharynx tumors (less common are lymphoma, adenocarcinoma, melanoma, plasmacytoma, rhabdomyosarcoma, and others). Nasopharyngeal carcinoma is classified according to a World Health Organization (WHO) schema. WHO-type 1 is keratinizing SCC. WHO-type 2 is nonkeratinizing SCC, and WHO-type 3 is undifferentiated carcinoma (lymphoepithelioma). EBV tumors are most closely associated with WHO types 2 and 3 histologies. A rare fourth subtype, basaloid squamous cell, has been recognized and carries a worse overall prognosis. E. Stage-directed approach to therapy 1. Early-stage disease is infrequently diagnosed in the Western world because of lack of symptoms and no screening programs because of the rarity of the disease. Radiation therapy alone is the usual treatment for early-stage disease. Surgical resection or repeat radiation therapy may be considered for the rare local recurrence. 2. Advanced-stage disease is treated with CRT. The Intergroup 0099 trial demonstrated better OS with CRT compared with radiation therapy alone (J Clin Oncol 1998;16:1310). This randomized trial compared radiation therapy (70 Gy) alone with CRT (with cisplatin 100 mg/m2 given every 21 days, a total of three doses) and three cycles of adjuvant cisplatin and 5-FU given every 4 weeks after completion of CRT. The 3-year PFS was 24% versus 69% (p < 0.001), and 3-year os was 47% versus 78% (p = 0.005) for radiation therapy alone versus CRT, respectively. This trial included all three WHO types. Other randomized trials confirmed the benefit of CRT over radiation therapy alone in populations enriched in EBV-driven tumors and in stage II disease. The added benefit from adjuvant chemotherapy has been an area of debate and active research. Randomized trials have established that adjuvant cisplatin/5-FU does not improve outcomes after CRT (Lancet Oncol 2012;13:163); however, a phase III

study demonstrated that three cycles of neoadjuvant cisplatin plus gemcitabine did improve OS in EBV-driven disease (N Engl J Med 2019;381:12). There is also evidence that carboplatin was noninferior to cisplatin when administered concurrently with radiation therapy (Euro J Cancer 2007;43:1399). F. Natural history of disease. Nasopharyngeal carcinoma is a disease with unique features. A younger age at presentation compared with that for other sites of head and neck cancers and a higher incidence in endemic geographic areas are seen. Most patients present with locally advanced disease; and for many decades, the most common pattern of recurrence was local–regional failure. However, with the advent of combined CRT and advanced radiation techniques, distant failure is now more common, and the risk of distant metastasis is higher than it is with other sites. The role of genetic factors and EBV are well recognized, but poorly understood. Viral titers assessed by PCR that remain elevated or rise after therapy may identify a group at risk for disease recurrence. VIII.LESS COMMON TUMORS OF THE HEAD AND NECK A. Salivary gland cancers most commonly arise in the parotid gland, but may arise in the submandibular, sublingual, or minor salivary glands that line the mucosa of the upper aerodigestive tract. 1. Pathology. The histology of salivary gland carcinoma is varied. Perineural invasion, high-grade tumors, and nodal metastases are adverse prognostic features. a. Mucoepidermoid carcinomas are the most common type arising in the parotid glands and are classified as low, intermediate, or high grade. Lowgrade tumors respond well to surgical resection, whereas high-grade tumors are associated with more aggressive local invasion, and nodal and distant metastases. b. Adenoid cystic carcinoma is the most frequent histology seen in the submandibular and minor salivary glands. Perineural invasion may lead to facial nerve (CN VII) paralysis and involvement of the skull base. It is also classified by grade and has a significant incidence of distant metastatic disease. Patients with distant metastasis to the lung have a much longer survival as compared with the more uncommon patients that develop metastasis to the liver or bones. c. Malignant mixed tumors (carcinoma ex-pleomorphic adenoma) arise from a preexisting benign mixed tumor (pleomorphic adenoma). d. Adenocarcinomas commonly arise from the minor salivary glands, but may also arise in the major salivary glands. They have an aggressive behavior and a significant risk of distant metastasis. Low-grade polymorphous

adenocarcinomas arise in the oral cavity and have an excellent prognosis with complete resection. e. Acinic cell carcinomas usually arise in the parotid glands. They are typically low-grade, slow-growing tumors, but may invade adjacent structures. Unpredictably, a small number will behave very aggressively. These tumors can be bilateral. Late recurrences and distant metastases may occur. f. SCCs arising from the excretory duct of the salivary glands have an aggressive course with a poor prognosis despite aggressive therapy. g. Mammary analog secretory carcinomas (MASC) are a rare subset typically with low-grade features, but almost universally carry an NTRK fusion. h. Salivary ductal carcinomas traditionally express androgen receptors on the cell surface, and androgen deprivation can serve as palliative line of therapy. i. Metastatic regional disease to intraparotid nodes can occur from skin cancers arising from the face, scalp, or ears. These are primarily from SCC, melanoma, and Merkel cell carcinoma. 2. Treatment. Management of salivary gland cancers is with surgical resection. In the parotid gland, this may consist of total or superficial parotidectomy, depending on the location of the tumor and histology tumor type. When possible, the facial nerve may be preserved. High-grade and low-grade tumors with a positive resection margin benefit from adjuvant radiation therapy. Recurrent or metastatic tumors may be treated with chemotherapy, including cisplatin, doxorubicin, 5-FU, and cyclophosphamide combinations. Recent reports have documented the expression of c-kit, HER2-neu, EGFR, and/or the androgen receptors in salivary gland cancers and case reports of tumor response to targeted therapy directed (J Clin Oncol 2006;24:2673). B. Tumors of the nasal cavity and paranasal sinuses are rare tumors that include a variety of histologies. Risk factors may include occupational exposures to wood dust, shoe manufacture, nickel refining, and Thorotrast contrast media. 1. SCC is the most common type in the nasal cavity and paranasal sinuses, and the maxillary sinus is the most common primary site. Minor salivary gland tumors may also occur. Surgical resection and POART is the preferred treatment approach. 2. Esthesioneuroblastoma (olfactory neuroblastoma) arises from the olfactory neuroepithelium. Surgical resection and adjuvant radiation therapy is the preferred treatment approach. The benefit of the addition of chemotherapy to radiation therapy is unclear. 3. Sinonasal undifferentiated carcinomas (SNUCs) are high-grade epithelial malignancies that may occur with or without neuroendocrine differentiation. Ideal treatment is controversial and may include surgery and adjuvant radiation

therapy, or CRT. IX. UNKNOWN PRIMARY A. The patient with a neck mass may not have a primary site identified on initial inspection of the oral cavity and pharynx. The location (level) of the neck mass should direct close evaluation of the head and neck mucosal sites that are drained by that nodal group. 1. Fine-needle aspiration cytology of the neck mass should be pursued as the primary diagnostic procedure. Open biopsy should be pursued if a lymphoma is suggested. Evaluation of the thyroid, parotid, and any suggestive skin lesions should be performed. A mass in the supraclavicular fossa should prompt evaluation of possible primary sites below the clavicles. 2. If SCC is suggested by the cytology, EUA with operative endoscopy should be used to try to identify the primary tumor site. Use of an operating microscope or surgical robot during the endoscopy might assist with identification of the primary tumor, particularly when small. If no primary is found, then bilateral or ipsilateral palatine tonsillectomy and ipsilateral lingual tonsillectomy should be performed, because these would be the most common sites for an occult primary, and the pathologist should perform serial step sectioning on the specimens. True occult primaries without an easily identifiable mucosal site are usually p16positive oropharyngeal cancers, especially if the nodal burden includes level 2 or 3. 3. If no primary site is found, several approaches are considered. If the neck mass is unresectable, then radiation therapy or CRT with a nasopharyngeal port, which will include the likely potential primary sites, may be used. If a nasopharyngeal primary is suggested by the cytology, CRT may be considered. If the neck mass is resectable, neck dissection with tonsillectomy and biopsy of the nasopharynx may be pursued as primary therapy. If the pathology shows extracapsular extension or if multiple nodes are involved, postoperative CRT may be given, with some controversy as to whether a nasopharyngeal port or involved neckonly port is most appropriate. If the neck mass is solitary, small (N1), and without extracapsular extension, adjuvant radiation therapy may be held and the patient closely observed. X. MANAGEMENT OF THE NECK A. Patients with clinically negative neck nodes that are at significant (≥20%) risk for occult disease may be treated effectively with selective neck dissection or radiation therapy. Clinically involved nodes may require both modalities, especially if there are multiple nodes involved or extracapsular extension.

B. Radical neck dissection consists of removing all five lymph node groups on one side of the neck, as well as the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessory nerve (CN XI). Modified radical neck dissections remove all five lymph node groups, but may spare one or more of the latter structures. In a selective neck dissection, only lymph node groups at the highest risk are excised, and the sternocleidomastoid, jugular vein, and CN XI are preserved. SUGGESTED READINGS Al-Sarraf M, LeBlanc M, Shanker Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Oncol 1998;16:1310–1317. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomized, open label phase 3 study. Lancet 2019;394:1915–1928. Chow LQ. Head and neck cancer, N Engl J Med 2020;382:60–72. Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and progression for patients with p16positive and p16-negative oropharyngeal cancer. J Clin Oncol 2012;30:2102–2111. Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomized phase 3 trial. Lancet Oncol 2013;14:257–264. Laura SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol 2006;24:2673–2678.

BACKGROUND Epidemiology In 2020, approximately 29,745 new cases of small cell lung cancer (SCLC) will be diagnosed in the United States. The overall incidence of SCLC has been declining over the past few decades, although there has been a dramatic increase among women, with a current incidence ratio of 1:1 between men and women. It is most common in the elderly, with an average age of diagnosis of 71. Risk Factor Nearly all cases of SCLC are attributed to cigarette smoking, with more than 95% of affected individuals being current or former heavy smokers. The risk rises with the duration and intensity of tobacco use. PRESENTATION SCLC is a poorly differentiated, high-grade neuroendocrine carcinoma that represents about 15% of all lung cancers. It is predominantly a disease of smokers and is characterized by rapid tumor growth, early metastatic dissemination, and poor clinical outcomes. Signs and symptoms depend on the location and size of the primary tumor and whether disease is localized or disseminated. Initial symptoms may include cough, dyspnea, hemoptysis, and wheezing. Mediastinal lymph nodes are commonly involved in SCLC. Patients can, therefore, exhibit symptoms suggestive of superior vena cava (SVC) syndrome such as facial, neck, and upper extremity swelling and dyspnea, hoarseness from recurrent laryngeal nerve involvement, dysphagia from esophageal compression, and pleuritic chest pain from pleural involvement. Symptoms of widespread metastatic disease can include weight loss and bone pain as well as headache, focal weakness or numbness, and confusion from central nervous

system (CNS) disease. On occasion, patients with SCLC can present with symptoms that suggest an underlying paraneoplastic syndrome (Table 11-1). TABLE 11-1 Organ System

Paraneoplastic Syndromes Associated with SCLC Frequency (%)

Syndrome

Mechanism

Presentation

SIADH

ADH

• • • •

Headache Fatigue Muscle weakness Memory loss and confusion • Euvolemic hypoosmolar hyponatremia

7–16

Ectopic Cushing syndrome

ACTH

• • • •

2–5

Endocrine

Cushingoid face Acne Purple striae Proximal muscle weakness • Peripheral edema • Metabolic alkalosis with hypokalemia • Hyperglycemia

Neurologic

3–5 Lambert–Eaton myasthenic syndrome

Anti–voltage-gated calcium channel

• Proximal muscle weakness • Depressed reflexes • Autonomic dysfunction

Limbic encephalitis

Anti-Hu, anti-Ma2, anti-CRMP5

• • • • • •

Personality changes Irritability Depression Seizures Memory loss Confusion

Subacute cerebellar degeneration (or cerebellar ataxia)

Anti-Yo, anti-Hu, antiTr, anti-Ri

• • • • • • • •

Ataxia Diplopia Nystagmus Dysphagia Dysarthria Vertigo Dizziness Nausea/vomiting

ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; SCLC, small cell lung cancer; SIADH, syndrome of inappropriate antidiuretic hormone.

Patients with SCLC often present with widespread metastatic disease and can be very symptomatic at time of diagnosis, requiring prompt initiation of therapy to prevent rapid clinical deterioration. Attention should be paid to recognize signs typical of SVC syndrome. Diminished breath sounds with a dull percussion note may signify an underlying malignant effusion or a postobstructive pneumonia from bronchial obstruction. Epigastric pain and hepatomegaly can be indicative of liver involvement. The presence of focal neurologic signs is suggestive of CNS involvement. Back pain and bone tenderness can denote diffuse skeletal involvement, and it is critical to ascertain any signs characteristic of spinal cord involvement. Bone marrow involvement may be present, and when severe, can result in cytopenias. Signs of endocrine and neurologic paraneoplastic syndromes, including Cushing syndrome, syndrome of inappropriate antidiuretic hormone (SIADH), and Lambert–Eaton myasthenic syndrome, can be observed in patients with SCLC. WORKUP AND STAGING Workup Accurate staging is crucial, considering that limited stage disease is managed with curative intent, whereas extensive stage disease is incurable and treated with palliative intent. Staging workup includes a computed tomography (CT) scan of the chest and abdomen. Radiographically, SCLCs typically have a characteristic appearance with small primary tumors, bulky hilar and mediastinal lymph nodes, and distant metastases. Given the high propensity for brain metastases in patients with SCLC, brain imaging should be performed for all patients at presentation. Magnetic resonance imaging (MRI) with contrast is more sensitive than a CT for this purpose. Positron emission tomography (PET)-CT imaging constitutes an important part of the staging workup, especially in patients with limited stage disease on CT imaging, because PET scans can upstage the disease in up to 19% of patients. Ultimately, establishing a diagnosis of SCLC requires tissue confirmation through fineneedle aspiration (FNA), core biopsy, or resection. From a histopathologic point of view, SCLC is a high-grade neuroendocrine carcinoma characterized by small blue cells with scant cytoplasm and nuclear features of fine, dispersed chromatin without distinct nucleoli. Biopsy specimens often exhibit necrosis and crush artifacts. Most SCLCs express at least one neuroendocrine marker by immunohistochemistry including CD56, synaptophysin, or chromogranin, although this is not required for diagnosis. SCLCs are characterized by biallelic inactivation of tumor suppressors TP53 and RB1 along with dysregulation of MYC family genes (MYC, MYCL, or MYCN). Staging Staging systems for SCLC have undergone several revisions over the years. Conceptually,

the objective of these systems is to identify patients who are candidates for curative intent treatment with combined modality therapies. The Veterans Administration Lung Study Group (VALSG) classification system categorizes patients as having limited stage or extensive stage disease. Patients with disease confined to the ipsilateral hemithorax and regional lymph nodes that are subjectively considered to fit into one radiation field are defined as having limited stage disease (typically corresponds to stages I to III by tumor, node, metastasis [TNM] staging). Extensive stage disease (TNM stage IV), on the other hand, is defined as any disease that falls outside the designation of what constitutes limited stage disease and includes patients with malignant pleural or pericardial effusions. Generally, 30% to 40% of patients present with limited stage and 60% to 70% with extensive stage disease at diagnosis. MANAGEMENT SCLC is notable for its sensitivity to cytotoxic chemotherapy and radiotherapy (RT) in the first-line setting. However, despite this impressive initial responsiveness, the vast majority of patients with SCLC relapse in a few months with disease that is resistant to additional treatment. Unlike non–small cell lung cancer (NSCLC) where tumor genotype and level of programmed death ligand 1 (PD-L1) expression dictate choice of therapy, there are no molecular markers that currently guide treatment selection in SCLC. Limited Stage SCLC The standard of care is combined modality therapy with concurrent chemotherapy and thoracic RT. This regimen results in response rates of 70% to 90%, with a median overall survival (OS) that ranges from 24 to 30 months and a 5-year OS rate of 25% to 30%. • Chemotherapy. Chemotherapy plays an essential role in the management of SCLC. Combination chemotherapy, with a platinum agent (typically cisplatin) and etoposide, is presently the standard of care. Data from meta-analyses and small prospective studies suggest that carboplatin can substitute for cisplatin without differences in outcomes. Carboplatin is generally associated with fewer and less severe side effects compared to cisplatin, and therefore is considered in patients with comorbidities that preclude the use of cisplatin. • Radiation therapy. Administration of thoracic RT with concurrent systemic chemotherapy improves survival in limited stage disease. The optimal time to start RT is with the first or second cycle of chemotherapy. Studies have shown early-start RT to be associated with better outcomes than RT started later. The optimal radiation dose and schedule remains undefined. The randomized phase Intergroup (INT) 0096 trial demonstrated 45 Gy twice-daily (BID) RT administered over 3 weeks to be superior to 45 Gy administered once daily over 5 weeks, with 5-year OS of 26% versus 16%, although there was increased grade III to IV esophagitis with the twicedaily regimen. Nevertheless, this trial has been criticized for the low dose of RT administered in the once-daily RT arm. Whether a higher once-daily dose would be

•

•

equivalent to or better than the 45 Gy BID regimen continues to be a matter of debate. In this context, the phase III Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT) trial did not show superiority of 66 Gy administered once daily over 45 Gy administered BID with concurrent chemotherapy (Lancet Oncol 2017;18:1116). Although the median OS (30 vs. 25 months, p = 0.14), 2-year OS (56% vs. 51%), and toxicity were comparable between both arms in this study, it is worth noting that this trial was not powered to demonstrate equivalence. Secondary analysis of this trial confirmed better outcomes in patients with stage I to II disease compared to those with stage III disease. The Cancer and Leukemia Group B (CALGB) 30610/Radiation Therapy Oncology Group (RTOG) 0538 study, which was designed to assess outcomes in patients receiving 45 Gy BID RT over 3 weeks or 70 Gy once-daily RT over 7 weeks, will provide additional information on the comparison between once-daily and twice-daily RT in SCLC. Currently, either twice-daily RT to 45 Gy or once-daily RT to 60 to 70 Gy are both acceptable treatment approaches. Prophylactic cranial irradiation (PCI). PCI is offered to patients with limited stage disease demonstrating a complete response to initial therapy. A meta-analysis showed that PCI reduces the incidence of brain metastases and prolongs OS as well as disease-free survival (DFS) (N Engl J Med 1999;341:476). In patients who had a complete or partial response to chemoradiotherapy and had no brain metastases on imaging before and after primary treatment, median OS with PCI was improved (26 vs. 14 months). PCI is associated with acute and long-term toxicities. Acute side effects primarily include fatigue, headache, and nausea/vomiting. Late neurocognitive dysfunction may develop and careful consideration is imperative when treatment is offered to the elderly and/or patients with poor performance status (Eastern Cooperative Oncology Group [ECOG] 34). Administering PCI in low doses (3 months from the last day of initial treatment), compared to those with refractory (no initial response) or resistant relapses (1 cm but ≤2 cm, T1c >2 cm but ≤3 cm), T2 (>3 to ≤5 cm, with T2a >3 cm but ≤ 4 cm, and T2b >4 cm but ≤5 cm), T3 (>5 to ≤7 cm, or one that invades the chest wall [includes superior sulcus tumors], phrenic nerve, parietal pericardium, separate nodules in the same lobe of primary), T4 (tumor >7 cm, invasion of the mediastinum, diaphragm, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate nodules in an ipsilateral different lobe). N stage is subdivided into N1 (ipsilateral peribronchial or hilar lymph node), N2 (ipsilateral mediastinal or subcarinal lymph node), and N3 (contralateral mediastinal, contralateral hilar, or any scalene or supraclavicular lymph node). M stage is subdivided into M1a (contralateral nodules, pleural nodules, malignant pleural or pericardial effusion), M1b (single distant metastasis), and M1c (multiple extrathoracic metastases). Stage

TNM

IA

T1a-cN0M0

IB

T2aN0M0

IIA

T2bN0M0

IIB

T1a-cN1M0, T2a-bN1M0, T3N0M0

IIIA

T1a-cN2M0, T2a-bN2M0, T3N1M0, T4N0M0, T4N1M0

IIIB

T1a-cN3M0, T2a-bN3M0, T3N2M0,T4N2M0

IIIC

T3N2M0, T4N3M0

IVA

Any T, any N, M1a or M1b

IVB

Any T, any N, M1c

Adapted from the eighth edition of the IASLC (Rami-Porta et al. CA Cancer J Clin, 2017).

VIII.THERAPY AND PROGNOSIS A. Stages I and II. The initial treatment modality is complete resection if possible. Preoperative assessment should determine the stage, cardiopulmonary reserve, and perioperative risk of intended procedure. Suitable surgical candidates are those with estimated forced expiratory volume in 1 second (FEV1) or diffusing lung capacity for carbon monoxide (DLCO) after pneumonectomy of more than 40% and maximal O2 consumption greater than 20 mL/kg/minute. Stage of disease, age of the patient, and extent of resection significantly affect mortality, which averages approximately 3% to 7%. When complete resection is feasible, lobectomy is preferred over pneumonectomy and is the most commonly performed procedure. Segmentectomy and wedge resection are associated with 2- to 3-fold increased risk of local recurrence (and should be reserved for situations in which the tumor is 1 to 5 mm); T1b (>5 to 10 mm); T1c (>10 to 20 mm) T2 (>2 to 5 cm) T3 (>5 cm) T4 (direct extension to the chest wall, skin ulceration, or skin nodules): T4a (chest wall); T4b (skin ulceration, nodule and/or edema); T4c (both T4a and T4b); T4d (inflammatory carcinoma) N1mi micrometastases (>0.2 mm or more than 200 cells) N1 (movable ipsilateral level I, II axillary lymph nodes)

N2: N2a (ipsilateral level I, II axillary lymph node fixed to one another or to other structures); N2b (ipsilateral internal mammary nodes in the absence of clinically evident axillary node) N3: N3a (ipsilateral infraclavicular lymph nodes); N3b (ipsilateral internal mammary lymph nodes and axillary lymph nodes); N3c (ipsilateral supraclavicular lymph nodes) M1 (distant metastases) In addition, the AJCC eighth edition also incorporates the prognostic molecular markers including histologic grade, hormone receptor (HR) and HER2 status, and Oncotype DX with the classic TNM anatomic criteria (AJCC Cancer Staging Manual 8th ed. New York, NY: Springer, 2017), providing more detailed prognostic staging system. The 5-year overall survival (OS) rates stratified by the AJCC eighth edition staging system has not yet been reported. Survival rate based on SEER stage in women with breast cancer between 2008 and 2014 was published by the ACS. The 5-year relative survival rate for localized, regional, and distant breast cancer was 99%, 85% and 27%, respectively. C. Staging workup of breast cancer 1. Clinical examination. A clinical examination as described earlier is required with careful inspection and palpation of the local lymph nodes, including supraclavicular and cervical nodes, skin, both breasts, abdomen, and spine. 2. Laboratory tests. Laboratory tests help physicians focus their workup for metastasis. An abnormal complete blood count (CBC) should prompt evaluation of the bone marrow for metastatic disease. Elevated levels of liver enzymes may suggest liver metastasis, and an elevated calcium/alkaline phosphatase level suggests bone metastasis. Levels of tumor markers CA 15-3, CA 27-29, and carcinoembryonic antigen (CEA) can be elevated in breast cancer. The ASCO 2007 guideline recommends against using tumor markers for screening, diagnosis, staging, predicting recurrence of breast cancer after curative therapy, and monitoring treatment response. In the metastatic setting, the ASCO 2015 guideline indicated that CEA, CA 15-3, and CA 27-29 may be used as an adjunctive assessment, but not alone, to help guide treatment decisions, in conjunction with standard clinical monitoring and imaging, if initial values are elevated at the diagnosis of disseminated disease. Circulating tumor DNA (ctDNA) analysis has gained more popularity in recent years as an alternative method to detect genomic variants mainly in the clinical trial setting. The use of ctDNA remains investigational and the 2018 ASCO guideline did not recommend using ctDNA in early-stage cancer, treatment monitoring, residual disease detection, or for screening because of insufficient evidence of clinical validity and utility.

3. Radiologic tests. Radiologic studies complete the clinical staging for breast cancer by detecting metastatic disease. A computed tomographic (CT) scan of the chest and abdomen (with or without a CT of the pelvis) is recommended in patients who have T3N1 or higher disease, localizing symptoms, or abnormal laboratory values suggesting liver disease. A bone scan should be obtained in patients with T3N1, or localizing symptoms, or abnormal alkaline phosphatase. The role of fluorodeoxyglucose-positron emission tomography (FDG-PET) scan in staging breast cancer is evolving, but has not been shown to be superior to CT and bone scan for staging purpose. It may be useful to detect occult systemic metastasis, but care should be taken to never consider a patient to have advanced disease on the basis of PET alone without other corroboration, preferably by biopsy, because the false-positive rate associated with inflammatory conditions is high. Cardiac systolic function should be evaluated with multiple gated acquisition (MUGA) scan or echocardiogram before and during treatment with HER2-targeted agents and anthracyclines. IV. CARCINOMA IN SITU AND EARLY-STAGE BREAST CANCER A. Ductal carcinoma in situ. DCIS is a direct precursor of invasive breast cancer. The incidence of DCIS has increased with screening mammography, where it is often diagnosed through the presence of a cluster of microcalcifications in more than 90% of the cases. Uncommonly, patients may have a mass, nodule, or other soft-tissue changes. Although MRI may detect some foci that are not visible by mammography, it may also miss some mammographically visible foci. The pathologic subtypes of DCIS are the comedo, cribriform, micropapillary, papillary, and solid subtypes. Prognostically, they can be divided into comedo and noncomedo subtypes, the former being more often associated with subsequent recurrence. The modified Van Nuys prognostic index (VNPI; Table 13-1) system, which takes into account several factors to predict the likelihood of recurrence after local excision, may be useful in clinical decision-making. TABLE 13-1

Modified Van Nuys Prognostic Index

Score

1

2

3

Size (mm)

≤15

16–40

>41

Margins (mm)

≥10

1–9

4/2 mm2), nuclear crowding

Type AB

Bland, spindle-shaped cells with abundance of immature (TdT+) T cells focally or throughout

Type B1

Thymus-like architecture and cytology: abundance of immature T cells, medullary islands

Type B2

Increased numbers of single or clustered polygonal or dendritic epithelial cells with abundant immature T cells

Type B3

Sheets of polygonal, slightly to moderately atypical epithelial cells; absent or rare intercellular bridges; paucity/absence of TdT+ T cells

WHO, World Health Organization.

D. Staging. The most commonly used staging system is the one proposed by Masaoka et al. in 1981 (Table 14-3). In this system, four clinical stages are created on the basis of the degree of invasion through the capsule, and into the surrounding structures. The tumor, node metastasis (TNM) eighth edition is also used according to the International Association for the Study of Lung Cancer (IASLC)/International Thymic Malignancies Interest Group (ITMIG) staging. TABLE 14-3

Masaoka Staging System for Thymoma

Stage

Description

I

Completely encapsulated tumor

IIa

Microscopic transcapsular invasion

IIb

Macroscopic invasion into fatty tissue or grossly adherent to but not through the mediastinal pleura or pericardium

III

Macroscopic invasion into neighboring organs (pericardium, great vessels, lung)

IVa

Pleural or pericardial metastases

IVb

Lymphatic or hematogenous metastases

III. THERAPY AND PROGNOSIS A. Resectable disease 1. Surgery. Surgery is a treatment of choice for thymoma and should be offered to all patients except those with clinically grossly unresectable disease or in cases of metastatic disease. Before any surgical procedure, however, patients with suspected diagnosed or suspected thymomas should be tested for serum antiacethylcholine receptor levels to rule out MG, which may result in respiratory

failure during the surgery. If present, MG should be treated before the surgery. In patients with grossly encapsulated lesions, the procedure of choice is a complete excision with total thymectomy via median sternotomy. Video- or roboticassisted thoracic surgery can be considered in tumors less than 5 cm (Cancer Manag Res 2019;11:6803). Patients with gross fixation of the tumor to nonvital adjacent structures such as the lung, pleura, or pericardium should undergo resection of the adjacent involved tissues. The presence of intrapulmonary metastasis does not constitute a contraindication for the surgery if accomplished by lobectomy. The role of pneumonectomy in this setting is questionable. Patients with unilateral phrenic nerve involvement should undergo surgery with curative intent, provided that they can tolerate the loss of function in that hemidiaphragm, which can be particularly problematic in patients with MG. N1 stations are defined as the anterior region including the lower anterior cervical, perithymic, prevascular, para and ascending aortic, superior and inferior phrenic, supradiaphragmatic, and pericardial node groups. N2 stations are deep and include the deep cervical, supraclavicular, lower (4 R) and upper paratracheal (2 R), subaortic (4 L), subcarinal (7), hilar (10 R, 10 L), and internal mammary. The operative mortality is approximately 2.5% and overall survival (OS) for patients with resected thymoma is usually very good (Table 14-4). Patients with stage III or IV are considered unresectable when there is extensive involvement of the trachea, great arteries or heart, extensive bilateral pleural metastases, or distant metastases. The role of debulking or subtotal resection in advanced stages remains controversial. Patients with relapsed disease following a complete resection should be considered for a second operation. TABLE 14-4 Masaoka Stage

Overall Survival for Resected Thymomas 5-Year Survival (%)

10-Year Survival (%)

I

92

88

II

82

70

III

68

57

Iva

60

38

2. Adjuvant therapy. Adjuvant radiation therapy is not indicated for R0 resections in stage I disease, should be considered for R0 resections in stages II to IV, and is indicated in cases of R1 resection. In case of R2 resections, patients should be considered for the addition of chemotherapy to adjuvant radiotherapy. B. Locally advanced disease 1. Neoadjuvant therapy. Although the use of preoperative single- modality

radiation therapy has not been associated with survival benefit, several studies suggest improvement in both resectability and survival with the use of multimodality treatment in patients with Masaoka stages III and IV. The National Comprehensive Cancer Network currently recommends chemotherapy as the initial treatment for patients with potentially resectable, locally advanced thymomas followed by surgical evaluation. In case of resectable disease, the treatment of choice is surgery followed by adjuvant radiation therapy. There is also evidence that neoadjuvant chemotherapy followed by resection is associated with similar survival rates when compared with upfront surgery (Ann Thorac Surg 2019;107:355). Unresectable tumors should be treated with chemoradiotherapy (J Natl Compr Cancer Netw 2013;11:562). C. Advanced disease. Thymomas are sensitive to chemotherapy, and several chemotherapeutic agents, either as a single agent or in combination regimens have been shown to be active (Table 14-5). The intergroup phase II trial evaluated the PAC regimen (cisplatin 50 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 3 weeks) in 30 patients with metastatic or recurrent thymoma and thymic carcinoma (J Clin Oncol 1994;12:1164). The overall response rate was 50%, with median survival of 38 months and a 5-year estimated survival of 32%. PAC is currently the standard treatment for thymoma. In a small study involving 16 patients, the combination of cisplatin (60 mg/m2 on day 1) and etoposide (120 mg/m2 on days 1 to 3) resulted in a 56% response rate and median OS of 4.3 years (J Clin Oncol 1996;14:814). In a phase II trial involving 51 patients including 32 with thymoma and 19 with thymic carcinoma treated with everolimus 10 mg/day, 3 patients with thymoma (9.3%) achieved partial response (PR), with disease control in 30 patients (93.8%), median progression-free survival (PFS) of 16.6 months, with median OS not reached (J Clin Oncol 2018;36:342). TABLE 14-5

Treatment Options for Thymoma

AUC, area under the curve; OS, overall survival; PFS, progression-free survival; RR, response rate.

D. Prognosis. Prognosis is related to the stage at presentation, presence or absence of complete resection, and the histologic subtype. Most thymomas are slow-growing encapsulated tumors that can be cured by surgical resection. Staging, regardless of the system used, remains the single most important prognostic determinant, and the outcomes are significantly better in patients undergoing complete resection. There is a linear progression of malignancy among the WHO histologic subtypes, with A and AB thymomas behaving as benign tumors, B1 and B2 as low-grade tumors, and B3 as an aggressive tumor similar to thymic carcinoma. This correlation is reflected in both the likelihood of invasion and the OS. IV. THYMIC CARCINOMA

Thymic carcinomas are rare tumors characterized by overt histologic and cytologic features of malignancy such as nuclear atypia, increased mitotic activity, and necrosis. Tumors are usually located in the anterosuperior mediastinum and patients usually present with symptoms of local invasion such as dyspnea, cough, and chest pain. Most patients present with advanced disease, with invasion of contiguous mediastinal structures and lymphadenopathy seen in approximately 80% and 40% of patients, respectively. Paraneoplastic syndromes are rarely seen. Owing to the paucity of cases, the optimal treatment remains undefined. Surgical resection is the mainstay of treatment, but complete resection is possible in only a few patients because of the advanced stage. Adjuvant radiation therapy should be considered in patients with stages II to IV undergoing R0 resection. In case of R1 or R2 resection, patients should receive adjuvant chemoradiotherapy. In patients with advanced disease, a small study including 23 patients with thymic carcinoma showed a 22% response rate, 5-month PFS and 20month median survival with the combination of carboplatin (area under the curve [AUC] of 6) and paclitaxel (200 mg/m2) on day 1, every 21 days (J Clin Oncol 2011;29:2060), which has become the regimen of choice for thymic carcinoma. In a study involving 23 patients with thymic carcinoma, treatment with sunitinib was associated with a response rate of 26%, median PFS of 7.2 months, and OS not reached at 17 months (Lancet Oncol 2015;16:177). In a phase II study involving 41 patients with previously treated thymic carcinoma, pembrolizumab was associated with a response rate of 22.5% (9/40) with a median duration of response of 22.4 months, median PFS of 4.2 months, and median OS of 24.9 months (Lancet Oncol 2018;19:347). Similar results were observed in another phase II study involving 26 patients with thymic carcinoma treated with pembrolizumab, where 19.2% achieved stable disease and the median PFS was 6.1 months (J Clin Oncol 2018;37:2162). MESOTHELIOMA I.

INTRODUCTION A. Background. Malignant mesothelioma is an aggressive tumor of the serosal surfaces. There are approximately 2,500 new cases per year in the United States. The main risk of the development of mesothelioma is exposure to asbestos. Although approximately 80% of patients with mesothelioma have a history of asbestos exposure, only approximately 10% of those will develop mesothelioma. B. Clinical manifestations. The symptoms of mesothelioma are usually insidious and nonspecific. Therefore, a delay in diagnosis is typical. The median time between the onset of symptoms and the diagnosis is 2 to 3 months. The most common presenting complaints are dyspnea and nonpleuritic chest wall pain. Constitutional symptoms such as weight loss and fatigue are more frequent in the later stages of the disease, but may occur in approximately one-third of the patients at presentation. Some

patients may be asymptomatic, and their disease is first noticed incidentally on a routine chest radiograph. Common findings on physical examination include signs of unilateral pleural effusion, including dullness to percussion and decreased air entry in the involved lung base. Fixed hemothorax, characterized by the lack of expansion of the chest, is present in large tumors and usually represents a late finding. Occasionally, patients with advanced disease may have palpable supraclavicular lymph nodes or a palpable chest wall mass. Clubbing is rare. Some patients may have no physical signs because of the presence of a localized pleural mass without effusion. II. WORKUP AND STAGING A. Imaging studies. Radiographic evaluation begins with a posteroanterior and lateral chest radiograph, which usually demonstrates a unilateral pleural effusion and, occasionally, a pleural-based mass. Approximately 20% of the patients have radiologic evidence of asbestos exposure on chest radiographs, such as pleural plaques. CT scan often shows an effusion with or without pleural mass and allows the evaluation of tumor extent. In some patients, mesothelioma produces a localized lobular thickening, whereas in others, it causes a rind of tumor encasing the lung. MRI may help further define the local extension of pleural mesothelioma to the chest wall and diaphragm. PET scan can be used to differentiate between benign and malignant pleural masses. This functional imaging modality may also allow the detection of lymph node or extrathoracic involvement. B. Diagnosis. Despite the presence of typical, clinical, or radiographic findings, the definitive diagnosis of mesothelioma should be made by pathologic evaluation. The initial diagnostic procedure is usually a thoracentesis. Cytology of the pleural fluid does not always provide a definitive diagnosis because the yield can be low. Furthermore, when abnormal cells are present, it is often difficult to differentiate mesothelioma cells from reactive mesothelial cells and other malignancies, such as adenocarcinoma. The diagnostic value of cytology may improve with the use of immunohistochemical (IHC) stains. When the cytology is inconclusive, patients should undergo a pleural biopsy. Samples may be obtained via thoracoscopic biopsy, CT-guided core biopsy, or video-assisted thoracoscopy with open biopsy. C. Pathology. Mesothelioma is classified into three histologic subtypes: epithelial, sarcomatoid, and biphasic. The epithelial type is the most common, comprising 50% to 60% of all cases. The sarcomatoid type is present in approximately 15% of cases and is characterized by spindle cells that are similar to fibrosarcomas. The mixed or biphasic subtype contains features of both epithelioid and sarcomatoid elements. Because the diagnosis of mesothelioma may not be easily accomplished from the pathologic specimen, IHC studies are commonly used to differentiate between

mesothelioma and metastatic or primary lung adenocarcinomas. The most commonly used IHC markers to diagnose epithelioid mesothelioma are calretinin, CK5, WT-1, and D2-40 (podoplanin). Negative markers that are rarely expressed in malignant melanoma, but are expressed in metastatic carcinoma, include claudin 4, p40/p63, carcinoembryonic antigen (CEA), BerEP4, BG8, MOC31, tumor treating fields (TTF) 1, and napsin A. BAP1 loss also occurs in 60% to 65% of malignant mesothelioma (J Thorac Oncol 2019;14:1704). Programmed cell death ligand 1 (PDL1) is also assessed by IHC. Electron microscopy should be reserved for difficult cases with equivocal IHC results. The epithelial form is composed of polygonal cells with long microvilli, prominent desmosomes, and abundant tonofilaments. The electron microscopy on the sarcomatoid variant reveals elongated nuclei and abundant rough endoplasmic reticulum. D. Serum markers. Serum mesothelin-related protein (SMRP) is a soluble form of mesothelin, which is elevated in most of the patients with mesothelioma. SMRP levels correlate with disease progression or response to therapy, and may be useful in the early detection for patients at risk. E. Staging. The most commonly used staging system is the TNM staging system, as proposed by the International Mesothelioma Interest Group (IMIG) and the IASLC (Table 14-6). TABLE 14-6

IASLC Eighth Edition of TNM Classification for MPM Staging

IASLC, International Association for the Study of Lung Cancer; MPM, malignant pleural mesothelioma; TNM, tumor, node, metastasis.

III. TREATMENT Mesothelioma is an essentially incurable disease and the primary goal of therapy is to improve the quality of life and prolong survival. In most cases, the tumor spreads along the serosal surface and infiltrates the underlying vital thoracic organs, preventing a complete surgical resection. Furthermore, mesothelioma often arises from multiple sites in the parietal pleura. Patients are commonly elderly with significant comorbidities, and the insidious symptoms frequently delay the diagnosis. The choice of treatment is determined by the stage of the disease and the patient’s comorbidities. A. Surgery. There are several surgical procedures used in the management of patients

with mesothelioma, including pleurodesis, pleurectomy with decortication (P/D), and extrapleural pneumonectomy (EPP). Pleurodesis is commonly used in the treatment of persistent dyspnea caused by large pleural effusions. This procedure is effective in preventing fluid accumulation and should be performed early during management. As the disease progresses, the tumor grows along the visceral pleura and encases the lung, preventing reexpansion. The resultant trapped lung is usually refractory to pleurodesis. P/D refers to the surgical removal of the visceral, parietal, and pericardial pleura from the lung, apex to diaphragm, without the removal of the lung. A complete resection is only possible in very early stages of the disease, and most of the patients develop a disease recurrence. EPP is the most aggressive procedure and involves the en bloc resection of the visceral and parietal pleura, lung, pericardium, and ipsilateral diaphragm. EPP achieves the greatest degree of cytoreduction and allows for higher doses of adjuvant radiation to be delivered to the ipsilateral hemithorax. The goal of both approaches is to achieve maximal cytoreduction. There remains controversy regarding the preferred surgical approach. The Mesothelioma and Radical Surgery (MARS) study assessed the clinical outcomes of patients assigned to EPP or no EPP (Lancet Oncol 2011;12:763). From 2005 to 2008, 112 patients were registered and 50 were randomized: 24 to EPP and 26 to non-EPP in the setting of trimodality therapy. The median OS was 14.4 months in the EPP group versus 19.5 months in the non-EPP group, with a hazard ratio (HR) of 1.90. Furthermore, there were 10 serious adverse events in the EPP group and 2 in the nonEPP group. Given the low numbers of patients enrolled, no definitive conclusions were drawn regarding OS, although EPP was associated with significant morbidity. A retrospective study analyzed 154 patients who underwent EPP, P/D, or exploratory/diagnostic procedures (J Thorac Carciovasc Surg 2018;155:2724). Of the 132 patients who underwent surgical resection, 57% achieved maximal cytoreduction via macroscopic completed resection (MCR). The median OS of patients who achieved MCR was 21.4 months versus 16.3 months in those who did not (p = 0.60). It was concluded that MCR was not associated with increased survival. B. Radiation therapy. Mesothelioma cells are relatively sensitive to radiation therapy and the goal is for local control but does not have significant effects on OS. Advances in radiation therapy have led to the use of intensity-modulated radiation therapy (IMRT). It has been evaluated in the adjuvant, neoadjuvant, postsurgical, and palliative settings. Both traditional radiation and IMRT are used in the treatment of mesothelioma. Several studies have shown improved locoregional control with adjuvant radiation, although the more recent Swiss Group for Clinical Cancer Research (SAKK) 17/04 study did not show a difference in locoregional control in patients who had received neoadjuvant chemotherapy and EPP and were then

randomized to receive adjuvant therapy or not (Lancet Oncol 2015;16:1651). The Intensity-Modulated Pleural Radiation Therapy (IMPRINT) trial evaluated 27 patients who received adjuvant IMRT. Of these, eight patients (29%) had grade 2 or 3 pneumonitis. The median PFS and OS were 12.4 and 23.7 months, respectively (J Clin Oncol 2016;34:2761). There have also been studies using IMRT before EPP. A study of 62 patients received 25 Gy in five daily fractions followed by a 5-Gy boost and EPP (J Thorac Oncol 2016;151:468). They found a median OS of 51 months and disease-free survival of 47 months in patients with epithelial subtype. Because mesothelioma is characterized by direct local invasion, it often invades tracts after local procedures. In these cases, prophylactic radiation may be used as a prophylactic measure. C. Systemic therapy. Chemotherapy has been used in the neoadjuvant or adjuvant setting in patients treated with multimodality treatment or as single modality in advanced cases where the role of chemotherapy remains palliative, because even trimodality therapy does not appear to achieve cure or significantly prolong survival. Among several regimens, the combination of pemetrexed and cisplatin emerged as the standard of care after a phase III study showed improved survival compared with single-agent cisplatin (J Clin Oncol 2003;21:2636). In this study, 456 patients were assigned to cisplatin alone (75 mg/m2 day 1 every 3 weeks) or in combination with pemetrexed (500 mg/m2 day 1 every 3 weeks). The combination arm resulted in significant benefit including improved response rate (41% vs. 16%, p < 0.0001), median time to progression (5.7 months vs. 3.9 months, p = 0.001), and median survival (12.1 months vs. 9.3 months, p = 0.02). The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) reported in 2016 combined this regimen with bevacizumab (Avastin) (Lancet 2016;387:1405). In this randomized, controlled phase 4 trial, 448 patients were randomly assigned to receive cisplatin plus pemetrexed with or without bevacizumab. PFS was improved in the bevacizumab group at 9.2 months compared to 7.3 months in the control group (HR 0.61; p < 0.0001). os was also significantly longer in the bevacizumab group at 18.8 months compared to 16.1 months (hr 0.77; p = 0.0167). Carboplatin combined with pemetrexed with or without bevacizumab is an acceptable alternative for patients who cannot tolerate cisplatin. This combination with bevacizumab had a response rate of 34% and a median survival of 15.3 months in a first-line phase II study (Br J Cancer 2013;109:552). Tumor treating fields have been approved by the U.S. Food and Drug Administration (FDA) in combination with pemetrexed and platinum in the first line. This is based on the phase 2 STELLAR trial, which showed a median OS was 18.2 months compared to 12.1 month in the historical control (Lancet Oncol 2019;20:170). Single-agent options include pemetrexed or vinorelbine in either firstor second-line settings.

There is no standard second-line treatment in malignant pleural mesothelioma (MPM). It is recommended that pemetrexed be given in the second line if not given initially or as a rechallenge in patients who had a prolonged initial response. A phase II study investigated sunitinib in patients progressive after systemic chemotherapy. Median time to progression was 3.7 months and median OS was 8.2 months (J Thorac Oncol 2012;9:1449). There have been several studies evaluating checkpoint inhibitors in MPM. The Keynote-028 trial was a phase 1b trial evaluating pembrolizumab, a monoclonal antibody against programmed cell death 1 (PD-1), in patients with greater than 1% positive PD-L1 tumor cells. This study had a response rate of 20% and a PFS of 5.4 months, with an OS of 18 months (Lancet Oncol 2017;18:623). The MAPS2 clinical trial is a phase 2 study evaluating nivolumab, an anti-PD-1 monoclonal antibody, or nivolumab plus ipilimumab, an anti-cytotoxic Tlymphocyte antigen-4 (CTLA-4) monoclonal antibody, in patients previously treated with MPM (Lancet Oncol 2019;2:239). A total of 125 patients were enrolled with a primary endpoint of 12-week disease control, which was achieved in 40% of the single-agent nivolumab group and 52% of the combination group. There are many clinical trials evaluating other investigational therapeutic strategies, including checkpoint inhibition, chimeric antigen receptor T-cell therapies, chimeric monoclonal antibodies, antibody drug conjugates, and immunotoxins. IV. PROGNOSIS The prognosis for patients with mesothelioma is poor, with median survival of approximately 12 months from diagnosis. Factors associated with poor prognosis include advanced stage, poor performance status, male sex, chest pain, weight loss, thrombocytosis, leukocytosis, anemia, older age, and sarcomatoid histology. Two prognostic systems have been developed on the basis of data collection from patients enrolled into large cooperative group trials. In the European Organization for Research and Treatment of Cancer (EORTC) study, the risk factors identified were Eastern Cooperative Oncology Group (ECOG) performance status 1 or 2, white blood cells more than 8,300/μL, hemoglobin decrease equal to or greater than 1 g/dL, probable or possible diagnosis, and sarcomatoid histology (J Clin Oncol 1998;16:145). Patients were subdivided into two prognostic groups: good prognosis with up to two risk factors and poor prognosis with three or more risk factors. Outcomes were significantly better for patients in the good prognosis category, with improved median survival (10.8 months vs. 5.5 months), 1-year OS (40% vs. 12%), and 2-year survival (14% vs. 0%). In the Cancer and Leukemia Group B (CALGB) study, the significant risk factors included poor performance status, chest pain, dyspnea, platelet count greater than 400,000/μL, weight loss, serum lactate dehydrogenase (LDH) greater than 500 IU/L, pleural involvement, anemia, leukocytosis, and age older than 75 (Chest 1998;113:723). There were six identified prognostic subgroups with median survival times ranging from 1.4 to 13.9

months. SUGGESTED READINGS Thymoma Berghmans T, Durieux V, Holbrechts S, et al. Systemic treatments for thymoma and thymic carcinoma: a systematic review. Lung Cancer 2018;126:25–31. Cho J, Kim HS, Ku BM, et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial. J Clin Oncol 2018;37:2162–2170. Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg 2004;77:1860–1869. Drevet G, Collaud S, Tronc F, et al. Optimal management of thymic malignancies: current perspectives. Cancer Manag Res 2019;11:6803–6814. Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum. Chest 2005;128:2893–2909. Ettinger D, Riely GJ, Akerley W, et al. Thymomas and thymic carcinomas. J Natl Compr Cancer Netw 2013;11:562–576. Evoli A, Lancaster E. Paraneoplastic disorders in thymoma patients. J Thorac Oncol 2014;9:S143–S147. Giaccone G. Treatment of malignant thymoma. Curr Opin Oncol 2005;17:140–146. Giaccone G, Wilmink H, Paul MA, et al. Systemic treatment of malignant thymoma. A decade of experience at a single institution. Am J Clin Oncol 2006;29:336–344. Kelly RJ, Petrini I, Rajan A, et al. Thymic malignancies: from clinical management to targeted therapies. J Clin Oncol 2011;29:4820–4827. Marx A, Chan JK, Coindre JM, et al. The 2015 World Health Organization classification of tumors of the thymus: continuity and changes. J Thorac Oncol 2015;10:1383–1395. Merveilleux du Vignaux C, Dansin E, Mhanna L, et al. Systemic therapy in advanced thymic epithelial tumors: insights from the RHYTHMIC prospective cohort. J Thorac Oncol 2018;13:1762–1770. Suster S, Moran CA. Thymoma classification. Current status and future trends. Am J Clin Pathol 2006;125:542–554. Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art. J Clin Oncol 1999;17:2280–2289. Zucali PA, De Pas T, Palmieri G, et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. J Clin Oncol 2018;36:342–349.

Mesothelioma Berzenji L, Van Schil PE, Carp L. The eighth TNM classification for malignant pleural mesothelioma. Transl Lung Cancer Res 2018;7(5):543–549. Carbone M, Adusumilli, PS, Alexander HR Jr. Mesothelioma: scientific clues for prevention, diagnosis and therapy. CA Cancer J Clin 2019;69:402–429. Ceresoli GL, Aerts JG, Dziadkiuszko R, et al. Tumor treating fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, singlearm phase 2 trial. Lancet Oncol 2019;20:1702–1709. Ceresoli GL, Zucali PA, Mencoboni M, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab as first line therapy in malignant pleural mesothelioma. Br J Cancer 2013;109:552–558. Dowell JE, Dunphy FR, Taub RN, et al. A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma. Lung Cancer 2012;77:567–571. Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135:620–626. Gooijer CJ, Baas P, Burgers JA. Current chemotherapy strategies in malignant pleural mesothelioma. Trans Lung Cancer Res 2018;7(5):574–583. Kim RY, Sterman SH, Haas AR. Malignant mesothelioma: has anything changed? Semin Respir Crit Care Med 2019;40:347–360. Tsao MS, Carbone M, Galateau-Salle F, et al. Pathologic consideration and standardization in mesothelioma clinical trials. J Thorac Oncol 2019;10:1704–1717. Volgelzang NJ, Rusthoven JJ, Symanowsky J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636–2644. Wald O, Sugarbaker DJ. New concepts in the treatment of malignant pleural mesothelioma. Annu Rev Med 2018;69:365–

377. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomized, controlled, open lab, phase 3 trial. Lancet 2016;387:1405–1414.

I.

ESOPHAGEAL CANCER A. Epidemiology. Esophageal cancer is a commonly found neoplasm and is the sixth most common cause of cancer deaths in the world and the eighth most common cancer in the world. There is vast geographic variation in the incidence of this cancer. The incidence in the United States has increased to approximately 8 per 100,000. China and Iran have an incidence of 23 per 100,000. In parts of Africa, Central America, and Western Asia, the incidence is approximately 2 per 100,000. The incidence of esophageal cancer increases with age and peaks in the seventh decade of life. Squamous cell carcinoma affects African American men six times more than it affects Caucasian men, whereas adenocarcinoma affects Caucasian five times as much. All subtypes of esophageal cancers affect men three times as often as they do women. Several factors can increase the risk of developing esophageal cancer. The longterm use of tobacco and alcohol are predisposing factors for development of squamous cell carcinoma of the esophagus. Obesity is a strong emerging risk factor and these individuals are three times more likely to develop esophagus cancer. Dietary factors such as inadequate vegetable and fruit intake, hot tea drinking, and excessive red meat intake may also increase the risk of the development of this cancer. Nitrosamines and their precursors (found in pickled vegetables, moldy or fermented foods, and smoked fish) are known to promote cancerous changes in the esophagus. Tylosis, a rare genetic syndrome characterized by hyperkeratosis of the palms and soles, carries the highest risk of developing squamous cell carcinoma from chronic inflammation and stasis (1,000-fold risk). Variants in antidiuretic hormone (ADH) and/or ALDH2 genes are associated with increased risk of developing squamous cell carcinoma. Other conditions associated with esophageal cancer are

head and neck malignancies, celiac disease, and gastroesophageal reflux disease. Patients with Barrett’s esophagus have a 50 to 100 times increased risk of developing adenocarcinoma than that of the healthy patient. In this disorder, the normal squamous epithelium of the esophagus is destroyed by chronic gastroesophageal reflux of acid, pepsin, and bile, and is ultimately replaced by columnar-lined metaplastic epithelium. The two most common pathologic subtypes of esophageal cancer are squamous cell carcinoma and adenocarcinoma. Other histologic types such as sarcomas, small cell carcinomas, and lymphomas are extremely rare. Previously, squamous cell carcinoma was the most frequent subtype, but over the past 30 years, the incidence of adenocarcinoma has been increasing rapidly in the Western world. In non-Western countries, squamous cell cancers represent the majority of esophageal cancers, with adenocarcinomas remaining relatively unusual. Adenocarcinomas are more frequently found in the distal esophagus, arising from chronic gastroesophageal reflux–induced Barrett’s esophagus. This precursor lesion is defined as the presence of metaplastic columnar epithelium with intestinal-type goblet cells. Specific guidelines have been established for screening Barrett’s esophagus and subsequent surveillance and treatment upon development of dysplasia. In contrast, squamous cell tumors make up the majority of malignancies in the upper and middle one-third of the esophagus, arising from the normal squamous lining of esophagus in the setting of chronic inflammation. Squamous dysplasia or intraepithelial neoplasia is the known precursor condition to esophageal squamous cell carcinoma. B. Clinical presentation. Patients with esophageal cancer often do not have symptoms until the esophageal lumen is greatly narrowed. The most common symptom in patients with esophageal cancer is dysphagia. It typically begins with solid food only but often progresses to occurring with liquids as the esophageal lumen becomes blocked by the cancer. Other common symptoms include weight loss, regurgitation, pain on swallowing, cough, heartburn unresponsive to medication, and chest pain. Patients with tracheoesophageal fistulas often present with postprandial coughing and may sometimes have aspiration pneumonitis. Physical examination findings are varied. It may be normal, show cachexia only, or there may be evidence of metastases such as supraclavicular lymphadenopathy, hoarseness from recurrent laryngeal nerve involvement (4 to 7 cm), T2 (tumor >7 cm limited to the kidney), T3 (tumor extending into major veins or perinephric tissues), and T4 (tumor invades beyond the Gerota fascia). N stage is divided into N0 (no regional lymph node metastases) and N1 (metastasis in regional lymph nodes), whereas M stage is categorized into M0 or M1 according to the absence or presence of distant metastases. Stages I and II are defined by T1 and T2 categorization, respectively, without regional lymph node or distant metastases. The presence of T3 or N1 defines stage III, whereas stage IV is defined by T4 or M1. Separate prognostication models have been developed for patients with localized and metastatic disease. For patients with localized disease, commonly used models include the University of California Los Angeles Integrated Staging System (UISS model), the Mayo Clinic Stage, Size, Grade and Necrosis model (SSIGN), or the Leibovich score, which is a modification of SSIGN. These models analyze tumor histology, stage, and grade as well as type of nephrectomy and patient performance status to stratify patients into low, intermediate, or high-risk groups. Similarly, the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and the MSKCC risk models stratify patients into favorable, intermediate, or poor-risk categories according to the presence of anemia, neutrophilia, thrombocytosis, or hypercalcemia; the patient performance status; and time from diagnosis to systemic therapy (Nat Rev Dis Primers 2017;3:17009). VI. TREATMENT A. Localized disease (stages I and II). The standard therapy for localized disease is surgical resection with either a radical nephrectomy or nephron-sparing partial nephrectomy, followed by surveillance. Radical nephrectomy involves the complete removal of the Gerota fascia and its contents including the kidney perirenal fat, ipsilateral adrenal gland, and sometimes regional lymph nodes. More recently, adrenalectomy has been indicated predominantly for patients with large upper pole lesions or abnormal gland by CT imaging in an attempt to avoid the complications from adrenal insufficiency ( J Urol 2009;181:2009). Regional lymphadenectomy provides some prognostic value but has no established therapeutic value. The main complication from radical nephrectomy is the development of chronic kidney disease, which increases the risk of cardiovascular events and overall mortality. With the pervasive use of modern imaging techniques, more patients are diagnosed with stage T1a disease. Partial nephrectomy is indicated for patients with T1a disease and selected cases with T1b disease. This approach is not indicated for patients with stage II disease. Both radical and partial nephrectomies can be performed through a laparoscopic approach, depending on the size of the primary tumor. Patients with stage T1a disease who are not candidates for surgery may be treated with ablation,

including cryoablation and radiofrequency ablation (RFA), which should be preceded by a biopsy to establish the histologic diagnosis for future follow-up. Patients with T1a disease carrying high surgical risk may be offered close surveillance because approximately 20% of small tumors are benign and the overall risk of developing metastasis in small RCCs is low ( J Urol 2017;198:520). B. Locally advanced disease (stages III and T4). Patients with higher stage RCC are managed with radical nephrectomy. Following complete surgical resection, the estimated risk of relapse in patients with RCC within 5 years ranges from approximately 10% in stage II, through 25% in stage III, to approximately 66% in T4N1 stage IV disease. Before the development of targeted therapy and immune checkpoint inhibitors (ICIs), the only adjuvant treatment option was either interferon alpha (IFN-α) or interleukin-2 (IL-2) immunotherapy, which failed to improve the disease-free survival (DFS) or overall survival (OS). The success of small-molecule tyrosine kinase inhibitors, antibody against vascular endothelial growth factor (VEGF) or mechanical target of rapamycin (mTORC1) inhibitors, and anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti–programmed cell death and its ligand (PD-1/PD-L1) checkpoint inhibitors in treating metastatic RCC has led to randomized clinical trials studying their use in adjuvant settings. Nearly all adjuvant trials using either VEGFR2 or mTORC1 inhibitors failed to show survival benefit (Curr Treat Options Oncol 2019;20:44). Surveillance in these patients should include history, physical examination, metabolic panel, and imaging every 3 to 6 months for the first 2 years, and annually starting in the third year. C. Metastatic disease. The standard approach for patients with metastatic RCC disease is systemic therapy, whereas surgical removal of primary tumor (cytoreductive nephrectomy) and/or limited oligometastases (metastasectomy) may have a role in selected cases. 1. Cytoreductive nephrectomy. The removal of the primary cancer followed by interferon alpha (INF-α) has been associated with a significant improvement in the median OS compared with INF-α alone in two identical large randomized trials including a total of 331 patients (13.6 vs. 7.8 months, p = 0.002) ( J Urol 2004;171:1071). Patients considered for cytoreductive nephrectomy should have resectable primary tumor, good performance status, and adequate organ function. Further investigation about the role of cytoreductive nephrectomy in the context of ICIs is needed to determine its role in the management of metastatic RCC (JAMA Oncol 2019;5:171). 2. Resection of metastases. Patients with oligometastatic disease may still be cured with surgery, particularly for those with single-site and metachronous presentation. For patients who have multiple RCC metastases in proximity within the same organ such as the lung, surgical resection of all metastatic lesions

should be considered if complete resection is possible. A retrospective study of 877 patients with metastatic RCC, 125 of whom underwent resection of metastatic lesions, showed that complete metastasectomy was associated with longer cancer-specific survival (CSS) of 4.8 years for those undergoing metastasectomy and 1.3 years for those who did not. This was best highlighted in patients with lung metastases, where complete resection led to a 5-year CSS of 73.6% compared to 17% for those who did not. This correlation was most predictive for patients who had more than three metastatic lesions (Cancer 2011;117:2873). 3. Systemic therapy. Immunotherapy with IL-2 and IFN-α were the only systemic therapy options for the treatment of metastatic RCC until the approval of targeted therapies and ICIs, which have revolutionized the field of improved survival outcomes for patients with metastatic RCC. Immunotherapy with cytokines has been used for several years, with IL-2 and IFN-α as the main drugs. However, with the development of targeted agents and ICIs, these are no longer used as first-line therapies because of the low response rate and significant toxicities. Of the 259 patients treated with high-dose IL-2 at the National Cancer Institute between 1986 and 2006, 23 patients (9%) achieved complete response (CR) and 30 patients (12%) achieved objective response. Although all patients with partial response (PR) eventually developed disease recurrence with a median of 15 months, only 4 of the 23 patients with CR developed recurrence by the time of the last follow-up, with the median OS not reached (Cancer 2008;113:293). 4. Targeted therapy. Several drugs have been approved for the treatment of metastatic RCC including multiple VEGF tyrosine kinase inhibitors, a VEGF monoclonal antibody (bevacizumab), and two mTOR inhibitors (everolimus and temsirolimus). Sorafenib was the first VEGF small-molecule inhibitor approved for RCC followed by the approval of sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib. In a randomized trial, patients treated with sunitinib had prolonged progression-free survival (PFS) (11 vs. 5 months), OS (26.4 vs. 21.8 months) and response rate (47% vs. 12%) compared to IFN-α (J Clin Oncol 2009;27:3584–3590). Head-to-head comparison between sunitinib and pazopanib demonstrated similar PFS and OS, but patients treated with pazopanib experienced fewer cytotoxic side effects and reported a better quality of life (N Engl J Med 2014;370:1769). Similarly, the AXIS trial compared axitinib to sorafenib, and axitinib was found to be superior with increased PFS (6.7 vs. 4.7 months), objective response rate (19% vs. 9%), and lower toxicity-related discontinuation rates (4% vs. 8%) (Lancet 2011;378:1931). The METEOR trial compared cabozantinib to everolimus for patients who have failed first-line

therapy with other VEGF inhibitors and demonstrated improved OS (21.4 vs. 16.5 months), PFS (7.4 vs. 3.9 months), and objective response rate (17% vs. 3%) for cabozantinib (Lancet Oncol 2016;17:917). In a randomized clinical trial including 153 patients previously treated with VEGF-targeted therapy, the combination of lenvatinib with everolimus was associated with a significant increase in PFS compared to everolimus alone (14.6 vs. 5.5 months) but not to lenvatinib alone (7.4 months), whereas patients treated with everolimus had fewer grade III or IV adverse events (50%) compared to lenvatinib alone (79%) and the combined regimen (71%) (Lancet Oncol 2015;16:1473). Bevacizumab is a monoclonal antibody that binds circulating VEGF-A, preventing its interaction with VEGFR2. Two large randomized clinical trials initially showed a significant benefit from the combination of bevacizumab and IFN-α compared with IFN-α alone. Nevertheless, the updated results from the Cancer and Leukemia Group B (CALGB) 90206 trial showed no significant benefit from the combination arm (18.3 vs. 17.4 months) (J Clin Oncol 2010;28:2137). The two mTOR inhibitors approved for the treatment of metastatic RCC are the intravenous temsirolimus and the oral everolimus. The ARCC trial randomized high-risk but treatmentnaive patients to temsirolimus, IFN-α, or both. The study showed improved PFS and OS for temsirolimus alone compared with IFN-α and increased toxicity without survival benefit from the combination (N Engl J Med 2007;356:2271). The RECORD-1 trial demonstrated that patients who have failed first-line sorafenib and/or sunitinib and were then initiated on everolimus had prolonged PFS (4.9 vs. 1.9 months) but not OS compared to the placebo group, although the lack of improved OS was thought to be secondary to the high rate of crossover in the placebo group. Patients receiving everolimus also experienced a lower rate of grade III or IV adverse events (Cancer 2010;116:4256). Subsequent trials that evaluated the sequential delivery of first-line everolimus followed by second-line sunitinib or the reverse order demonstrated superior OS for sunitinib followed by everolimus (29.5 vs. 22.4 months) (Ann Oncol 2017;28:1339). Although pazopanib and sunitinib still remain first-line agents for patients with favorablerisk disease, the development of ICIs has led to their decreased use as first-line agents for poor or intermediate disease. However, some are now being used in combination with ICIs such as axitinib, cabozantinib, and lenvatinib. Indeed, axitinib plus pembrolizumab has efficacy over sunitinib in all risk groups. a. Immune checkpoint inhibitors. The two main classes of ICIs ​targeting either CTLA-4 or PD-1/PD-L1 have been successfully used in RCC. Nivolumab, a PD-1 inhibitory antibody, was the first ICI to be studied in RCC (CheckMate 025), and it led to prolonged OS and decreased adverse events compared to everolimus. This was followed by the CheckMate 214

trial, which compared the use of nivolumab in combination with ipilimumab, a CTLA-4 inhibitory antibody, with sunitinib alone in treatment-naive patients. Seventy-five percent of patients treated with combination ICI therapy were alive at 18 months compared to 60% of those treated with sunitinib. Effects in OS could not yet be calculated because of durable response to therapy in the combination group. Moreover, patients experienced fewer toxicities and reported a higher quality of life. As a result, ICIs quickly became the first-line treatment option, especially for patients with poor/intermediate-risk disease (N Engl J Med 2018;378:1277). The KEYNOTE-426 trial showed increased survival at 12 months (90% vs. 78%) for patients treated with axitinib plus pembrolizumab compared to sunitinib alone as first-line treatment and improved PFS (15.1 vs. 11.1 months). However, the combination treatment group experienced slightly more grade III or IV adverse events. This combination is also currently used as first-line therapy for patients with metastatic RCC (N Engl J Med 2019;380:1116). D. Treatment of non–clear cell renal cell cancer (nccRCC). Most clinical trials have focused on ccRCC, and clinical data for treatment options for nccRCC is sparse, especially because they are less common. Both immunotherapy and VEGF-targeted therapies may be less effective in patients with nccRCC, and clinical trials are highly recommended in the front-line setting. SUGGESTED READINGS Cho E, Adami H-O, Lindblad P. Epidemiology of renal cell carcinoma. Hematol Oncol Clin North Am 2011;25:651–665. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomized, open-label, phase 3 trial. Lancet Oncol 2016;17:917–927. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171:1071–1076. Flippot R, Escudier B, Albiges L. Immune checkpoint inhibitors: toward new paradigms in renal cell carcinoma. Drugs 2018;78:1443–1457. Heng DY, Xie W, Regan NM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor targeted agents: results from a large multicenter study. J Clin Oncol 2009;27:5794–5799. Hsieh JJ, Purdue MP, Signoretti S, et a. Renal cell carcinoma. Nat Rev Dis Primers 2017;3:17009. Linehan WM, Ricketts CJ. The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications. Nat Rev Urol 2019;16:539–552. Moch H. An overview of renal cell cancer: pathology and genetics. Semin Cancer Biol 2013;23:3–9. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomized, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16:1473–1482. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–1290. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–1127. Vera-Badillo FE, Templeton AJ, Duran I, et al. Systemic therapy for non-clear cell carcinomas: a systematic review and meta-analysis. Eur Urol 2015;67:740–749.

I.

BACKGROUND A. Epidemiology. Bladder cancer is relatively common, with approximately 80,000 cases diagnosed in the United States in 2019. The median age at diagnosis is 73 years, and this disease is uncommon in patients younger than 40. Bladder cancer is more common in men than in women (3:1) and in Caucasians. Superficial tumors account for 75% of disease at diagnosis, whereas muscle-invasive disease accounts for 25%. B. Risk factors. The most well-defined risk factor for bladder cancer in the United States is cigarette smoking, responsible for approximately 50% of cases. Other risk factors include exposure to occupational carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and benzene. Chronic cystitis from prolonged indwelling catheters or in patients with spinal cord problems is associated with an increased risk of bladder cancer, with a higher percentage of squamous histology. Infection with Schistosoma haematobium, a parasite found mostly in Africa, the Middle East, and India, increases the risk of bladder cancer, primarily of squamous histology. Iatrogenic bladder cancer may occur because of pelvic radiation therapy or prolonged exposure to cyclophosphamide.

II. CLINICAL PRESENTATION The most common presenting symptom of bladder cancer is hematuria, which is usually gross, intermittent, and total (present during the entire urine stream). Virtually all patients with bladder cancer have at least microscopic hematuria. Because the hematuria is usually intermittent, further evaluation after the first episode should be pursued even if the repeated subsequent urinalyses are negative. In a prospective study evaluating 1,930 patients with either microscopic or gross hematuria, 230 patients (11.9%) had bladder cancer ( J Urol 2000;163:524). Irritative lower urinary tract symptoms including frequency, urgency, and dysuria may indicate the presence of microscopic hematuria, and

should prompt additional workup. Obstructive lower urinary tract symptoms such as incomplete emptying and decreased force of the urinary stream may occur in patients with tumor located at the bladder neck or prostatic urethra. Symptoms related to distant metastases are uncommon at presentation. Most patients have no disease-specific findings in the physical examination. With more advanced disease, a pelvic mass may become palpable. III. WORKUP AND STAGING A. Workup. Evaluation of patients with hematuria includes urinalysis, cystoscopy, and imaging of the upper urinary tracts. Hematuria is considered to be clinically significant when there are more than three red blood cells (RBCs) per high-power field (HPF). The gold standard for the diagnosis of bladder cancer is cystoscopy with transurethral resection of the bladder tumor (TURBT). Urine cytology, which has a low sensitivity but a very high specificity, should also be performed to increase the detection of upper urinary malignancies. Imaging studies help define the extent of the tumor and the presence of additional synchronous lesions. B. Pathology and staging 1. Pathology. Urothelial or transitional cell carcinoma is the most common histologic subtype of bladder cancer, representing more than 90% of cases in the Western countries. The most common nonurothelial malignancies are squamous cell carcinomas, adenocarcinoma, and small cell carcinomas. Pathologic features such as the “nested” variant of urothelial carcinoma, as well as the presence of sarcomatoid or plasmacytoid elements predict for a more aggressive clinical course. 2. Staging. Bladder cancer may be broadly subdivided into three categories including non–muscle-invasive, muscle-invasive, and metastatic tumors. Noninvasive tumors belong to stages 0 to I and are divided into Ta (noninvasive papillary carcinoma), T1 (invasion of the subepithelial connective tissue), and Tis (carcinoma in situ). Stage II is defined as invasion of the muscularis propria, and stage III indicates the invasion of perivesical tissue, either microscopically or macroscopically as a vesical mass or invasion of adjacent organs. Invasion of the pelvic or abdominal wall indicates T4b, which is classified as stage IVA. Involvement of lymph nodes beyond the common iliacs and the presence of distant metastases indicate stage IVB. The prognosis and goals of therapy are distinct for each category, ranging from prevention of relapse in non–muscleinvasive tumors to palliation in those with metastatic disease. IV. NON–MUSCLE-INVASIVE BLADDER CANCER Approximately 75% of the bladder tumors are non–muscle-invasive ones. The treatment

of choice for these tumors is TURBT with bimanual examination under anesthesia. The resection should sample the muscle to evaluate for invasion. Without additional therapy after a complete TURBT, more than half of the patients will have recurrence, with 10% of recurrences progressing to muscle-invasive disease. The probability of recurrence may be classified as low risk (low-grade solitary Ta ≤ 3 cm), intermediate risk (solitary low grade > 3 cm, low-grade Ta multifocal, high-grade Ta ≤ 3 cm, low-grade T1 or recurrence within 1 year with low-grade Ta), or high risk (high-grade T1, recurrent highgrade Ta, CIS, any bacillus Calmette–Guérin (BCG) failure in high-grade, any variant histology) (J Urol 2016;196:1021–1029). Most patients with metastases have concurrent or prior diagnosis of muscle-invasive tumor, with the development of metastasis in patients without history of previous muscle invasion being rare. The use of immediate intravesical chemotherapy using mitomycin, thiotepa, or epirubicin decreases the risk of recurrence (J Urol 2004;171:2186). The International Bladder Cancer Group recommends immediate intravesical chemotherapy for patients with low-risk disease (solitary and primary tumor, low-grade Ta). The most commonly used drug in this setting is mitomycin. Patients with intermediate (multiple or recurrent low-grade tumors) or high risk (T1, Tis, or grade 3) should be treated with BCG with 6-weekly instillations starting after bladder healing from surgery (J Urol 2011;186:2158). Maintenance BCG is usually offered to patients after the 6-week induction. BCG has been associated with decreased risk for both recurrence and progression. A large randomized trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) showed that there was no benefit from maintenance BCG for 3 years compared to 1 year in patients with intermediate risk. For patients with high-risk disease, 3 years of BCG decreased the risk of recurrence but not progressions or deaths (Eur Urol 2013;63:462). BCG is contraindicated in patients with bleeding, urethral stricture, active tuberculosis, urinary tract infection, immunosuppression, and within 14 days of TURBT (Semin Oncol 2012;39:559). Patients who are at high risk for progression, including those with multiple recurrences and high-grade T1, should be considered for immediate cystectomy. As an alternative to cystectomy, single agent systemic immunotherapy with pembrolizumab was granted FDA approval for the treatment of BCG-unresponsive, high-risk non-muscle invasive bladder cancer in January 2020. Pembrolizumab was evaluated in KEYNOTE-057 study, a single-arm trial that included 96 patients with BCG-unresponsive CIS with or without papillary tumors. The complete response rate in these patients was 41% (95% CI: 31, 51) and median response duration was 16.2 months (0.0+, 30.4+). Forty-six percent (46%) of responding patients experienced a complete response lasting at least 12 months. V. MUSCLE-INVASIVE DISEASE The standard therapy for patients with muscle-invasive bladder cancer is radical cystectomy with removal of the bladder, adjacent organs, and pelvic lymph node

dissection followed by urinary diversion through an ileal conduct or an internal urinary reservoir. The survival after radical cystectomy depends on the tumor extension and lymph node status. For patients who refuse cystectomy or who have comorbidities that prohibit a major surgical intervention, “bladder-sparing” approaches utilizing a combination of radiotherapy and chemotherapy have been studied and found to be effective (J Clin Oncol 1998;16:3576). A. Neoadjuvant chemotherapy theoretically provides benefit via the treatment of occult metastatic disease and has been tested in multiple trials. The Southwest Oncology Group (SWOG) 8710 randomized 317 patients to muscle-invasive bladder cancer stages T2 to T4a to radical cystectomy alone or preceded by three cycles of methotrexate 30 mg/m2 on days 1, 15, and 22, vinblastine 3 mg/m2 on days 2, 15, and 22, and doxorubicin 30 mg/m2 plus cisplatin 70 mg/m2 on day 2 (M-VAC) (N Engl J Med 2003;349:859). The median overall survival (OS) by intention-to-treat analysis was increased in the neoadjuvant M-VAC arm (77 vs. 46 months, p = 0.06). The BA06 30894 trial randomized 900 patients with muscle-invasive bladder cancer staged T2 to T4a to three cycles of neoadjuvant cisplatin 100 mg/m2 on day 2 and methotrexate 30 mg/m2 plus vinblastine 3 mg/m2 on days 1 and 8 (CMV) followed by definitive standard management according to the enrolling site (radical cystectomy or radiation therapy) or local therapy alone (Lancet 1999;354:533). The 10-year OS increased from 30% in the control group to 36% in the neoadjuvant CMV (hazard ratio [HR] 0.84, p = 0.037). In a meta-analysis including 3,005 patients enrolled in 11 randomized trials comparing neoadjuvant chemotherapy to local therapy alone, the former was associated with an increase in the 5-year OS from 45% to 50% (HR 0.86, p = 0.02) (Lancet 2003;361:1927). Because the combination of cisplatin and gemcitabine (GC) has been associated with similar outcomes compared to M-VAC in patients with advanced disease, it is also commonly used in the neoadjuvant setting despite the lack of prospective data, particularly because retrospective analyses have shown similar rates of pathologic complete response and survival between the two regimens (Cancer 2008;113:2471; Urology 2012;79:384). Dose-dense M-VAC (ddMVAC) in combination with pegfilgrastim appears as effective and less toxic than is standard dose M-VAC, but has not been directly compared in M-VAC in a prospective neoadjuvant study (J Clin Oncol 2014;32:1889). B. Adjuvant chemotherapy. Owing to the lack of completed randomized studies with adequate sample sizes, there is no level I evidence of benefit with this approach, with conflicting results from the reported studies (Eur Urol 2012;62:523). The ABC metaanalysis evaluated data from 491 patients in six trials, showing a 25% reduction in the risk of death with adjuvant chemotherapy, with most of the benefit observed in patients with pathologic T3 to T4 disease or lymph node involvement (Eur Urol

2005;48:189). More recently, the EORTC attempted to compare immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder in a prospective phase III study. Chemotherapy improved progression-free survival (PFS; HR 0.54, p = 0.0001) and led to a nonsignificant improvement in OS (HR 0.78, p = 0.13), but the study was underpowered because of poor accrual and was closed after recruitment of 284 of the planned 660 patients. Therefore, patients who did not undergo neoadjuvant chemotherapy should at least have a discussion regarding the use of adjuvant chemotherapy, particularly in patients with high-risk features such as extravesical involvement or positive lymph nodes. C. Radiation therapy. In many countries, external-beam radiation is considered standard therapy for muscle-invasive bladder cancer. In the BA06 30894 trial, the local therapy consisted of radiation, surgery, or both at the discretion of the treating physicians. Radiation was used in 50% of the patients, including 42% as the only modality for local therapy. Although the local therapies were not compared, there was no evidence for a preferential benefit from neoadjuvant chemotherapy in either group. Owing to the high risk of local relapse in patients with pathologic T3 or T4 disease, these patients may be considered for adjuvant radiotherapy. Because neoadjuvant radiation therapy does not improve survival compared to surgery alone, it is not indicated in this setting. D. Bladder preservation options are alternatives to radical cystectomy in selected patients with stage T2 or T3a who are not fit for surgery or who are not interested in such an aggressive approach, which is associated with a significant morbidity. These patients may be treated with transurethral resection (TUR) alone, TUR followed by adjuvant chemotherapy, radiotherapy, or chemoradiotherapy. Another option is partial cystectomy, which allows the complete resection of the bladder tumor with wide surgical margins. In medically operable patients, trimodality therapy with maximal TUR followed by chemoradiotherapy appears to be associated with the best outcomes. The presence of persistent or recurrent muscle-invasive bladder cancer after any form of bladder preservation represents a formal indication for radical cystectomy (BJU Int 2013;112:13). VI. METASTATIC DISEASE A. Chemotherapy. The currently recommended regimens for patients with advanced bladder cancer and eligible for cisplatin therapy include GC and ddMVAC. A large clinical trial randomized 405 patients to GC (gemcitabine 1,000 mg/m2 on days 1, 8, and 15 plus cisplatin 70 mg/m2 on day 2) to standard dose M-VAC for a maximum of six cycles (J Clin Oncol 2000;18:3068). The study showed no significant differences in response rate (55% in both arms), time to progression (7.4 months in both arms),

and median OS (13.8 months with GC and 14.8 months in M-VAC). Because GC was associated with lower rate of toxicities, it became a more commonly used regimen than was M-VAC. The EORTC 30924 randomized 263 patients with untreated unresectable or metastatic bladder cancer to standard M-VAC or ddMVAC (methotrexate 30 mg/m2 on day 1, vinblastine 3 mg/m2 on day 2, doxorubicin 30 mg/m2 on day 2, and cisplatin 70 mg/m2 on day 2, with granulocyte colony– stimulating factor on days 3 to 7, repeating every 15 days) (Eur J Cancer 2006;42:50). ddMVAC was associated with increased response rates (64% vs. 50%, p = 0.009), median PFS (9.5 vs. 8.1 months, HR 0.73, p = 0.017), and 5-year OS (21.8% vs. 13.5%, p = 0.042). Several drugs have activity in patients with bladder cancer and may be used in the second-line setting, including taxanes, ifosfamide, pemetrexed, and gemcitabine, if not previously used. Patients who are not candidates for cisplatin may be treated with gemcitabine combinations, most commonly with either carboplatin or taxanes (Int J Urol 2014;21:630). B. Immunotherapy. Several immune-checkpoint blockade agents have been tested in the second-line setting following platinum-based chemotherapy or in the first-line setting in patients ineligible for cisplatin chemotherapy. The KEYNOTE-045 trial demonstrated that, compared to single-agent chemotherapy, PD-1 blockade with pembrolizumab significantly improved median OS in patients previously treated with platinum-based chemotherapy (7.4 vs. 10.3 months). The objective response rate was also significantly higher in the pembrolizumab group (21.1%) than that in the chemotherapy group (11.4%). No difference in PFS, however, was observed (N Engl J Med 2017;376:1015). Four other PD-1 or PD-L1 targeting agents are also utilized in the second line (nivolumab, atezolizumab, durvalumab, and avelumab), but none are yet supported by prospective randomized studies. Pembrolizumab and atezolizumab are also approved by U.S. regulatory agencies for use in patients with metastatic urothelial carcinoma and unfit for cisplatin chemotherapy, based on nonrandomized studies suggesting favorable survival and toxicity profiles compared to historical data. Treatment selection for cisplatin-ineligible patients deemed reasonable candidates for either carboplatin-based doublet therapy or immunotherapy involves individualized treatment discussions and may be assisted by PD-L1 staining status. In June 2020, the FDA granted accelerated approval for the use avelumab for maintenance treatment of UC based on the results of the JAVELIN Bladder 100 trial (NCT02603432), a phase 3 randomized study which compared maintance avelumab to best supportive care (BSC) in patients with unrespectable, locally advanced or metastatic UC that had not progressed with four to six cycles of first-line platinumcontaining chemotherapy. Avelumab 800 mg was administered intravenously every 2 weeks and was initiated within 4-10 weeks after last chemotherapy dose. The median

OS in all patients was 21.4 months in the avelumab arm and 14.3 months in the BSC alone arm (HR: 0.69; 95%CI: 0.56, 0.86; p=0.001). C. Other systemic treatments. Approximately 15% of advanced bladder cancers have gain-of-function mutations in FGFR3. The pan–fibroblast growth factor receptor (FGFR) inhibitor erdafitinib was tested in a phase II study in patients with advanced urothelial carcinoma who had previously been treated with chemotherapy (N Engl J Med 2019;381:338). The use of erdafitinib was associated with an objective tumor response in 40% of patients and median duration of response was of 5.6 months. Erdafinitib is now approved by U.S. regulatory agencies for the treatment of FGFR3altered bladder cancers. In December 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv, a Nectin-4-directed antibody-drug conjugate, for patients with locally advanced or metastatic urothelial cancer previously treated with a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy. Approval was granted based on EV-201 (NCT03219333), a single-arm, multicenter trial enrolling 125 patients. The ORR was 44% (95% CI: 35.1, 53.2) with estimated median response duration of 7.6 months (95% CI: 6.3, not estimable). The recommended enfortumab vedotin-ejfv dose is 1.25 mg/kg (up to a maximum dose of 125 mg) administered on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. SUGGESTED READINGS Bellmutnt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015–1026. Brausi M, Witjes JA, Lamm D, et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J Urol 2011;86:2158–2167. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol 2016;196:1021–1029. Grossman H, Natale R, Tangen C, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–866. Khadra MH, Pickard RS, Charlton M, et al. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol 2000;163:524–527. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019;381:338–348. Meeks JJ, Bellmunt J, Bochner BJH, et al. A systematic review of neoadjuvant and adjuvant chemotherapy for muscleinvasive bladder cancer. Eur Urol 2012;62:523–533. Powles T. Inhibition of PD-L1 by MPDL3280A and clinical activity with metastatic urothelial bladder cancer. J Clin Oncol 2014;32:325s. Sathianathen NJ, Regmi S, Gupta S, et al. Immuno-oncology approaches to salvage treatment for non-muscle invasive bladder cancer. Urol Clin North Am 2020;47:103–110. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 98-03. J Clin Oncol 1998;16:3576–3583. Sio TT, Ko J, Gudena VK, et al. Chemotherapeutic and targeted biological agents for metastatic bladder cancer: a comprehensive review. Int J Urol 2014;21:630–637. Smith ZL, Christodouleas JP, Keefe SM, et al. Bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC): a review of the literature and practical approach to therapy. BJU Int 2013;112:13–25. Von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin,

and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;17:3068–3077.

I.

BACKGROUND Prostate cancer is the most common malignancy in males and the second most common cause of cancer-related death in men in the United States. The lifetime risk of a prostate cancer diagnosis is approximately 12%, but the lifetime risk of prostate cancer death is only 3.4%, with approximately 98% of patients with prostate cancer surviving 5 years. With the widespread adoption and use of prostate-specific antigen (PSA) screening in the late 1980s and early 1990s, the clinical presentation of prostate cancer has changed from advanced to localized disease in more than 80% at the time of diagnosis. The current challenge of research is to use this lead time bias to an advantage to achieve better overall survival and quality of life (QOL) with new treatments. However, the price of early detection and screening is “overdiagnosis,” which results in diagnosis, treatment, side effects, and anxiety in tens of thousands of men who would not have manifested symptoms of prostate cancer within their lifetime. With improved understanding of the molecular aberrations and their influence on clinical outcomes, it is likely that we will individualize therapy for this common malignancy.

II. PRESENTATION Prostate cancer rarely causes symptoms early in the course of the disease because most of the adenocarcinomas arise in the periphery of the gland away from the urethra. In the PSA era, the most common clinical finding is the absence of symptoms. The presence of symptoms because of prostate cancer often suggests locally advanced or metastatic disease. Growth of prostate cancer around or into the urethra, or involvement of the bladder neck can result in decreased urinary force of stream, frequency, urgency, nocturia, or hematuria. However, many of these symptoms are not specific and may occur with benign prostatic hyperplasia and aging. The differential diagnosis for hematuria should also include consideration of other cancers, such as bladder or kidney,

in addition to nonmalignant etiologies. Involvement of ejaculatory ducts can cause hemospermia, and extraprostatic disease involving the branches of pelvic plexus can cause erectile dysfunction (ED). Metastatic disease can cause a wide variety of symptoms related to the sites of metastases. Bone is the favored site of metastasis, with pain being a common and, at times, debilitating symptom. Men with spinal metastases, however, may live for years. Therefore, careful and thoughtful serial histories and examinations are mandatory. The most devastating consequences of bone involvement are pain, fractures, and spinal cord or nerve root compression. Spinal cord compression is usually accompanied by back pain that is often made worse by coughing, sneezing, straining, and other activities that increase intradural pressure. Unlike nonmalignant causes of back pain, the back pain of metastatic prostate cancer is usually worse at night. If a peripheral nerve is pinched by tumor, the back pain may radiate around to the front of the patient in the thorax or abdomen or down the legs. Patients with early spinal cord compression will have weakness, with progression to paralysis occurring, on the one hand, over a period of weeks to even months. In contrast, late spinal cord compromise leads to loss of sensation distal to the level of metastasis, urinary retention, and incontinence in a matter of minutes to hours. The classic symptoms of cauda equina syndrome are low back pain, bilateral sciatica, sensory and motor deficits, including sacral and perianal anesthesia, and loss of sphincter control of bladder and anus. Delays in management result in permanent loss of sensation, motor function, and continence. Fatigue is a prominent complaint of patients, but it may occur for very different reasons depending on the state of the tumor and the patient. If owing to advanced or metastatic disease, it may be an indicator of bone marrow infiltration by tumor with associated anemia. Liver involvement occurs in only 15%, usually at the end of life. Hepatic metastases are usually due to poorly differentiated adenocarcinomas or to tumors with small cell (neuroendocrine) differentiation. Androgen deprivation therapy (ADT) and/or chemotherapy can cause anemia; but the former is usually mild, whereas the latter may be moderate or severe. Lower limb edema can result from pelvic lymph node involvement, compression of iliac veins, and/or deep vein thrombosis (DVT). Lymphadenopathy around and compressing the ureters may result in hydronephrosis and/or renal insufficiency, with resultant symptoms of renal failure. Shortness of breath may be due to chemotherapy treatment, anemia, pulmonary embolism, and/or lung metastases, but the latter occurs late in only 15% of patients. Later in the course of the disease, older men complain of fatigue and gradually fail to thrive at home, with debilitating bone pain, weakened legs, decreased activity, poor appetite, weight loss, and other symptoms of advanced metastatic disease. With the widespread use of PSA screening and early detection programs, the most common finding on examination of the prostate is the absence of findings. Despite the

lead time bias that PSA screening introduces, physicians must be able to perform an excellent digital rectal examination (DRE) to diagnose and clinically stage localized prostate cancer. Attention should be directed to defining the presence or absence of a nodule and its location with respect to the right or left lobe and median raphe. Clearly, the absence of a nodule does not preclude the diagnosis of prostate cancer, and hardness of the prostate may simply indicate the presence of tumor. As patients become more obese, the DRE becomes more difficult to perform, but one should try to define extracapsular extension and/or involvement of the seminal vesicles. The sensitivity and specificity of the DRE is modest to poor, depending on the examiner, which can lead to both over- and underdiagnosis. However, any distinct nodule felt on DRE should be further evaluated, even in the setting of a normal PSA because there are low PSAproducing tumors. As with all cancer patients, the oncologist must do a careful, comprehensive physical examination, with special attention to signs of anemia, lymphadenopathy, bone tenderness, neuropathy, and lower extremity edema. For men treated with ADT, the testicular examination ought to show atrophy, whereas its absence should alert the physician that the patient does not have castrate levels of testosterone. Because of the potential for extended periods of good QOL and survival, even with metastatic disease, prostate cancer remains one of several neoplasms that physicians must rule out in the evaluation of carcinoma of unknown primary tumor. III. WORKUP AND STAGING Autopsy studies have shown localized prostate cancer in approximately 30% of men older than 50 years and 70% of men older than 80 years. However, with the availability of serum PSA and transrectal ultrasonogram (TRUS)-guided needle biopsy of the prostate, clinically organ-confined prostate cancer is increasingly diagnosed, with continuing uncertainty regarding the clinical significance of some tumors. Defining the grade of the tumor and anatomic stage is critical in understanding the prognosis and formulation of a treatment plan. Various predictive models (e.g., Partin table, Kattan nomograms) have been developed and are available for use in clinical practice for counseling patients and for planning a rational management plan. Most of these validated models include prognostic variables such as PSA, Gleason score, and clinical stage of the cancer. A. Laboratory testing 1. Prostate-specific antigen. PSA is a serum marker that is central to the diagnosis and management of prostate cancer. PSA is made and secreted by both normal and malignant cells of the prostate. The use of PSA testing has helped identify cases of prostate cancer that are or will become clinically significant, rather than simply identifying cases of cancer that are unlikely to be detected until autopsy.

PSA is directly associated with tumor volume and clinical stage in the vast majority of patients with prostate cancer. Normal PSA ranges depend on factors such as age and race. PSA level can be potentially affected by several factors, including prostatic biopsy, benign prostatic hypertrophy (BPH), prostatitis, and DRE. In the absence of a positive DRE or other symptoms concerning for prostate cancer, PSA testing should be repeated before the pursuit of a TRUS biopsy. If prostatitis is suspected, a course of appropriate antibiotic (e.g., ciprofloxacin) with or without a nonsteroidal anti-inflammatory drug (NSAID) should be administered after initial evaluation with DRE and urinalysis. PSA should be rechecked after approximately 6 weeks, because normalization of PSA may occur if caused by inflammation/infection rather than prostate cancer. Persistent elevations in PSA after treatment should trigger consideration of TRUS biopsy, especially in the setting of increased prostate cancer risk factors such as family history, ethnicity, and genetics. Absolute PSA levels and the rate of change of those levels with respect to time can predict the likelihood of organ-confined disease and influence opinions on the likelihood of a cure. PSA levels greater than 10 μg/L are associated with increased risk of extracapsular extension. The positive predictive value for a PSA between 4 and 10 ng/mL in patients with normal DRE is only 30% approximately. To improve the performance of the PSA test, modifications, such as PSA velocity, PSA density, and free-to-total PSA ratio, have been used. Some physicians advocate the use of free PSA versus bound PSA to quantify further the risk of cancer and need for biopsy; higher percentage free PSA levels are associated with more favorable histopathologic features in prostate tumors. A cutoff of 25% free PSA detects 95% of cancer while avoiding 20% of unnecessary biopsies. PSA kinetics has been explored to improve PSA testing. A study showed men whose PSA level increased by more than 2.0 ng/mL during the year before diagnosis of prostate cancer were at high risk for cancer-specific death even if they had “favorable” clinical parameters (such as a PSA level 72 Gy) remain to be determined. An additional unanswered question is the role of whole-pelvic versus prostate-only XRT. The combination of hormonal therapy with brachytherapy in locally advanced disease has not yet shown convincing evidence of survival benefit. 3. Increasing PSA after prostatectomy or radiation. Asymptomatic progressive increase in PSA is a common problem in patients with prostate cancer after XRT or surgery, termed biochemical recurrence (BCR). Prognostic factors to consider in this setting are doubling time of PSA, time from definitive therapy to increase in PSA, age of the patient, and comorbidities. Many methods have been used to predict failure, and most physicians consider higher risk patients to be those with seminal vesicle involvement, aggressive histology (Gleason >6), and PSA greater than 10. PSA doubling time of less than 6 months is highly predictive of disease progression compared to doubling time of more than 10 months. Local control after initial failure can be attempted. XRT (with or without ADT) may provide additional local control after RP, but it has not shown a consistent survival benefit and may be associated with higher rates of radiation-related complications. Ongoing trials will attempt to determine whether combined hormonal and XRT is beneficial in patients with increasing PSA after definitive surgery. Salvage prostatectomy after XRT is an option, but is associated with higher surgical complication rates. Other surgical options in this setting include cryotherapy and brachytherapy, but no conclusive clinical trials supporting use of these modalities are available. Most men who have increasing PSA levels after initial management (e.g., RP followed by adjuvant or salvage XRT) are given medical therapy (i.e., ADT), which, while not curative, may result in long term suppression. It is important to note that for most patients, the time from BCR to development of detectable metastatic disease and death from prostate cancer is usually several years. Thus, while currently not curable, these patients will typically have long prostate-cancer specific survivals. C. Metastatic disease (N1 or M1) 1. Initial therapy (hormone-sensitive disease). Medical or surgical castration remains the first-line therapy for metastatic disease, because it is associated with a response rate greater than 80% and can often reduce PSA levels to undetectable levels. In the recent past, metastatic prostate cancers have remained sensitive to the effects of hormonal blockade for an average of 12 to 18 months. Currently, with lead time bias of diagnosis, more widespread use of PSA as a serum marker,

improved imaging, and early hormonal intervention, men can respond to androgen deprivation for 2 or more years, with some living up to a decade. Given the psychological impact of surgical castration, most men in the United States prefer medical androgen blockade to bilateral orchiectomy. However, surgery is certainly the most cost-effective treatment. Gonadotropin-releasing hormone (GnRH) receptor agonists are the most commonly employed first-line agents. Because these agents are agonists, they will initially increase serum testosterone levels (and thus PSA levels; “flare”) and could result in progression of pain, disease, and even spinal cord compression. Therefore, before GnRH injection, treatment with an androgen receptor antagonist (bicalutamide 50 mg daily, nilutamide 150 mg daily, or flutamide 250 mg three times a day) is warranted. Routinely, these drugs are started 2 weeks before injections and are prescribed for 1 month. Then, leuprolide acetate (Lupron) may be given as 4month (30 mg), 3-month (22.5 mg), or 1-month (7.5 mg) intramuscular injections. Another GnRH agonist, goserelin (Zoladex), is introduced as a depot injection into the anterior abdominal wall, subcutaneously (SC), every 3 months (10.6 mg) or every month (3.6 mg). A newer GnRH receptor antagonist, degarelix (Firmagon) was recently developed and is now in clinical use (240 mg SC × 1, followed by 80 mg monthly). This therapy avoids the testosterone “flare” and pretreatment with antiandrogens is not required. This affords another treatment option in cases of pending cord compression where rapid suppression of testosterone is desired. The most common side effects are hot flashes and ED. However, over the first year of ADT, many men will become anemic and fatigued, lose muscle mass and gain fat tissue, and lose bone density. Combined androgen blockade (CAB), with both a GnRH agonist and an androgen receptor blockade (ARB), shows minimal improvement over GnRH agonist alone, although meta-analyses have shown significant outcomes benefit. Long-term side effects of ADT include the possibility of developing osteoporosis, cardiovascular effects, and cognitive deficits, although conflicting data obscure the exact incidence and significance. Failure of first-line ADT is often marked by an asymptomatic rise in PSA, although symptoms of urinary tract outlet obstruction, bone pain, and so on may be observed as well. This transition may be referred to as castrate-resistant disease, but the androgen receptor is still present and can respond to androgens. Therefore, it is important to maintain patients on ADT with GnRH agonists/antagonists. If the patient was treated with a GnRH analog alone, then one may add an ARB. If the patient was managed with CAB, then it is wise to stop treatment with the ARB, to rule out “antiandrogen withdrawal syndrome.” Only approximately 10% of these patients will respond, but sometimes it may

take 6 weeks to observe a decrease in PSA levels. Some data suggest that in tumors of a subset of patients, mutations of the androgen receptor result in these agents (e.g., bicalutamide, flutamide) acting as an agonist, instead of an antagonist of the androgen receptor. Eventually, second-line hormonal therapy will no longer work, and this stage may be treated with inhibitors of adrenal androgen synthesis (ketoconazole, hydrocortisone, or a combination), estrogens, and progestins. Although randomized trials have not shown a clear benefit in the use of third-line hormonal therapy, there is clearly a subset of patients that respond. However, with newer effective agents approved in the castrate-resistant setting, additional hormonal manipulation (e.g., with ketoconazole/hydrocortisone or estrogens) at this stage has become a less common treatment practice. Given the lack of survival benefit with these agents, the majority of castrate-resistant patients should be treated with newer U.S. Food and Drug Administration (FDA)-approved agents (discussed in Section IV.D). 2. High-risk/high-volume metastatic hormone-sensitive disease. In a subset of patients with “high-risk/high-volume” metastatic hormone-sensitive prostate cancer (mHSPC), the addition of a second therapeutic to ADT has been shown to significantly improve outcomes and survival. “High risk/high volume” is defined variably, but typically includes patients with greater than four sites of metastatic disease (with at least one outside the spine/pelvis) and/or visceral (e.g., lung, liver) involvement of metastatic prostate cancer. In several trials, the addition of either chemotherapy (i.e., docetaxel) or hormonal therapy (i.e., abiraterone, apalutamide, enzalutamide) to ADT resulted in a significant improvement in overall survival in these patients compared to treating them with ADT alone. Given the comparable outcomes with all the agents tested, the choice of which to add should be based on comorbidities (e.g., avoid docetaxel in patients with neuropathy) as well as other factors, such as financial toxicity. D. Castrate-resistant disease. Once the tumor has progressed through ADT plus antiandrogen therapy, it is considered to be castration-resistant prostate cancer (CRPC). Nevertheless, the tumor can still respond to androgens, so it is important to maintain castrate levels of testosterone. This can occur in two settings: (1) in the nonmetastatic setting or (2) in the presence of metastatic disease (either de novo or developed after initial treatment). 1. Nonmetastatic castration-resistant prostate cancer (nmCRPC). Those patients with clinically localized disease who underwent initial treatment (and any salvage therapy) for prostate cancer and subsequently had PSA recurrences will typically be treated with ADT (as mentioned earlier). However, once evidence of castrate resistance emerges—defined by consistently rising PSA in the setting of .

castrate levels (10 mm)

IIIA2

Microscopic extrapelvic peritoneal involvement

IIIB

Macroscopic extrapelvic peritoneal metastases ≤2 cm

IIIC

Macroscopic extrapelvic peritoneal metastases>2 cm

IVA

Pleural effusion with positive cytology

IVB

Metastases to liver, spleen, or extra-abdominal organs including lymph nodes

FIGO, International Federation of Gynecology and Obstetrics.

Five-year survival in patients with early-stage disease (stage I or II) is often as high as 80% to 95%. However, patients with advanced disease (stage III or IV) have much lower survival rates of 30% to 50%.

E. Postoperative treatment 1. Epithelial tumors of low malignant potential (LMP). Also called borderline tumors, this subgroup represents approximately 10% to 15% of all epithelial ovarian tumors. The tumors are usually stage I (80%) and are characterized pathologically by epithelial cell stratification, increased mitoses, nuclear abnormalities, and atypical cells without stromal invasion. Surgical staging is usually recommended, but given that these tumors tend to occur in younger patients, conservation of fertility is often possible. Cystectomy with ovarian preservation can be considered, but recurrence is higher. Standard treatment is simple surgical resection with salpingo-oophorectomy, and lymph node removal is usually not required. Chemotherapy does not appear to have a role in treating most of these tumors. However, LMP tumors are, on rare occasions, found to have invasive implants (metastases), in which case the treatment should be similar to that for frankly invasive disease with adjuvant chemotherapy. By convention, however, the tumor is still considered LMP because the diagnosis is based on the primary tumor only. Recurrent disease is usually treated with repeat surgical debulking. The prognosis for patients without invasive implants is excellent, with very few patients dying of disease, with the average time to recurrence being 10 years. Patients are often followed up with serum CA-125 determinations every 3 to 12 months, but it is unclear whether this provides any survival benefit. In addition, patients have been known to have recurrence with invasive disease. 2. Early-stage disease with invasive tumors. Patients with stage IA or IB with grade 1 or 2 disease are considered low risk, with excellent survival chances (90% to 95%). Treatment with full surgical staging followed by close follow-up is typically all the treatment that is required. For those patients who wish to preserve fertility, a unilateral salpingo-oophorectomy with adequate staging may be considered in some patients with stage IA grade 1 disease. Patients with stage IC disease, stage I grade 3 disease, stage I grade 2, or stage II disease are considered at high risk for recurrence and are treated with platinum-based adjuvant chemotherapy to reduce the risk of relapse. With chemotherapy, diseasefree survival is approximately 80%. The number of chemotherapeutic cycles for treatment of early-stage disease is debatable and in 2006, the Gynecology Oncology Group (GOG) 157 showed that, compared to three cycles, six cycles of carboplatin and paclitaxel do not significantly alter the recurrence rate in high-risk, early-stage ovarian cancer but are associated with more toxicity. However, some question the statistical power of this study because there was a strong trend toward decreased recurrence in stage I disease with six cycles (p = 0.073). Given these findings, in 2010, an

exploratory analysis of the patients included in GOG 157 was undertaken to determine whether there were subsets of patients with high-risk, early-stage ovarian cancers that may benefit from more cycles of chemotherapy (Gynecol Oncol 2010;116:301). The authors found that compared to three cycles, six cycles of adjuvant chemotherapy may decrease the recurrence in women with serous histologies, with a statistically significant difference at 2-year recurrence-free survivals (93% for six cycles vs. 80.8% for three cycles, p = 0.007). Unfortunately, this benefit did not extend to overall survival (OS). In addition, the utility of subset analyses in shaping clinical treatments is debated, and a prospective randomized clinical trial would be necessary to confirm these findings. 3. Advanced disease. Most patients with ovarian cancer present with advanced stage disease (stages III and IV). Maximal efforts for surgical cytoreduction of the tumor before chemotherapy or following three to four cycles of platinum taxane therapy (“interval cytoreduction”) should be made because studies have consistently demonstrated improved survival in those patients with resection to no gross residual disease. Optimal cytoreduction has been defined in a variety of ways in the literature; currently, the GOG defines optimal cytoreduction as no residual tumor nodules with a diameter greater than or equal to 1 cm, but many are now using an international standard of no gross residual to be considered “optimal.” Patients with less than 2 cm residual disease have a median progression-free survival (PFS) and OS of 22 and 50 months, respectively (GOG 158), compared to 18-month PFS and 38-month OS (GOG 111) in patients with greater than 2 cm of residual disease. A study assessing survival rates at specific residual disease diameters to determine the optimal goal of primary cytoreduction found that patients with no gross disease or less than 1 mm had significantly longer overall median survival compared with patients with macroscopic residual disease greater than 1 mm (Gynecol Oncol 2006;103:559). Patients with advanced stage disease will require postoperative adjuvant chemotherapy to treat residual disease. Taxane and platinum-based chemotherapy is the current standard of postoperative care and has been shown to extend PFS as well as OS. This current standard of care is based on clinical trials demonstrating similar efficacy of carboplatin/paclitaxel to cisplatin/paclitaxel with less chemotherapyrelated toxicity and a shorter administration time. The regimen consists of intravenous (IV) administration of paclitaxel (175 mg/m2) given over 3 hours and carboplatin dosed with an area under the curve (AUC) of 5 to 6, utilizing the Jelliffe formula to estimate creatinine clearance and the Calvert formula to determine AUC. This regimen is given every 3 weeks for a total of six cycles. Response rates (complete response [CR] + partial response [PR]) are

approximately 80% with this combination, and more than 50% of patients will have a complete clinical response. Although most patients tolerate platinum- and taxane-based chemotherapy relatively well, some develop severe peripheral neuropathy and the use of docetaxel has been shown to result in less neuropathy with similar efficacy (J Natl Cancer Inst 2004;96:1682). Recent clinical trials have investigated the role of maintenance chemotherapy in improving both PFS and OS. A Cochrane review from 2013 evaluated eight trials including 1,644 women in total, and it determined that there was no significant difference in 3-, 5-, and 10-year PFS and OS between women who received maintenance chemotherapy and those who did not. The trials included regimens with platinum agents, doxorubicin, and paclitaxel. However, two welldesigned phase III clinical trials (International Collaborative Ovarian Neoplasm [ICON] 7 and GOG 218) investigated the use of bevacizumab, a monoclonal antibody inhibiting vascular endothelial growth factor A (VEGF-A), alongside standard chemotherapy in women with newly diagnosed advanced ovarian, primary peritoneal, and fallopian tube cancer. GOG 218 included a maintenance bevacizumab arm as well, and a significant improvement in PFS of 3.8 months was noted in the maintenance bevacizumab arm when compared to both the standard paclitaxel and carboplatin and the paclitaxel, carboplatin, and bevacizumab arm (N Engl J Med 2011;365:2473). ICON7 compared two arms, a standard carboplatin and paclitaxel arm, with six cycles of therapy and the experimental carboplatin, paclitaxel, and bevacizumab arm, which included 5 to 6 cycles plus up to an additional 12 cycles of maintenance therapy (N Engl J Med 2011;365:2484). Bevacizumab did improve PFS; however, final analysis of OS revealed no clinically important improvement in the randomized population, with a 4.8-month improvement in mean survival time in a subgroup of women at high risk for progression. However, the use of bevacizumab did expand the number of toxic effects in both studies, including hypertension and bowel perforation. Currently, the National Comprehensive Cancer Network (NCCN) guideline considers the administration of chemotherapy plus bevacizumab in the first-line setting, a reasonable option especially for high-risk patients (stage IV, suboptimal cytoreduction). The use of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors was implemented on the basis of the SOLO-1 trial, where patients with advanced ovarian cancer harboring germline or somatic mutation in BRCA1 or BRCA2 were randomized to olaparib or placebo after completing platinum-based chemotherapy (N Engl J Med 2018;379:2495). The results were astounding with a hazard ratio (HR) of 0.30 (0.23 to 0.41, p < 0.001). the estimated pfs was 36 months longer in the olaparib group than that in the placebo group, which was

approximated because at 41 months of follow-up, the experimental group had not reached median recurrences. at this point, the os is not mature. the paola-1 trial included olaparib maintenance in combination with bevacizumab for patients with advanced ovarian cancer regardless of BRCA mutational status (N Engl J Med 2019;381:2416). Patients were given platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance and then randomized to olaparib versus placebo. The olaparib group had a PFS advantage in comparison with the placebo group of 22.1 versus 16.6 months (HR 0.59, 0.49 to 0.72). Patients were enrolled regardless of BRCA status; however, in subgroup analysis, it was clear that those who benefit most were homologous recombination deficient (HRD) with a PFS advantage of 37.2 versus 17.7 months (HR 0.42, 0.28 to 0.66). Those patients who had HRD-negative tumors had no significant PFS advantage of 16.6 versus 16.2 months (HR 1.00, 0.75 to 1.35). Similar to SOLO-1, the OS data are immature. One limitation of this study is that there was no single-agent olaparib arm for comparison. In 2013, the Japanese Gynecologic Oncology Group (JGOG) published its results of a prospective randomized clinical trial (JGOG 3016) comparing standard treatment with carboplatin and paclitaxel every 3 weeks to the experimental arm of carboplatin every 3 weeks concurrently with weekly paclitaxel. In both arms, the regimen was repeated every 3 weeks for up to nine cycles. The dose-dense therapy arm resulted in a significant improvement in PFS (28 vs. 17.5 months) and OS (100.6 vs. 62 months), with women who had greater than 1 cm of residual disease following surgical treatment showing the greatest benefit in PFS (17.6 vs. 12 months) and OS (51 vs. 33 months). However, this benefit did not extend to patients with mucinous or clear cell histologies. Also, there was a higher rate of treatment discontinuation and delay secondary to toxicity in the dose-dense arm. It should be noted that better survival outcomes with standard chemotherapy have been noted in other trials, as well as a potential difference in outcomes based on race, with Asian patients appearing to fare better in this trial than in other trials with a predominately Caucasian enrollment (Lancet Oncol 2013;14:1020). Intraperitoneal (IP) chemotherapy has also been investigated over the past several decades. Three large prospective trials have shown survival improvements for patients treated with IP chemotherapy (N Engl J Med 2006;354:34; N Engl J Med 1996;335:1950; J Clin Oncol 2001;19:1001). The GOG 172 reported a PFS of 23.8 months for combination IP and IV chemotherapy versus 18.3 months for IV alone (N Engl J Med 2006;354:34). Similarly, OS was longer with the combined IP/IV therapy (65.6 vs. 49.7 months). Patients who receive IP therapy do experience greater toxicity and even

report worse quality of life in some studies. Therefore, many oncologists are still reluctant to use this method of treatment. A small study investigated the use of IP chemotherapy in the community-based practice setting. They identified 288 women with FIGO stage II or greater ovarian cancer diagnosed between 2003 and 2008 at three integrated delivery systems in the United States. They noted that 12.5% (n = 36) of women received IP chemotherapy between 2003 and 2008, with a height of use at 26.9% of patients in 2006. These results demonstrate that the use of IP chemotherapy for patients with newly diagnosed advanced ovarian cancer in the community setting was uncommon (Front Oncol 2014;4:43). Recently published GOG 252 and GOG 262 have challenged both the IP and dose-dense (weekly) regimens, and most providers and clinical trials are using every 3-week platinum taxane regimens. Maintenance therapies following front-line standard platinum taxane chemotherapy have been widely adopted, and in addition to the previously mentioned bevacizumab, the addition of PARP inhibitors has recently been approved. Single-agent olaparib for patients with BRCA mutations or niraparib for all patients regardless of mutation status has been approved for use by the U.S. Food and drug administration (FDA) on April 29, 2020. Hyperthermic intraperitoneal chemotherapy (HIPEC) has had some promising results when used at the time of interval cytoreduction for patients who underwent neoadjuvant chemotherapy, but most consider this investigational until additional confirmatory studies are completed (N Engl J Med 2018;378:230). Radiation of the abdomen and pelvis is rarely employed as treatment for advanced stage and/or recurrent disease. Following adjuvant chemotherapy, patients are monitored with physical examination, CA-125 measurements, and imaging studies (CT, magnetic resonance imaging [MRI], and positron emission tomography [PET]) as clinically indicated for recurrent disease). Low-grade serous advanced stage ovarian cancer has a significantly different biology, and therapeutic and clinical trial implications. Currently, a trial is ongoing comparing the use of aromatase inhibition to cytotoxic chemotherapy. 4. Recurrent disease. Despite standard treatment with cytoreductive surgery and chemotherapy, up to 75% of patients experience recurrence and will eventually succumb to disease. Median survival following relapse from initial therapy is approximately 2 years. Patients found to progress with upfront therapy or with a recurrence should be offered additional treatments that will hopefully allow for control of their disease and maintain the best quality of life possible. One must realize that very few of these patients are ultimately cured of their disease, and enrollment in clinical trials is strongly encouraged. A common first sign of recurrence is a rising CA-125, which is usually followed by evidence of recurrence on examination or by a CT scan of the abdomen and pelvis. It is not

clear whether early retreatment (before the onset of symptoms or radiographic evidence of disease) of a patient with an elevating CA-125 has any effect on disease control or OS. Treatment of recurrent or persistent disease is based on the timing and location of the recurrence. “Platinum-sensitive” patients are defined as experiencing a recurrence more than 6 months from the time of their initial CR. These patients can be successfully retreated with platinum-based regimens with reasonable responses (20% to 40%). The ICON4 trial showed that in patients with platinum-sensitive disease, combination chemotherapy (platinum plus paclitaxel) led to higher CRs or PRs (66% vs. 54%) as well as PFS (13 vs. 10 months) compared to platinum therapy alone for recurrent disease (Lancet 2003;361:2099). Patients with a treatment-free interval of greater than 12 months received the greatest benefit from retreatment with combination platinum, paclitaxel therapy. The GOG 213 trial was designed to assess two interventions: whether bevacizumab and secondary cytoreduction were efficacious in recurrent platinum-sensitive ovarian cancer (Lancet Oncol 2017;18:779). The addition of bevacizumab to standard chemotherapy plus bevacizumab maintenance added just over 3 months of PFS advantage with no significant OS advantage. Similar results were seen in the OCEANS trial, which combined bevacizumab with gemcitabine and carboplatin resulting in a 4-month PFS advantage, but no significant OS advantage (J Clin Oncol 2012;17:2039). PARP inhibitors (olaparib, niraparib, and rucaparib) have also been approved for maintenance therapy in the recurrent setting after significantly improved PFS advantages in all three medications (Lancet Oncol 2017;390:1949; Lancet Oncol 2017;18:1274; J Clin Oncol 2019;37:2968). Patients with recurrence before 6 months (“platinum-resistant”) can be treated with a variety of agents. Many authorities recommend that single-agent therapy be used in this setting to minimize toxicity and to more easily identify nonresponding agents. Given that there is no ideal second-line salvage agent(s), patients should be encouraged to participate in available study protocols. Secondline agents have an approximate response rate of 15% to 40%, depending on the agent and the amount of previous chemotherapeutic treatments. Treatment is usually continued until the CA-125 normalizes, toxicity precludes further therapy, or disease progresses. Patients with progressive disease are then offered a different regimen, usually with a differing side effect profile to minimize toxicity. Because recurrent disease is typically not curable, symptom palliation and prevention of complications such as bowel obstruction remain the goals of management. Radiation and/or surgical resection have been used to successfully treat localized disease. Indications for repeat surgery (secondary debulking) traditionally have been controversial; however, the recently published GOG 213

shed some light on this issue (N Engl J Med 2019;381:1929). Patients with platinum-sensitive recurrent ovarian cancer were randomized 1:1:1:1 to receive bevacizumab or not and secondary cytoreduction or not. Generally, the results showed no significant differences in PFS or OS between groups. There was a PFS advantage in the surgical group versus the nonsurgical group if they were able to be debulked to R0 (22.4 vs. 16.4 months), which did not correspond to an OS advantage. Although not significant, there was an OS advantage favoring the nonsurgical group (50.6 vs. 64.7 months); however, this discrepancy was much smaller when looking at those patients who opted to receive bevacizumab in the trial (58.5 vs. 61.7 months). It is important to note that the platinum-free interval for this cohort was 18 to 20 months and patients were selected on the basis of resectable disease. The DESKTOP-III trial has a similar design and is currently ongoing. Complications of therapy are primarily related to continued growth of the tumor (bowel obstruction) and toxicities of the chemotherapy. Bowel obstructions should initially be managed conservatively with IV fluids and gastric decompression. Studies such as abdominal plain films, small bowel followthrough, contrast enemas, and abdominal/pelvic CT may be necessary to further evaluate cause of obstruction. Persistent obstructions can be managed with chronic decompression (G-tube) or surgical exploration in cases where the imaging studies suggest a limited focus of obstruction. Toxicities of chemotherapy are related to the specific agents and are covered elsewhere in this book. Several ongoing trails are investigating front-line use of immunotherapy, mostly anti-programmed death (PD) or its ligand (PD-L1) inhibitors, in combination with standard chemotherapy, bevacizumab, and PARP inhibitors. The NRG GY 003 evaluated the combination of nivolumab, a PD-1 inhibitor, with ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor, in recurrent or persistent ovarian cancer (J Clin Oncol 2020;38:1). This was a heavily pretreated population with a platinum-free interval of less than 12 months and included patients who were platinum resistant. Although there was an improvement in PFS for the nivolumab plus ipilimumab arm compared to nivolumab alone, the results were underwhelming (3.9 vs. 2.0 months). II. FALLOPIAN TUBE CARCINOMA Fallopian tube carcinoma is a rare gynecologic malignancy that behaves biologically like serous epithelial ovarian carcinoma. Fallopian tube carcinoma is staged and treated in a manner similar to that of ovarian carcinoma. The classic presentation is intermittent, profuse, watery vaginal discharge (hydrops tubae profluens). The diagnosis is seldom made preoperatively, but has been detected by Pap smear. Prognosis is related to stage of

disease with long-term survival of approximately 50% for stages I and II. As with ovarian carcinoma, long-term survival is rare with advanced disease. III. GERM CELL OVARIAN CANCERS These cancers typically occur in young women, are highly curable, and account for approximately 3% of ovarian cancers. The majority present as early-stage lesions confined to one ovary except for dysgerminomas, which are bilateral in 15% of cases. Dysgerminoma, endodermal sinus tumor (yolk sac tumor), embryonal carcinoma, choriocarcinoma, immature (embryonal) teratoma, and malignant mixed germ cell tumors are the cell types seen. Fertility-sparing surgery is nearly always possible. Surgical cytoreduction appears to be important and is likely associated with increased survival. Most of these tumors will have a tumor marker available to follow (human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP], lactate dehydrogenase [LDH], CA-125, or neuron-specific enolase [NSE]). Following surgery, most tumors are treated with chemotherapy, except for some well-staged IA/IB cancers. The bleomycin, etoposide, and cisplatin (BEP) regimen is the most commonly used and consists of a 5day regimen, although a 3-day regimen has also been studied (cisplatin 20 mg/m2 IV days 1 to 5, bleomycin 30 units IV weekly, etoposide 100 mg/m2 IV days 1 to 5—cycle repeated every 3 weeks). Some support observation only for localized, completely resected malignant germ cell tumors based on French survival data and pediatric oncology group trials. IV. STROMAL TUMORS OF THE OVARY Stromal tumors are classified by the World Health Organization (WHO) into five main classes: (1) granulosa-stromal cell tumors (adult and juvenile granulosa cell tumor and tumors in the thecoma/fibroma group); (2) Sertoli-stromal cell tumors (Sertoli, Leydig, or Sertoli–Leydig cell tumor); (3) gynandroblastoma; (4) sex cord tumor with annular tubules; and (5) unclassified. These tumors are rare and are usually of early stage and low grade, which make them readily curable with simple surgical resection. Primary metastatic or recurrent disease is usually treated with surgical cytoreduction followed by combination chemotherapy. The BEP regimen is most often used; however, recent data from Brown et al. suggest that taxanes demonstrate activity against ovarian stromal tumors and have less toxicity than do BEP regimens. Carboplatin plus paclitaxel is currently being compared in a randomized trial to BEP for these patients. SUGGESTED READINGS Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. Bowles EJ, Wernli KJ, Gray HJ, et al. Diffusion of intraperitoneal chemotherapy in women with advanced ovarian cancer in community settings 2003–2008: The effect of the NCI clinical recommendation. Front Oncol 2014;34:43. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N

Engl J Med 2011;365:2473–2483. Chan JK, Brady MF, Penson RT, et al. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med 2016;374:738–748. Chan JK, Tian C, Fleming GF, et al. The potential benefit of 6 vs. 3 cycles of chemotherapy in subsets of women with earlystage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology Group study. Gynecol Oncol 2010;116:301–306. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017;18:779–791. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017;390:1949–1961. Coleman RL, Spiritos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med 2019;381:1929–1939. Katsumata N, Yasuda M, Isonishi S, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013;14:1020–1026. Kauff ND, Satagopan JM, Robson ME, et al. Risk reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346: 1609–1615. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495–2505. Ozols RF. Challenges for chemotherapy in ovarian cancer. Ann Oncol 2006;17:v181–v187. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer. J Clin Oncol 2003;21:3194–3200. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365:2484– 2496. Prat J. Staging classification for cancer of the ovary, fallopian tube and peritoneum. Int J ​Gynaecol Obstet 2014;124:1–5. Pujade-Lauraine E, Ledermann, JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinumsensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1274–1284. Rubin SC, Benjamin I, Behbakht K, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 1996;335:1413–1416. Walker JL, Brady MF, Wenzel L, et al. Randomized trial of intravenous versus intraperitoneal chemotherapy plus bevacizumab in advanced ovarian carcinoma: an NRG Oncology/​Gynecologic Oncology Group Study. J Clin Oncol 2019;37:1380–1390. Young RC. Early-stage ovarian cancer: to treat or not to treat. J Natl Cancer Inst 2003;95:94–95.

I.

UTERINE NEOPLASIA A. Premalignant disease of the endometrium 1. Background. Endometrial hyperplasia is a spectrum of proliferative disorders, primarily of the endometrial glands, and, to a lesser extent, the stroma. In the normal menstrual cycle, estrogen stimulation leads to growth and proliferation of the endometrium, whereas progesterone leads to predecidual changes and inhibition of endometrial proliferation. In the absence of progesterone, unopposed estrogen stimulation can lead to a spectrum of endometrial abnormalities varying from simple endometrial hyperplasia to several histologic types of endometrial malignancies. Some risk factors are chronic anovulation (polycystic ovarian syndrome and perimenopause), obesity (increased peripheral estrogen production), estrogen-producing ovarian neoplasms (granulosa cell tumor), exogenous estrogen administration (hormone replacement therapy), and the use of selective estrogen receptor modulators (SERMs) such as tamoxifen that has estrogen-like properties on the endometrium. In addition, known genetic abnormalities such as Lynch syndrome can cause a predisposition to endometrial abnormalities. 2. Presentation. The majority of patients with endometrial hyperplasia remain asymptomatic and therefore these precursor lesions can go unrecognized for years. Some patients are diagnosed because of symptoms of abnormal or postmenopausal bleeding. Other patients may be diagnosed because of incidental abnormal findings on an ultrasound ordered for other reasons or abnormal endometrial cells noted on Papanicolaou (Pap) test. Normal menstrual cycles occur every 28 days (range 21 to 35 days) with a normal duration of 2 to 7 days and an average blood loss of less than 80 mL. Bleeding outside of these ranges or

any postmenopausal bleeding should be evaluated. Any age group can be affected, but one should be especially concerned with abnormal bleeding in patients aged 35 years and older. Obesity, a history of anovulatory cycles, use of tamoxifen, and use of exogenous estrogens without concurrent progesteronal agents are also known risk factors. 3. Workup and staging. Typically, the diagnosis can be made with an office endometrial (pipelle) biopsy. If this procedure is nondiagnostic or if technically not feasible, a dilation and curettage (D&C), with or without hysteroscopy, can be performed to obtain more tissue for accurate histologic diagnosis. The International Society of Gynecological Pathologists classifies endometrial hyperplasia into four distinct categories on the basis of a 1994 classification system looking at architectural structure and cytologic features: simple and complex hyperplasia, both with and without atypia. 4. Therapy and prognosis a. Simple or complex hyperplasia without atypia. Treatment is usually conservative and depends on the fertility desires of the patient. The risk of developing malignancy over a 13- to 15-year untreated period is 1% for simple and 3% for complex hyperplasia (Table 24-1). TABLE 24-1

Comparison of Follow-Up of Patients with Simple and Complex Hyperplasia and Simple and Complex Atypical Hyperplasia (170 Patients)

Histology

No. of Patients

Regressed No. (%)

Persisted No. (%)

Progressed to Carcinoma No. (%)

Simple hyperplasia

93

74 (80%)

18 (19%)

1 (1%)

Complex hyperplasia

29

23 (80%)

5 (17%)

1 (3%)

Simple atypical hyperplasia

13

9 (69%)

3 (23%)

1 (8%)

Complex atypical hyperplasia

35

20 (57%)

5 (14%)

10 (29%)

Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985;56:403–412.

Patients desiring pregnancy. Typically, providers want to treat the endometrium before attempting pregnancy. This can be done with progesteronal agents and surveillance with endometrial biopsy. ii. Patients not considering pregnancy. Management usually consists of oral (PO), intramuscular (IM), or intrauterine progestins followed by repeat biopsy after 3 to 6 months. Accepted regimens include medroxyprogesterone 10 mg PO for 7 to 13 days/month, depot i.

medroxyprogesterone 150 mg IM every month, oral contraceptive pills, and levonorgestrel intrauterine device (IUD). Regression of hyperplasia occurs in up to 92% of patients treated with levonorgestrel IUD. b. Simple or complex hyperplasia with atypia. Cellular atypia is a significant risk factor for development of malignancy. Twenty-three percent of untreated atypical hyperplasia progress to endometrial cancer (8% for simple atypical and 29% for complex atypical hyperplasia) over 11 years, although recent studies suggest a near 40% chance of progression to endometrial cancer if complex atypical hyperplasia is present. More importantly, there is a 13% to 43% rate of concurrent endometrial cancer with atypical hyperplasia. In the Gynecologic Oncology Group (GOG) 167 prospective cohort study of women with atypical endometrial hyperplasia, the rate of concurrent endometrial cancer was 43% for analyzed specimens, with 31% of these demonstrating myometrial invasion, and 11% invading the outer 50% of the myometrium (Cancer 2006;106:812). Owing to these findings, patients with atypical hyperplasia may need to undergo D&C with or without hysteroscopy to rule out the presence of invasive cancer in the unsampled endometrium or with a negative endometrial biopsy, but high suspicion for endometrial abnormalities. i. Patients desiring pregnancy. Progesteronal agents including megestrol acetate 80 to 160 mg/day and levonorgestrel IUD have been used for treatment. The goal of therapy is complete regression of disease and reversion to normal endometrium followed by ovulation induction or assisted reproductive techniques for pregnancy. Repeat sampling with biopsy or D&C is recommended after 3 to 6 months of therapy, and it often takes at least 6 months for regression of these lesions. ii. Patients not considering pregnancy. Medical treatment: Regression occurs in up to 90% of patients treated with progesteronal agents including oral medroxyprogesterone (40 mg PO per day) and megestrol acetate (160 to 320 mg PO per day in divided doses) as well as levonorgestrel IUD (Obstetric Gynecol 2012;120:1160). Repeat biopsy or D&C to check for persistence or progression is recommended every 3 to 6 months till regression. iii. Surgical treatment. Extrafascial hysterectomy with gross inspection and frozen section of the endometrium for evidence of endometrial cancer 5. Complications are rare and minor, usually related to surgical complications of D&C including risk of anesthesia, infection, hemorrhage, and uterine perforation. An underlying concern is inappropriate surgical management because of misdiagnosed cancer.

6. Follow-up. Medically managed patients should be resampled at regular intervals (3 to 6 months) until regression of endometrial pathology. Those with normal histology can then either be taken off therapy or be cycled with progesteronal agents and should undergo periodic endometrial sampling to ensure continued regression. Follow-up interval for patients after hysterectomy is not well established, but annual examinations should be adequate. B. Endometrial cancer 1. Background. Endometrial cancer represents the most common gynecologic cancer with an expected 61,880 new cases and more than 12,000 deaths in the United States in 2019. This is up from 53,911 and over 10,000 in 2015 (CA Cancer J Clin 2019;69:7; MMWR Morb Mortal Wkly Rep 2018;67:1333). Fiveyear survival for localized disease is 96%, whereas relative survival for all stages is approximately 82%. There are two morphologically and molecularly distinct histologic subtypes: type I and type II. Risk factors for type I endometrial cancer include unopposed exogenous estrogenic stimulation (estrogens or tamoxifen), chronic anovulation, obesity, diabetes mellitus, nulliparity, and late age of menopause (older than 52 years). Type II histology tends to be more sporadic and is not associated with the factors described for type I. Molecular characterization has recently provided a distinct way to classify these tumors apart from type I and II, based on type and number of mutations from the Cancer Genome Atlas analysis, which identified four genotypes that portend prognosis: polymerase ε exonuclease (POLE) ultramutated, microsatellite instability hypermutated, copynumber low, and copy-number high. This is important because some histologically identified type I tumors share the genetic makeup of histologically identified type II tumors. These tumors can be more aggressive than was originally thought on the basis of histology (Nature 2013;497:67). 2. Presentation. More than 90% of patients are first seen with abnormal uterine bleeding. Patients with any postmenopausal bleeding or discharge deserve evaluation. Patients with abnormal pre- or perimenopausal bleeding, especially those with a history of anovulatory cycles, older than 35 years, or morbidly obese warrant evaluation as well. Pap tests with atypical glandular cells of undetermined significance (AGUS) in patients of any age should be evaluated with a colposcopy, endocervical curettage (ECC), and endometrial biopsy. Pap test with endometrial cells in a postmenopausal patient should also be evaluated. However, the Pap test is not a screening test for endometrial cancer and is less than 50% sensitive. 3. Workup and staging. An office endometrial biopsy (pipelle) is an extremely sensitive method of obtaining a tissue diagnosis. A meta-analysis of 39 studies involving 7,914 women demonstrated a detection rate for endometrial cancer of

91% and 99.6% in pre- and postmenopausal women, respectively (Cancer 2000;89:1765). Patients with a nondiagnostic office biopsy, persistent bleeding abnormality despite a normal office biopsy, or those unable to undergo an office biopsy should undergo a fractional D&C, with or without hysteroscopy. All patients should be screened for other malignancies as appropriate for age and family history (Pap test, ultrasound, mammogram, and colorectal cancer screening). Cystoscopy, proctoscopy, and radiologic imaging may be necessary, as clinically indicated, if advanced stage is suspected. Surgical staging of endometrial carcinoma was adopted by the International Federation of Gynecologists and Obstetricians (FIGO) in 1988 and then revised in 2009 (Table 24-2). All patients who are medically able should first undergo surgical exploration with appropriate staging. Extrafascial hysterectomy with bilateral salpingo-oophorectomy, collection of peritoneal cytology, pelvic and para-aortic lymph node dissection, and biopsy of any suspicious areas are necessary for staging, except in small well-differentiated tumors without myometrial invasion. Omentectomy or omental biopsy is also indicated for high-grade tumors and in particular uterine clear cell and uterine serous tumors. TABLE 24-2

FIGO Surgical Staging and Grade of Endometrial Cancer, 2009

Stage

Description

IA

Tumor limited to uterus, no or less than half myometrial invasion

IB

Tumor limited to uterus, equal to or more than half myometrial invasion

II

Cervical stromal invasion

IIIA

Uterine serosal and/or adnexal involvement

IIIB

Vaginal metastasis and/or parametrial involvement

IIIC1

Positive pelvic lymph nodes

IIIC2

Positive para-aortic lymph nodes (with or without pelvic nodes)

IVA

Bladder and/or bowel/rectal mucosal invasion

IVB

Distant metastases including intra-abdominal and/or inguinal lymph nodes

Grade

Description

1

Less than 5% of tumor is solid sheets of undifferentiated neoplastic cells

2

6%–50% of tumor is solid sheets of undifferentiated neoplastic cells

3

>50% of tumor is solid sheets of undifferentiated neoplastic cells

Cytology is mentioned separately and does not change stage. FIGO, International Federation of Gynecologists and Obstetricians.

4. Therapy and prognosis. The first step of treatment is hysterectomy and surgical staging (abdominal, laparoscopic, or robotic). Total laparoscopic staging is being performed with increasing frequency for suspected early-stage endometrial cancer, and lymph node count and survival appear similar when compared to laparotomy. Hysterectomy removes primary tumor, and intraoperative findings such as size of tumor, myometrial invasion, and grade can help estimate risk or lymph node involvement and need for adjuvant therapy. Removal of adnexa is important because of the risk of metastasis to the ovary, synchronous ovarian cancers, and risk of future recurrence or primary cancer in the ovary. Lymphadenectomy (LND) is somewhat more controversial. Lymph node status is prognostically important and is helpful in the decision of postoperative adjuvant therapy. But because there are rare but substantial risks and complications associated with the procedure, the benefit of LND is controversial in patients with low risk of positive nodes, high risk of morbid complication, and in patients who will receive adjuvant therapy because of other findings. Historically, radiation therapy (RT) had been the preferred choice of adjuvant therapy for patients with high risk of recurrence. However, the role of chemotherapy in all stages of endometrial cancer is evolving. Although low-risk stage I disease can be treated with surgery alone, adjuvant treatment for other stages is variable and includes vaginal brachytherapy (VB), external beam pelvic radiation therapy (EBRT), and chemotherapy (Table 24-3). TABLE 24-3

Treatment of Endometrial Cancer

Condition

Possible Adjuvant Therapies to Consider

Stage IA or IB and grade 1 or 2

No further therapy or vaginal brachytherapy

Stage I and II with HIR

VB vs. pelvic RT VB with chemotherapy (currently under investigation, GOG 249)

Stage IIIA (serosal and/or adnexal involvement)

Systemic chemotherapy

Stage IIIB (vaginal involvement)

Systemic chemotherapy

Stage IIIC (microscopic nodal involvement)

Systemic chemotherapy

Stage IIIC (macroscopic nodal), stage IV, and recurrent disease (extrapelvic)

Systemic chemotherapy

Recurrent disease (pelvic)

Combination chemotherapy vs. immunecheckpoint therapy

HIR

Risk factors:

Any age with three risk factors

1. Moderately to poorly differentiated tumor

Age >70 with two risk factors

2. Lymphovascular space invasion

Age 50–70 with one risk factor

3. Outer 1/3 myometrial invasion

GOG, Gynecologic Oncology Group; HIR, high-intermediate risk; RT, radiation therapy; VB, vaginal brachytherapy.

a. Early stage. Results from GOG 33 and GOG 99 helped define a highintermediate risk (HIR) category for patients with stage I or II disease with a higher risk of recurrence (Gynecol Oncol 2004;92:744). GOG 33 provided prognostic indicators for pathologic spread of disease and how those correlated with recurrence and survival. GOG 99 and Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC), PORTEC-1 showed that EBRT, compared to no adjuvant treatment, decreased local recurrence in patients with HIR stage I or II disease, but overall survival (OS) benefit was not significant. PORTEC-2 compared EBRT to VB and showed that both were comparable in local recurrence rate, with VB having less toxicities. Therefore, adjuvant radiation treatment is recommended on the basis of HIR criteria and patient desires of further treatment to decrease risk of recurrence or treatment when recurrence occurs. The pooled data from two randomized controlled trials showed a significant decrease in progressionfree survival (PFS), cancer-specific survival (CSS), and OS for HIR stage I and II patients treated with combination chemotherapy and pelvic RT compared to pelvic RT alone. Two randomized trials compared chemoradiation versus pelvic radiotherapy (PORTEC-3) or VB followed by chemotherapy (GOG 249) to pelvic RT alone in the treatment of HIR earlystage endometrial cancer. GOG 249 failed to show superiority of the VB and chemotherapy group versus pelvic RT, and PORTEC-3 showed PFS advantage for chemoradiation versus EBRT, but no OS difference. b. Advanced stage. Cytotoxic chemotherapy for advanced-stage endometrial cancer includes the following agents (response rate): cisplatin (20% to 35%), carboplatin (30%), doxorubicin (Adriamycin; 20% to 35%), epirubicin (25%), and paclitaxel. The combination of doxorubicin (60 mg/m2) plus cisplatin (50 mg/m2) every 3 weeks showed an improved response rate of 42%, progression-free interval of 6 months, and median OS of 9 months in a randomized trial by the GOG (J Clin Oncol 2004;22:3902). Combination of doxorubicin (60 mg/m2 × 7 cycles) and cisplatin (50 mg/m2 × 8 cycles) (AC) was superior to whole-abdominal irradiation (WAI; 30 Gy in 20 fractions with a 15-Gy boost) in a phase III trial of 202 randomized patients with stage III/IV endometrial cancer optimally debulked to less than or equal to 2 cm of

residual disease with PFS of 50% versus 38% and OS 55% versus 42%, respectively (J Clin Oncol 2006;24:36). In 2004, a GOG trial demonstrated improved survival in patients with advanced or recurrent endometrial cancer treated with TAP (paclitaxel, doxorubicin, cisplatin) as compared to cisplatin and doxorubicin alone, although with increased toxicity (J Clin Oncol 2004;22:2159). In GOG 184, patients with stage III/IV endometrial cancer were treated with pelvic RT followed by AC versus TAP. There was no patient outcome benefit by adding paclitaxel, but the study showed that combination radiation and chemotherapy was a feasible treatment option with acceptable toxicity. Most recently, GOG 258 showed that chemoradiation was not associated with a longer relapse-free survival than platinum-based chemotherapy alone in patients with stage III or IVA endometrial carcinoma and has shifted the treatment paradigm for patients with advanced disease. In addition, immune-checkpoint inhibitors (ICIs), in particular pembrolizumab (programmed death 1 [PD-1] inhibitor), have shown activity in mismatch repair (MMR)-deficient endometrial cancers. For advanced MMR-proficient tumors, the U.S. Food and Drug Administration (FDA) recently released approval for the combination of lenvatinib and pembrolizumab, which showed great activity in a phase II trial (Lancet Oncol 2019;20:711). 5. Complications. Complications of staging surgery include pain, hemorrhage, infection, and damage to surrounding structures including bowel, bladder, and blood vessels. Lymphocysts and lymphedema of the lower extremities are rare complications of LND. Immediate toxicities from chemotherapy include hematologic, gastrointestinal (GI), and infectious complications. Immediate and late effects of radiation are usually related to bowel and bladder dysfunction. Concurrent treatment with chemotherapy and RT is currently under investigation, and the toxicities of combination treatment remain a major concern. 6. Follow-up. Typically, patients are evaluated with physical examination, Pap test, and pelvic examination every 3 months for the first year, every 3 to 4 months for the second year, every 6 months for third to fifth year, and then at 6- to 12-month intervals thereafter. C. Sarcomas 1. Background. These are uncommon tumors arising from the mesenchymal components of the uterus and comprise 3% to 8% of uterine tumors. The GOG has broadly classified the sarcomas based on histology: (1) nonepithelial neoplasms including endometrial stromal sarcoma (ESS), leiomyosarcoma (LMS), and smooth muscle tumor of uncertain malignant potential (STUMP) and (2) mixed epithelial–nonepithelial tumors including adenosarcoma and carcinosarcoma. Homologous types contain sarcomatous components that are

unique to uterine tissue, whereas heterologous types produce stromal components that are not native to the uterus. 2. Presentation varies depending on type of tumor. Carcinosarcomas usually present with postmenopausal bleeding, whereas ESS and LMS can present as abnormal bleeding, rapidly enlarging pelvic pain, or pelvic pressure and pain. Uterine sarcomas are often incidental diagnoses on hysterectomy specimens, and reoperation for complete surgical staging is usually not recommended. 3. Workup and staging. Workup is similar to that for endometrial cancer and involves endometrial biopsy or core biopsy of any masses protruding through the cervix. Pelvic imaging can be performed to delineate the size and origin of protruding masses. Staging for LMS and ESS is summarized in Table 24-4. As more is discovered about the biology and activity of these rare cancers, uterine carcinosarcomas may be considered more closely related to poorly differentiated endometrial carcinomas, and therefore they are staged using the 2009 FIGO staging for endometrial cancer (Table 24-2). Patients should be treated primarily with surgical exploration with appropriate staging, because primary radiotherapy and chemotherapy have very disappointing results. TABLE 24-4 Stage

FIGO Surgical Staging of Uterine Sarcomas, 2009

Description

LMS IA

Tumor limited to the uterus, 5 cm

IIA

Adnexal involvement

IIB

Tumor extends to extrauterine pelvic tissue

IIIA

Tumor invades abdominal tissue, one site

IIIB

Tumor invades abdominal tissue, more than one site

IIIC

Metastasis to pelvic and/or para-aortic lymph nodes

IVA

Tumor invades bladder and/or bowel mucosa

IVB

Distant metastases

Endometrial Stromal Sarcoma/Adenosarcoma IA

Tumor limited to endometrium/endocervix, no myometrial invasion

IB

Less than or equal to half myometrial invasion

IC

More than half myometrial invasion

IIA

Adnexal involvement

IIB

Tumor extends to extrauterine pelvic tissue

IIIA

Tumor invades abdominal tissue, one site

IIIB

Tumor invades abdominal tissue, more than one site

IIIC

Metastasis to pelvic and/or para-aortic lymph nodes

IVA

Tumor invades bladder and/or bowel mucosa

IVB

Distant metastases

FIGO, International Federation of Gynecologists and Obstetricians.

4. Therapy and prognosis. Although each histologic subtype of sarcoma behaves differently, in general, survival is poor, with more than half the number of patients dying of the disease. For stage I and II disease, adjuvant RT often improves local recurrences, but has little impact on long-term survival. Cytotoxic chemotherapy may have a role in the adjuvant setting. Hormonal therapy with high-dose progestin therapy (megestrol acetate, 240 to 360 mg PO daily) has shown activity against ESSs, especially those that are low grade. Advanced stage (III/IV) and recurrent disease have been treated with radiotherapy with minimal success. Chemotherapy is most often used in this setting because phase II trials have shown tolerable toxicities and improved response compared to historical data. Single-agent doxorubicin (60 mg/m2 intravenous [IV] q3 weeks) or ifosfamide (1.2 to 1.5 g/m2 IV qd × 4 to 5 days) have shown activity against LMS with approximate response rates of 25% and 20%, respectively. Combination gemcitabine (900 mg/m2 IV on day 1 and 8, q3 weeks) and docetaxel (75 mg/m2 IV q3 weeks) showed favorable response rates for completely resected stage I to IV disease as well as for advanced and recurrent disease (Gynecol Oncol 2009;112:563). For carcinosarcomas, ifosfamide plus mesna, with or without cisplatin, showed response rates of 30% to 50% in patients with advanced, persistent, or recurrent disease (Gynecol Oncol 2000;79:147). The combination therapy produced higher response rates but greater toxicity and no survival advantage over single-agent ifosfamide (GOG 117). This combination chemotherapy regimen had patient outcomes similar to that of WAI for stage I to IV disease in a phase III GOG trial (GOG 150). Survival in patients with advanced disease was improved by the addition of paclitaxel (135 mg/m2 IV q3 weeks up to eight cycles of ifosfamide). A phase II trial also showed acceptable response rates with paclitaxel and carboplatin in the treatment of patients with advanced carcinosarcoma (J Clin Oncol 2010;28:2727). Surgical resection of recurrent sarcoma and chemotherapy has shown to be beneficial in other softtissue sarcomas, and may provide a survival advantage in uterine sarcomas as

well. D. Gestational trophoblastic disease (GTD) 1. Background. Abnormal growth of the human trophoblast is called GTD. GTD encompasses a spectrum of abnormalities of trophoblastic tissue including classic (complete) hydatidiform moles, partial hydatidiform moles, invasive hydatidiform moles, choriocarcinoma, and placental-site trophoblastic tumors. The most common abnormality, the hydatidiform mole, has two pathologic varieties—complete and partial moles. Complete moles are the most common subtype of GTD and typically occur as a result of dispermy, with both chromosomes paternal in origin resulting from fertilization of an empty ovum (46,XX). Partial moles are the result of fertilization of a normal egg by two sperms (69,XXY), resulting in an abnormal pregnancy with fetal parts usually identifiable. The reported incidence of mole varies widely throughout the world, with 1:1,500 pregnancies affected in the United States. Invasive mole is a pathologic diagnosis of a benign tumor that invades the uterine myometrium or, on occasion, metastasizes. The incidence is estimated at 1:15,000 pregnancies. Choriocarcinoma is a malignant tumor that has a propensity for early metastasis and an aggressive course, arising in 1:40,000 pregnancies. Fifty percent of choriocarcinomas develop after a molar gestation, 25% after a term pregnancy, and 25% after an abortion or an ectopic pregnancy. Placental-site trophoblastic tumor is the rarest variant, arising from the intermediate trophoblast, and is relatively chemotherapy resistant. The tumors often secrete human placental lactogen (HPL), which can be used as a tumor marker. GTD is more common in extremes of reproductive age (teenagers and women aged 40 to 50 years). 2. Presentation. Most cases of malignant/persistent GTD are seen after a hydatidiform mole. Hydatidiform moles usually present with vaginal bleeding and a positive pregnancy test finding. Nearly all hydatidiform moles are now diagnosed by ultrasound examination, demonstrating the “snowstorm” appearance of the vesicle-filled intrauterine cavity. Occasionally, patients will have symptoms of preeclampsia, hyperthyroidism, and/or severe hyperemesis. Physical examination demonstrates uterine size larger than estimated gestational dates, bilateral ovarian enlargement (because of thecal lutein cysts), and, usually, an absence of fetal heart sounds or fetal parts. GTD can also occur after a normal pregnancy, abortion (spontaneous or induced), or ectopic pregnancy, and the diagnosis is often easily missed in these patients. Presentation is the same in these patients, although the delay in diagnosis may lead to widely metastatic disease. 3. Workup and staging. After diagnosis of a molar pregnancy (usually by ultrasound), the patient should undergo chest radiograph (CXR; if positive, a

metastatic workup should follow; see later), blood type and cross-matching, and serum quantitative beta-human chorionic gonadotropin (hCG) evaluation. Mainstay of treatment is an ultrasound-guided suction D&C followed by sharp curettage. Intravenous oxytocin, 20 to 40 units/L or other uterotonic agents should be used shortly after the beginning of the procedure and continued for several hours to avoid excessive bleeding. Patients with Rh-negative blood should receive Rh immune globulin (RhoGAM), as indicated to prevent isoimmunization in future pregnancies. Patients are followed up after surgery with quantitative pregnancy tests (beta-hCG) weekly until normal and then monthly for 1 year. Eighty percent of moles will resolve with D&C alone. Persistent gestational trophoblastic neoplasia (GTN) is diagnosed with any of the following conditions (note that histologic verification is not required): (1) after evacuation of a hydatidiform mole, the hCG level does not decrease appropriately (plateau or 2 consecutive weeks with an increasing titer), (2) metastatic disease is discovered, or (3) pathologic diagnosis of choriocarcinoma or placental-site trophoblastic tumor. Once the diagnosis of persistent GTN is made, a further metastatic workup should include a complete history and physical examination and computed tomography (CT) of the chest, abdomen, pelvis, and, possibly, the head, if indicated. A pelvic ultrasound should also be performed to rule out an early pregnancy in patients with inadequate contraception. Complete blood count (CBC) and metabolic panel (hepatic and renal) are also indicated. An anatomic staging system (FIGO, 1992) does exist but is seldom clinically used. Prognosis and subsequent therapy are usually based on the World Health Organization (WHO) scoring system or the National Institutes of Health (NIH) system used by most U.S. trophoblastic disease centers (Table 24-5). TABLE 24-5

Prognostic Classification of GTN

I. Nonmetastatic disease II. Metastatic disease A. Low-risk/good-prognosis GTN 1. Short duration since last pregnancy event (40,000 mIU/mL serum) 3. Brain or liver metastasis 4. Prior chemotherapy failure 5. Antecedent term pregnancy

GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin.

4. Therapy and prognosis. Therapy is directed by the NIH class or the WHO score. Prognosis is generally excellent, and the key is to limit toxicity of the therapy as much as possible. Therapy should be started immediately, because delays can be devastating. The primary therapy of malignant GTD is chemotherapy. Surgery is used to decrease the amount of chemotherapy required for remission or to remove resistant foci of disease. Treatment of nonmetastatic GTN includes hysterectomy for those no longer desiring fertility and for all with placental-site trophoblastic tumors. Chemotherapy is recommended for all patients, even if hysterectomy is performed, and is usually given as a single agent (Table 24-6). TABLE 24-6

Chemotherapeutic Regimens for Persistent GTN

Nonmetastatic and Low-Risk Metastatic GTN Methotrexate, 30–50 mg/m2 IM q wk (preferred method) Methotrexate, 0.4 mg/kg IV/IM qd × 5 d, repeat every 2 wk Methotrexate, 1–1.5 mg/kg IM days (1, 3, 5, 7) + folinic acid, 0.1–0.15 mg/kg IM days (2, 4, 6, 8), repeat every 15–18 d Actinomycin D, 10–13 mg/kg IV/day × 5 d, repeat every 14 d Actinomycin D, 1.25 mg/m2 IV q14 d (superior to weekly methotrexate in GOG 174) Etoposide, 200 mg/m2/day PO × 5 d q14 d High-risk metastatic GTN: EMA-CO regimen EMA-CO Regimen Day 1, etoposide, 100 mg/m2 IV (over 30 min); actinomycin D, 0.35-mg IV push; methotrexate 100 mg/m2 IV push, then 200 mg/m2 IV infusion over 12 h Day 2, etoposide, 100 mg/m2 IV over 30 min; actinomycin D, 0.35-mg IV push; folinic acid, 15 mg PO, IM or IV q12 h × 4 doses Day 8, vincristine, 1 mg/m2 IV plus cyclophosphamide, 600 mg/m2 IV Repeat entire cycle every 2 wk. Patients with CNS metastasis should also receive radiation therapy and intrathecal methotrexate (12.5 mg on day 8) (Gynecol Oncol 1989;31:439) Triple-Agent (MAC) Regimen Day 1–5, methotrexate, 15 mg IM; actinomycin D 0.5 mg IV; cyclophosphamide 3 mg/kg IV Repeat cycle every 15 d CNS, central nervous system; GOG, Gynecologic Oncology Group; GTN, gestational trophoblastic neoplasia; IM intramuscular; IV, intravenous; PO, orally.

Low-risk metastatic GTN is treated primarily with single-agent chemotherapy; both methotrexate and actinomycin D should be used individually before resorting to multiagent chemotherapy. Single-agent actinomycin D IV q14 days was found to have superior complete response rates than did methotrexate IM weekly (GOG 174), but this methotrexate regimen should be reserved for very low-risk patients because of a high failure rate. One should always consider daily methotrexate per the National Comprehensive Cancer Network (NCCN) guidelines. All patients with low-risk disease should eventually be cured after switching to alternative single-agent or multiagent regimens (J Clin Oncol 2011;29:825). High-risk metastatic disease is treated with multiagent chemotherapy with the addition of radiation if a brain metastasis is present and surgery to remove resistant foci in the uterus or chest, as needed. All patients receiving chemotherapy should be evaluated with appropriate laboratory studies (CBC and hepatic and/or renal panel) for the specific regimens plus a serum beta-hCG every cycle. Treatment should continue until three consecutive normal hCG levels are obtained. At least two courses should be given after the first normal hCG level. 5. Complications. Complications are related mainly to the specific chemotherapeutic regimen used. Single-agent therapy is normally well tolerated with minimal side effects. Any suspicious metastatic sites should not be biopsied because of the risk of hemorrhage. 6. Follow-up. Patients should be monitored with serum hCG monthly for 1 year. Contraception is needed for a minimum of 6 months, but 12 months is preferred. If pregnancy should develop, an early ultrasound should be performed to document an intrauterine pregnancy. 7. Current focus. Chemotherapy for low-risk GTN was being studied by the GOG 275 in a randomized manner with multiday methotrexate regimen versus pulsed dactinomycin (1.25 mg/m2 IV push q14 days), but it was recently closed to poor accrual. The study has not been published to this point. The predictive value of modeled hCG residual production is also being validated in patients treated in GOG 174. II. UTERINE CERVIX NEOPLASIA A. Preinvasive lesions of the cervix 1. Background. More than 2.5 million women in the United States have Pap test abnormalities, with more than 200,000 new cases of dysplasia diagnosed annually. Human papillomavirus (HPV) has been detected in more than 90% of preinvasive and invasive carcinomas, and there is strong evidence that HPV is the

etiologic factor in the vast majority of dysplasias and cervical cancers. HPV subtypes 16, 18, 45, and 56 are considered high risk HR-HPV; 31, 33, 35, 51, 52, and 58 are of intermediate risk; and 6, 11, 42, 43, and 44 are of low risk for progression to cancer. Other risk factors for the development of cervical dysplasia include smoking, multiple sexual partners, low socioeconomic status, young age at coitarche, presence of HR-HPV, or immunodeficiency. 2. Presentation. Preinvasive lesions of the cervix are often asymptomatic, but can reliably be detected with cytology or biopsy. Median age is approximately 28 years and risk factors are often present. 3. Screening. The goal of screening programs is to identify women with preinvasive disease and manage them appropriately so as to decrease the incidence and mortality rate from cervical cancer. It is estimated that approximately 4 million women per year will have an abnormal Pap result in the United States. Communities that implement cervical cancer screening programs reduce deaths from cervix cancer by approximately 90%, making it one of the most successful cancer screening programs. Unfortunately, most women in whom cervical cancer develops have not been adequately screened. The American Cancer Society and the American College of Obstetrics and Gynecology recommend that annual cervical cytology screening (Pap test) and pelvic examination be initiated at age 21 regardless of onset of sexual activity. Exceptions to this are women with a history of cervical intraepithelial neoplasia (CIN) 2 or greater, diethylstilbestrol (DES) exposure, or who are immunocompromised. In 2012, the American Society for Colposcopy and Cervical Pathology (ASCCP) together with its partner organizations revised the consensus guidelines to reflect improved understanding of (1) the natural history of HPV infection and cervical cancer precursors and (2) future pregnancy implications of treatment for CIN among younger women. On the basis of these new guidelines, women aged 21 to 29 years should undergo Pap screening every 3 years. Because of the high prevalence of HPV in this age group, HPV testing should not be used for either cotesting or as a stand-alone test because of potential harm (e.g., psychosocial impact, discomfort from additional diagnostic/therapeutic procedures, and even longer term increased risk of pregnancy complications because of excision procedures). The preferred recommendation for women aged 30 to 64 years is cytology with HPV cotesting every 5 years. Alternatively, cytology alone every 3 years is acceptable. 4. Terminology. In 1988, the Bethesda system for the reporting of cervicovaginal cytologic results was developed in an effort to simplify and bring uniformity to the reporting of cytology results. This was revised in 1991 and 2001 for clearer terminology and larger application. Specimens are now specifically described

with regard to specimen adequacy (“satisfactory” or “unsatisfactory”), presence of the transformation zone (“present” or “absent”), and evaluation of epithelial cell histology (“negative for intraepithelial lesion or malignancy” or abnormal) (Table 24-7). More recently in 2012, the Lower Anogenital Squamous Terminology (LAST) project incorporated changes in their classification terminology to reflect HPV-associated squamous lesions of the anogenital tract. Specifically, CIN 2 is stratified on the basis of p16 immunostaining—specimens that are p16-negative are referred to as low-grade squamous intraepithelial lesions (LSILs) and those that are p16-positive are considered high-grade squamous intraepithelial lesions (HSILs). TABLE 24-7

Bethesda System of Categorizing Epithelial Cell Abnormalities, 2001

Squamous Cell Atypical squamous cells (ASCs) Of undetermined significance (ASCUS) Cannot exclude high-grade squamous intraepithelial lesions (ASC-Hs) Low-grade squamous intraepithelial lesions (LSILs) Encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3 Squamous cell carcinoma High-grade squamous intraepithelial lesions (HSILs) Encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3 Squamous cell carcinoma Glandular cell Atypical glandular cells (AGCs) (Specify endocervical, endometrial, or not otherwise specified) Endocervical adenocarcinoma in situ (AIS) Adenocarcinoma CIN, cervical intraepithelial neoplasia.

5. Workup. Colposcopy is performed in specific circumstances for further evaluation of an abnormal Pap result. It is performed with a colposcope that allows magnification of the cervix, which is treated with a 4% acetic acid solution. Colposcopic characteristics of dysplasia include acetowhite changes, punctuations, and abnormal vascularity (mosaicism). Biopsies are performed of abnormal areas, and a histologic diagnosis is made (normal, inflammation, or

CIN 1, 2, or 3). ECC is part of most routine colposcopic examinations, especially those with high-grade cytologic abnormalities or if no ectocervical abnormalities are appreciated on colposcopy. The following is a highly simplified approach to managing the abnormal Pap test based on ASCCP guidelines and will not apply to all situations. For atypical squamous cells of undetermined significance (ASCUS), HR HPV DNA testing is at least 80% effective in detecting CIN 2 or 3 and, therefore, HPV testing is commonly performed. Patients aged 25 and older with ASCUS who are HR HPV-positive should undergo colposcopy, whereas ASCUS HR HPV-negative patients may undergo screening again in 1 year. If the result is ASCUS or worse, colposcopy is recommended; if the result is negative, cytology testing at 3-year intervals is recommended. Atypical squamous cells that cannot exclude HSIL (ASC-H) represent approximately 15% of ASCUS Pap results with a much higher predictive value for detecting CIN 2 to 3. These patients and those with low-grade squamous intraepithelial lesion (LGSIL) and high-grade squamous intraepithelial lesion (HGSIL) cytology results need colposcopic examination. However, HR HPV testing is not indicated for ASC-H, LGSIL, and HGSIL cytology because the test is almost always positive and management decisions are not affected (i.e., colposcopy is needed for these groups regardless of HPV results). “Screen and treat” protocols are often implemented if there is a concern for noncompliance with follow-up and is acceptable for women with HSIL cytology. For women with all subcategories of atypical glandular cells (AGCs) and endocervical adenocarcinoma in situ (AIS) except atypical endometrial cells, colposcopy with ECC is recommended regardless of HPV result. Endometrial sampling should be performed in conjunction with colposcopy and ECC in women 35 years of age and older because they may be at risk for endometrial hyperplasia/carcinoma. Women with AGCs not otherwise specified in whom CIN 2+ is not identified, cotesting at 12 and 24 months is recommended. For women with AGCs that “favor neoplasia” or endocervical AIS cytology, if invasive disease is not identified during colposcopic workup, an excisional procedure is recommended. In addition to these diagnoses, a diagnostic cervical conization may also be necessary in the following situations: (1) inadequate colposcopy, (2) ECC results are positive for CIN 3, (3) there is a high-grade lesion on Pap test not accounted for by colposcopy, or (4) a biopsy suggesting microinvasion. Cervical conizations are also sometimes therapeutic procedures depending on the extent of dysplasia or histologic abnormality. 6. Therapy and prognosis. Treatment of CIN is dependent on biopsy results. However, choice of therapy should take into consideration the patient’s age, desire for subsequent fertility, and physician experience. No therapy is 100%

effective and the risk and benefits should be thoroughly discussed. For CIN 1 preceded by ASCUS or LGSIL cytology, HPV 16/18 and persistent HPV can safely be monitored with cotesting at 12 months. If both the HPV test and cytology findings are negative, then age-appropriate retesting 3 years later is recommended. After two consecutive negative Pap tests, routine screening guidelines may be resumed. More than 60% of these abnormalities will spontaneously resolve. Repeated colposcopy should be performed if high-grade lesions (≥ASC or HPV-positive) are present on Pap test. CIN 2 remains the consensus threshold for treatment in the United States except in special circumstances (i.e., young women aged 21 to 24 with a histologic diagnosis of CIN 2, 3 not otherwise specified, and pregnant women, etc.). Treatment options (and their respective failure rates) for CIN include electrocautery (2.7%), cryosurgery (8.7%), laser (5.6%), cold coagulation (6.8%), loop electrosurgical excisional procedure (LEEP) (4.3%), “cold” knife conization (CKC) (4%), and hysterectomy. LEEPs have gained widespread acceptance and use because of the fact that they are well-tolerated outpatient procedures that have diagnostic and therapeutic effects. For CIN 2 lesions, it appears that 40% to 58% will regress if left untreated, whereas 22% progress to CIN 3, and 5% progress to invasive cancer. The estimated spontaneous regression rate for CIN 3 is 32% to 47%, with up to 40% progressing to invasive cancer if untreated. Management of AIS, however, remains controversial because many assumptions used to justify conservative management for CIN 2 and 3 do not apply. For example, determination of depth of invasion is more obscure because of the extension of AIS into the endocervical canal. Furthermore, AIS can be multifocal and discontinuous. Therefore, negative margins on a specimen do not provide assurance of complete resection. Therefore, total hysterectomy remains the treatment of choice in women who have completed childbearing. Alternatively, women who desire fertility should be counseled that observation is an option, although it carries a less than 10% risk of persistent AIS. Should a patient forego conservative management, if the margins of the specimen are positive or ECC at time of excision contains CIN or AIS, re-excision is preferred. 7. Complications. Complications following an excisional procedure occur in about 1% to 2% of patients. Acute complications include bleeding, infection of the cervix or uterus, anesthesia risk, and injury to surrounding organs such as vaginal sidewall, bladder, and bowel. However, given that the majority of patients are of childbearing age, the more concerning issues to patients are long-term complications related to the integrity of the cervix and its impact on future pregnancy outcomes. Cervical stenosis after a LEEP has been reported to be between 4.3% and 7.7%. Not only does this impair complete examination of the

transformation zone of the cervix but it also occludes access to the uterine cavity, leading to a hematometra or pyometra. In pregnancy, cervical scarring/stenosis may also inhibit the cervix from dilating normally during labor. Other obstetric complications following a LEEP, although controversial, include increased risk of spontaneous abortion especially in women with a shorter time interval from LEEP to pregnancy, second-trimester pregnancy loss, preterm premature rupture of membranes, and preterm delivery. 8. Follow-up. In general, women undergoing observation for CIN 1 to 2 should have Pap tests every 6 months with repeat colposcopy for ASC or worse until 24 months, and then return to routine screening. Unfortunately, many women do not follow up promptly after abnormal cervical cytology. In a retrospective study of over 8,571 women with abnormal cervical cytology, 18.5% were lost to followup including 8% of those with HSIL. Follow-up rates were higher for those patients with a higher degree of cytologic abnormality (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.17 to 1.42), older patients (OR 1.03, 95% CI 1.02 to 1.030), and those receiving index Pap test at a larger health care facility (OR 1.13, 95% CI 1.01 to 1.27). For women with CIN 1, if disease persists for 2 years, either continued follow-up or treatment is acceptable. For women treated for CIN 2 to 3, cotesting at 12 months and 24 months is recommended. If both cotests are negative, then retesting in 3 years is recommended, but if any test is abnormal then colposcopy with ECC is recommended. If CIN 2 or 3 is identified at the margin of an excisional procedure or in an ECC sample obtained immediately after the procedure, follow-up with cytology and ECC is preferred 4 to 6 months after treatment. Alternatively, repeating the excisional procedure is also acceptable. B. Cervical cancer: Invasive disease 1. Background. Cervix cancer is the third most common gynecologic malignancy in the United States, with approximately 15,000 new cases and 5,000 deaths per year. Worldwide, it is the second leading cause of death from cancer among women, with approximately 275,100 deaths annually in 2011 (CA Cancer J Clin 2011;61:69). Areas of the world that have implemented screening and treatment programs for preinvasive cervical lesions have decreased the mortality by approximately 90%. HPV infection has been well established as the underlying etiology for the development of cancer, with 70% of cases attributed to HPV genotypes 16 and 18. 2. Presentation. The majority of patients with cervical cancer present between ages 45 and 55 years with abnormal vaginal bleeding or discharge, which is often serosanguinous and foul smelling. Late symptoms or indicators of more advanced disease include flank or leg pain, dysuria, hematuria, rectal bleeding, obstipation,

and lower extremity edema. Invasive cancer detected by Pap test is much less common. Visually, cervical cancer lesions are exophytic (most common), endophytic, or ulcerative. They are usually very vascular and bleed easily. Biopsies should be performed on all lesions with pathologic confirmation of disease before initiation of therapy. 3. Workup and staging. Women with biopsies suggesting microinvasive cervical cancer without a gross lesion on the cervix should undergo a large cone biopsy to fully evaluate depth of invasion. FIGO staging of cervical cancer is clinical and is determined mainly by physical examination, CXR, intravenous pyelography (IVP), cystoscopy, proctosigmoidoscopy, and results of cone biopsy (if necessary). CT, magnetic resonance imaging (MRI), lymphangiography, and positron emission tomography (PET) scans are used to guide treatment, but should not be used to change the stage. Table 24-8 summarizes FIGO staging of cervix cancer. TABLE 24-8

FIGO Staging of Cervix Cancer

Stage

Description

0

Carcinoma in situ, intraepithelial carcinoma

I

The carcinoma is confined to the cervix

IA

Microscopic disease. All visible lesions are stage IB

IA1

Invasion of stroma ≤3 mm in depth

IA2

Invasion of stroma >3 mm and ≤5 mm in depth

IB

Invasive carcinoma with measured deepest invasion ≥5 mm (greater than stage IA), lesion limited to the cervix uteri

IB1

Invasive carcinoma ≥5 mm depth of stromal invasion and 3 mm and ≤5 mm in depth, and ≤7 mm width

II

Tumor of any size with extension to adjacent perineal structures (one-third lower urethra, one-third lower vagina, anus)

III

Tumor of any size with or without extension to adjacent perineal structures (one-third lower urethra, one-third lower vagina, anus) with positive inguinofemoral lymph nodes

IIIA(i)

With 1 lymph node metastasis (≥5 mm), or

IIIA(ii)

1–2 lymph node metastasis(es) (50), history of greater than five clinically atypical nevi, large congenital nevi, and history of immune suppression with solid organ transplantation. B. Primary cutaneous melanoma 1. Diagnosis. Cutaneous melanomas commonly arise de novo, with the absence of a clinically apparent precursor, although in some instances benign nevi are associated with melanoma on histologic examination. Patients may report the appearance of a new skin lesion or change in an existing lesion and will occasionally note associated symptoms such as itching and bleeding. Nonpigmented, or amelanotic, primary lesions comprise approximately 5% of cutaneous melanomas. a. Physical examination. While evaluating a pigmented skin lesion, the ABCDE (Asymmetry, Border irregularity, Color variation [a heterogeneous mixture of tan, brown, black, red, white, or blue], Diameter >6 mm, and Evolution) morphologic criteria are helpful but not absolute. Particular attention should be given to lesions that are evolving. Other important characteristics that should prompt evaluation and biopsy include itching, bleeding, and the presence of ulceration. A comprehensive skin examination by a dermatologist is critical in evaluating and monitoring patients with multiple or atypical nevi, a family history of melanoma, a history of excessive sun exposure or tanning bed exposure, or a personal history of melanoma or nonmelanoma skin cancer. Full-body examination is essential, including scalp, hands and feet, genitalia, and oral cavity. b. Biopsy. The differential diagnosis of a pigmented skin lesion includes an atypical nevus, a benign growth such as melanocytic nevus, solar lentigo, seborrheic keratosis, angioma, and other malignant growths such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). When melanoma or other malignant lesion is a consideration, a biopsy is required to establish a

diagnosis. c. Excisional biopsy. Full thickness removal of the entire clinical lesion with 1 to 3 mm margins is optimal for diagnosis and accurate staging by Breslow’s depth. Avoiding wider margins facilitates accurate sentinel lymph node mapping if later required. d. Incisional biopsy. For large lesions or lesions on special sites like the palms and soles, face, ears, or digits, full thickness incision or punch biopsy of the thickest clinical portion may be appropriate. e. Deep shave (Saucerization). Wide sampling is preferred in superficial lesions such as lentigo maligna, where atypical melanocytes may extend beyond the clinically observed lesion. Superficial shave biopsy is not recommended for any lesion suspected to be melanoma. 2. Histologic reporting and classification. Breslow’s thickness in millimeters, presence or absence of histologic ulceration, dermal mitotic rate per mm2, microsatellitosis, and the presence or absence at the lateral or deep margins comprise the main elements to be reported with the histologic evaluation of melanoma. Reports may include additional elements such as angiolymphatic/lymphovascular invasion, histologic subtype, neurotropism/perineural invasion, pure versus mixed desmoplasia, the presence or absence of regression, tumor-infiltrating lymphocytes, and vertical growth phase. Melanoma histologic subtypes include superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. Superficial spreading melanoma is the most common subtype (75%), whereas lentigo maligna comprises 10% to 15% and is thought to have an extended radial growth phase. Nodular melanomas are by definition in vertical growth phase. Acral lentiginous melanoma is the least common type and characteristically arises on specialized sites including palmar, plantar, and subungual locations. Aside from the four dominant subtypes, there are rare variants including nevoid melanoma and desmoplastic melanoma. Although histologically distinct, the subtype does not affect staging, and it does not influence initial management. Distinguishing melanoma from benign lesions can be challenging in some cases. Immunohistochemistry (IHC) highlights cells of melanocytic origin, including S100, MART-1, and HMB-45. These antigens are not specific to melanoma but can highlight the architecture of the lesion as well as identify cells of melanocyte lineage in a sentinel lymph node. In borderline lesions, or those nondiagnostic in cellular morphology or growth, additional testing for chromosomal aberrations and copy number variability with fluorescence in situ hybridization (FISH) or comparative genomic hybridization (CGH) can help distinguish benign from malignant lesions.

3. Staging. The most commonly used staging system is found in the AJCC Cancer Staging Manual, eighth edition. The most important prognostic factors in the staging of melanoma are the thickness of the primary lesion measured in millimeters, the presence of histologic ulceration, and regional lymph node involvement. The thickness of the primary melanoma is known as the Breslow thickness and is measured in millimeters from the top of the granular layer in the epidermis to the base of the deepest tumor nest in the dermis. The Breslow thickness cutoffs for primary tumor classification are 1.0, 2.0, and 4.0 mm and are recorded to the nearest 0.1 mm, while ulceration modifies tumor staging. Tumor staging, in combination with clinical findings, guides the next steps of the staging workup. The T stage is defined by the tumor thickness measured to the nearest 0.1 mm. T0 is defined by no evidence of primary tumor or unknown primary. In the setting of a T0 tumor, staging relies on the clinician’s suspicion of primary organ site. Tis or melanoma in situ describes malignant cells confined to the epidermis. T1 ≤ 1.0 mm, T1a < 0.8 mm without ulceration, t1b < 0.8 mm with ulceration or 0.8 to 1.0 mm with or without ulceration. t2 > 1.0 to 2.0 mm with ulceration status unknown or unspecified, T2a > 1.0 to 2.0 mm without ulceration, T2b > 1.0 to 2.0 mm with ulceration. T3 > 2.0 to 4.0 mm with ulceration status unknown or unspecified. T3a > 2.0 to 4.0 mm without ulceration, T3b > 2.0 to 4.0 mm with ulceration. T4 > 4.0 mm with ulceration status unknown or unspecified, T4a > 4.0 mm without ulceration, T4b > 4.0 mm with ulceration. The N stage is defined by the number of regional lymph nodes and non-nodal locoregional sites (microsatellites, satellites, and in-transit metastases). NX refers to regional nodes not evaluated (either a sentinel lymph node biopsy [SLNB] was not obtained or the nodes were taken out previously for other reasons). N0 indicates no regional metastases detected. “Clinically occult” nodal disease, designated as “a,” describes patients without clinical or radiographic evidence of lymph node disease but with microscopically identified node metastasis confirmed by SLNB. “Clinically detected” nodal metastasis, designated as “b,” describes patients with regional node metastasis detected by clinical, radiographic, or ultrasound imaging. Microsatellite, satellite, or in-transit metastases are designated as N1c, N2c, or N3c, respectively. N1 subcategory designates one tumor-involved node (N1a/b) or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes (N1c). N2 subcategory refers to two or three tumor-involved nodes (N2a/b) or in-transit, satellite, and/or microsatellite metastases with one tumor-involved node (N2c). N3 subcategory designates four or more tumor-involved nodes (N3a/b), any number of matted nodes (N3b), or in-transit, satellite, and/or microsatellite metastases with two or

more tumor-involved nodes, or any number of matted nodes (N3c). The M1 stage is defined by the site of distant metastatic disease and serum lactate dehydrogenase (LDH) value for all anatomic site subcategories. M0 stage refers to no evidence of metastatic disease. The M1 stage is subdivided as follows: M1a (distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node); M1b (distant metastasis to lung with or without M1a sites of disease); M1c (distant metastasis to non–central nervous system [CNS] visceral sites with or without M1a or M1b sites of disease); M1d (distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease). LDH value is designated as either 0 (not elevated or normal) or 1 (elevated). Both clinical and pathologic classifications are used in melanoma staging. The melanoma clinical stages are as follows: 0 (Tis), IA (T1a), IB (T1b or T2a), IIA (T2b or T3a), IIB (T3b or T4a), IIC (T4b), III (Any T, Tis and ≥N1), IV (any T, any N, M1). a. Sentinel lymph node biopsy. Stage 0, I, and II melanoma is localized to the skin, whereas stage III melanoma denotes regional metastasis, which is detected by clinical examination or by SLNB. The National Comprehensive Cancer Network (NCCN) guidelines recommend SLNB for patients with T1b melanomas (0.8 to 1.0 mm thick or 1.0 to 4.0 mm thick) and for patients with thick melanomas (T4 or tumors >4.0 mm in thickness). b. Imaging. Routine imaging is not recommended in stage I or II disease unless used to evaluate specific signs and symptoms. The exception is ultrasonography of a nodal basin for an indeterminate lymph node clinical examination, which can help guide decisions for fine-needle aspiration (FNA) or sentinel biopsy. For stage III disease as determined by sentinel biopsy, clinically positive nodes, or in-transit metastases, recommended imaging modalities include a contrast-enhanced computed tomography (CT) chest/abdomen/pelvis or a whole-body positron emission tomography with CT (PET-CT) and brain magnetic resonance imaging (MRI), based on clinical context. For suspected stage IV disease, in addition to a CT scan or PET/CT, a gadolinium-enhanced brain MRI is recommended in the initial staging because of its increased sensitivity for detecting small posterior fossa lesions (1 mm) and stage IIIB-C disease but no in-transit metastases. In this clinical trial ipilimumab was given at 10 mg/kg every 3 weeks for four doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until disease recurrence or unacceptable toxicity. EORTC 18071 showed that ipilimumab improved RFS and OS compared to placebo. Severe toxicities (grade 3 to 4 adverse events) were common with ipilimumab (54%) versus placebo (26%), and there were fatal cases in five patients (1%) that included colitis (n = 3), myocarditis (n = 1), and multiorgan failure with Guillain–Barré syndrome (n = 1). Based on these results, high-dose ipilimumab was approved by the Food and Drug Administration (FDA) in 2015 as adjuvant treatment in melanoma. Nivolumab. The anti-PD-1 monoclonal antibody nivolumab demonstrated an improvement in RFS when compared to high-dose ipilimumab in the adjuvant setting. CheckMate-238 is a randomized, doubleblind trial that enrolled 906 patients with completely resected, stage IIIB/C or stage IV (AJCC seventh edition) melanoma (N Engl J Med 2017;377:1824). Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses then every 12 weeks for up to 1 year. Treatment with nivolumab was associated with a significant improvement in RFS and distant metastasis–free survival (DMFS). RFS was defined as the time between the date of randomization and first recurrence (local, regional, or distant metastasis) or death from any cause, whichever occurred first. Patients treated with nivolumab had fewer recurrences/deaths, 34% (n = 154), compared with 45.5% (n = 206) in the ipilimumab arm (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.53, 0.80; p < 0.0001). nivolumab was better tolerated with fewer severe adverse events compared to ipilimumab. the most common adverse reactions were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. the most common immunemediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). subgroup analyses showed superiority of nivolumab over ipilimumab regardless of BRAF mutation status or PD-L1 expression status. Additional follow-up is needed to determine the impact of nivolumab on OS compared to ipilimumab. Based on these results, 1 year of adjuvant nivolumab therapy was approved by the FDA in 2017. Pembrolizumab. The FDA approved the anti-PD-1 monoclonal antibody

pembrolizumab in 2019 for the adjuvant treatment of patients with completely resected melanoma and positive lymph node involvement. Pembrolizumab was tested in the KEYNOTE-054, a randomized, doubleblind, placebo-controlled trial in patients with completely resected, stage IIIA (>1 mm lymph node metastasis), IIIB, or IIIC melanoma (AJCC seventh edition) (N Engl J Med 2018;378:1789). A total of 1,019 patients were randomized to receive pembrolizumab 200 mg every 3 weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. At a median follow-up of 1.2 years, patients receiving pembrolizumab experienced fewer recurrences/deaths, 26% (n = 135), compared with 43% (n = 216) on the placebo arm (HR 0.57; 95% CI: 0.46, 0.70; p < 0.001). pembrolizumab was superior to placebo regardless of tumor pd-l1 expression. median rfs was 20.4 months in the placebo arm and not reached for those receiving pembrolizumab. the most common adverse reactions were diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenza-like illness, weight loss, and hyperthyroidism; 14% of patients discontinued pembrolizumab for adverse reactions. Nivolumab and pembrolizumab are approved adjuvant therapeutic options for patients with high-risk (stage III/IV) completely resected melanoma regardless of BRAF or PD-L1 status. The results from CheckMate-238 and KEYNOTE-054 suggest that these agents have similar efficacy and safety in the adjuvant setting. b. Adjuvant BRAF-targeted therapy Dabrafenib plus trametinib. Adjuvant treatment with the BRAF/MEK inhibitor combination dabrafenib/trametinib was approved by the FDA in 2018 for selected patients with completely resected melanoma with BRAF V600E or V600K mutations and lymph node involvement. COMBI-AD is a multicenter randomized, double-blind, placebo-controlled trial that enrolled 870 patients with stage III melanoma with BRAF V600E or V600K mutations and pathologic involvement of regional lymph node(s) (N Engl J Med 2017;377:1813). Patients were randomized 1:1 to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily or two placebos for up to 1 year. Patients who received the combination treatment had a statistically significant improvement in RFS compared with those receiving placebo (58% vs. 39%, HR 0.47, p < 0.001), and os rate was superior in the combination treatment versus placebo (3-year os 86% vs. 77%, hr = 0.57, p = 0.0006); however, the p value did not meet the prespecified interim boundary (p = 0.000019). The most common adverse reactions in at least 20% of patients receiving the combination in the

COMBI-AD trial were pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. The most common adverse effects resulting in discontinuation, dose reduction, or dose interruption of dabrafenib were pyrexia and chills. The most common adverse effects resulting in dose reduction of trametinib were pyrexia and decreased ejection fraction. Based on these results, adjuvant dabrafenib plus trametinib combination therapy is an option for stage III melanoma patients who harbor a BRAF V600-activating mutation. 6. Metastatic disease. Regional and distant lymph nodes, skin, lung, liver, and brain are the most common distant sites of metastases from cutaneous melanoma. Prognosis depends on the sites of metastases, with brain and hepatic metastases having the shortest survival followed by lung metastases; nodal and skin metastases have the most favorable prognosis. Historically, metastatic melanoma was associated with poor outcomes. However, the outcomes of patients with metastatic melanoma have greatly improved with the introduction of BRAF/MEK targeted therapies and immune checkpoint inhibitors. To date, multiple checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) and BRAF/MEK inhibitors (vemurafenib/cobimetinib, dabrafenib/trametinib, encorafenib/binimetinib) have received regulatory approval for unresectable or metastatic (stage III/IV) melanoma. a. Dual inhibition of BRAF and MEK. The revolution in melanoma treatment began with the pivotal discovery of the B-Raf proto-oncogene serine/threonine kinase (BRAF) V600 as an oncogenic driver. BRAF V600 is a critical driver mutation that is present in approximately 50% of cutaneous melanoma samples (Nature 2002;417:949). BRAF encodes the B-Raf protooncogene that leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and unregulated cell growth. Among patients with BRAF-mutated cutaneous melanoma, the BRAF V600E mutation is detected in 80% to 85% of patients and the BRAF V600K is detected in approximately 10% of cases. It appears that non-V600E genotypes occur more frequently in older (>65 years of age) patients. Monotherapy with the BRAF inhibitors vemurafenib and dabrafenib showed significant clinical benefit compared to chemotherapy in patients with BRAF V600-mutant metastatic melanoma in the BRIM-3 (N Engl J Med 2011;364:2507) and BREAK-3 (Lancet 2012;380:358) studies. Time to response for BRAF inhibitors was approximately 1.5 months and median PFS 6 to 7 months. However, despite high initial response rates, acquired resistance to BRAF inhibitors develops through reactivation of the MAPK pathway, and there is a paradoxical activation of the MAPK pathway in cells

without a BRAF mutation. Addressing these limitations, several phase III trials have demonstrated that combination of BRAF and MEK inhibitors has better efficacy with improved response rates, duration of response, PFS, and OS over single-agent BRAF inhibitors. The COMBI-d phase III study led to the approval of the combination of dabrafenib and trametinib in 2014 based on improved response rates (69% vs. 53%, p = 0.0014), median PFS (11.0 vs. 8.8 months, p = 0.0004), and OS (25.1 vs. 18.7 months, p = 0.0107) compared to dabrafenib alone (N Engl J Med 2014;371:1877). The results of a pooled analysis of two phase III trials of combined BRAF and MEK inhibition with dabrafenib plus trametinib in patients with advanced melanoma and BRAF mutations were also reported recently (N Engl J Med 2019;381:626). Those results showed a median OS of 25.9 months and a 5year OS of 34%. Co-BRIM is a phase III study that compared the combination of vemurafenib and cobimetinib versus vemurafenib and placebo (N Engl J Med 2014;371:1867). The combination arm led to improved response rates (70% vs. 50%, p < 0.0001), median pfs (12.3 vs. 7.2 months, p < 0.0001), and os (22.3 vs. 17.4 months, p = 0.005). More recently, a phase III randomized trial (COLUMBUS) demonstrated that encorafenib, a BRAF inhibitor, when combined with binimetinib, a MEK inhibitor, improves median PFS (14.9 vs. 7.3 months, p < 0.0001) and os (33.6 vs. 16.9 months, p = 0.0001) compared with vemurafenib or encorafenib monotherapy (Lancet Oncol 2018;19:603). b. Immunotherapy for advanced melanoma. Almost parallel with the development of BRAF/MEK targeted therapy, the field of cancer immunotherapy flourished, delivering novel and effective anticancer therapies with durable clinical responses in melanoma. Targeting T-cell checkpoints to trigger and rescue T-cell activity has led to the approval of several checkpoint inhibitors for the treatment of advanced melanoma. c. Anti-CTLA-4 therapy. Ipilimumab is a human IgG1 kappa monoclonal antibody that blocks CTLA-4 (cytotoxic T-lymphocyte antigen 4) promoting T-cell activation. Ipilimumab allows T-cell activation and proliferation to continue after antigen stimulation by interfering with a homeostatic checkpoint (CTLA-4) that normally inhibits T-cell growth. Ipilimumab works primarily in the priming phase, in the lymph nodes, promoting activation of T cells. Ipilimumab was the first checkpoint inhibitor that showed significant clinical benefit in cancer patients. The FDA approved ipilimumab in March 2011 for use in patients with unresectable or metastatic melanoma administered every 3 weeks (at 3 mg/kg IV) for four doses. The objective response rate (ORR) is 10% to 15%, with a small subgroup of patients

exhibiting disease progression at the initial assessment prior to tumor regression. Ipilimumab has been shown in randomized phase III clinical trials to prolong OS in patients with metastatic melanoma (New Engl J Med 2010;363:711; N Engl J Med 2011;364:2517). More importantly, a recent pooled analysis of melanoma patients treated on various clinical trials with ipilimumab showed that ipilimumab resulted in long-term survival in approximately 20% of patients (5-year OS: 18% vs. 9% for dacarbazine). Remarkably, the survival curve reached a plateau at approximately 20%, which extended up to 10 years (J Clin Oncol 2015;33:1191). Ipilimumab can cause serious side effects leading to severe, and sometimes fatal, autoimmune reactions. Severe adverse events have been reported in 10% to 15% of patients treated with single-agent ipilimumab. Any organ can be affected by an autoimmune reaction, most commonly dermatitis, diarrhea/colitis, hepatitis, endocrinopathies (e.g., hypophysitis, adrenal insufficiency, hypo- or hyperthyroidism), nephritis, pneumonitis, neuropathy, and myocarditis. Patients should be evaluated at the start and prior to each ipilimumab dose along with appropriate laboratories (including liver enzymes and thyroid function tests). Prompt initiation of corticosteroids and prolonged tapers are needed for the management of moderate to severe immune-mediated toxicities. Adverse event management guidelines have been published with treatment algorithms for specific toxicities. d. Anti-PD-1 therapy. PD-1 is expressed on antigen-stimulated T cells and induces downstream signaling that inhibits T-cell proliferation, cytokine release, and cytotoxicity. PD-1 inhibitors block the interaction of the PD-1 receptor with its ligands (PD-L1/PD-L2), releasing the PD-1 pathway– mediated inhibition of the T-cell response, including the anti–tumor immune response. Randomized clinical trials in patients with unresectable III or stage IV melanoma have shown that the PD-1 inhibitors, pembrolizumab and nivolumab, demonstrated increased efficacy and better tolerability compared with ipilimumab. PD-1 inhibitors as single agents or in combination with ipilimumab are now first-line treatment options for metastatic melanoma. Pembrolizumab (Keytruda) is a fully human monoclonal IgG4 kappa antibody that targets PD-1 expressed on activated T cells, B cells, monocytes, and natural killer cells. Pembrolizumab was granted accelerated approval in 2014 based on the results of an expansion cohort of a phase I trial that showed responses in 26% of patients with ipilimumab-refractory metastatic melanoma. The pivotal phase III KEYNOTE-006 trial confirmed the efficacy and superiority of pembrolizumab over ipilimumab. KEYNOTE-006 randomized 834 patients to receive pembrolizumab at two different dosing

schedules for up to 24 months versus ipilimumab at 3 mg/kg for four cycles (N Engl J Med 2015;372:2521). Patients treated with pembrolizumab had a median OS of 32.7 versus 15.9 months with ipilimumab (HR: 0.73; 95% CI: 0.61–0.89). Lower side effects were reported with pembrolizumab compared to ipilimumab (grade 3 to 5 adverse events: 13.3% vs. 19.9%). Across trials, median duration of responses to pembrolizumab is long, with median duration ranging from 23 months to not reached after 33.9 months follow-up in KEYNOTE-006. Pembrolizumab is approved as first-line therapy in patients with unresectable or distant metastatic disease. Nivolumab (Opdivo) is another fully human monoclonal IgG4 kappa antibody that targets PD-1. Two large phase III clinical trials demonstrated superiority of nivolumab when compared to ipilimumab or dacarbazine. The CheckMate-037 trial compared nivolumab versus investigator’s choice chemotherapy in patients with stage III or IV melanoma previously treated with ipilimumab, and if BRAF V600-mutation positive after progressing on a BRAF inhibitor (Lancet Oncol 2015;15:375). This trial showed response rates of 32% with nivolumab versus 10% with chemotherapy. In this trial, the benefit on OS was not statistically significant, likely due to high rate of crossover to anti-PD-1 after progression on chemotherapy. CheckMate-066 randomized 418 treatment-naïve, BRAF-wild-type patients with unresectable stage III or IV melanoma to nivolumab (3 mg/kg) every 2 weeks or dacarbazine at 1,000 mg/m2 every 3 weeks. Primary endpoint was OS (N Engl J Med 2015;372:320). Results from CheckMate-066 showed that nivolumab improved ORR, PFS, and OS compared with chemotherapy. The ORR of patients treated with nivolumab was 40% compared to 13.9% with dacarbazine (p < 0.001). patients in the nivolumab arm had a 58% reduced risk of death compared to dacarbazine. nivolumab is approved as first-line therapy in patients with unresectable or metastatic disease. e. Anti-PD-1/Anti-CTLA-4 combination therapy. Early-phase trials demonstrated better outcomes with the combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in patients with advanced melanoma compared to monotherapy with ipilimumab. The randomized phase III CheckMate-067 trial, published in 2015, showed that patients with previously untreated unresectable stage III or IV malignant melanoma treated with the combination of ipilimumab plus nivolumab had higher ORR, higher rates of complete response, and longer PFS compared to monotherapy with either ipilimumab or nivolumab (N Engl J Med 2015;373:23). The median PFS was 11.5 months in the ipilimumab/nivolumab group, 6.9 months in the nivolumab group, and 2.9 months in the ipilimumab group. The ORRs were

58% with combination therapy, 45% with nivolumab, and 19% with ipilimumab. CheckMate-067 showed that OS was significantly improved with combination therapy versus ipilimumab. Updated results with a minimum follow-up of 60 months showed a median OS of 19.9 months among patients receiving ipilimumab, 36.9 months in patients receiving nivolumab, and not reached on the combination arm. The 5-year survival rates in this trial are 52% for ipilimumab/nivolumab, 44% for nivolumab, and 26% for ipilimumab (N Engl J Med 2019;381:1535). However, CheckMate067 also showed a significant increased toxicity with the combination therapy versus monotherapy. The incidence of severe (grade 3 or 4) adverse events was 59% with the combination as opposed to 23% with nivolumab and 28% with ipilimumab. Because this study was not powered to compare the combination arm versus nivolumab alone, and taking into account the high toxicity with combination therapy, further studies are needed to clarify predictors for treatment response and identify the patient population who would benefit from combination therapy versus anti-PD-1 monotherapy. In CheckMate-067, both nivolumab-containing arms let to better outcomes (ORR, PFS, and OS) regardless of BRAF mutation status and PD-L1 expression. Across trials, clinical outcomes for anti-PD-1 therapy tend to improve with increasing PD-L1 expression. Descriptive analyses in CheckMate-067 showed that combination therapy seems to have a bigger impact improving outcomes among patients with low PD-L1 expression relative to nivolumab monotherapy. However, tumor PD-L1 expression alone is an insufficient predictive marker of efficacy outcomes in this population. Ongoing studies are investigating lower doses of ipilimumab in combination with anti-PD-1 therapy with the goal to decrease toxicity and maintain efficacy. Studies comparing first-line BRAF-targeted therapy to immunotherapy, with crossover at progression, are pending results (NCT02224781). Therefore, current first-line recommendations for advanced melanoma are either immunotherapy (combination anti-PD-1/CTLA-4 or anti-PD-1 monotherapy) or combination BRAF/MEK inhibition (in BRAFmutated patients). f. Talimogene laherparepvec (T-VEC). T-VEC is a genetically modified herpes simplex virus, type 1 (HSV-1), a highly lytic, double-stranded DNA virus. T-VEC is injected into cutaneous, subcutaneous, or nodal melanoma sites. T-VEC provokes antitumor effect in two ways: by directly infecting and destroying local tumor and by introducing a local and systemic immune response. The first human study of T-VEC was a phase I trial including 30 patients with cutaneous or subcutaneous metastasis from melanoma and other

cancers (Clin Cancer Res 2006;15:6737). The injections were well tolerated and the most common reported side effects were fatigue, nausea, chills, and local injection-site reactions. A phase III trial (OPTiM) studied patients with stage IIIB to IV melanoma, randomizing patients to receive either T-VEC or granulocyte-macrophage colony-stimulating factor (GM-CSF) (J Immunother Cancer 2019;7:145). Median OS was superior in the T-VEC arm (23 months) compared to GM-CSF (19 months) (p = 0.049). ORR was 31.5% with TVEC. T-VEC was subsequently approved as a monotherapy for unresectable cutaneous, subcutaneous, or nodal melanoma. T-VEC can be considered a first-line therapy for patients with injectable cutaneous or subcutaneous unresectable stage III or IV disease or patients with advanced BRAF-WT melanoma and contraindications to checkpoint inhibitors. T-VEC is also being studied in combination with checkpoint inhibitors like ipilimumab and pembrolizumab. The combination of T-VEC with pembrolizumab in the MASTERKEY-265 trial (NCT02263508) reported an impressive ORR of 62%. T-VEC is the first FDA-approved oncolytic virus, but there are many ongoing clinical trials studying the use of oncolytic viruses in the treatment of malignancy. 7. Brain metastases. Among all cancers, melanoma is the third most common cause of brain metastases. Approximately 40% of patients with metastatic melanoma experience brain metastasis. Patients with melanoma brain metastases (mBM) have a poor prognosis and account for up to 54% of deaths in patients with melanoma. Surgery and stereotactic radiotherapy are highly effective for local control in patients with brain oligometastases. Whole-brain radiotherapy is reserved for large or multiple brain metastases with limited efficacy. Recently, prospective and retrospective trials evaluating checkpoint inhibitors and targeted therapies have demonstrated clinical activity in patients with mBM. In BRAFmutant patients, the combination of dabrafenib and trametinib showed a high intracranial (IC) response rate (58%) in asymptomatic patients with untreated mBM and reported a median PFS of 5.6 months and a median OS of 10.8 months (Lancet Oncol 2017;18:863). A retrospective analysis in a heavily pretreated population showed that BRAF/MEK inhibition with the combination of encorafenib plus binimetinib demonstrated IC activity with an IC objective response of 33% and IC clinical benefit rate of 63%. The median duration of response was 22 weeks. Interestingly, in patients previously treated with BRAF/MEK inhibitors who discontinued treatment for either poor tolerability or disease progression, the ORR was 24%. This combination was tolerable with no new safety concerns (Cancer 2020;126:523). With immune checkpoint inhibitors, the intracranial clinical benefit (ICB) observed with the combination of

ipilimumab/nivolumab (ICB 57%) is significantly higher than that previously reported with ipilimumab monotherapy (ICB 24%) and with anti-PD-1 therapy alone (ICB 20% to 22%). CheckMate-204 is a phase II study evaluating the efficacy and safety of nivolumab combined with ipilimumab in patients with melanoma and untreated brain metastasis (N Engl J Med 2018;379:722). Patients were eligible if the tumor diameter was 0.5 to 3 cm by brain MRI, asymptomatic without corticosteroid therapy within 10 days before treatment. The combination of ipilimumab plus nivolumab showed a rate of IC objective response of 55% (26% had a complete response and 30% a partial response). Similar rates of objective response (50%) and clinical benefit (56%) were observed for extracranial lesions. In a preliminary assessment of OS, the 6- and 9-month survival rates were 92.3% and 82.8%, respectively, and the estimated 12-month survival rate was 81.5. This study shows that combination therapy with ipilimumab and nivolumab has a clinically meaningful activity and should be considered first line for patients with asymptomatic, untreated mBM. C. Special considerations 1. Melanoma of unknown primary. Patients may present with metastatic disease without an identifiable primary cutaneous melanoma. Cases of melanoma with unknown primary represent less than 5% of melanomas overall. Most patients present with subcutaneous disease or localized lymph node metastasis clinically manifesting as lymphadenopathy; however, patients with solitary pulmonary metastasis as well as solitary brain metastasis are frequently found to have metastatic melanoma after pathologic examination. In these rare instances, BRAF and KIT mutational analysis should be requested. All patients should have a thorough evaluation including examination of the skin, scalp, perineum, eyes, and mucosal membranes, as melanocytes are also present in the eye (conjunctiva and uvea), gut, inner ear, and nasopharynx. 2. Mucosal melanoma. Mucosal melanomas are rare, accounting for only 1% of all melanomas. Mucosal melanomas are associated with poor prognosis, with most patients developing metastatic disease despite surgical excision. The 5-year survival rates reported are as low as 14%. Mucosal melanomas can arise from any mucosal surface including the nasopharynx, oral mucosa, larynx, vulva, rectum, and anus. BRAF V600 mutations are only found in 3% to 15% of all cases. KIT mutations can be found in 8% to 25% of cases of mucosal melanoma. Treatment is WLE with negative histologic margins. However, local and distant recurrences are common. Clinical responses to checkpoint inhibitors have been reported in patients with advanced mucosal melanoma. However, the response rates are lower compared to metastatic cutaneous melanoma. In a recent pooled analysis, including 121 patients with mucosal melanoma, combination therapy

with ipilimumab plus nivolumab was associated with an ORR of 37% (as compared to 60% in patients with cutaneous primary), whereas the ORR with nivolumab monotherapy was 23%. Therefore, combination therapy is recommended in patients with good performance status. BRAF/MEK inhibitors and tyrosine kinase inhibitors are treatment options for patients with BRAF V600 and KIT mutations, respectively. 3. Uveal melanoma. Uveal melanoma (UM) is the most common primary intraocular tumor in adults. UM arises from the melanocytes that reside in the uveal tract. Approximately 90% of UMs involve the choroid, the remainder being confined to the iris or the ciliary body. The mutation profile of UM is distinct from cutaneous melanoma, with >85% UM showing a GNAQ/GNA11 mutation; conversely, BRAF and NRAS mutations are rare. Treatment options for the primary ocular tumor include enucleation and radiotherapy usually in the form of plaque brachytherapy, proton beam therapy, or stereotactic radiotherapy. Unfortunately, up to 50% of patients with UM will ultimately develop metastatic disease. UM generally metastasizes hematogenously to the liver and is commonly fatal within a year of symptom development. The DecisionDx-UM GEP test (Castle Biosciences) for primary UM is a widely adopted molecular classifier that highly correlates to metastatic potential. This prognostic test stratifies UM into three groups based on the expression of 12 genes that influence metastatic spread. The DecisionDx-UM test generates a result of Class 1, Class 1b, or Class 2 with a corresponding 5-year metastasis-free survival prediction of 98%, 79%, and 28%, respectively. This prognostic information guides surveillance plans, with more aggressive follow-up recommended for Class 2 versus Class 1 patients. To date, there are no FDA-approved systemic treatments for metastatic UM. Participation in clinical trials is highly encouraged. For patients with hepatic-dominant metastases, liver-directed therapies such as radiofrequency ablation, radioembolization, and chemoembolization are considered. Systemic chemotherapy has no meaningful clinical activity in UM. Kinase inhibitors such as sorafenib, selumetinib, and trametinib have been investigated with disappointing results. Compared to cutaneous metastatic melanoma, checkpoint inhibitor therapy in UM has been associated with low response rates likely influenced by the overall low PD-L1 expression and low mutational burden in UM. A recent meta-analysis of patients with metastatic UM treated with PD-1/L1 inhibitors reported an ORR of only 3.6% and a median PFS as short as 2.6 months. Preliminary data from a phase II study with the combination of ipilimumab/nivolumab in UM showed a partial response in 17% of patients and stable disease in 53% of patients. Median OS was 1.6 years, and 1-year OS was 62%. Novel agents are being investigated in UM. Tebentafusp is an ImmTAC

(immune-mobilizing monoclonal T-cell receptor against cancer) that binds cells presenting the melanocyte-specific antigen gp100 and recruits T cells to lyse the target cells. Tebentafusp has shown promising clinical activity in metastatic UM, and trials (IMCgp100-102 phase II, IMCgp100-202 phase III) are ongoing to confirm its clinical benefit and safety. II. SQUAMOUS CELL CARCINOMA OF THE SKIN A. Background 1. Epidemiology. SCC is the second most common type of skin cancer in the United States, with around 700,000 new cases diagnosed each year. The overwhelming majority of SCCs occur on chronic sun-exposed skin in older individuals. Men are twice as likely to develop SCC, and its incidence is more than 20 times higher in fair-skinned individuals than in patients with pigmented skin. Incidence also increases with latitudes closer to the equator, reflecting the importance of UV exposure in the pathogenesis of SCC. 2. Risk factors. The major risk factor for the development of SCC is UV exposure. Therapeutic sources of UV radiation such as psoralen plus ultraviolet A (PUVA) greatly increase the risk for SCC as do cosmetic sources of UV radiation. Indoor tanning accounts for approximately 72,000 excess cases of SCC each year (BMJ 2012;345:5909). Other risk factors include immunosuppression, especially in the context of solid organ transplant patients who have a 65 times increased risk compared to the population, fair skin, exposure to ionizing radiation, infection with certain human papillomavirus subtypes, burn scars, nonhealing ulcers, increased age, and hereditary disorders such as xeroderma pigmentosum or recessive dystrophic epidermolysis bullosa. B. Diagnosis and staging. SCC generally presents as an enlarging, erythematous, scaly papule or plaque on sun-exposed skin that is persistent and may bleed and be tender. It is generally thought to exist on a continuum from precursor lesions, known as actinic keratoses, to SCC in situ (Bowen disease) to invasive SCC. A biopsy is necessary to make a definitive diagnosis. Several biopsy techniques are adequate, including shave, punch, incisional, or excisional biopsies. Additionally, a full dermatologic examination and palpation of the draining lymph nodes should be performed. In the absence of clinically suspected metastatic disease, further workup with imaging and laboratory studies is not necessary. Staging of cutaneous SCC in the tumor, node, metastasis (TNM) system has been revised in the seventh edition of the AJCC guidelines to include tumor thickness, as it may have prognostic value. One prospective study of SCC in 615 patients demonstrated no metastases in tumors less than 2.0 mm thick, whereas the rate increased to 4% in tumors 2.1 to 6.0 mm and 16% in tumors larger than 6.0 mm (Lancet Oncol 2008;9:713). However, the existing

system tends to cluster poor outcomes to T2 tumors and therefore renders T3 or T4 classifications less meaningful given the rare occurrence of bone metastases. Because of this, an alternative staging scheme was released in the eighth edition of the AJCC for head and neck SCC. In the revised AJCC, T2 describes tumors that are 2 cm or larger but less than 4 cm without any risk factors. T3 now includes tumors that are 4 cm or larger or have 1 or more risk factors (including deep invasion beyond subcutaneous fat or >6 mm and perineural or bony invasion). T4a includes tumors with bone and/or marrow invasion and T4b includes tumor with skull base or foramen invasion. These revisions improved the stratification of higher-risk tumors. C. Therapy. Several treatment options exist for the treatment of SCC. In situ or lowrisk lesions in non–hair-bearing locations may be treated with curettage and electrodessication. Most lesions are removed surgically, with 0.4-cm margins for lesions smaller than 2 cm in size and more than 0.6 cm margins for lesions larger than 2 cm or with ill-defined borders. Such margins provide cure rates of 90% to 95%. Mohs micrographic surgery can be employed for lesions that are at high risk for recurrence and metastasis, for example, SCC on the central face, ears, eyelids, lips, recurrent tumors, SCCs larger than 2 cm, SCCs with aggressive histologic subtypes, SCCs that develop in scars, or SCCs developing in immunocompromised patients. Mohs micrographic surgery involves the use of frozen or permanent sections to evaluate as close to 100% of the surgical margin as possible by evaluating the circumferential and deep margins. Additional therapies for SCCs include radiation and, rarely, intralesional chemo- or immunotherapy. Radiation therapy is generally reserved for patients who are poor surgical candidates or with extensive perineural invasion. In metastatic disease, multidisciplinary management and clinical trial participation are encouraged. In a phase I study, an anti-PD-1 monoclonal antibody, cemiplimab-rwlc, demonstrated a 50% response rate in a cohort of 26 patients. In a phase II study enrolling patients with metastatic or locally advanced cutaneous SCC and treated with cemiplimab-rwlc, the ORR was 47%, with 61% of responses durable for 6 months or longer (N Engl J Med 2018;379:341). In September 2018, the FDA approved cemiplimab-rwlc for patients with metastatic or locally advanced cutaneous SCC. In the second-line setting, patients with advanced disease may benefit from cetuximab, the anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), which has been studied in patients with advanced SCC showing modest clinical activity. Cytotoxic chemotherapy with platinum and 5-fluorouracil (5-FU)-based regimens are palliative options. D. Prognosis. The vast majority of SCCs can be cured surgically. However, the incidence of local recurrence is 1% to 10%, depending on the method used and can be approximately 20% for high-risk lesions in high-risk locations such as the ear. The incidence of metastasis from cutaneous SCC is 2% to 6%. High-risk SCCs carry a

metastatic risk >10% and include lesions on the lips and ears, lesions larger than 2 cm, thicker lesions, SCCs in scars, recurrent SCCs, SCCs with perineural invasion, and SCCs in immunosuppressed patients. E. Follow-up and prevention. Low-risk SCCs are followed up with full-body skin examinations every 3 to 12 months for the first 2 years, every 6 to 12 months for the next 3 years, and annually thereafter. High-risk SCCs should be followed up with skin and lymph node examinations every 1 to 3 months for the first year, every 2 to 4 months for the next year, then every 4 to 6 months for the next 3 years, then every 6 to 12 months thereafter, according to the 2019 NCCN guidelines. Sun protection and sun avoidance need to be stressed in these patients. In high-risk patients, including solid organ transplant or otherwise immunosuppressed patients, precancerous actinic keratoses should be aggressively treated and threshold for biopsy of suspicious lesions should be low. III. BASAL CELL CARCINOMA A. Background 1. Epidemiology. BCC is the most common cancer in the United States, with over 2 million new cases each year. It is more common in men than in women, and its incidence is increasing in all age groups (JAMA 2005;294:681). 2. Risk factors. Environmental exposure to UV light from the sun or tanning beds confers significant risk for the development of BCC, both of which are preventable exposures. Approximately 98,000 additional cases of BCC are attributable to indoor tanning. Additionally, a history of immunosuppression, increasing age, exposure to ionizing radiation or arsenic, and a history of prior nonmelanoma skin cancer increase risk. Genetic susceptibility to UV damage from fair skin and hereditary disorders such as xeroderma pigmentosum confer risk for BCC. Rare patients will present with numerous, early-onset BCCs as a feature of the nevoid BCC syndrome, or Gorlin syndrome, which is due to mutations in the PTCH1 gene. Additional syndromes with early-onset BCC include Bazex–Dupré–Christol and Rombo. Patients with multiple or early BCC or extensive family history should be referred for dermatologic evaluation. B. Diagnosis. BCC classically presents as a pink, pearly papule with a rolled border and arborizing telangiectasias on sun-exposed skin, although common variants include pigmented, ulcerated, or morpheaform morphology. Patients may report that the lesion bleeds easily, does not heal, or is tender. Although in many instances the diagnosis of BCC is strongly suspected based on clinical appearance, biopsy confirms the diagnosis of BCC. Metatypical, infiltrative, morpheaform, sclerosing, or micronodular features on histology represent an aggressive growth pattern. Any one of several biopsy techniques is acceptable, including shave, punch, incisional, or

excisional biopsies. BCCs rarely metastasize, and further workup, beyond a full skin examination, is generally not necessary. C. Therapy. BCC is typically treated with destructive or surgical measures. Curettage and electrodessication provide a rapid and effective method to destroy BCCs, with a cure rate more than 90%. Surgical excision of BCCs with at least a 4-mm margin provides a cure rate of approximately 95%. Similar to SCCs, BCCs in high-risk locations, including the “mask areas” of the face and genitals, larger tumors on lowrisk areas, tumors with aggressive histology, and recurrent BCCs can be treated with Mohs micrographic surgery. Cryotherapy and radiation therapy are also options for patients with low-risk BCCs who are poor surgical candidates. For superficial BCC, topical 5-FU can clear more than 90%, whereas imiquimod has been shown to clear over 80% of such BCCs. For locally advanced BCC or metastatic BCC, systemic therapy with a hedgehog (Hh) pathway inhibitor (vismodegib or sonidegib) is recommended. Vismodegib is an oral small-molecule inhibitor of smoothened homolog (SMO), a downstream target of PTCH1, and has significant clinical activity because most BCCs depend on the activation of the Hh pathway. In a multicenter phase II clinical trial enrolling patients with either locally advanced BCC (n = 63) or metastatic BCC (n = 33), treatment with vismodegib demonstrated significant clinical activity, with ORR of 43% in locally advanced disease and 30% in metastatic disease (N Engl J Med 2012;366:2171). The recommended dose is 150 mg daily. The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia. An ongoing phase II study is investigating the PD-1 inhibitor cemiplimab in metastatic BCC. D. Prognosis. The prognosis for patients with BCC is excellent. Most patients are cured by the aforementioned modalities. If left untreated, BCCs continue to enlarge and are locally destructive. Metastases occur in less than 0.1% of patients, and common sites are the lymph nodes, lungs, and bones. Although considered incurable, patients with metastatic BCC should be considered for systemic therapy with a hedgehog (Hh) pathway inhibitor or enrollment in a clinical trial. E. Follow-up and prevention. Patients with a history of BCC have a 50% chance of developing a second BCC within 5 years. Therefore, similar to patients with SCC, close follow-up is recommended with full skin examinations. Avoidance of precipitating factors such as sun exposure, tanning beds, and ionizing radiation needs to be stressed in these patients. IV. MERKEL CELL CARCINOMA A. Background 1. Epidemiology. Merkel cell carcinoma (MCC) is an uncommon high-grade,

highly metastatic cutaneous cancer. Since the 1990s, the incidence of MCC has increased by 5% to 10% each year. In the United States, approximately 1,500 cases are diagnosed a year. MCC is more common in fair-skinned, elderly individuals, with a mean age of diagnosis between 74 and 76 years and 95% of all cases arising in white patients. 2. Risk factors and pathogenesis. MCC is thought to arise from the Merkel cell in the basal layers of the epidermis and has both epithelial and neuroendocrine features. Although the pathogenesis is not clear, there are identifiable risk factors for the development of MCC. These include exposure to UV light, man-made sources of UV radiation, immunosuppression, fair skin, and advancing age. The Merkel cell polyomavirus (MCPyV), discovered in 2008, is thought to play an etiologic role in MCC development and is present in 80% to 100% of examined cases, although the Merkel virus can be found on normal skin or in SCCs. At the time of diagnosis, a baseline Merkel polyoma virus serology test may be performed, to determine whether patients make antibodies to the virus. Patients who do not make antibodies are at higher risk for disease recurrence, possibly influencing follow-up regimens. In addition, if present, antibody levels fall following treatment and will increase with disease recurrence. B. Diagnosis and staging. MCC typically presents as an asymptomatic, rapidly growing, pink-to-red, dome-shaped papulonodule on the head and neck or the upper limbs. Tumors are primarily dermal, although around 10% arise in the epidermis. Biopsy and histologic examination are required to make the diagnosis of MCC, whereas special stains with a profile of CK-20 and neurofilament-positive and TTF1-negative aid in distinguishing MCC from other neuroendocrine tumors such as small cell carcinoma of the lung. For equivocal lesions, additional neuroendocrine markers should be considered, including chromogranin A, CD56, and synaptophysin. The eighth edition of the AJCC staging manual uses 2 and 5 cm as size cutoffs for T1, T2, and T3 lesions. T1 is defined as tumors with a maximum diameter less than 2 cm, T2 tumors have a maximum diameter greater than 2 cm, and T3 tumors have a maximum diameter greater than 5 cm. Lesions invading the bone, muscle, fascia, or cartilage are considered T4. Stage I disease is defined as a T1 tumor without nodal or distant metastasis. Stage IIA are T2 or T3 tumors without nodal disease or distant metastasis. Stage IIB are T4 tumors without nodal disease or distant metastasis. Stage IIIA is T1 to T4 tumor with clinically occult regional lymph node metastasis or an unknown tumor with clinically detected or radiographically detected lymph node disease. Stage IIIB includes clinically apparent primary with clinically detected lymph nodes (T1-4N1b), in-transit metastases (N2), or both (N3). Any distant disease defines stage IV. For patients with clinically advanced disease at presentation, fluorodeoxyglucose (FDG)-PET/CT can be used to screen for both

regional lymph nodes and distant metastases. If lymph nodes are negative by clinical examination, it is recommended that patients with stage I or II disease receive a SLNB. With clinically positive nodes, FNA should be attempted, and if negative, open biopsy should be considered. C. Therapy. The mainstay of therapy for primary disease is WLE with 2-cm margins or Mohs micrographic surgery when 2-cm margins are not feasible. Despite resection, the probability of local recurrence is high. It is also important to note that the SLNB should be done prior to definitive excision, particularly in the head and neck, where the drainage pattern is complex. Although the NCCN guidelines recommend SLNBs for staging, their effects on survival remain in question. There is some evidence that a WLE, combined with adjuvant radiation therapy, may provide a survival benefit. In one retrospective analysis of nearly 5,000 patients presenting with stage I to III MCC in the US National Cancer Database, there was a 29% and 23% reduction in hazard of death with adjuvant radiotherapy for stage I and II MCC, respectively (J Natl Cancer Inst 2016;108). Patients with recurrent MCC may be treated with surgical excision, definitive radiation, or systemic therapy. For unresectable and metastatic disease, immune checkpoint inhibitor therapy with a PD-1/L1 inhibitor is now the standard first-line therapy. In 2017, the FDA granted accelerated approval for avelumab, an anti-PD-L1 monoclonal antibody, based upon the results of the JAVELIN Merkel 200 trial (Lancet Oncol 2016;17:1374). This multicenter trial showed a response rate of 62%, with more than 80% ongoing at 6 months. The PD-1 inhibitor pembrolizumab showed an ORR of 56% and 69% survival rate at 24 months (N Engl J Med 2016;374:2542). A study including MCC cohorts treated with nivolumab alone or nivolumab in combination with ipilimumab is ongoing (NCT02488759). Avelumab, pembrolizumab, and nivolumab are all included as systemic treatment options for MCC. Platinum-based chemotherapy regimens are now considered second line in this population. A phase II trial of T-VEC, with or without concurrent radiotherapy, for patients with unresectable skin or nodal MCC is ongoing (NCT02819843). Immune checkpoint inhibitor therapy is being investigated as adjuvant therapy for stage III MCC in a large phase III trial (NCT03271372). D. Prognosis. The 5-year OS for MCC varies by stage, with stage I having the best prognosis, around 70%, falling to 40% to 55% for stage II, 30% to 40% for stage III, and 15% to 20% for stage IV. Outcomes are worse for immunocompromised patients. E. Follow-up. Given the high rates of local recurrence and metastatic disease, patients should be followed closely with complete physical examination every 3 to 6 months for the first 3 years, including skin and lymph node examinations followed by every 6 to 12 months. The median time to recurrence is 8 months, with 90% of recurrences in the first 24 months. For high-risk patients, routine imaging with brain MRI, CT

scans, or whole-body FDG-PET/CT can be used to identify metastases. Patients with positive MCPyV oncoprotein antibodies at the time of active disease can track recurrence with a serial examination of their oncoprotein titers. SUGGESTED READINGS Algazi, AP; Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer 2016;122:3344–3353. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016;17:1248–1260. Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 2008;9:713–720. Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA 2005;294:681–690. D’Angelo SP, Larkin J, Sosman JA, et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis. J Clin Oncol 2017;35:226–235. D’Angelo SP, Russell J, Lebbé C, et al. Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma: a preplanned interim analysis of a clinical trial. JAMA Oncol 2018;4:e180077. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017;18:863–873. Dréno B, Kunstfeld R, Hauschild A. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomized, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol 2017;18:404–412. Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018;19:1315–1327. Eggermont AM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 2018;378:1789–1801. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomized, double-blind, phase 3 trial. Lancet Oncol 2015;16:522–530. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 2017;376:2211–2222. Gerami P, Cook RW, Wilkinson J, et al. Development of a prognostic genetic signature to predict the metastatic risk associated with cutaneous melanoma. Clin Cancer Res 2015;21:175–183. Hansson J, Bartley K, Karagiannis T, et al. Assessment of quality of life using Skindex-16 in patients with advanced basal cell carcinoma treated with vismodegib in the STEVIE study. Eur J Dermatol 2018;28:775–783. 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. Ives NJ, Suciu S, Eggermont AM, et al. Adjuvant interferon-α for the treatment of high-risk melanoma: an individual patient data meta-analysis. Eur J Cancer 2017;82:171–183. Keller J, Schwartz TL, Lizalek JM, et al. Prospective validation of the prognostic 31-gene expression profiling test in primary cutaneous melanoma. Cancer Med 2019;8:2205–2212. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381:1535–1546. Leachman SA, Lucero OM, Sampson JE, et al. Identification, genetic testing, and management of hereditary melanoma. Cancer Metastasis Rev 2017;36:77–90. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017;377:1813–1823. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379:341–351. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J

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I.

THYROID CARCINOMA A. Definition. Thyroid cancer consists of a group of uncommon neoplasms, including differentiated (papillary, follicular, and Hürthle cells), medullary (sporadic and hereditary), anaplastic histologies, and thyroid lymphoma. 1. Differentiated. Papillary carcinoma is the most common subtype, accounting for 85% of cases, and commonly metastasizes to the lymph nodes. In contrast, follicular carcinomas are more prone to systemic metastases. 2. Poorly differentiated. These tend to be more aggressive, more often are not iodine avid, and have a poorer prognosis. 3. Anaplastic. These carcinomas are rarely curable. Management includes surgical excision, if possible, and experimental protocols or palliative radiation. Survival is usually measured in weeks to months. 4. Medullary thyroid carcinomas (MTCs). These can present as either sporadic tumors (80%) or part of the multiple endocrine neoplasia syndromes (MEN2A and MEN2B). The MEN2A syndrome is characterized by MTC (100% penetrance), hyperparathyroidism (2 times normal increases the risk of veno-occlusive disease

Radioventriculogram or echocardiogram

LVEF >40%–45% desirable

ECG

Evaluate for underlying cardiovascular disease

Chest radiograph

Evaluate for underlying pulmonary disease or infection

Pulmonary function tests

FEV1, FVC, DLCO >50% predicted

Viral serologies (CMV, HSV, HIV, HTLVI, hepatitis A, hepatitis B core antigen and surface antibody, and hepatitis C)

HSV seropositivity requires antiviral prophylaxis; hepatitis seropositivity without evidence of active disease increases the risk of veno-occlusive disease, but is not a contraindication to HSCT

Radiation oncology evaluation

TBI-conditioning regimen candidates

Nutrition evaluation Pregnancy test (premenopausal women) Sperm/oocyte banking ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMV, cytomegalovirus; DLCO, carbon monoxide diffusion in the lung; ECG, electrocardiogram; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplant; HSV, herpes simplex virus; HTLV-I, human T-cell lymphoma virus type 1; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; TBI, total-body irradiation.

IV. DONOR SELECTION A. HLA typing. For allo-HCT, donors are selected on the basis of their histocompatibility with the recipient. The major histocompatibility complex (MHC) locus, also called “HLA locus,” on chromosome 6 encodes class I and class II HLA antigens that allow for the immune recognition of foreign antigens. In hematopoietic

and solid organ transplantation, HLA molecules function as alloantigens that can trigger immune recognition and graft rejection in mismatched recipients. 1. HLA alleles. HLA antigens are defined serologically by testing for reactivity against a panel of monoclonal antibodies. DNA-based testing has largely replaced serologic testing and utilizes sequence-specific DNA primers and probes to define HLA alleles. High-resolution molecular typing of 10 HLA genes (HLAA, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1) is the current standard. Highresolution molecular typing permits precise HLA matching between donors and transplant patients, which has resulted in improved patient outcomes. Because the MHC complex is tightly clustered on chromosome 6, HLA alleles are inherited as a set, also referred to as the patient’s haplotype. The chance of any individual sibling being HLA matched is 25%, whereas the probability of having a fully HLA-matched sibling donor is 1 − (3/4)n, where n is the number of full siblings. 2. HLA matching of unrelated donor transplants. Typing of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 is routinely used to select unrelated donors. In addition, other class II loci HLA-DPB1 and HLA-DRB3/4/5 are often tested, although there is no definite association with the patient outcomes. In the United States, unrelated donor transplant searches are coordinated by the National Marrow Donor Program (NMDP). The likelihood of finding an unrelated donor for a given patient depends upon the frequency of the patient’s HLA haplotype in the general population. The likelihood of finding a potential unrelated marrow or peripheral blood stem cells (PBSCs) donor in the donor registries is largely tied to race. In the United States, Caucasians are much more likely to find a match than African Americans or Asian Americans. 3. HLA matching of haploidentical donor transplants. Haploidentical donors are matched at three of the six loci (HLA-A, HLA-B, and HLA-DR). The likelihood of finding a successful haploidentical relative is significantly higher than that of finding a successful MUD match. In addition, the time and cost of a donor search may be spared when seeking a haploidentical donor. B. Non-HLA factors. Other factors are often considered when donors are selected, including cytomegalovirus (CMV)-negative serology (for patients with CMVnegative serology), male sex, younger age, ABO compatibility, larger body weight, and matched race. Multiparous female donors are associated with a higher risk of cGVHD, but with no effect on overall survival. V. SOURCES OF HSCS A. Bone marrow. Historically, the bone marrow was used as the sole graft source in transplantation. Bone marrow is collected from the posterior iliac crest by performing repeated aspirations while the donor is under general or regional

anesthesia. The volume collected varies, but generally ranges from 10 to 15 mL/kg of donor weight. Improved survival has been correlated with higher transplanted HSC dose with more robust engraftment and fewer infectious complications. A total nucleated cell (TNC) dose of approximately 2 × 108 cells/kg in the harvested bone marrow product is considered adequate for HCT. Side effects of marrow collection include fatigue and pain at the collection site and effects related to general anesthesia, such as nausea and vomiting. B. Peripheral blood as a graft source. HSCs normally circulate in low levels in the peripheral circulation, but can be recruited into the peripheral blood from the marrow in response to stressors, such as inflammation or infection. In addition, the exogenous administration of hematopoietic growth factors can increase the numbers of PBSCs by 40- to 80-fold in a process termed stem cell mobilization. These mobilized HSCs along with other mononuclear cells can then be harvested and used for HCT. Currently, the majority of autologous and allogeneic transplants are performed using peripheral blood as a graft source. 1. Stem cell mobilization. Although a number of cytokines and cytokine combinations can mobilize HSCs, the Food and Drug Administration (FDA)– approved medications for stem cell mobilization include granulocyte colonystimulating factor (G-CSF) (filgrastim, 10 to 16 μg/kg), granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim), and plerixafor. Donors may experience myalgia, bone pain, headache, nausea, and low-grade fevers with GCSF. Splenic rupture resulting from extramedullary hematopoiesis has been reported as a rare complication. HSCs also increase in the peripheral circulation during neutrophil recovery after the administration of chemotherapy. For autologous stem cell collection, high-dose cyclophosphamide or other forms of chemotherapy may be used to mobilize HSCs, and this can be augmented with the administration of G-CSF or GM-CSF to increase the stem cell yield. Plerixafor is a CXCR4 antagonist used for the mobilization of stem cells. CXCR4 is a receptor for the chemokine CXCL12 (stromal-derived factor 1 [SDF-1]) produced by marrow stromal cells and is critical for the homing and retention of HSCs in the marrow. By disrupting the CXCR4/CXCL12 axis, plerixafor has been shown to be effective for the mobilization of stem cells, either alone or in combination with G-CSF. 2. HSC harvesting from peripheral blood. Following mobilization, HSCs are collected by large-volume apheresis (up to 20 L) through the antecubital veins or a central venous catheter. The mononuclear fraction containing the HSCs along with other mononuclear cells like lymphocytes and monocytes is retained, and the remainder is reinfused into the patient. Hypocalcemia from the

anticoagulation with acid-citrate-dextrose solution used during apheresis may cause perioral numbness, paresthesias, and carpopedal spasm and is treated with calcium supplementation. A minimum of 2 × 106 CD34+/kg recipient weight is required for an autologous transplant, whereas a goal of 5 × 106 CD34+/kg increases the probability of early platelet recovery. Similarly ideal dose of CD34+ collected for allo-HCT is around 5 × 106/kg recipient weight, but doses greater than or equal to 3 × 106/kg are considered sufficient, especially in the absence of donor–recipient HLA mismatch. Most normal donors require only a single apheresis session to collect adequate numbers of stem cells, whereas autologous donors may require multiple sessions, depending on their age and degree of exposure to previous chemotherapy. Compared with the marrow, PBSCs contain higher numbers of CD34+ cells than the bone marrow and are associated with faster neutrophil and platelet recovery. In addition, PBSC grafts have approximately 10 times as many T lymphocytes, which are associated with higher rates of cGVHD but without an effect on overall survival. Aplastic anemia is an exception to the expanding use of peripheral blood as a graft source, as for these patients, bone marrow is the preferred graft source and has been associated with better outcomes. C. Umbilical cord blood. Blood present in the umbilical cord and placenta following childbirth is a rich source of HSCs. After delivery of the placenta, the umbilical cord is clamped, and approximately 50 to 100 mL remaining in the placenta and umbilical cord is drained and cryopreserved. Cord blood typically contains about a 10- to 20fold smaller dose of nucleated and CD34+ cells than an adult bone marrow. Because of the limitations in stem cell dose, cord blood transplants have been primarily performed in pediatric populations, with a minimum of 2.0 × 107 mononuclear cells/kg typically required for successful transplantation and greater than 3.0 × 107 mononuclear cells/kg for optimal results. In the adult population, typically, two cord blood units (double-cord allo-HCT) are pooled for a single recipient, which can result in a more rapid hematopoietic recovery. Of interest, in double-cord allo-HCT, only one of the two cord blood units dominates hematopoiesis over the long term. Cord blood transplants are associated with lower risks of GVHD and can be performed successfully with a greater degree of HLA mismatch than adult stem cell sources. In addition, cord blood units are more readily available than stem cells from adult donors and are associated with lower rates of viral transmission. Cord blood registries, unlike adult donor registries, do not suffer from loss to the donor pool owing to advancing age or difficulties in locating potential donors. Major problems with cord blood transplantation include delayed engraftment, higher risk of posttransplant infections, mildly increased rates of graft failure, and the inability to collect additional donor cells for patients with graft failure and/or relapse.

VI. CONDITIONING REGIMENS A. Myeloablative conditioning. Traditional conditioning regimens used in HCT include myeloablative doses of alkylating agents (cyclophosphamide, busulfan, melphalan) with or without total-body irradiation (TBI) before transplant to (a) eliminate residual disease and (b) suppress immune function to allow engraftment of donor stem cells. Standard conditioning regimens vary by disease, with commonly used regimens listed in Table 29-4. In addition to severe myelosuppression, agents used in HCT are typically associated with side effects such as mucositis, alopecia, and nausea and may cause significant organ damage, including hepatic or pulmonary dysfunction. TABLE 29-4 Regimen

Common Myeloablative Conditioning Regimens Total Dose

Daily Dose

TBI

1,225 cGy

175 cGy b.i.d. d−6/−5/−4, 175 cGy d−3

Cyclophosphamide

120 mg/kg

60 mg/kg/day IV × 2, d−3/−2

MESNA

120 mg/kg

60 mg/kg CIVI over 24 h × 2, d−3/−2

Busulfan

16 mg/kg

1 mg/kg p.o. q6h, d−7/−6/−5/−4

Cyclophosphamide

120 mg/kg

60 mg/kg/day IV × 2, d−3/−2

MESNA

120 mg/kg

60 mg/kg CIVI over 24 h × 2, d−3/−2

200 mg/m2

100 mg/m2 IV × 2, d−3/−2

BCNU

450 mg/m2

450 mg/m2, d−7

Etoposide

800 mg/m2

100 mg/m2 IV b.i.d. × 4 d, d−6/−5/−4/−3

Ara-C

800 mg/m2

100 mg/m2 IV b.i.d. × 4 d, d−6/−5/−4/−3

Melphalan

140 mg/m2

140 mg/m2, d−2

Allogeneic Regimens Cy/TBI

Bu/Cy

Autologous Regimens Multiple Myeloma Mel-200 Melphalan Lymphoma BEAM

Solid Tumors

MEC Etoposide

1,200 mg/m2

300 mg/m2 × 4, d−6/−5/−4/−3

Carboplatinum

1,400 mg/m2

700 mg/m2 × 2, d−4/−3

Melphalan

140 mg/m2

140 mg/m2, d−2

Ara-C, cytosine arabinose; b.i.d., two times a day; BCNU, 1,3-bis-(2-chloroethyl)-1-nitrosourea; CIVI, continuous intravenous infusion; IV, intravenous; MESNA, [sodium-2]-mercaptoethanesulfonate; p.o., oral; TBI, total-body irradiation.

B. Reduced-intensity conditioning. In the allogeneic setting, nonmyeloablative or reduced-intensity conditioning (RIC) regimens were designed to reduce the toxicity associated with high-dose therapy. These regimens do not attempt to completely eliminate malignant cells before transplant, but instead provide enough immunosuppression to allow donor engraftment and rely predominantly upon a GvT effect mediated by the donor-derived T cells to achieve their therapeutic goal. Some of the commonly used RIC regimens are listed in Table 29-5. RIC regimens allow the elderly and patients with significant comorbid conditions to be eligible for alloHCT. In retrospective analyses conducted in myeloid malignancies, RIC regimens are associated with lower treatment-related mortality but with higher relapse rates and no change in overall survival. Rates of aGVHD and cGVHD after RIC are comparable to those observed in standard high-dose transplants, but the onset of aGVHD is often delayed by weeks to months. In view of the increased risk of relapse, these regimens are best suited to patients who are in complete remission at the time of transplant. TABLE 29-5 Regimen

Common Reduced-Intensity and Nonmyeloablative Conditioning Regimens Total Dose

Daily Dose

Cyclophosphamide

120 mg/kg

60 mg/kg/day × 2, d−7/−6

Fludarabine

125 mg/m2

25 mg/m2 × 5, d−5/−4/−3/−2/−1

MESNA

120 mg/kg

60 mg/kg CIVI over 24 h × 2, d−4/−3

Cyclophosphamide

200 mg/kg

50 mg/kg/day × 4, d−6/−5/−4/−3

Thymic RT

700 cGy

d−1

ATG

45–90 mg/kg

15–30 mg/kg × 3, d−2/−1/+1

MESNA

200 mg/kg

50 mg/kg CIVI over 24 h × 4, d−6/−5/−4/−3

Flu/Cy

Cy/Thymic RT/ATG

Flu/Bu and/or ATG Busulfan (oral)

8 mg/kg

4 mg/kg/day × 2, d−6/−5

Fludarabine

150 mg/m2

30 mg/m2/day × 5, d−10/−9/−8/−7/−6/−5

ATG

40 mg/kg

10 mg/kg/day × 4, d−4/−3/−2/−1

ATG, antithymocyte globulin; RT, radiation therapy.

VII. HEMATOPOIETIC CELL GRAFT INFUSIONS Cells collected for autologous transplant are cryopreserved in the liquid or vapor phase of liquid nitrogen with 10% dimethyl sulfoxide (DMSO) used as a cryoprotectant. Before reinfusion of the cells, a bicarbonate infusion is used to alkalinize the urine to protect against renal injury caused by the hemolysis of contaminating red cells. Stem cells products are rapidly thawed at 37-degree water bath and typically infused over a 15-minute period as longer infusion times potentially subject the HSCs to DMSO toxicity. Side effects associated with DMSO include flushing, unpleasant taste, nausea, and vomiting, with rare hypotension, atrial arrhythmias, and anaphylactic reactions. Allogeneic grafts are usually infused fresh, with patients monitored for any hypersensitivity reactions. Large-volume bone marrow products should be infused over the period of 3 to 4 hours, and the patient monitored for fluid overload. In addition, in case of major ABO donor–recipient blood group mismatch, the grafts for allo-HCT typically undergo red blood cell (RBC) reduction prior to the cell infusion. VIII.POSTTRANSPLANT CARE AND COMPLICATIONS A. Hematopoietic complications 1. Engraftment. Following stem cell infusion, progenitor cells home to the marrow microenvironment, guided by interactions between adhesion molecules and their receptors expressed on hematopoietic cells and the marrow stroma. These cells must then proliferate and differentiate to repopulate the peripheral blood with mature blood cells in a process termed engraftment. Neutrophil engraftment (absolute neutrophil count [ANC] >500/mm3) typically occurs between 10 and 15 days posttransplant with HLA-identical PBSC transplants and slightly later in haploidentical and bone marrow transplants. The administration of colonystimulating factors, either G-CSF or GM-CSF, posttransplant has been demonstrated to shorten the duration of neutropenia, though without improving survival. Platelet recovery tends to be much more variable posttransplant. Donor/recipient chimerism is evaluated post-HCT by analyzing either peripheral blood or bone marrow for differences in donor- and recipient-specific short tandem repeats (STRs) using polymerase chain reaction (PCR)-based assays. In the case of sex-mismatched transplantation, chimerism can also be analyzed by

the ratio of sex chromosomes using fluorescence in situ hybridization (FISH) probes. 2. Transfusion support. Transfusions of RBCs and platelets are common in HCT. Although transfusion parameters are somewhat arbitrary, it is reasonable to maintain hemoglobin levels greater than 8 g/dL and platelet counts greater than 10,000/mm3. To reduce the risk of transfusion-associated GVHD, all blood products should be irradiated with 2,500 cGy before administration. 3. ABO incompatibility. Because stem cell products are matched on the basis of HLA compatibility, ABO-incompatible hematopoietic cell transplantations (HSCTs) frequently occur (30% to 40%). Red cell incompatibility is classified according to whether donor isoagglutinins or isoantigens or both are incompatible with those of the recipient. Major incompatibility occurs when the recipient has antibodies directed against donor RBC antigens (e.g., A donor, O recipient); minor incompatibility occurs when donor plasma contains antibodies directed against patient red cells (e.g., O donor, A recipient). Mixed or bidirectional incompatibility occurs when there is both major and minor ABO incompatibility (e.g., A donor, B recipient, or vice versa). Minor ABO incompatibility can result in passenger lymphocyte syndrome (PLS) that is due to proliferation and antibody production from lymphocytes in the graft, resulting in rapid and massive hemolysis 3 to 15 days after transplant. Major ABO incompatibility can result in immediate or delayed hemolysis or delayed red cell engraftment or pure red cell aplasia. Red cells are typically reduced from the harvested grafts in major incompatible allo-HCT, especially when using the bone marrow as the graft source to reduce the risk of clinically significant hemolysis of large quantities of red cells contained in the cell product. Immune-mediated hemolysis is indicated by a positive direct antiglobulin test (direct Coombs) in the setting of other markers of hemolysis, such as an elevated lactate dehydrogenase (LDH) or indirect hyperbilirubinemia. In cases of mild hemolysis, RBC transfusion support is adequate. In more severe cases, plasma exchange may be used. In contrast, patients receiving minor incompatible transplants have a risk of immediate hemolysis from the infusion of incompatible plasma. Immediate hemolysis can be prevented by removal of plasma from the bone marrow grafts by centrifugation. In transplants using peripheral blood mononuclear cells, apheresis used to collect the cells product effectively removes most of the donor plasma, and there is significantly less contamination with RBCs. 4. Graft failure. Rejection of the donor hematopoietic cells by the immune system of the recipient is termed graft failure and may be classified as primary (ANC 15 mg/dL

Pain and/or ileus

3. GVHD prophylaxis a. Pharmacologic prophylaxis. Because of the high morbidity and mortality associated with the development of aGVHD, routine prophylaxis against GVHD is required in all patients undergoing allo-HCT. Although a number of different pharmacologic agents can be used, a typical regimen uses an antimetabolite agent like methotrexate (at a dose of 10 mg/m2 on days 1, 3, 6, and/or 9) or mycophenolate mofetil (MMF) and continued until day 30 after allo-HCT combined with a calcineurin inhibitor, either cyclosporine or tacrolimus. Pretreatment with antithymocyte globulin (ATG) in unrelated donor transplants has been shown to decrease the need for immunosuppression at 1-year post-HCT. Immunosuppression with a calcineurin inhibitor is generally continued until day 100 posttransplant and gradually tapered in the absence of GVHD or disease relapse. GVHD prophylaxis using high-dose cyclophosphamide (50 mg/kg given on days 3 and 4 after allo-HCT) has revolutionized haploidentical transplantation as its use has dramatically reduced both aGVHD and cGVHD rates after haploidentical transplantation. Posttransplant cyclophosphamide has also been successfully used in HLA-matched sibling and unrelated donor transplants with very favorable GVHD rates. b. T-cell depletion. T-cell depletion may be used as either an alternative or adjuvant to pharmacologic prophylaxis for GVHD. Because donor-derived T cells are central to the pathogenesis of aGVHD, T-cell depletion of the donor graft can effectively reduce the incidence of GVHD. A number of methods for T-cell depletion have been used and include physical adsorption of T cells to proteins such as lectins, elutriation, or depletion with T-cell or lymphocytespecific antibodies. A loss of donor T cells is associated, however, with higher rates of graft rejection mediated by residual host T cells and a disease relapse because of partial loss of the GvT effect. In addition, T-cell depletion

results in delayed immune reconstitution in recipients, leading to higher rates of viral infections and, in particular, CMV and Epstein–Barr virus (EBV) infections. 4. Treatment. Corticosteroids are the primary treatment for aGVHD. For mild (grade I) GVHD of the skin, topical steroids may be sufficient. For grade II or higher disease, prednisone or methylprednisolone 1 to 2 mg/kg/day is usually initiated. Steroid doses are then generally tapered gradually after clinical improvement. For patients with steroid-refractory disease, a number of agents have been used with modest success. Ruxolitinib, a JAK1/2 inhibitor, is approved for the treatment of steroid-refractory aGVHD based on an open-label, singlearm, multicenter study that showed a day 28 overall response rate of 100% for grade II, 40.7% for grade III, and 44.4% for grade IV steroid-refractory GVHD. Further studies, including a randomized phase III study, are pending. Other agents, such as MMF, cyclosporine, tacrolimus, sirolimus, pentostatin, thalidomide, and monoclonal antibodies including daclizumab, basiliximab, and infliximab, have also been studied. The use of extracorporeal photopheresis (ECP) has also been tested for the treatment of aGVHD with variable results. C. Infections 1. Timing of infectious complications. HCT recipients are at increased risk for opportunistic infections. The risk of developing specific types of infections seen in stem cell transplant recipients varies by the type of transplant (autologous or allogeneic) and the length of time since undergoing the transplant. Before neutrophil engraftment, patients are at increased risk for infection because of neutropenia caused by the conditioning regimen and breaks in mucosal barriers from chemotherapy or indwelling vascular access devices. During this period, febrile neutropenia caused by both gram-positive and gram-negative organisms are common. In addition, Candida infections and herpes simplex virus (HSV) reactivation may occur. The postengraftment period (days 30 to 100) is characterized by impaired cell-mediated immunity. After engraftment, the herpes viruses, particularly CMV, are major pathogens. Other dominant pathogens during this phase include Pneumocystis carinii and Aspergillus species (Biol Blood Marrow Transplant 2009;15:1143). 2. Prophylaxis and management of specific infections a. Cytomegalovirus (CMV). CMV infections in HSCT recipients most commonly present as fever or interstitial pneumonitis. Other clinical manifestations include bone marrow suppression, retinitis, or diarrhea. Patients at risk for developing CMV infection include those undergoing alloHSCT where either the donor or the recipient is CMV positive. Prevention of CMV disease in allogeneic transplant can be accomplished using either a

prophylactic or a preemptive strategy. Prophylactic letermovir in CMVseropositive transplant recipients administered through week 14 after transplant has been shown to lower the risk of clinically significant CMV infection. A preemptive strategy uses sensitive PCR techniques to detect viremia and initiates therapy with ganciclovir before the development of overt disease. For patients with resistant disease, foscarnet or cidofovir may be used. To reduce the risk of transfusion-acquired CMV infection, all donors and recipients are screened for their CMV serostatus. CMV antibody– negative blood products should be given to CMV-negative recipients. Alternatively, leukofiltration to reduce the white cell fraction in the transfused produce may be used as an alternative if no CMV-negative products are available. b. HSV and varicella zoster virus (VZV). Routine prophylaxis with either acyclovir 400 mg t.i.d. or valacyclovir 500 mg qd to prevent reactivation of HSV and VZV is given to patients until 6 months after autologous transplants. In patients undergoing allo-HCT, acyclovir or valacyclovir prophylaxis should be continued for 1 year or until immunosuppressive agents are discontinued. c. Pneumocystis pneumonia (PCP) prophylaxis. Prophylaxis with trimethoprim–sulfamethoxazole (TMP-SMX) one DS tablet b.i.d. 2× a week, dapsone 100 mg daily, or aerosolized pentamidine monthly should be given to all patients undergoing allogeneic transplant and selected patients undergoing autologous transplant. PCP prophylaxis is usually prescribed from engraftment and continued until at least 6 months following allo-HSCT. Prophylaxis will be continued for more than 6 months in patients who remain on immunosuppressive medications. D. Veno-occlusive disease (VOD) of the liver. VOD of the liver is a clinical diagnosis based on the presence of hyperbilirubinemia associated with fluid retention and painful hepatomegaly. Histologically, VOD is associated with central vein occlusion, centrilobular hepatocyte necrosis, and sinusoidal fibrosis. Ultrasonography may reveal reversal of flow in the portal and hepatic veins. The etiology of VOD is believed to arise from damage to the hepatic endothelium secondary to high-dose chemotherapy and/or radiation. Risk factors for VOD include preexisting hepatic disease (e.g., viral hepatitis, cirrhosis), high-dose radiation as part of the conditioning, mismatched or unrelated donor HSCT, and the use of cyclosporine and methotrexate for GVHD prophylaxis. Spontaneous resolution of VOD is observed in approximately 70% of cases, but can frequently evolve into fatal multisystem organ failure. Low-dose heparin or ursodeoxycholic acid may provide some protection when used in a prophylactic manner. Supportive care measures are the mainstay of

treatment for VOD with attention to fluid and electrolyte management. Defibrotide has been shown in a phase 3 study to improve survival at day +100 in patients with VOD and multiorgan failure and is FDA approved. E. Management of relapsed disease. For relapsed disease following allogeneic transplant, maneuvers that attempt to maximize the GvL effect of the allograft may be useful. Withdrawal of immunosuppression is usually attempted first. If no effect is seen, a DLI can augment the immunologic effect of the allograft. DLI can result in significant toxicity, including aGVHD and cGVHD and severe pancytopenia. Responses are seen more frequently in diseases thought to be most sensitive to a graft-versus-disease effect such as chronic myeloid leukemia (CML) and in those patients who develop GVHD. Currently, the outcomes of patients who relapse after allo-HCT and are unable to achieve remission with salvage therapies remain extremely poor. IX. LATE COMPLICATIONS OF ALLOGENEIC TRANSPLANTATION A. Chronic GVHD 1. Clinical manifestations. The clinical manifestations of cGVHD are heterogeneous in terms of the organ systems involved, the disease severity, and the clinical course. Historically, GVHD was classified as chronic when it occurred after day +100 post-HSCT. However, currently, if patients have features of aGVHD even after day +100 in the absence of features diagnostic of cGVHD, it is still classified as persistent, recurrent, or late-onset aGVHD. Based on the National Institutes of Health (NIH) consensus guidelines, cGVHD includes classic cGVHD when patients have manifestations that are only present in cGVHD and overlap syndrome, which has diagnostic or distinctive features of cGVHD along with features typical of aGVHD (skin, GI tract, liver). Based on the NIH scoring system (Biol Blood Marrow Transplant 2015;21:389, Blood 2017;12:30), cGVHD is classified into mild, moderate, or severe disease, depending on the number of affected organs and organ-specific severity (scored from 0 to 3). Mild cGVHD involves two or fewer organs/sites with no clinically significant organ impairment. Moderate cGVHD involves three or more organs/sites with no clinically significant impairment or at least one organ/site with clinically significant functional impairment, but no major disability. Severe cGVHD involves major disability caused by cGVHD. The most frequently affected organs in cGVHD include the skin, liver, GI tract (predominantly esophagus), and lungs. Epidermal involvement is characterized as an erythematous rash that may appear papular, lichen planus like, papulosquamous, or poikiloderma. Dermal and subcutaneous involvement is characterized by sclerosis, fasciitis, and ulcerations. Oral manifestations of

cGVHD include erythema, lichenoid hyperkeratosis, ulcerations, or mucoceles. Lacrimal gland dysfunction frequently results in keratoconjunctivitis sicca, also known as the “dry eye syndrome,” and can manifest as burning irritation, pain, blurred vision, and photophobia. GI symptoms include nausea, vomiting, anorexia, and unexplained weight loss. Liver involvement is characterized by rising bilirubin and transaminases. Pulmonary cGVHD can result in a debilitating bronchiolitis obliterans syndrome, with pulmonary function testing often demonstrating decreases in the forced expiratory volume in the first second (FEV1) and the diffusing capacity of the lung for carbon monoxide (DLCO). 2. Diagnosis and treatment. The diagnosis of cGVHD can often be made on the basis of classic features of skin involvement, manifestations of GI involvement, and a rising serum bilirubin concentration. Often, the diagnosis is less clear, in which case histologic confirmation may be desirable. Systemic immunosuppression with corticosteroids and other agents are often required to treat cGVHD. In addition, ancillary and supportive care measures tailored to the organ system involved are critical for the management of cGVHD and, in many circumstances, reduce or eliminate the need for systemic immunosuppression. Ibrutinib, a Bruton tyrosine kinase inhibitor, has shown efficacy in cGVHD in patients who have failed prior treatments and allowed for reduction or elimination of corticosteroid use. B. Late infections. Auto-HCT patients have a more rapid recovery of immune function and a lower risk of opportunistic infections than allo-HSCT patients. Because of cellmediated and humoral immunity defects and impaired functioning of the reticuloendothelial system, allo-HSCT patients with cGVHD are at risk for various infections during this phase. Late infections include EBV-related posttransplant lymphoproliferative disease, community-acquired respiratory virus infection, and infections with encapsulated bacteria. In addition, fungal infections with Aspergillus species and zygomycosis can be seen in the late period, particularly in patients with cGVHD. C. Secondary malignancies. Patients undergoing both autologous and allogeneic transplantations are at risk for the development of either treatment-related myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) because of the high-dose alkylators and irradiation typically used as part of the conditioning regimens. Exposure to radiation and the photosensitizing effects of many commonly used transplantation-related medications increase the risk of skin cancers among recipients. Posttransplant lymphoproliferative disorders because of EBV can be observed particularly in patients receiving T-cell–depleted grafts. D. Other complications. Although stem cell transplantation can result in long-term survival with an excellent quality of life, late sequelae of the transplantation can

result in significant morbidity. For example, TBI is associated with hypothyroidism and development of cataracts. Patients receiving prolonged corticosteroids can develop muscle weakness and bone loss. Recommendations for screening and preventive practices for long-term survivors of HSCT have been published. SUGGESTED READINGS Bashey A, Solomon SR. T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standardof-care option for patients who lack and HLA-identical sibling donor. Blood Marrow Transplant 2014;49:999–1008. Bashey A, Zhang X, Sizemore CA, et al. T-cell replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol 2013;31:1310–1316. Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft-versus-host disease. Br J Haematol 2012;158:46–61. Eapen M, O’Donnell P, Brunstein CG, et al. Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biol Blood Marrow Transplant 2014;20:1485–1492. Gerard S, Jerome R. Current issues in chronic graft-versus host disease. Blood 2014;124:374–384. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 2014;371:339–348. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood 2014:124:344–353. Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 2012;119:296–307. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplant 2012;47:337–341. Marty FM, LJungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;377:2433–2444. Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood 2017;130:2243–2250. Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 2016;127:1656–1665. Walker I, Panzarella T, Couban S, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomized, controlled, open-label, phase 3, multicenter trial. Lancet Oncol 2016;17:164–173. Zeiser R, Blazer B. Acute graft-versus-host disease—biologic process, prevention, and therapy. N Engl J Med 2017;377:2167–2179.

I.

HODGKIN LYMPHOMA A. Background 1. Epidemiology and risk factors. Approximately 9,000 cases of Hodgkin lymphoma (HL) are diagnosed annually in the United States. HL has a bimodal age distribution in developed countries, with the first peak occurring in the third decade of life and the second peak occurring after the age of 50 years. Men have a slightly higher incidence than women. There is an association between HL and factors that decrease exposure to infectious agents at an early age, including advanced maternal education, early birth order, decreased number of siblings, and living in a single-family residence. A history of infectious mononucleosis increases the risk of HL by 2- to 3-fold and suggests Epstein–Barr virus (EBV) as an etiologic agent. Although 30% to 50% of patients with HL have detectable EBV DNA in the Hodgkin and Reed–Sternberg (HRS) cells, direct evidence of a causative role is lacking. There is a slightly increased risk of HL in patients infected with human immunodeficiency virus (HIV), but not in other conditions associated with chronic immunosuppression. An increased incidence among firstdegree relatives, a significant concordance rate among identical but not fraternal twins, and linkage with certain human leukocyte antigen types suggest a genetic predisposition for HL. 2. Molecular biology. The amplification and analysis of genes of single HRS cells have provided overwhelming evidence that at least 95% of HL cases represent monoclonal B-cell disorders. Clonal immunoglobulin gene rearrangements are present in the HRS cells of both classical HL (cHL) and nodular lymphocytepredominant HL (NLPHL). 3. Genetics. Cytogenetic analysis in lymph nodes involved by HL is limited

because of the low number of obtainable mitoses from lymph node suspensions and the inability to attribute abnormalities to the malignant cells. A specific chromosomal marker of HL has not been identified, but a variety of numeric and structural abnormalities have been found in approximately half of the HL cases analyzed. Gene expression profiles demonstrate that variations in the tumor microenvironment correlate with outcome. Classical Hodgkin cells are characterized by alterations at the 9p24.1 locus, leading to overexpression of programmed death 1 (PD-1) ligands. B. Presentation. cHL usually presents as painless lymphadenopathy in the cervical and/or supraclavicular regions. Isolated subdiaphragmatic lymphadenopathy or organ involvement is rare. Although staging studies reveal mediastinal adenopathy in more than 85% of patients, symptoms of cough, chest pain, dyspnea, and superior vena cava (SVC) syndrome are uncommon, even in patients with bulky mediastinal disease. Systemic symptoms or “B”-symptoms, including fevers (temperature >38°C), drenching night sweats, or weight loss (>10% of baseline body weight in the preceding 6 months), occur in 30% to 40% of patients with stage III or IV disease, but in fewer than 10% of patients with stage I or II disease. In most series, the presence of B-symptoms portends a worse prognosis. Generalized, severe pruritus (with or without associated rash) occurs in approximately 25% of patients with HL, can be a presenting symptom of both early- and advanced-stage disease, and has no known prognostic significance. Alcohol-induced pain in involved lymph nodes is a rare symptom of HL (1

Extranodal sites >1

1

Renal involvement

1

Adrenal involvement

CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group.

D. Therapy and prognosis 1. Follicular lymphoma. FL is generally considered “incurable,” although the prognosis for most patients is excellent with median overall survival (OS) over 15 years. FL is distinguished histologically into grades 1 to 2, grade 3A and 3B. The distinction is made by counting the number of centroblasts per high power field. If the centroblasts are present in confluent sheets, the case is designated grade 3B and those patients should be managed following paradigms for DLBCL. FL grade 1 to 2 and 3A are managed similarly. Prognosis can be estimated by the Follicular Lymphoma International Prognostic Index (FLIPI) that includes five independent poor prognostic factors, including age equal to or greater than 60, stage III or IV, greater than four involved nodal areas, elevated serum LDH, and hemoglobin less than 12 g/dL (Blood 2004;104:1258). Although the index was developed in the pre-rituximab era, the FLIPI remains prognostic in the rituximab era. Once newly diagnosed patients have been fully staged, a determination whether the patient requires treatment or is a candidate for a “watch and wait” strategy must be made. In general, patients who are asymptomatic and have low tumor burden can be considered for watch and wait, as immediate treatment has not demonstrated an OS benefit in this population. Tumor burden can be estimated using the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria. High tumor burden criteria are met if patients have any one of the following: (a) B symptoms, (b) a single nodal mass over 7 cm, (c) three nodal masses over 3 cm, (d) splenomegaly over 16 cm, (e) risk of vital organ compression, (f) significant cytopenias caused by marrow infiltration, and (g) a leukemia phase. Patients who meet the criteria for low tumor burden can be observed without treatment until high tumor burden criteria are met. It is

important to emphasize that these criteria are guidelines only and some degree of individualization is appropriate. For patients with symptoms and/or high tumor burden, initiation of treatment is warranted. The current standard of care for patients with FL requiring therapy is a combination of rituximab and chemotherapy. The most commonly utilized chemotherapy regimens are bendamustine-rituximab (BR) or the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. One randomized clinical trial showed a significant improvement in remission duration and toxicity profile with BR compared with R-CHOP (Lancet 2013;381:1203). A different randomized clinical trial (BRIGHT) suggested BR and R-CHOP had comparable efficacy, with toxicity profiles that were different but without a clear advantage for one over the other (J Clin Oncol 2019;37:984). Maintenance rituximab following first-line chemoimmunotherapy is frequently adopted on the basis of data demonstrating improved progression-free survival (PFS) compared with observation (59% vs. 43% at 6 years); however, an OS benefit has yet to be described (Lancet 2011;377:42). Interestingly, long-term follow-up from the PRIMA study demonstrates that 40% of the patients who received R-CHOP induction followed by maintenance rituximab remain in remission at 10 years, raising some questions about the notion of “incurability.” The maintenance schedule most commonly employed is with rituximab administered once every 2 months for a duration of 2 years. No convincing data are available to recommend maintenance rituximab beyond 2 years. The toxicities of rituximab are mild and are limited primarily to infusion-related reactions such as fevers, chills, and myalgias. An alternative approach for patients with low-volume disease, older patients, and patients with serious comorbid conditions is with single-agent rituximab administered for four weekly doses. The response rates are lower and the response duration is shorter compared with BR but for some patients, the toxicity trade-off makes single-agent rituximab the treatment of choice. The role of maintenance rituximab is more controversial following induction rituximab and no clinical benefit was seen with maintenance rituximab compared to a retreatment strategy (J Clin Oncol 2014;32:3096). However, the low toxicity profile as well as the improved response duration may potentially justify the role of maintenance rituximab following both chemoimmunotherapy and rituximab alone upfront approaches. Given the improved sensitivity of staging studies including CT scans, PET/CT scans, and the use of flow cytometry to evaluate bone marrow specimens, the diagnosis of limited-stage FL is uncommon. Observation, involved-field radiotherapy (IFRT), single-agent rituximab, a combination of rituximab and chemotherapy, and combined modality therapy

with rituximab plus or minus chemotherapy with IFRT are all options for patients with this unusual presentation. There are no randomized trials comparing these approaches, and treatment decisions should be based on the site and bulk of disease and patients’ age, with the more aggressive approaches being preferred for younger patients and those with bulky stage I and stage II disease. The management of relapsed FL requires a patient-specific approach. Variables influencing treatment decisions include the history of prior therapies, patient age, fitness, and comorbidities, and goals of therapy. If the first remission was highly durable, patients can respond well to the same regimen given as firstline therapy. However, remission durations are usually shorter with each subsequent treatment. The immunomodulatory agent lenalidomide, combined with rituximab, is highly active in relapsed FL (J Clin Oncol 2019;37:1188). Three phosphoinositide 3 kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib) have received regulatory approval in this space. Radiation can be given to patients with local, symptomatic disease. Response rates of approximately 80% have been reported with radioimmunotherapy (RIT) agents such as (90)Y-ibritumomab tiuxetan, an anti-CD20 monoclonal antibody conjugated with the radioisotope yttrium 90. Despite the early promise of RIT, the approach is underutilized because of concerns about damaging stem cells as well as the risk for developing secondary leukemias. Stem cell transplants are another option for relapsed indolent lymphoma. The only randomized trial of autologous transplant versus standard chemotherapy for relapsed indolent lymphoma showed both a PFS and OS advantage to transplant. Treatment-related mortality rates for allogeneic transplants have decreased significantly with the use of reduced intensity conditioning, but serious complications of both acute and chronic graft-versus-host disease continue to restrict this approach to patients with short remissions or refractory disease following standard approaches. 2. Marginal zone lymphoma. There are three types of MZL: nodal, splenic, and MALT. a. Nodal MZL. This lymphoma subtype is rare. It can be managed according to the principles outlined for FL. In patients with relapsed or refractory disease who need treatment, ibrutinib, the bruton tyrosine kinase inhibitor, has also received regulatory approval. b. Splenic MZL. Patients present with isolated splenomegaly, often massive, with minimal lymphadenopathy. Diagnosis is often obtained from a bone marrow biopsy but occasionally splenectomy is required. Splenectomy can also be therapeutic in this disorder and may obviate the need for systemic therapy. If systemic therapy is preferred, single-agent rituximab (with or without maintenance rituximab) is highly effective with response rates over

90% and durability lasting several years on average. c. MALT. MALT lymphomas are extranodal by definition and paradoxically tend to arise in locations devoid of lymphoid tissue. For purposes of management, it is most useful to separate gastric and nongastric MALT lymphomas. Gastric and other extranodal MALT lymphomas commonly present with early-stage disease. Gastric MALT lymphomas appear to occur as a direct result of antigenic stimulation from H. pylori infection. Approximately 80% of patients with gastric MALT lymphoma will have complete regression of disease with appropriate therapy for H. pylori, including antibiotics and proton pump inhibitors. Long-term studies have demonstrated excellent durability of these remissions, with 80% to 90% of patients remaining in continuous histologic remission. For the subset of patients with gastric MALT lymphoma who do not respond to or relapse after H. pylori therapy, or are H. pylori negative, results with IFRT are excellent, with one series reporting 10-year freedom from treatment failure and OS of 70% and 88%, respectively. Other isolated extranodal presentations such as salivary gland, thyroid, breast, conjunctiva, or a unifocal skin site are also effectively treated with low-dose IFRT (30 Gy). 3. Small lymphocytic lymphoma. This entity is the nodal equivalent of chronic lymphocytic leukemia (CLL) and is termed CLL/SLL according to the WHO classification system. Please see chapter 33 discussing management of CLL for fundamentals of disease management. 4. Mantle cell lymphoma. MCL has a moderately aggressive clinical course and is considered largely incurable. There are a subset of patients with a leukemic nonnodal version of MCL who often have an indolent clinical course and such patients can be managed initially with a watch and wait strategy. MCL occurs most frequently in men older than 60 years. Intensive approaches, utilizing induction therapy with high-dose cytarabine and autologous stem cell transplantation (ASCT) consolidation have produced the best PFS, with median remission durations in the 7- to 9-year range (Lancet 2016;388:565). A beneficial OS impact of intensive approaches has not been conclusively demonstrated. Patients who cannot receive intensive treatment approaches because of age or comorbidities should be managed with less intensive regimens such as BR or VR-CAP (bortezomib [Velcade] rituximab, cyclophosphamide, and doxorubicin [Adriamycin] plus prednisone), with median remission durations in the 3- to 4year range. Maintenance rituximab has shown both a PFS and OS benefit following ASCT in younger patients (N Engl J Med 2017;377:1250) and after RCHOP induction in older patients (N Engl J Med 2012;367:520). The benefit of maintenance rituximab after BR is unclear at this time. For patients with relapsed

MCL, the BTK inhibitors ibrutinib and acalabrutinib have demonstrated ORR of 70% to 80% with median remission durations of 18 months. Allogeneic stem cell transplantation remains an appropriate option for younger MCL with relapsed disease. 5. Diffuse large B-cell lymphoma. The IPI helps predict prognosis for individual patients with advanced-stage large-cell lymphoma. The presence or absence of five independent poor prognostic features (age older than 60 years, stage III or IV disease, more than one extranodal site, performance status ≥2, and elevated serum LDH) effectively predicts an individual’s risk of relapse and death from lymphoma after standard chemotherapy. For patients treated with R-CHOP, 3year OS rates according to the IPI are approximately 87% for patients with zero to one risk factor, 75% for patients with two risk factors, and 56% to 59% for those with three or more factors (J Clin Oncol 2010;28:2373). The nongerminal center B cell (non-GCB), also known as the activated B-cell (ABC) subtype, is associated with a worse prognosis compared with GCB. Immunohistochemistry using Hans criteria (CD10, BCL-6, MUM1) as a surrogate for molecular profiling adequately discriminates the subtypes, with 5-year OS rates of 76% for the GCB group compared with 34% for the non-GCB group (Blood 2004;103:275). However, clinical trials evaluating outcomes by cell of origin have repeatedly shown a much smaller difference in outcomes, possibly because of patient selection issues inherent in prospective clinical trials. The historical standard of care for limited-stage nonbulky large-cell lymphoma is three cycles of R-CHOP followed by IFRT. A phase 2 study of this approach showed 4-year PFS and OS rates of 88% and 92%, respectively (J Clin Oncol 2008;26:2258). Emerging data suggest that many patients do not require radiation therapy. The “FLYER” trial, presented at the 2018 American Society of Hematology meetings, demonstrated that patients with nonbulky disease (less than 7.5 cm) and IPI scores of 0 achieve 4-year PFS rates of 96% with four cycles of R-CHOP without radiation. Patients with limited-stage bulky disease or other risk factors such as an elevated LDH should be considered for six cycles of R-CHOP with or without IFRT. Given the complications of radiation that tend to occur many years after exposure (20 to 30 years), it is often prudent to try and avoid external beam radiation therapy (XRT) in younger patients whereas it may be more appropriate to consider inclusion of XRT in older patients. The standard of care for advanced-stage DLBCL remains six cycles of RCHOP. The dose-adjusted EPOCH-R regimen was compared to R-CHOP in a randomized controlled trial. No difference was observed between the two regimens although subset analysis suggested DA-EPOCH-R may perform better in the highest risk IPI patients. Two studies have evaluated the addition of novel

agents (ibrutinib and lenalidomide) with known activity in the ABC subtype of DLBCL, but neither agent was able to improve results over standard R-CHOP. Another negative trial evaluated the addition of bortezomib to R-CHOP but found no benefit in either the ABC or the GCB patients. More recent work on the molecular classification of DLBCL suggests that the distinction of ABC versus GCB may not be as precise as necessary if one is to improve outcomes with novel targeted agents. One study revealed five distinct molecular clusters (Nat Med 2018;24:679), and future work is likely to explore the addition of novel agents based upon this type of framework. Selected patients have relatively high risk for CNS recurrence and should be considered for prophylactic intrathecal therapy or high-dose methotrexate. The CNS IPI estimates risk, and patients with a score of 4 to 6 are considered high risk and should be considered for prophylaxis (J Clin Oncol 2016;34:3150) (Table 31-3). The score is calculated by assigning individual patients an IPI score plus adding an additional point for kidney or adrenal involvement. Similarly, patients with testicular involvement with DLBCL are at high risk for CNS involvement and should be given CNS prophylaxis. The best treatment for prophylaxis is unknown, though cross-study comparisons of retrospective studies may suggest lower CNS recurrences with high-dose methotrexate (Cancer 2010;116:4283). DLBCL that relapses after frontline therapy is potentially curable with highdose chemotherapy and ASCT. Typically patients must be younger than 70 years and without significant comorbidities to be considered for such an approach. Several effective salvage regimens are available as cytoreduction before transplant, including most commonly ICE (ifosfamide, carboplatin, and etoposide), ESHAP (etoposide, methylprednisolone [Solu-Medrol], high-dose cytarabine, cisplatin), or DHAP (dexamethasone, high-dose cytarabine, and cisplatin). Rituximab is typically added to these regimens for patients with B-cell lymphomas. In patients with chemosensitive relapse, the 5-year disease-free survival (DFS) rate after transplant is approximately 50%, whereas in patients with refractory relapse, it is less than 15%. A major development has been the introduction of chimeric antigen receptor T cells (CAR-T). Autologous T cells are harvested from the patient, transduced with a receptor for CD19, expanded ex vivo, and then reinfused into the patient. It appears as though this approach may be curative in 30% to 40% of patients who relapse after ASCT. The major risks include cytokine release syndrome and severe, but usually transient, neurotoxicity. Please see Chapter 7 for more details regarding CAR-T therapy. Allogeneic stem cell transplant can be considered for patients who fail all standard approaches. For patients with relapsed/refractory DLBCL who are

6.

7.

8.

9.

10. 11.

treated with palliative intent, options include rituximab, gemcitabine, and oxaliplatin; lenalidomide ± rituximab (especially for non-GCB DLBCL subtype); and BR with the antibody drug conjugate polatuzumab vedotin. Primary mediastinal B-cell lymphoma. This is a unique subtype of large-cell lymphoma characteristically affecting young women and presenting with a massive mediastinal mass. Historically, patients were treated with R-CHOP followed by consolidative mediastinal radiation. However a phase 2, prospective study of infusional dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) without radiation demonstrated outstanding results with event-free survival and OS of 93% and 97%, respectively, at a median of 5 years (N Engl J Med 2013;368:1408) and is the preferred frontline regimen at many centers. High-grade B-cell lymphomas with abnormalities of MYC and BCL-2/BCL6. This entity was previously known as “double-hit” DLBCL as patients have dual translocations of c-MYC plus either BCL-2 or, less commonly, BCL-6. These patients have a significantly worse prognosis with standard R-CHOP therapy. Retrospective data suggest that the dose-adjusted EPOCH-R may be more effective here. CNS prophylaxis is recommended for all patients. Burkitt lymphoma. BLs have a poor prognosis with standard R-CHOP chemotherapy, and short-duration intensive therapies are indicated. Most current protocols prescribe four to six cycles of chemotherapy including intensive doses of alkylating agents such as cyclophosphamide or ifosfamide, vincristine, anthracyclines, and high-dose methotrexate alternating with high-dose cytarabine and etoposide. Two-year event-free survival rates of 70% to 90% are reported with this approach. CNS prophylaxis is an essential component of therapy. The dose-adjusted EPOCH-R regimen has produced impressive results, particularly in low-risk patients. Patients with an elevated LDH and bulky disease should be treated with allopurinol or rasburicase and vigorous hydration during initiation of therapy to minimize the risk of tumor lysis. Lymphoblastic lymphoma. These entities are the nodal version of acute lymphoblastic leukemia (ALL) and require utilization of ALL regimens as discussed in Chapter 30. HIV-associated lymphoma. Treatment approaches have changed with the advent of highly active antiretroviral therapy (HAART) and are discussed in Chapter 33. Primary CNS lymphoma. Patients with primary CNS lymphoma should be treated with specialized protocols using high-dose methotrexate, cytarabine, and rituximab with consideration for ASCT consolidation in eligible patients (J Clin Oncol 2013;31:3061). Treatment with high-dose methotrexate combined with whole brain radiotherapy (WBRT) increases the incidence of cognitive deficits

and is avoided when possible. WBRT as a single modality is mostly reserved for elderly patients who are not eligible for chemotherapy. 12. Posttransplant lymphoproliferative disorders. Patients undergoing solid organ transplantation require long-term immunosuppressive therapy to prevent graft rejection. A potential complication is the development of PTLD, which can vary considerably in clinical behavior. Some cases are aggressive (similar to DLBCL) and require multiagent chemotherapy, whereas others will respond to simply withdrawal of immunosuppression. Many PTLD cases appear to be driven by EBV. EBV-driven PTLDs are more likely to present in the first 5 years after organ transplantation and are more likely to respond to withdrawal of immunosuppression than EBV-negative “late” PTLDs. Off-the-shelf EBVspecific cytotoxic lymphocyte (EBV-CTL) has shown promising results in EBVpositive PTLD patients (Blood 2010;115:925; Blood 2012;119:2644) and currently phase 2 and 3 trials using this treatment are ongoing. 13. Peripheral T-cell lymphoma. Patients with PTCL represent a heterogeneous subset of aggressive NHLs. The most common subtypes (peripheral T-cell, not otherwise specified; angioimmunoblastic T-cell lymphoma, and anaplastic largecell lymphoma kinase (ALK)) have a 5-year OS of approximately 30% and PFS of approximately 20% with CHOP-based chemotherapy. The addition of etoposide to CHOP (CHOEP) and the addition of brentuximab vedotin (BV) to CHOP for fit individuals have resulted in improved outcomes. Many advocate that those who achieve a complete remission at the end of treatment should be considered for a consolidative autologous transplant although this has not been studied in a randomized fashion. BV is a CD30 antibody drug conjugate also approved in Hodgkin lymphoma. In patients who have CD30 expressing PTCL, BV is approved with combination chemotherapy in previously untreated patients. This is on the basis of a randomized, placebo-controlled phase 3 study of BV with cyclophosphamide, doxorubicin, and prednisone (CHP) against CHOP, which showed that 3-year PFS improved from 44% to 57% with BV-containing therapy that was associated with improvement in OS (Lancet 2019;393:229). Importantly, 70% of the patients on this study had anaplastic large-cell lymphoma (ALK+ and ALK–) and the differences in outcomes were most pronounced in this patient population. In the relapsed or refractory patients, allogeneic transplant for appropriate candidates can be curative. However, the majority of patients have poor outcomes, with median survival of 6 to 10 months. Pralatrexate, romidepsin, and belinostat are approved for relapsed or refractory PTCL and carry an overall response rate of 20% to 30% with median duration of response of 4 to 6 months. BV has an overall response rate of 41% with a median duration of response of 2.6

months in PTCL, not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma. In contrast, BV has an overall response rate of 86% and median duration of response of 20 months in anaplastic large-cell lymphoma. Multiple novel agents and combinations are being investigated for this rare subset of diseases. 14. Cutaneous T-cell lymphoma. Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of T-cell lymphomas but the majority of patients have mycosis fungoides or Sézary syndrome. Mycosis fungoides predominantly presents in the skin but can also involve the blood, lymph nodes, and, less commonly, other organs. Sézary syndrome is a variant of the disease associated with erythroderma and blood involvement. Patients are treated for palliative intent but patients with early-stage disease often have normal life expectancy, whereas only 20% of those with advanced-stage disease are alive at 5 years. Close coordination of care with dermatology for skin directed care is essential to patient care. Commonly used treatments include topical steroids, ultraviolet (UV) light–based therapy, oral methotrexate, bexarotene, and single-agent chemotherapies (gemcitabine, liposomal doxorubicin). Histone deacetylase inhibitors such as romidepsin and vorinostat are approved for the treatment of CTCL. Vorinostat was approved based on a phase 2 study with an overall response rate of 30% and a median duration of response of 5.5 months. In a phase 2 study, romidepsin showed an overall response rate of 34% with a median duration of response of 15 months. More recently, BV was approved for CTCL that expressed CD30 in a randomized study against standard therapy (either methotrexate or bexarotene) and showed an overall response rate of 67% compared to 20% with standard therapy and improved median PFS from 3.5 to 17.2 months (Lancet 2017;309:555). Mogamulizumab is a humanized antibody against CCR4, which was studied in a randomized study in comparison to vorinostat and showed an overall response rate of 28% compared to 5% for vorinostat and treatment with mogamulizumab conferred an improvement in median PFS from 3.1 to 7.7 months (Lancet Oncol 2018;19:1192). Pembrolizumab has also shown a 38% overall response rate with a median duration of response of 64 weeks in this patient population. E. Complications 1. Therapy related. Most first-line therapies for indolent lymphomas are well tolerated, with minimal risk of severe toxicity. Most patients experience moderate to severe infusion-related symptoms, including fevers, chills, dyspnea, and hypotension, during administration of the first dose of rituximab. These side effects are uncommon with subsequent doses. Rituximab has rarely been

associated with reactivation of hepatitis B. Concurrent administration of entecavir for patients with positive antibodies is recommended (J Clin Oncol 2013;31:2765). Potential complications of CHOP chemotherapy include hair loss, a moderate risk of fever and neutropenia, minimal risk of nausea and vomiting, peripheral neuropathy secondary to vinca alkaloids, cardiomyopathy related to anthracyclines, and, rarely, hemorrhagic cystitis related to cyclophosphamide. Cardiomyopathy occurs in approximately 5% of patients treated with anthracycline-based therapy but as high as 21% in high-risk individuals within the first year of therapy. Later manifestations of cardiomyopathy have been less well studied. Prophylactic hematopoietic colony-stimulating factors are recommended for patients older than 65 years treated with CHOP (J Clin Oncol 2015;33:3199) and should be considered in patients with extensive marrow involvement and cytopenias at diagnosis. First-line regimens for Burkitt as well as most salvage regimens for relapsed aggressive NHL can be associated with significant toxicities, including severe cytopenias and increased risk of life-threatening infection. Prophylactic growth factors should be used with these regimens. Renal insufficiency and mucositis occur frequently with regimens containing high-dose methotrexate. Cerebellar toxicity, somnolence, and, rarely, coma are reported with high-dose cytarabine, particularly in older patients. Therefore, these regimens are usually administered in a hospital setting with close monitoring of electrolytes, creatinine, and fluid balance. Patients with advanced-stage BL or high-grade B-cell lymphomas are at risk of acute tumor lysis during initiation of therapy. Therapy-related MDS and secondary acute myelogenous leukemia (AML) are rare, but are the devastating late complications of therapy for NHL. These complications can occur in patients with indolent lymphomas as a consequence of years of intermittent alkylator therapy. There is also an increased risk of lifethreatening MDS/AML after stem cell transplantation with 2% to 12% of patients developing this complication, a median of 4 years after transplant. Most have complex karyotypes with deletions in chromosomes 5 and 7. RIT drugs are also associated with an increased risk of MDS and AML, particularly in heavily pretreated patients. F. Follow-up. The goals of follow-up are to detect recurrent or progressive NHL and to monitor for long-term complications of therapy. Anxiety and depression, often related to fear of recurrence, are common in the early period. Individual counseling, support groups, and occasionally short-term use of antidepressants may be needed. Asymptomatic patients with indolent lymphoma are often observed without therapy. Appropriate follow-up for these patients includes a history and physical

examination with laboratory evaluation every 3 to 6 months for the first 2 years after diagnosis. As therapy is initiated for patients with higher disease burden or symptoms from disease, routine imaging surveillance can be performed every 2 years in patients without signs or symptoms of recurrence and should not be performed more frequently than every 6 months in this population. In addition to close monitoring, patients must be educated to report potential symptoms of progression including new or enlarging lymph nodes, abdominal or back pain, bloating, lower extremity edema, or B symptoms. Because of the recurring nature of the disease, most patients with indolent lymphoma need lifelong follow-up with an oncologist. For patients with aggressive lymphomas who achieve remission with initial therapy, the majority of recurrences occur within the first 2 years of therapy and rarely after 5 years. Routine imaging rarely identifies relapses in asymptomatic patients and therefore is not recommended in asymptomatic patients. Clinical evaluation with history, physical examination and laboratory evaluation including LDH can be done every 3 months for 2 years and every 6 months for the next 3 years. In patients without evidence of relapse at 5 years from the end of treatment, future follow-up can be performed by a primary care physician annually with an established survivorship care plan. SUGGESTED READINGS Abramson JS, Hellmann M, Barnes JA, et al. Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer 2010;116:4283–4290. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med 2018;24:679–690. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 2013;368:1408–1416. Flinn IW, van der Jagt R, Kahl B, et al. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol 2019;37:984–991. Hans, CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004;103:275–282. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stemcell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 2016;388:565–575. Horwitz S, O’Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 2019;393:229–240. Huang Y-H, Hsiao L-T, Hong Y-C, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol 2013;31:2765–2772. Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol 2014;32:3096–3102. Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol 2018;19:1192– 1204. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med 2012;367:520–531.

Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med 2017;377:1250–1260. Leonard, JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 2019;37:1188–1199. Persky DO, Unger JM, Spier CM, et al. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group Study 0014. J Clin Oncol 2008;26:2258–2263. Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet 2017;390:555–566. Rubenstein JL, Hsi ED, Johnson JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 2013;31:3061–3068. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 noninferiority trial. Lancet 2013;381:1203–1210. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011;377:42–51. Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol 2016;34:3150–3156. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015;33:3199–3212. Solal-Celigny P, Roy P, Colombat, P, et al. Follicular lymphoma international prognostic index. Blood 2004;104:1258–1265. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28:2373–2380.

I.

EPIDEMIOLOGY AND RISK FACTORS Approximately 27,000 new cases of acute leukemia (approximately 21,000 new cases of acute myeloid leukemia [AML] and 6,000 new cases of acute lymphoblastic leukemia [ALL] estimated in 2019) are diagnosed in the United States each year. The annual incidence of AML is approximately 4.2 per 100,000 and of ALL is approximately 1.9 per 100,000 persons. Although acute leukemia represents only 1.5% of all new cancer cases, it is the most common cause of cancer death for persons younger than 35 years. Most cases of ALL occur in childhood, with a peak incidence at approximately age 5 years. More than half of the cases are diagnosed below the age of 20 and the rest are somewhat evenly distributed among older adults in different age groups. The incidence of AML increases steeply beyond 50 years, and the median age is approximately 68 years. Fewer than 5% of cases of acute leukemia can be attributed to prior exposure to a leukemogenic agent. Ionizing radiation and benzene are clearly associated with an increased risk of acute AML, with an average latency of approximately 5 years. Two classes of chemotherapeutic agents are associated with an increased risk of acute leukemia (secondary leukemia). Alkylating agents can cause AML approximately 4 to 8 years after exposure. AML that arises in this setting is often associated with a preceding myelodysplastic syndrome (MDS) and adverse cytogenetics, particularly abnormalities of chromosomes 5 and 7. Topoisomerase II inhibitors such as etoposide or anthracyclines are associated with AML associated with rearrangement in the mixed lineage leukemia (MLL) gene located on 11q23. MLL rearrangement–associated AML develops after a short (1- to 2-year) latency without a preceding MDS. Given the poor prognosis of treatment-related leukemia, allogeneic transplantation in first complete remission (CR)

should be considered if a donor is available. Rare families with a genetic predisposition to acute leukemia have been described, but in the vast majority of cases, there is no clear hereditary risk. However, acute leukemia does occur more frequently in family members than would be expected by chance. Full siblings have an approximately 2-fold increase in risk, and the concordance rate of infantile leukemias in identical twins has been reported to be as high as 25%. The only infectious agent associated with acute leukemia is human T-lymphocyte leukemia virus (HTLV)-1, which causes T-cell adult leukemia/lymphoma. Congenital disorders that have an increased risk of acute leukemia include Down syndrome, disorders associated with increased chromosomal fragility (Bloom syndrome and Fanconi anemia), and those associated with immunodeficiency (X-linked agammaglobulinemia and ataxia telangiectasia). II. PRESENTATION Acute leukemia often presents with symptoms or signs related to bone marrow infiltration resulting in cytopenias. Severe neutropenia (absolute neutrophil count [ANC] 50% erythroid precursors are present in the bone marrow and myeloblasts should account for >20% of nonerythroid cells. Additionally, t(8;21), inv(16), t(16;16), and t(15;17) are diagnostic of AML regardless of blast percentage in the bone marrow. The presence of myeloid sarcoma and CNS involvement are diagnostic of acute leukemia regardless of blast count. The diagnosis of ALL requires demonstration of at least 20% lymphoblasts in the bone marrow. Cytochemistry can be helpful in the diagnosis of acute leukemia (for instance, myeloid blasts are positive for myeloperoxidase), but now flow cytometry is the primary method for determining the leukemia subtype. Lymphoid cells are identified by the presence of CD10, CD19, and CD20 (B cell) or CD2, CD3, CD4, CD5, and CD8 (T cell). Myeloid markers include CD13, CD33, and CD117/c-KIT; CD14 and CD64 (monocytic markers); glycophorin A (erythroid); and CD41 (megakaryocytic). Subtypes of AML and ALL as defined by the FAB system are of limited prognostic or therapeutic importance. The WHO classification, however, incorporates cytogenetic and clinical features of known prognostic significance. In the WHO system, AML subtypes are organized into six categories: AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, AML not otherwise categorized, myeloid sarcoma, and myeloid proliferations of Down syndrome (Table 32-2). Therapy-related AML and AML with multilineage dysplasia have a generally poor prognosis, and patients with these subtypes may be candidates for early allogeneic stem cell transplantation. In the WHO classification, ALL is categorized as precursor B-cell ALL or precursor T-cell ALL. Burkitt lymphoma/leukemia is grouped with the mature B-cell neoplasms. TABLE 32-2

World Health Organization Classification of AML and Related Neoplasms

AML witd recurrent genetic abnormalities AML with t(8;21) (q22;q22.1); RUNX1-RUNX1T1 AML with inv(16) (p13.1q22) or t(16;16) (p13.1;q22); CBFB-MYH11 APL with PML-RARA AML with t(9;11) (p21.3;q23.3); MLLT3-KMT2A AML with t(6;9) (p23;q34.1); DEK-NUP214 AML with inv(3) (q21.3q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM AML (megakaryoblastic) with t(1;22) (p13.3;q13.3); RBM15-MKL1 AML with mutated NPM1 AML with biallelic mutations of CEBPA AML with myelodysplasia-related changes Therapy-related myeloid neoplasms AML, NOS AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic leukemia Pure erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis (TAM) Myeloid leukemia associated with Down syndrome AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; MDS, myelodysplastic syndrome; NOS, not otherwise specified.

It must be emphasized that cytogenetic studies including conventional karyotype and FISH, and molecular studies for FLT3-ITD or TKD, IDH1, IDH2, DNMT3A, ASXL1, NPM1, TP53, c-KIT, and CEBPA mutations are crucial for the prognosis and treatment

of acute leukemia. Therefore, cytogenetic studies and the abovementioned molecular studies should be obtained on an initial bone marrow and/or peripheral blood sample. Early recognition of APL (FAB-M3, AML with t[15;17]) is particularly important, as these patients are at risk for DIC, and optimal initial treatment includes all-trans-retinoic acid (ATRA; see Section IV.B.). Advantages and pitfalls of diagnostic tools commonly used in the diagnosis of APL are summarized in Table 32-3. TABLE 32-3

Advantages and Pitfalls of Diagnostic Tools Commonly Used in the Diagnosis of APL

Methods

Markers

Time

Advantages

Drawbacks

Morphology

Dysplastic promyelocytes

30 min

Diagnostic >90%

M3 variant difficult

Immunophenotype

CD13+, CD33+, CD9+, HLA-DR−, CD34–/dim

2–3 h

Informative for uncertain morphology, detects CD56+ cases

Specificity, 95%

Karyotyping/FISH

t(15, 17)

48 h

Specific for APL

Quality of mitosis, false negatives

RT-PCR/Southern blot

PML/RAR-a

6–12 h

Hallmark of APL

Qualified laboratory

APL, acute promyelocytic leukemia; FISH, fluorescence in situ hybridization; PML, promyelocytic leukemia; RAR, retinoic acid receptor; RT-PCR, real time–polymerase chain reaction.

IV. THERAPY AND PROGNOSIS In the absence of antileukemic therapy, the median survival of newly diagnosed patients is 2 to 4 months. Chemotherapy induces responses in most patients with acute leukemia, although for many patients remission is short-lived. The goal of induction chemotherapy is CR, which is a prerequisite for cure. Morphologic CR is defined as normalization of blood counts (ANC more than 1,000/μL, platelet 100,000/μL or more), with bone marrow aspirate/biopsy demonstrating fewer than 5% blasts. Postremission therapeutic options include additional chemotherapy or stem cell transplantation. Chemotherapy given during CR can include consolidation (intensity similar to that for induction) and maintenance (reduced intensity administered for 18 to 36 months). A. Acute Myeloid Leukemia. The prognosis for patients with AML is largely determined by the leukemia risk group. Based on cytogenetic profiles, AML is classified into three risk groups. Molecular abnormalities including FLT3-ITD, NPM1, DNMT3A, c-KIT, TP53, RUNX1, ASXL1, and CEBPA mutations have significant prognostic impacts. National Comprehensive Cancer Network (NCCN) guidelines have included these mutations in risk classification of AML (Table 32-4). Translocation between chromosomes 8 and 21 (AML-ETO, t[8;21]), inversion

chromosome 16 and translocation t(16;16) present in about 16% of newly diagnosed patients and have a favorable prognosis with chemotherapy alone. Unfavorable cytogenetics, found in approximately 25% of AML patients, include monosomies or deletions of chromosomes 5 and 7 (–5, –7, 5q–, 7q–), inversion chromosome 3, 17p abnormalities or monosomy 17, 11q23 abnormalities and equal to or greater than three chromosomal abnormalities. More than half of the patients with AML have intermediate-risk cytogenetics, primarily a normal karyotype. In a large series from the Cancer and Leukemia Group B (CALGB), the 5-year survival rate was 55%, 24%, and 5% for patients with favorable, intermediate, and unfavorable cytogenetics, respectively. Management of newly diagnosed AML is summarized in Figure 32-1 and Table 32-5.

FIGURE 32-1 Schematic overview of the treatment of AML. AML, acute myeloid leukemia CBC, complete blood count; CMP, comprehensive metabolic panel; CNS, central nervous system FISH, fluorescence in situ hybridization; HSCT, hematopoietic stem cell transplantation INR, international normalized ratio; LDH, lactate dehydrogenase; PT, prothrombin time; PTT partial thromboplastin time. TABLE 32-4 Favorable

Non-APL AML Risk Stratification by NCCN t(8;21) (q22;q22.1); RUNX1-RUNX1T1 inv(16) (p13.1;q22) or t(16;16) (p13.1;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow

Biallelic mutated CEBPA Intermediate

Mutated NPM1 and FLT3-ITDhigh Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions) t(9;11) (p21.3;q23.3); MLLT3-KMT2A Cytogenetic abnormalities not classified as favorable or adverse

Adverse

t(6;9)(p23;q34.1); DEK-NUP214 t(v;11q23.3); KMT2A rearranged t(9;22) (q34.1;q11.2); BCR-ABL1 inv(3) (q21.3q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM(EVI1) –5 or del(5q); –7; –17/abn(17p) Complex karyotype, monosomal karyotype Wild-type NPM1 and FLT3-ITDhigh Mutated RUNX1 Mutated ASXL1 Mutated TP53

AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; NCCN, National Comprehensive Cancer Network. TABLE 32-5

AML Chemotherapeutic Regimens

7+3 chemotherapeutic regimen for newly diagnosed AMLa Cytarabine, 100 mg–200 mg/m2/day, as a continuous infusion for 7 d in combination with either daunorubicin 60–90 mg/m2/day or idarubicin 12 mg/m2/day on days 1, 2, 3 of cytarabine Consider adding midostaurin during induction for FLT3-mutated AML and gemtuzumab ozogamicin for CD33+ AML with intermediate or favorable-risk cytogenetics Administration of additional chemotherapy: Perform bone marrow on day 14 of chemotherapy; if cellularity is >20% and blasts are >5%, administer second cycle of chemotherapy (5 and 2): same doses as above with 5 d of cytarabine and 2 d of daunorubicin High-dose ara-C consolidation regimenb Cytosine arabinoside: 3.0 g/m2 in 500-mL D5W infused IV over a 3-h period every 12 h twice daily, days 1, 3, 5 (total, six doses) Before each dose, patients must be evaluated for cerebellar dysfunction; if present, stop drug and do not resume; one way to monitor cerebellar function is to have patients sign name on sheet of paper before each dose; for significant change in signature, physician should evaluate patient before any further therapy is given To avoid chemical keratitis, administer dexamethasone eye drops, 0.1% two drops both eyes q6h starting 1 h before first dose and continued until 48 h after last dose APL regimens Low riskc ATRA+ATO regimen: Remission induction: Daily ATO (0.15 mg/kg) IV, plus oral ATRA (45 mg/m2) until morphologic CR or for a maximum of 60 d Consolidation therapy: ATO (0.15 mg/kg) IV, 5 days/week, 4 wk on 4 wk off, for a total of four courses, and ATRA (45 mg/m2) daily 2 wk on and 2 wk off for a total of seven courses Maintenance therapy: None d

High riskd APML4 regimen: Remission induction: ATRA (45 mg/m2 d1–36), Idarubicin (IDA) (12 mg/m2 d2,4,6,8), ATO (0.15 mg/kg d9–36), prophylactic prednisone (1 mg/kg d1–10) Consolidation therapy: ATRA and ATO (continuous in cycle one, intermittent in cycle two) Maintenance therapy: 2 yr oral maintenance with ATRA, 6-mercaptopurine, and methotrexate aFrom Bloomfield CD, James GW, Gottlieb A, et al. Treatment of acute myelocytic leukemia: a study by cancer

and leukemia group B. Blood 1981;58:1203–1212, and Bob L, Gert JO, Wim van P, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235–1248, with permission. bFrom Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:896, with permission. cFrom Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111–121, with permission. dFrom Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012;120(8):1570–1580; quiz 1752. AML, acute myelogenous leukemia; APL, acute promyelocytic leukemia; ara-C, cytosine arabinoside; ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete remission.

An active area of investigation is the identification of molecular prognostic factors that can guide therapeutic decisions in patients with normal cytogenetics (Table 32-6). In a study, NPM1, DNMT3A, and FLT3ITD represented the most frequent three-gene cooccurrence identified in about 6% of the cohort and was associated with poor prognosis. When FLT3ITD was present without both NPM1 and DNMT3A, its effect on survival was less pronounced. TP53, complex karyotype, ASXL1, and SRSF2 are all associated with poor prognosis independently and co-occurrence is associated with an even worse prognosis. CEBPA mutations can be found in approximately 10% and 15% of all AML patients and patients with NK-AML, respectively. NK-AML with CEBPA mutation has a better remission duration and overall survival (OS) similar to core binding factor AML (CBF-AML, another term for AML with t[8;21] and AML with inv[16]). Double mutation of CEBPA (mutation of both alleles) is less common (5% of NK-AML). A recent study showed that OS benefit of CEBPA mutation is limited to patients with double mutations. This study showed the 8-year OS rates of 54%, 31%, and 34% in double mutations of CEBPA, single-mutated CEBPA, and wild-type CEBPA, respectively. c-KIT mutation is another molecular abnormality with significant prognostic impact in AML with t(8;21) and AML with inv(16). The main mutation clusters are in exon 17 and exon 8. c-KIT mutations are seen in approximately 20% to 30% of patients with CBF-AML. In good-risk CBF-AML, c-KIT mutation increases the risk of relapse and decreases OS, especially in patients with t(8;21). TABLE 32-6

Molecular Abnormalities in AML

Mutated Gene

Frequency

Prognostic Impact

Targeted Rx

NPM1

25%–35%

Favorable

No

FLT3-ITD

20% (30% of cytogenetically normal AML)

Adverse

Midostaurin

FLT3-TKD

5%–10%

Controversial

Midostaurin

DNMT3A

15% (20% of cytogenetically normal AML)

Adverse

No

IDH1

8%

Adverse

Ivosidenib

IDH2

8%

Adverse

Enasidenib

Biallelic mutated CEBPA

10%

Favorable

No

KIT

20% of core binding factor AML

Adverse

Imatinib, sunitinib, and others

ASXL1

5%

Adverse

No

TP53

60%–80% of patients with a complex karyotype

Adverse

No

AML, acute myeloid leukemia.

For more than 30 years, standard remission induction chemotherapy for AML has included treatment with cytarabine (cytosine arabinoside, ara-C) and an anthracycline that has recently changed (Fig. 32-1). The most common regimen combines 7 days of continuous infusion cytarabine (100 to 200 mg/m2/day) with 3 days of daunorubicin or idarubicin (7 + 3; Table 32-5). A bone marrow examination is repeated 14 to 21 days after starting treatment, and patients with bone marrow cellularity 20% or greater and more than 5% blasts are considered to have residual disease. Patients with persistent disease may achieve a remission after a second, usually abbreviated, course of cytarabine and anthracycline (5 + 2). Sixty percent to 70% of patients achieve a CR after standard induction chemotherapy, with neutrophil (ANC >500/mL) and platelet (>20,000/mL) recovery occurring an average of 21 to 25 days after the start of therapy. Failure to achieve CR with induction chemotherapy can result from resistant leukemia or early death. Therapy-related mortality increases with age, poor performance status, and underlying organ dysfunction and can be as high as 30% to 40% in elderly patients. Resistant leukemia is associated with a preceding hematologic disorder and adverse cytogenetics, both of which are found more commonly in elderly patients. CPX-351 is a liposomally encapsulated formulation of cytarabine and daunorubicin that preserves a 5:1 molar ratio. A phase 3 trial performed in patients aged 60 to 75 with secondary or MDS related AML comparing CPX-351 with 7 + 3 showed that CPX-351 resulted in higher OS and overall remission rate and lower treatment-related mortality. Another practice changing phase 3 trial was the RATIFY trial which evaluated the benefit of addition of midostaurin to induction and consolidation regimens in patients with FLT3

mutation (TKD or ITD). This resulted in longer OS and event-free survival. As a result, all patients with newly diagnosed AML should have FLT3 testing performed at the time of diagnosis (Fig. 32-1 and Table 32-5). Patients will invariably relapse if they do not receive additional therapy after achieving CR. In contrast, postremission treatment can result in a cure rate of up to 40%. Commonly used consolidation strategies include highdose cytarabine (HDAC) or allogeneic stem cell transplantation. HDAC (Table 32-5) can overcome resistance to conventional doses of the drug, producing CR in approximately 40% of patients with resistant leukemia. On this basis, trials of HDAC consolidation for AML in first CR (CR1) were carried out. The value of HDAC consolidation was demonstrated in a CALGB trial, which randomized 596 patients in CR1 to consolidation with four cycles of conventional-dose (100 mg/m2/day 3 to 5 days), intermediate-dose (400 mg/m2/day 3 to 5 days), or high-dose (3.0 g/m2, total of six doses over 5 days) cytarabine. Among patients less than or equal to 60 years, 4-year progression-free survival was 44% for HDAC consolidation versus 24% for conventional-dose cytarabine. Patients older than 60 years did poorly regardless of the type of consolidation they received, with fewer than 20% achieving durable remission. The subgroup analysis of this trial underlines the critical role of cytogenetics for predicting the outcome of consolidation therapy for AML. The estimated likelihood of cure among patients with favorable cytogenetics (t[8;21] and inv16) who received HDAC was 84% versus less than 25% for patients with unfavorable cytogenetics. HDAC can produce significant neurotoxicity, primarily cerebellar dysfunction and, less commonly, somnolence or confusion. Cerebellar function should be assessed before each dose, and the drug should be stopped if there is evidence of neurotoxicity. A sensitive way to assess cerebellar function is to ask the patient to sign his or her name on a signature record before each dose. Another unique toxicity of HDAC is keratitis, which can be prevented by administration of dexamethasone eye drops, 0.1%, two drops to each eye every 6 hours, from the time treatment is started until 48 hours after HDAC ends. Other potential toxicities of HDAC include an erythematous rash, often worse on the palms and soles, and hepatic dysfunction. Several trials have examined the role of consolidation with allogeneic transplantation for younger patients with AML in CR1. In these studies, transplantation was associated with improved leukemia-free survival compared with chemotherapy. However, the studies did not consistently show improvement in OS, probably because transplantation is associated with higher treatment-related mortality and because some patients who relapse after consolidation chemotherapy can be salvaged with transplantation. These trials also found that the cytogenetic risk group was the major determinant of survival, regardless of whether consolidation was with chemotherapy or transplantation. The available data from clinical trials allow therapeutic recommendations to be made for some groups. Because 60% to 70% of patients with favorable-risk AML achieve 3-

year survival with intensive consolidation that includes HDAC, chemotherapy is the treatment of choice for this group. However, patients with poor-risk AML have a very low disease-free survival (DFS) with conventional chemotherapy. For these patients, allogeneic transplant in CR1 is the treatment of choice, if a matched sibling, matched unrelated donor (MUD), or haploidentical donor can be identified. Optimal treatment for patients with intermediate risk is not clear. Consolidative chemotherapy and allogeneic stem cell transplantation are both accepted postremission strategies for intermediate-risk patients. There is a trend toward improved OS with allogeneic stem cell transplantation for intermediate-risk patients younger than 35 years likely because they are better able to tolerate the allogeneic hematopoietic cell transplantation (HCT) morbidity. When patients with AML relapse after conventional chemotherapy, they generally do so within 3 years. The risk of relapse more than 5 years after diagnosis is 5% or less. The role of minimal residual disease (MRD) in AML disease monitoring is evolving and there seems to be a trend toward higher risk of relapse with persistently positive MRD. For patients with relapsed AML and for those who do not achieve CR despite optimal induction chemotherapy, the only treatment option with curative potential is stem cell transplantation. For patients with an HLA-matched donor, allogeneic transplant is the treatment of choice among those younger than 60 years. Medically fit older adults can be considered for nonmyeloablative or reduced intensity conditioning allogeneic HCT. However, relapse is common, and only 20% to 30% of those transplanted in second CR (CR2) are cured. Because outcomes are poor when patients are transplanted with active AML, an attempt is often made to achieve CR before transplant. Salvage chemotherapeutic regimens for relapsed or refractory disease include HDAC ± an anthracycline, etoposide with mitoxantrone, or fludarabine-containing regimens. Participation in a clinical trial is strongly recommended. In addition, recently various targeted agents have been approved for the treatment of relapsed refractory AML (Table 32-7). These agents can be used for relapsed or refractory disease when more aggressive regimens might not be appropriate. A combination of hypomethylating agents such as decitabine or azacitidine with venetoclax is well tolerated. A single-arm study in treatment-naïve, elderly patients with AML showed a 67% remission rate with a median duration of remission of 11.3 months. Based on the results of the ADMIRAL trial, gilteritinib is now approved for adult patients with relapsed or refractory AML with an FLT3 mutation. Patients randomized to gilteritinib had significantly longer OS (9.3 months) than salvage chemotherapy (5.6 months). The CR/CR with partial hematologic recovery rates for gilteritinib and salvage chemotherapy were 34.0% and 15.3%, respectively. IDH2 mutations are identified in approximately 12% of the patients with AML. In a phase 1/2 trial of patients with IDH2-mutant patients, enasidenib, an oral selective inhibitor of mutant IDH2 was associated with an overall response rate of 40.3% with a median duration of response of 5.8 months. IDH1

mutations occur in approximately 6% to 10% of the patients with AML. In a phase 1 study, the mutant IDH1 inhibitor ivosidenib was associated with a CR or CR with partial hematologic recovery of 30.4%. The median durations of these responses were 8.2 months. These agents have been associated with IDH differentiation syndrome (DS) similar to the DS seen in patients with APL during treatment with ATRA or arsenic trioxide (ATO). The mechanism is similar, as IDH inhibition results in myeloid differentiation. At first suspicion of IDH inhibitor-induced DS, dexamethasone 10 mg twice daily is recommended until signs and symptoms resolve followed by a taper. Hydroxyurea can be considered for leukoreduction. In addition, any evidence for infections or TLS should be appropriately managed. Gemtuzumab ozogamicin is another agent that is approved for relapsed or refractory CD33-positive AML. TABLE 32-7

Targeted Therapy for AML

FLT3-ITD or TKD mutation

Gilteritinib

FLT3-ITD mutation

Sorafenib (used with hypomethylating agents)

IDH1 mutation

Ivosidenib

IDH2 mutation

Enasidenib

CD33-positve AML

Gemtuzumab ozogamicin

AML, acute myeloid leukemia.

B. Acute Promyelocytic Leukemia. APL is a distinct clinical and pathologic subtype of AML, characterized by a reciprocal translocation between the long arms of chromosomes 15 and 17. The breakpoint on chromosome 17 disrupts a gene that encodes a nuclear receptor for retinoic acid (RAR-a), and its translocation, most commonly to chromosome 15, results in a fusion protein, PML-RAR-a (promyelocytic leukemia/retinoic acid receptor alpha). Detection of PML-RAR-a is associated with a good prognosis. Indeed, patients with APL who achieve CR have better long-term survival than do other patients with AML. Given its unique response to specific therapy, rapid and accurate diagnosis is crucial. It is now commonly accepted that molecular evidence of the PML/RAR-a rearrangement is the hallmark of this disease, as it may be found in the absence of t(15,17). As soon as the diagnosis of APL is entertained, it is critical to identify and manage APL-associated coagulopathy. Initial suspicion for APL arises on detection of disproportionately large number of promyelocytes on the peripheral smear. Five percent to 10% of patients with APL die of hemorrhagic complications during induction chemotherapy, and approximately half these deaths occur within the first week of diagnosis. Consequently, monitoring DIC with twice-daily serum fibrinogen levels and aggressive replacement with cryoprecipitate (5 to 10 units for fibrinogen less than 100

mg/dL) is common clinical practice during the first weeks of treatment of APL. Patients may also require liberal transfusions of fresh frozen plasma. If coagulopathy or bleeding is present, the platelet count should be maintained greater than 30 to 50,000/μL. It is recommended to delay central line placement in these patients till resolution of DIC. APL is categorized to three risk groups based on white blood count and platelet count: (1) low risk with WBC lesser than or equal to 10,000/mL and platelet count greater than 40,000/mL, (2) intermediate risk with WBC lesser than or equal to 10,000/mL and platelet count less than 40,000/mL, and (3) high risk with WBC greater than 10,000/mL. Outcomes of intermediate-risk and low-risk APL are similar when ATO is used in consolidation treatment; as a result, APL is mainly categorized to high risk with WBC greater than 10,000/mL, and low/intermediate risk with WBC lesser than or equal to 10,000/mL. Treatment of APL has three phases: induction, consolidation, and maintenance. The goal of induction treatment is morphologic CR. Molecular CR (absence of PML/RAR-a in the bone marrow by RT-PCR) is the goal of consolidation. A distinguishing feature of APL is its sensitivity to ATRA. The advantage of including ATRA in the front-line therapy for APL has now been clearly established in several randomized trials, with CR rates ranging from 72% to 95%, and a 3- to 4-year DFS of 60% to 90%. These studies also found that DFS is improved when ATRA is given concurrently with anthracycline-based chemotherapy. ATRA with an anthracycline, often combined with cytarabine, remains the standard of care for patients with high-risk APL. In some studies, cytarabine was omitted inconsequently from induction and/or consolidation regimens. Given the lack of randomized trials, long-term results of these trials are needed to clarify the role cytarabine plays in the management of APL. A recent randomized phase 3 trial (N Engl J Med 2013;369:111) compared ATRA plus ATO with ATRA plus idarubicin in low-/intermediate-risk APL. The investigational arm received ATRA plus ATO daily until morphologic CR followed by consolidation with ATO 5 days a week for 4 weeks every 8 weeks for four courses and ATRA daily for 2 weeks every 4 weeks for seven courses. The control arm received ATRA plus idarubicin induction followed by consolidation with ATRA plus idarubicin followed by maintenance treatment with ATRA and low-dose chemotherapy. The CR rate was 100% in the ATRA plus ATO arm and 95% in the ATRA plus idarubicin arm. Two-year event-free survival rates were 97% in the ATRA plus ATO arm and 86% in the ATRA plus idarubicin arm, confirming noninferiority and maybe superiority of ATRA plus ATO for induction and consolidation in low-/intermediate-risk APL. On the basis of these results, ATRA plus ATO and ATRA plus idarubicin are both acceptable induction regimens for low/intermediate-risk patients, but ATRA plus ATO is often preferred for its efficacy and tolerability. No maintenance therapy in ATRA plus ATO arm was given in this study. The single-arm, phase 2 APML4 trial (Blood 2012;120:1570) included four doses of idarubicin during induction, thereby limiting anthracycline exposure compared to

traditional regimens. It was associated with 5% cumulative incidence of relapse and is currently used for high-risk patients. Maintenance is the final phase in APL treatment. Several studies have shown that the addition of maintenance therapy with ATRA and/or chemotherapy after intensive postremission consolidation is associated with improved disease-free and OS. However, many questions remain unanswered. There is controversy regarding the benefit of maintenance therapy in APL patients who receive ATO as a part of consolidation and are in molecular CR after consolidation. Additionally, the optimal maintenance regimen is still unknown. In one study, the combination of ATRA (45 mg/m2/day, 15 days every 3 months) with 6-mercaptopurine (90 mg/m2/day, orally) and methotrexate (15 mg/m2/week, orally) was associated with the lowest relapse rates, especially for APL patients with a high WBC. Initial response evaluation to induction treatment should be done by bone marrow aspiration and biopsy upon count recovery (approximately 5 weeks after the start day of induction). Owing to differentiation effects of ATRA, early response evaluation (day 14 bone marrow biopsy) will be misleading. The goal of induction treatment is morphologic CR. Cytogenetic studies are usually normal at this time. PCR for PML/RAR-a is usually positive at this time and is not considered induction failure. Molecular CR (PCR negativity) is the goal of consolidation treatment; therefore, evaluation for molecular CR should be done after at least two cycles of consolidation. Patients who have not achieved a molecular remission at the completion of consolidation should receive salvage therapy (discussed in the subsequent text). RTPCR should be used to monitor for disease relapse, and patients with emergence of detectable PML-RARa transcript should be considered for salvage therapy. Although ATRA is usually well tolerated, some patients develop a unique complication called differentiation syndrome (DS), formerly known as retinoic acid syndrome (RAS). DS occurs usually early after initiation of ATRA and/or ATO (7 to 12 days) and is diagnosed on clinical grounds. It is characterized by unexplained fever (80%), weight gain (50%), respiratory distress (90%), lung infiltrates (80%), pleural (50%) or pericardial effusion (20%), hypotension (10%), and renal failure (40%). It is the most serious toxicity of ATRA and/or ATO and is often, but not always, associated with the development of hyperleukocytosis. Its incidence varies from 6% to 25%, and mortality is variable (7% to 27%). The best approach to predict, prevent, or treat this syndrome has not been established. Early institution of corticosteroids (dexamethasone, 10 mg IV twice daily) simultaneous with cytoreduction (induction chemotherapy or hydroxyurea) is associated with rapid resolution of the syndrome in most patients. Discontinuation of ATRA and/or ATO is common practice after onset of DS. DS has not been observed when ATRA was given as maintenance therapy. Toxicities of ATO include QT prolongation, which rarely may lead to torsades de pointes. Approximately 10% to 25% of patients treated with ATRA-based therapy ultimately

relapse. The duration of CR1 and the achievement of a second PCR-negative remission after reinduction have been shown to be prognostic determinants. The first choice for salvage therapy is usually ATO. In a U.S. trial, 85% of patients treated with relapsed APL treated with ATO achieved a CR, 91% of whom had a molecular remission. However, most patients will relapse without additional therapy, which may include additional course of ATO, chemotherapy, and/or autologous or allogeneic stem cell transplantation. Patients with APL who undergo autologous stem cell transplantation while in second remission have a 30% 7-year leukemia-free survival. However, after stratification according to PCR status of the grafted marrow, it appears that patients transplanted with PML-RARa–negative marrow cells are more likely to have prolonged clinical and molecular remissions. In contrast, relapse after autologous transplant is inevitable in patients with persistently positive PCR before transplant. Allogeneic stem cell transplantation may be the preferable treatment modality in this setting. C. Acute Lymphoblastic Leukemia. For ALL, clinically meaningful subtypes are defined by immunophenotype (B-progenitor, B cell, and T cell) as determined by flow cytometry (Table 32-8). As for AML, cytogenetics is of critical prognostic and therapeutic value (Table 32-9). Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene expression profile similar to that of BCR–ABL1-positive ALL and associated with a poor outcome. It is found in about 10% of the children and 27% adults with ALL. Genetic alterations targeting Blymphoid transcription factors, including IKZF1, are common. They may be amenable to a tyrosine kinase inhibitor (TKI) or JAK inhibition and clinical trials are ongoing in this poor-risk subtype of ALL. Accurate subtyping of ALL is essential for appropriate treatment. Approximately 70% to 75% of patients have B-precursor, 20% to 25% have T-cell, and approximately 5% have mature B-cell ALL. Mature B-cell ALL expresses surface-membrane immunoglobulin and is characterized by the t(8;14), which results in fusion of the myc oncogene with part of the immunoglobulin heavy-chain gene. Variant translocations involve myc and light-chain genes (t[2;8], t[8;22]). Mature B-cell ALL is the leukemic equivalent of Burkitt lymphoma and is arbitrarily defined by the presence of more than 20% blasts in the bone marrow. Bcell ALL/Burkitt is a rapidly proliferating neoplasm, and treatment is often complicated by TLS. Treatment for mature B-cell ALL differs from that for other types of ALL in that intensive chemotherapy is given over a relatively short period (2 to 8 months) without maintenance chemotherapy. Important components of this therapy include high total doses of cyclophosphamide and/or ifosfamide given in fractions over several days along with HDAC and high-dose methotrexate. Addition of the anti-CD20 monoclonal antibody rituximab to the chemotherapeutic regimen appears to improve CR rate and DFS. Intrathecal chemotherapy is included in the

therapy of mature B-cell ALL, because without adequate prophylaxis, CNS relapse is common. With an aggressive combination of chemotherapy and intrathecal therapy, 50% to 70% of patients achieve long-term DFS. TABLE 32-8

World Health Organization Classification of Acute Lymphoid Leukemia

B-lymphoblastic leukemia/lymphoma B-lymphoblastic leukemia/lymphoma, not otherwise specified B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities B-lymphoblastic leukemia/lymphoma with t(9;22) (q34.1;q11.2); BCR-ABL1 B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged B-lymphoblastic leukemia/lymphoma with t(12;21) (p13.2;q22.1); ETV6-RUNX1 B-lymphoblastic leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with hypodiploidy B-lymphoblastic leukemia/lymphoma with t(5;14) (q31.1;q32.3) IL3-IGH B-lymphoblastic leukemia/lymphoma with t(1;19) (q23;p13.3); TCF3-PBX1 Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21 T-lymphoblastic leukemia/lymphoma Provisional entity: Early T-cell precursor lymphoblastic leukemia Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma TABLE 32-9

Cytogenetic Risk Groups for B-ALL

Good risk

Hyperdiploidy (51–65 chromosomes) t(12;21) (p13;q22) (ETV6–RUNX1 fusion)

Poor risk

Hypodiploidy ( 500/mL), even if fever resolves. Otherwise, the choice and duration of antimicrobial therapy is dictated by the source of infection. Bacteremia is treated with a 10- to 14day course of antibiotics. Indwelling catheters should be removed for fungemia, persistent bacteremia, or Staphylococcus aureus or Pseudomonas bacteremia. Patients with a history of Aspergillus or Mucor sp. infection should receive prolonged antifungal therapy, especially if profound neutropenia is likely during subsequent courses of chemotherapy. Typhlitis (neutropenic enterocolitis) is a syndrome of colonic inflammation in neutropenic patients. It presents with fever, abdominal pain, and tenderness. The etiology is unclear. Treatment is with broad-spectrum antibiotics, including anaerobic coverage, and nasogastric suction. Surgical intervention is reserved for patients with bowel perforation or suspected bowel necrosis. Growth factors. The use of myeloid growth factors in acute leukemia remains controversial despite multiple randomized trials. Treatment with granulocyte colonystimulating factor (G-CSF) or granulocyte–macrophage colony-stimulating factor (GM-CSF) after induction chemotherapy shortens the duration of ANC less than 500/mL by 3 to 6 days. The duration of hospitalization and antibiotic use are also shortened by treatment with growth factors. Although the effectiveness of chemotherapy is not compromised by the use of these agents, most evidence indicates that growth factors do not improve the likelihood of CR or long-term survival. Often, growth factors are reserved for older patients or for those with lifethreatening infection. Intravenous access. All patients with acute leukemia should have a central venous catheter placed. Temporary catheters, such as the Hohn catheter, are usually chosen because fever, coagulopathy, or poor increments with platelet transfusion represent relative contraindications to placement of a more permanent, tunneled catheter. Tumor lysis syndrome. TLS is a complication of rapid tumor breakdown after

chemotherapy. Clinically, it is marked by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute oliguric renal failure. Risk factors for TLS include B-cell ALL, WBC greater than 50,000/mL, LDH greater than 1,000 IU/L, renal dysfunction, and elevation of the uric acid or phosphorus before treatment. All patients with newly diagnosed acute leukemia should be vigorously hydrated to maintain urine output at more than 2.5 L/day, and volume status should be closely monitored. If the patient’s renal function is normal, allopurinol, 600 mg, is given the day before chemotherapy, followed by 300 mg daily until the WBC is less than 1,000/μL. If the pretreatment uric acid is more than 9 mg/dL, rasburicase can be used in place of allopurinol to reduce the uric acid level rapidly. Patients at high risk for TLS should have electrolytes, calcium, magnesium, and phosphorus monitored two to three times daily for the first 2 to 3 days of induction chemotherapy. J. CNS involvement with acute leukemia. Patients with acute leukemia who develop neurologic symptoms or signs should be evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) of the head and, in the absence of a mass lesion, proceed to lumbar puncture. Cerebrospinal fluid (CSF) should be sent for glucose, protein, routine cultures, Gram stain, cryptococcal antigen, cell count with differential, cytology, and flow cytometry. Patients with blasts in the CSF should receive intrathecal chemotherapy. Cranial radiotherapy can also be considered. Intrathecal therapy may include preservative-free methotrexate, 12 to 15 mg, or cytarabine, 50 to 100 mg. Cytology, flow cytometry, and cell count with cytospin differential should be repeated with each intrathecal treatment until blasts have cleared. Intrathecal therapy is given twice weekly until blasts have cleared and then weekly for 4 to 6 weeks. The sudden onset of unexplained cranial nerve palsy in a patient with acute leukemia is usually caused by CNS leukemia, regardless of whether the CSF shows blasts. Such patients should be treated as described above. Because isolated CNS relapse of leukemia is generally followed soon thereafter by systemic relapse, salvage chemotherapy followed by allogeneic transplant should be considered if patients relapse with CNS involvement. VI. FOLLOW-UP Patients who are in a CR after induction and consolidation therapy require close followup. The highest risk of relapse of acute leukemia is within the first 3 years of completion of treatment. During that time, patients should be evaluated with history, physical examination, and complete blood count (CBC) every 2 to 3 months. Bone marrow biopsy should be repeated routinely every 3 to 6 months, or if the blood counts fall or blasts are observed in the peripheral blood. Because patients may have disease relapse at extramedullary sites, suspicious skin or soft tissue lesions should be biopsied to rule out granulocytic sarcoma, and new neurologic deficits should be evaluated by brain imaging

and lumbar puncture to rule out CNS leukemia. Molecular monitoring of APL (i.e., RTPCR for PML-RARa) should be performed every 2 to 3 months for 3 years post consolidation for patients at high risk of relapse, particularly those with a presenting WBC of more than 10,000/μL. Relapse of acute leukemia is very uncommon after approximately 5 years, and follow-up can become less frequent thereafter. MYELODYSPLASTIC SYNDROMES AND RELATED DISEASES I.

EPIDEMIOLOGY AND RISK FACTORS MDS is the most common myeloid malignancy. According to the Surveillance, Epidemiology, and End Results (SEER) database, approximately 10,000 cases of MDS are diagnosed annually in the United States but the incidence is likely closer to 30,000 to 40,000 as many patients do not undergo a bone marrow biopsy for definitive diagnosis. MDS usually occurs in older adults with the median age of diagnosis over 65 years. The risk of developing MDS increased with age. MDS has been associated with exposure to environmental agents such as benzene, radiation, smoking, and chemotherapeutic agents. Certain genetic anomalies such as Fanconi anemia are also associated with MDS. Four recognized syndromes with germline mutations have been associated with MDStelomere biology disorders caused by mutation of TERC or TERT, familial AML with mutated CEBPA, familial MDS/AML with mutated GATA2, and familial platelet disorder with propensity to myeloid malignancy. Overall, familial MDS is rare compared to the total number of cases of MDS diagnosed every year.

II. PRESENTATION This group of clonal disorders is characterized by ineffective hematopoiesis and cytomorphologic features of affected blood cell lines. Most patients with MDS are diagnosed upon further workup of incidentally discovered abnormal blood counts. It is usually a result of acquired mutations and presents in older adults in their seventies. Anemia and fatigue are the most common findings. Some patients develop infections caused by neutropenia and granulocyte dysfunction. Most cases of MDS eventually evolve into AML. About 25% of patients present with clinical manifestations of thrombocytopenia such as petechiae. Occasionally some patients have a high platelet count at presentation. Younger adults with high-risk MDS might have physical stigmata of genetic bone marrow failure syndromes. Another cutaneous presenting finding is acute febrile neutrophilic dermatosis (Sweet syndrome). III. WORKUP AND STAGING Detailed history taking should include evaluation for nutritional deficiencies such as vitamin B12, folate, copper, and zinc, which can have findings similar to MDS, infections

12

such as HIV that can lead to cytopenias, and alcohol abuse that can cause bone marrow suppression. A peripheral smear and a bone marrow aspiration and biopsy should be performed. Presence of dysplasia in addition to cytopenias defined as hemoglobin less than 10 g/dL, ANC less than 1800/μL, and/or platelets less than 100,000/μL, and less than 20% blasts in the absence of previously mentioned AML-defining translocations is diagnostic of MDS (Table 32-10). Anemia is usually normocytic or macrocytic. Although fibrosis is frequently seen, a high degree of fibrosis could indicate MDS/myeloproliferative disorder overlap. TABLE 32-10

2016 WHO Myelodysplastic Syndrome Subtypes

aIf SF3B1 mutation is present. bOne percent peripheral blood blasts must be recorded on at least two separate occasions. cCases with ≥15% ring sideroblasts by definition have significant erythroid dysplasia, and are classified as MDS-

RS-SLD. From Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391. BM, bone marrow; MDS, myelodysplastic syndrome; PB, peripheral blood; WHO, World Health Organization.

Certain chromosomal abnormalities such as 5q and 7q deletion are indicative of MDS in the presence of unexplained cytopenia(s) and no evidence of dysplasia. Increasingly, next-generation sequencing (NGS) is being used for the workup of MDS. These cytogenetic and molecular abnormalities have both prognostic and therapeutic implications. An effort should be made to perform a detailed family history for the diagnosis of genetic bone marrow failure syndromes in younger adults who might have clinically silent phenotypes. The revised version of International Prognostic Scoring System (IPSS) stratifies patients into five risk groups (Table 32-11). TABLE 32-11

Revised International Prognostic Scoring System (IPSS-R) in Myelodysplastic Syndrome

Greenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring System for myelodysplastic syndromes. Blood 2012;120:2454–2465. AML, acute myeloid leukemia.

SF3B1 mutation defines a distinct subset of MDS patients with a distinct phenotype and a favorable prognosis. Recently, NGS has revealed recurrent mutations in MDS. Splicing factor mutations and epigenetic regulator mutations are seen in approximately 50% of patients of MDS. Patients with TP53 mutations frequently have complex karyotypes and have a poor prognosis. The poor prognosis of patients with TP53 mutation is seen even after HSCT. Only 10% of the patients lack these common

recurrently mutated genes. IV. PATHOGENESIS MDS typically is a result of acquired somatic mutations in older adults and germline predisposing mutations in younger adults. The mesenchymal niche is thought to be a critical contributor to malignant evolution. Aberrant innate immune system activation and proinflammatory signaling between driver mutations and the microenvironment are key drivers of this process. Most mutations in MDS are unbalanced gains or losses in chromosomal materials such as deletions in 7q and 5q and gains in chromosome 8. MDS overlap disorders such as MDS/myeloproliferative neoplasms (MPNs) are not consistent with a single diagnostic category and share features of both. MDS/MPNs are characterized by hematopoietic dysplasia in addition to increased proliferation of monocytes, neutrophils, or platelets. Hypoplastic MDS and aplastic anemia are sometimes difficult to distinguish but genetic features assist the pathologist in the diagnosis. Secondary AML (sAML) likely progresses from MDS based on genetic studies (Table 32-12). TABLE 32-12

MDS Cytogenetic Scoring System

Prognostic Subgroups, % of Patients

Cytogenetic Abnormalities

Median Survival

Median AML Evolution, 25%

Very good (3%−4%)

−Y, del(11q)

5.4

NR

Good (66%−72%)

Normal, del(5q), del(12p), del(20q), double including del(5q)

4.8

9.4

Intermediate (13%−19%) del(7q), +8, +19, i(17q), any other single or double independent clones

2.7

2.5

Poor (4%−5%)

−7, inv(3)/t(3q)/del(3q), double including −7/del(7q), complex: 3 abnormalities

1.5

1.7

Very poor (7%)

Complex: >3 abnormalities

0.7

0.7

From Greenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring System for myelodysplastic syndromes. Blood 2012;120:2454−2465. AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome.

V. THERAPY AND PROGNOSIS A. Myelodysplastic Syndrome. One of the major advances in MDS is the use of NGS in the description of the genetic landscape and demonstration of clonal heterogeneity. The integration of the genetic basis of MDS into diagnosis, prognosis, predictors of treatment response and relapse, and rational drug therapy is an active area of research. In cases where germline mutations leading to MDS are suspected, potential family member donors should be tested to avoid choosing a donor with the same

mutation. Also, allogeneic HSCT conditioning regimens are usually modified if there is an underlying genetic bone marrow failure syndrome. Prognosis and treatment of patients with MDS are based on revised IPSS score. Overall management of MDS is summarized in Table 32-13. Despite it being the most common myeloid malignancy, there have been no FDA-approved therapies for MDS since 2006. As patients with MDS are usually elderly, most cannot tolerate allogeneic HSCT, which is the only curative treatment. For patients with very low and low-risk MDS, in addition to patients with low life expectancy because of significant comorbidities, supportive care is a reasonable treatment option. Events such as worsening of cytopenias, increasing bone marrow blasts, and cytogenetic or molecular evolution will indicate need for change in treatment strategy in appropriate patients. TABLE 32-13

Treatment Algorithm for MDS

Initial Diagnosis of MDS Risk stratify–based bone marrow biopsy for morphology, flow cytometry, karyotyping, FISH analysis, and molecular studies. Determine need for treatment. If none then monitor. Intensify disease surveillance if mutant TP53 clone develops. Low-Risk MDS

High-Risk MDS

Anemia • 5 q deletion—lenalidomide • Erythropoietin level < 500—trial of erythropoietin stimulating agent with or without G-CSF • Luspatercept may become a second-line option in the near future

• Initial therapy with hypomethylating agent, induction chemotherapy versus or best supportive care • Iron chelation to prevent iron overload • Transplant-eligible allogeneic HSCT once donor identified

Thrombocytopenia Consider thrombopoiesis-stimulating agents

Transformation to AML Options include CPX-351, induction chemotherapy, targeted therapy, or clinical trial

Treatments at progression Hypomethylating agents, allogeneic HSCT or clinical trial AML, acute myelogenous leukemia; FISH, fluorescence in situ hybridization; G-CSF, granulocyte colonystimulating factor; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome.

Low transfusion burden anemia can be treated with erythropoiesis-stimulating agents (ESA) such as recombinant erythropoietin or darbepoetin in patients with low endogenous erythropoietin level (below 500 IU/L). Responses usually last about 1.5 years and addition of G-CSF may prove to be effective in 20% of the cases. Patients with 5q deletion usually respond to lenalidomide but response rate is lower in

patients harboring the TP53 mutation. Patients with hypoplastic MDS and normal karyotype can be treated with immunosuppressive therapy after progression on growth factors. The currently recommended regimen is horse antithymocyte globulin in combination with cyclosporine. There is some evidence that 10-day decitabine can result in clearance of bone marrow blasts in patients with TP53 mutations and MDS or AML but these responses are not durable. Hypomethylating agents are extensively used in patients with high-risk MDS but responses are short-lived. Patients with IPSS intermediate-2 or high-risk MDS, and those who have progressed on growth factors should be considered for allogeneic SCT. In most cases, this offers the only curative option but patient comorbidities and ability to tolerate transplant regimens should be considered. B. MDS/MPN overlap. These disorders present diagnostic challenges and the landscape is evolving with widespread use of NGS. Table 32-14 provides an overview of the diagnosis, prognosis, and treatment options for these entities. TABLE 32-14

WHO Myelodysplastic Syndrome/Myeloproliferative Neoplasm Diagnostic Criteria and Brief Overview of Treatment Options

1. Chronic myelomonocytic leukemia (CMML) WHO Diagnostic Criteria • Persistent peripheral blood monocytosis >1 × 109/L • No BCR-ABL or PDGFR fusion gene • Less than 20% blasts in the blood and bone marrow • Dysplasia in one or more lineages • If no dysplasia, then an acquired clonal cytogenetic or genetic abnormality • Monocytosis has persisted for greater than 3 mo • All other causes of monocytosis have been excluded Prognosis and Treatment • Prognosis based on risk stratification but overall poor • Consider allogeneic HSCT for high-risk patients with few comorbidities • Consider treatment with hypomethylating agents, hydroxyurea for cytoreduction, or best supportive care 2. Atypical chronic myeloid leukemia (aCML) WHO Diagnostic Criteria • WBC >13 × 109/L with increased and dysplastic neutrophils • No BCR-ABL or PDGFR fusion gene • 10% of leukocytes Prognosis and Treatment • Prognosis poor • Consider allogeneic HSCT for eligible patients

• Clinical trial or best supportive care 3. Refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T) WHO Diagnostic Criteria • Platelet count >450 × 109/L • 15% ring sideroblasts in the bone marrow or >5% with SF3B1 mutation • Presence of megakaryocytic atypia resembling essential thrombocythemia (ET) or myelofibrosis (MF) Prognosis and Treatment • Overall prognosis good • Thrombocytosis—cytoreductive therapy and aspirin • Anemia—erythroid stimulating agents, lenalidomide, and HMAs • Possibly luspatercept for management of anemia in the future 4. Juvenile myelomonocytic leukemia (JMML) WHO Diagnostic Criteria • Peripheral blood monocytosis >1 × 109/L • No BCR-ABL or PDGFR fusion gene • Less than 20% blasts in the blood and bone marrow • Two of the following must be present: • Hemoglobin F increase • Immature granulocytes in peripheral blood • WBC >10 × 109/L • Clonal chromosome abnormality • GM-CSF hypersensitivity of myeloid progenitors in vitro Prognosis and Treatment • Prognosis very poor • Allogeneic HSCT for eligible patients versus best supportive care 5. Myelodysplastic syndrome/myeloproliferative neoplasms-unclassified (MDS/MPN-U) WHO Diagnostic Criteria • Features of MDS category and less than 20% blasts in blood and bone marrow • Prominent myeloproliferative features • No preceding history of MPN or MDS, no recent cytotoxic or growth factor therapy • No BCR-ABL or PDGFR or FGFR fusion and no isolated del(5q), chr 3 inversion or features of mixed MDS MPN and cannot be assigned MDS, MPN, or MDS/MPN category Prognosis and Treatment • Prognosis very poor • Allogeneic HSCT for eligible patients versus best supportive care GM-CSF, granulocyte–macrophage colony-stimulating factor; HSCT, hematopoietic stem cell transplantation; HMA, hypomethylating agent; PDGFR, platelet-derived growth factor receptor; WBC, white blood cell; WHO, World Health Organization.

C. Clonal hematopoiesis. Recent widespread utilization of genetic analyses has led to recognition of clonal somatic mutations in hematopoietic cells thought to be acquired with aging. There are five entities which must be differentiated from MDS (Table

32-15). Clonal hematopoiesis of indeterminate potential (CHIP) is defined by a variant allele frequency (VAF) greater than or equal to 2% on NGS of DNA in the presence of normal peripheral blood counts, less than 5% blasts and less than 10% dysplastic cells in any lineage. If CHIP criteria are met in a patient with cytopenia, then the disorder is classified as clonal cytopenia of undetermined significance (CCUS). If VAF is less than 2%, it is classified as aging-related clonal hematopoiesis (ARCH). Patients with unexplained cytopenias, less than 10% dysplastic cells per lineage, and absence of established clonality are classified as idiopathic cytopenia of undetermined significance (ICUS). Patients with dysplastic bone marrow features in the absence of cytopenia are termed idiopathic dysplasia of unknown significance (IDUS). As per a study conducted analyzing 683 patients with unexplained cytopenias for the presence of mutations in 40 genes recurrently mutated in myeloid malignancies, carrying one or more somatic mutations was associated with a hazard ratio of 13.9 for developing a myeloid neoplasm. Highest risk mutations are SF3B1, SRSF2, U2AF1, or specific co-mutation patterns such as DNMT3A, TET2, or ASXL1 in combination with other mutations. TABLE 32-15

NCCN Guidelines for Spectrum of Indolent Myeloid Hematopoietic Disorders

Feature

ICUS

IDUS

CHIP

CCUS

MDS

Somatic mutation

–

–

±

±

±

Clonal karyotypic abnormality

–

–

±

±

±

Marrow dysplasia

–

+

–

–

+

Cytopenia

+

–

–

+

+

Risk of progression to MDS or AML

Low

Low

0.5%–1% per year

High

N/A

Management

History taking, physical examination, and CBC every 3–6 mo. More frequent monitoring for high-risk mutations such as TP53, VAF ≥20%, ≥2 distinct mutations, and severity of cytopenias

AML, acute myeloid leukemia; CBC, complete blood count; CCUS, clonal cytopenia of undetermined significance; CHIP, clonal hematopoiesis of indeterminate potential; ICUS, idiopathic cytopenia of undetermined significance; IDUS, idiopathic dysplasia of unknown significance; MDS, myelodysplastic syndrome; NCCN, National Comprehensive Cancer Network; VAF, variant allele frequency.

VI. COMPLICATIONS AND SUPPORTIVE CARE Thrombocytopenia and neutropenia are less common than anemia in patients with MDS.

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I.

INTRODUCTION Chronic leukemias are malignancies of the myeloid or lymphoid hematopoietic lineages that have historically been characterized as having an indolent course when compared with their acute counterparts. Although the indolent nature of these diseases results in a relatively long median survival as compared with other cancers, chronic leukemias have not typically been considered curable, except in some cases following allogeneic hematopoietic cell transplantation (HCT). Here we review clinical features and current treatment approaches to the most common chronic leukemias, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL).

II. CHRONIC MYELOID LEUKEMIA A. Epidemiology. CML accounts for 15% of adult leukemias, with an annual incidence of 1.9 cases per 100,000 adults. The median age at presentation is 65 and the incidence increases with age. The etiology is unclear, with no correlation with monozygotic twins, geography, ethnicity, or economic status. However, a significantly higher incidence of CML has been noted in survivors of the atomic disasters at Nagasaki and Hiroshima, in radiologists, and in patients treated with radiation to the spine for ankylosing spondylitis. The prognosis of patients with CML has improved dramatically since the introduction of tyrosine kinase inhibitors (TKIs), and patients who achieve complete cytogenetic response (CCyR) within 2 years now have a life expectancy approaching that of the general population. B. Pathogenesis. Historically, CML was the first disease in which a specific chromosomal abnormality was linked to the pathogenesis of the disease: the foreshortened chromosome 22, named the Philadelphia (Ph) chromosome. Subsequently, the BCR-ABL1 fusion gene resulting from the common t(9;22)

translocation has been detected in 90% to 95% of patients with CML. This fusion of the BCR (breakpoint cluster region) serine kinase with the human homologue ABL1 of the Abelson murine leukemia virus oncogene results in constitutive tyrosine kinase activity of ABL and thereby dysregulated activity of multiple signal transduction pathways controlling cell proliferation and apoptosis. The protein product of the BCR-ABL1 fusion may also play a direct role in signals leading to independence from external growth signaling, cell adhesion modulation, and DNA repair. The remaining 5% to 10% of patients (designated “Ph-negative”) have either variant translocations involving one or more additional chromosomes or cryptic translocations of 9q34 and 22q11.2. In these individuals, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) is required to detect the BCR-ABL1 fusion gene. A related but distinct clinical entity is so-called “atypical CML,” which refers to patients who truly lack the BCR-ABL1 fusion gene. Patients with this myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndrome may show mutations in genes including colony stimulating factor 3 receptor (CSF3R) and set-binding protein 1 (SETBP1) among others. Atypical CML is associated with advanced age at presentation and poorer prognosis relative to BCR-ABL1-positive (“typical”) CML. For this chapter, we will focus only on BCRABL1-positive CML. C. Clinical and laboratory features. CML is diagnosed incidentally in a significant proportion of patients (20% to 50%). Symptoms typically result from concurrent anemia and splenomegaly and may include fatigue, early satiety, the sensation of abdominal fullness, and weight loss; bleeding or bruising can be seen in advanced disease. Leukocytosis with a myeloid shift is universal. In contrast to acute leukemia, where a maturation arrest is the rule, granulocytes in all stages of maturation are observed on the peripheral smear. Anemia and thrombocytosis are common and basophilia (more than 7%) occurs in 10% to 15% of patients. Leukocyte alkaline phosphatase activity is usually reduced, in contrast to reactive leukocytosis where it tends to be elevated or normal, but can be increased with infections, stress, on achievement of remission, or on progression to blast phase (BP). The Ph chromosome t(9;22)(q34.1;q11.21) can be detected on conventional karyotyping in roughly 95% of cases. In the approximately 5% of patients lacking the Ph chromosome, the BCR-ABL fusion gene can be detected by FISH or PCR. Three common variants of BCR-ABL1 may arise depending on the exact breakpoint in the BCR gene: p210BCR-ABL1 (present in the majority of patients with CML), p190BCRABL1 (more common in Ph-positive acute lymphoblastic leukemia but also present in a minority of patients with CML), and p230BCR-ABL1 (rare in typical CML). The bone marrow is typically hypercellular with all stages of myeloid differentiation represented, suggesting that chronic phase (CP) CML is a disease of discordant

maturation where a delay in myeloid maturation results in increased myeloid cell mass. D. Natural history. The natural history of CML is a triphasic process: CP, accelerated phase (AP), and BP. Most patients present in CP characterized by an asymptomatic accumulation of differentiated myeloid cells in the bone marrow, spleen, and peripheral blood. Without therapy, CML patients almost invariably progress from CP to AP and ultimately into BP, though some patients in CP evolve directly into BP. In patients treated with first-line imatinib on the IRIS (International Randomized Study of Interferon vs. STI-571) trial, the risk of progression to AP or BP at 10 years was approximately 8% (N Engl J Med 2006;35:2408). AP and BP CML are characterized by progressive maturation arrest, cytogenetic evolution, and lack of response to therapy. Several definitions have been proposed relying on a combination of clinical and pathologic features (Table 33-1). The World Health Organization (WHO) and Center for International Blood & Marrow Transplant Research (CIBMTR) criteria categorize patients with 10% to 19% peripheral blood or bone marrow blasts as AP and greater than or equal to 20% as BP, whereas the Modified MD Anderson Cancer Center (MDACC) criteria categorize patients with 15% to 29% peripheral blood blasts as AP and greater than or equal to 30% as BP. Although blasts express myeloid markers in more than half of the cases, a significant proportion express lymphoid lineage markers or show an undifferentiated or mixed-lineage phenotype. BP is characterized by cytogenetic evolution in approximately 70% of patients. The most common chromosomal abnormalities are trisomy 8, trisomy 19, duplication of the Ph chromosome, and isochromosome 17. Acquisition of mutations in RUNX1, ASXL1, IKZF1, CDKN2A, and TP53 has been associated with progression to BP as well. As with de novo acute myelogenous leukemia (AML), complex cytogenetics are associated with decreased response rates and survival. Once accelerated or BP occurs, the success of any therapy declines dramatically. TABLE 33-1

Accelerated phase

Definitions of Accelerated and Blast Phase Chronic Myeloid Leukemia WHO Classification

Modified MDACC Criteria

CIBMTR Criteria

PB or BM blasts 10%–19%

PB blasts 15%–29%

PB or BM blasts 10%–19%

PB basophils ≥20%

PB basophils ≥20%

PB basophils ≥20%

Platelets 35%–65% Ph-positive metaphases

Major molecular response (MMR)

BCR-ABL1 (IS) ≤0.1% in peripheral blood

MMR 4.0

BCR-ABL1 (IS) ≤0.01% in peripheral blood

MMR 4.5

BCR-ABL1 (IS) ≤0.0032% in peripheral blood

Complete molecular response (CMR)

BCR-ABL1 transcripts below limit of detection in peripheral blood

CBC, complete blood count.

This term is falling out of favor as it can indicate varying levels of response depending on assay characteristics.

F. Treatment of CML: TKIs 1. Imatinib mesylate. Imatinib is a targeted TKI which antagonizes the activity of the ABL tyrosine kinase as well as c-KIT and platelet-derived growth factor receptor (PDGFR). At nanomolar concentrations, imatinib binds to the adenosine triphosphate (ATP)-binding pocket of the BCR-ABL fusion protein while in the inactive conformation, resulting in competitive inhibition. This nearly completely abolishes autophosphorylation of BCR-ABL and inactivates dysregulated downstream signaling through multiple pathways including JAK-STAT, phosphoinositide 3-kinase (PI3K), RAS, AKT, and ERK, thereby specifically inhibiting the growth of BCR-ABL1-positive bone marrow progenitor cells. In the phase III IRIS trial, an initial dose of 400 mg once daily followed by escalation to 400 mg twice daily dosing if needed resulted in 98% CHR and 87% CCyR rates at 60 months with an estimated 5-year overall survival (OS) of 89% (N Engl J Med 2006;355:2408). Higher dosing schedules of 600 and 800 mg have not been associated with improved survival outcomes. Side effects of imatinib are generally mild and include hematologic suppression (neutropenia, thrombocytopenia, and anemia), constitutional symptoms, diarrhea, edema, rash, hypophosphatemia, and rare organ damage (transaminitis and cardiotoxicity). These can usually be managed with growth factors or dose reduction but occasionally require temporary or permanent discontinuation. 2. Imatinib resistance. Resistance to imatinib has been noted in 2% to 4% of patients annually for the first 3 years of imatinib therapy and may decrease thereafter. Mechanisms proposed include the acquisition of point mutations in BCR-ABL1, overexpression of BCR-ABL1, activation of BCR-ABL1-independent pathways including SRC kinases, increased imatinib efflux through the multidrug resistance (MDR) pump, and progressively abnormal cytogenetics. Most reported point mutations are thought to act by either decreasing the affinity for imatinib binding in the ATP-binding pocket or shifting the kinetics of BCR-ABL1 to prefer the active conformation, which will not bind imatinib. Mutations have also been found in untreated CP patients, suggesting they may exist before treatment and are slowly selected out during therapy. Imatinib resistance can be overcome either with increasing doses or with the use of a second-generation TKI. Secondgeneration TKIs are effective in the setting of most mutations excluding T315I, which imparts a high degree of resistance to all currently available TKIs with the exception of ponatinib. Mutational analysis is therefore critical in selection of therapy when resistance is detected. 3. Second-generation TKIs. Several more potent TKIs have been developed since the initial introduction of imatinib. Careful attention to potential drug interactions is important when treating patients with these agents. Both imatinib and the

second-generation TKIs are metabolized by the CYP3A4 system and can also affect other cytochrome P450 enzymes. Proton pump inhibitor (PPI) therapy can impair the absorption of second-generation TKIs. This effect is most pronounced with dasatinib but is also seen with the other second-generation TKIs and concomitant administration of PPIs should be avoided. Both imatinib and the second-generation TKIs are contraindicated in pregnancy and breastfeeding. a. Dasatinib. Dasatinib is a potent inhibitor of ABL tyrosine kinase but also inhibits SRC family kinases, c-KIT, EPHA2, and PDGFRβ. In the phase III DASISION trial, first-line therapy for CP CML with dasatinib 100 mg daily produced faster and deeper response rates than imatinib. However, so far, no survival advantage has been demonstrated with the use of dasatinib over imatinib as first-line therapy in CP CML (J Clin Oncol 2016;34:2333). Dasatinib has also shown excellent response rates as a second-line agent in CP CML patients otherwise intolerant or resistant to imatinib. Overall, dasatinib is well tolerated with easily manageable cytopenias and diarrhea. Pleural effusion is a relatively common side effect and tends to be more common in patients with AP CML, prior cardiac history, hypertension, and those receiving higher doses of dasatinib (70 mg twice a day vs. 100 mg once daily). Pulmonary hypertension has been rarely reported as well. b. Nilotinib. Nilotinib is a highly potent inhibitor of ABL tyrosine kinase and also inhibits other tyrosine kinases including c-KIT and PDGFR, but unlike dasatinib, it has no activity against SRC family kinases. At a dose of 300 mg twice daily, patients achieve faster and deeper responses compared with imatinib. Nilotinib 300 mg twice daily was associated with decreased risk of progression to AP or BP compared to imatinib, although without survival improvement in the randomized ENESTnd trial (Leukemia 2016;30:1044). In addition to the common adverse effects including nausea, vomiting, diarrhea, and myelosuppression, nilotinib has been associated with significant QTc prolongation in some patients leading to a black box warning in its labeling from the Food and Drug Administration (FDA). It is therefore important to correct any electrolyte abnormalities prior to initiation of nilotinib and to monitor electrolytes and QTc periodically and after any dose modifications. Long-term data have also revealed an increased incidence of cardiovascular toxicities with nilotinib suggesting caution in those with underlying cardiovascular disease or associated risk factors. c. Bosutinib. Bosutinib has activity against BCR-ABL and SRC family kinases, but minimal activity against c-KIT and PDGFR. As first-line therapy in CP CML, bosutinib 500 mg daily led to faster and somewhat deeper responses compared to imatinib in the BELA trial (J Clin Oncol 2012;30:3486). Similar

results were seen with bosutinib 400 mg daily and this dose is currently preferred to minimize toxicity. As with the use of other second-generation TKIs, no survival advantage relative to imatinib has been demonstrated. Overall, bosutinib has a favorable toxicity profile with only minimal effect on QTc. Diarrhea and abnormal liver function tests are the most common nonhematologic side effects. d. Ponatinib. Ponatinib is a potent TKI with activity against a wide range of tyrosine kinases and is the only FDA-approved TKI active against the T315Imutant forms of the ABL1 tyrosine kinase. In patients with CP CML with resistance (including T315I mutations) or intolerance to prior TKI therapy treated on the phase II PACE trial, ponatinib 45 mg daily induced a major cytogenetic response (MCyR) in 60% and a major molecular response (MMR) in 40% of patients (Blood 2018;132:393). The probability of maintaining MCyR at 5 years for responders was 82% and the estimated 5year OS was 73%. The most common adverse effects were rash, abdominal pain, thrombocytopenia, headache, dry skin, and constipation. Importantly, the rates of arterial occlusive events and venous thromboembolic events were 31% and 6%, respectively. The risk of arterial events was increased in patients with established cardiovascular risk factors. Ponatinib is currently approved at a dose of 45 mg daily for adult CML patients harboring the T315I mutation and for patients where all other TKIs have failed. In addition to thromboembolic events, ponatinib also carries a black box warning for heart failure and liver toxicity. Patients being treated with ponatinib need to be closely monitored for thromboembolic events, and despite lack of evidence for its efficacy, some clinicians now advise concomitant low-dose aspirin barring any contraindications. 4. Selection of initial TKI. Imatinib 400 mg daily, dasatinib 100 mg daily, nilotinib 300 mg twice daily, and bosutinib 400 mg daily are all approved as first-line therapy for CP CML. Although the second-generation TKIs typically yield faster cytogenetic and molecular responses, an improvement in OS relative to imatinib has not been demonstrated in randomized trials. Second-generation TKIs are also associated with reduced risk of progression to AP and BP, and should therefore be considered in patients with intermediate or high-risk Sokal or Hasford scores where the baseline risk of progression is higher. Upfront use of secondgeneration TKIs might also be preferred in younger patients including female patients who desire pregnancy, as early achievement of MMR could permit a trial of TKI discontinuation. G. Discontinuation of TKI therapy. Although continuation of TKI therapy until progression or intolerance remains the standard of care, emerging data suggest that a

select group of patients with CP CML may safely discontinue TKI therapy. The first study to address this issue was the Stop Imatinib (STIM1) trial, which enrolled 100 patients with CP CML who had achieved undetectable minimal residual disease (MRD) on imatinib for at least 2 years (as assessed on qPCR with sensitivity of greater than or equal to 4.5-log reduction from standardized baseline) (J Clin Oncol 2017;35:298). With a median follow-up of 77 months after imatinib discontinuation, the molecular recurrence-free survival was 43% at 6 months and 38% at 60 months. Fifty-five of 57 patients who resumed TKI therapy after molecular recurrence achieved a second MRD-negative state. Similar data are now available for dasatinib and nilotinib (Blood 2017;129:846). The depth and duration of molecular response on TKI therapy have consistently been shown to predict the risk of molecular relapse during treatment-free intervals. Consensus guidelines recommend consideration of a treatment-free interval only if all of the following criteria are met: (a) age greater than or equal to 18 years, (b) CP CML with no history of AP or BP, (c) on approved TKI for at least 3 years, (d) attainment of MR4 (BCR-ABL1 ≤0.01% IS) for greater than or equal to 2 years documented on at least four tests performed at least 3 months apart, (e) access to reliable qPCR with sensitivity of at least MR4.5 (BCR-ABL1 ≤0.0032% IS) with turnaround time less than or equal to 2 weeks, (f) willingness to comply with close monitoring including monthly qPCR for at least the first year, and (g) immediate resumption of TKI in the setting of loss of MMR (MR3, or BCR-ABL1 ≤ 0.1% IS). H. Conventional chemotherapy. Until 1980, hydroxyurea and busulfan were the two most effective anti-CML agents. Both offer mild hematologic control associated with myelosuppression but without affecting the uniform transformation to the acute phase of the disease. Subsequently, interferon alpha used alone or in combination with cytarabine has demonstrated improved response over chemotherapy with MCyRs in 40% to 50% of patients, with up to 80% of these patients achieving a durable response resulting in a 10-year survival of 75%. However, interferon alpha therapy is complicated by significant side effects including flu-like symptoms, anorexia, weight loss, depression, autoimmune disorders, thrombocytopenia, alopecia, rashes, and neuropathies, resulting in discontinuation in approximately a fifth of the patients. Given the superior response to TKIs and their relatively benign side effect profile, conventional chemotherapy and interferon have fallen from common use in CML. There may be a limited role for interferon alpha during pregnancy, although data are limited to case reports. I. Role of allogeneic stem cell transplantation. The objective of allogeneic stem cell transplantation (SCT) is cure of CML by eradication of the leukemic clone with conditioning chemotherapy and restoration of hematopoiesis by transplantation of normal donor-derived stem cells. In addition, the donor-derived allogeneic immune

cells confer an important graft-versus-leukemia (GVL) effect, which acts to prevent recurrence of disease. The potential efficacy of the GVL effect in CML is supported by retrospective studies in the pre-TKI era demonstrating a much higher relapse rate after syngeneic vs HLA-matched sibling transplants (3-year relapse rate 40% vs. 7% in one study). Furthermore, patients with relapse after allogeneic transplant can frequently regain durable molecular remission after donor lymphocyte infusions. Although allogeneic transplantation was previously an important treatment modality for CP CML, the role of SCT is much more limited since the advent of TKIs. Allogeneic transplantation should be considered for the rare patients in CP who are intolerant of, or resistant to, all available TKIs or those with AP or BP CML. Transplantation from a matched sibling donor during CP is associated with a 10-year survival of 50% to 70%. Despite the cure achieved in many CML patients treated with transplant, the associated morbidity and mortality remain a significant problem. The cumulative incidence of severe graft-versus-host disease (GVHD) is approximately 20% to 35% in matched sibling transplantation and 40% to 55% in recipients of transplants from unrelated donors. Infection is a major cause of nonrelapse mortality in allogeneic transplantation as well. Allogeneic SCT is an important component of therapy for patients with AP and BP CML as described later. Relapse following SCT has been successfully treated with both donor lymphocyte infusion and tyrosine kinase inhibition. Mutational analysis of ABL kinase domain may help guide appropriate therapy choice. J. Treatment of AP and BP CML. Despite profound advances in the treatment of CP CML, outcomes of patients with AP and BP CML remain suboptimal. All patients should undergo BCR-ABL1 mutational analysis with early consideration for allogeneic SCT or a clinical trial. There are no randomized trials comparing upfront allogeneic SCT with TKI in AP CML, but retrospective data suggest better progression-free survival (PFS) and OS with transplantation. Presentation with de novo AP is associated with a better prognosis than progression from CP to AP while receiving a TKI, and transplantation might reasonably be deferred in this population if MMR to TKI therapy is achieved. For those with progression from CP to AP while on TKI therapy, however, transplantation should be considered the standard of care. Retrospective analyses have shown that outcomes are better if patients can be brought into a second CP prior to transplantation; therefore, TKI-based therapy is usually initiated while transplant evaluation is ongoing. The choice of TKI should be guided by BCR-ABL1 mutation analysis and treatment history. Although high-quality evidence is lacking, most providers treat with a second-generation TKI based on extrapolation from studies in CP CML where second-generation TKIs produced faster and deeper responses. Omacetaxine is another option for patients with AP CML irrespective of BCR-ABL1 mutation status. Data are lacking regarding the

optimal therapy for patients with AP who are not transplant candidates because of age or underlying comorbidities. Treatment with a second-generation TKI until progression or intolerance is usually pursued despite the usually poor outcomes. Treatment of BP CML remains a challenge and all patients should be considered for clinical trials. Patients are typically treated with a second-generation TKI in combination with either AML-type induction chemotherapy (for myeloid BP) or ALL-type chemotherapy (for lymphoid BP), with the choice of TKI again dictated by BCR-ABL1 mutation analysis. All patients should be evaluated for allogeneic SCT with the goal of induction therapy being conversion to CP prior to transplant. Central nervous system (CNS) involvement has been reported in patients with lymphoid BP and evaluation for CNS involvement as well as CNS prophylaxis should be considered. Dasatinib has been shown to cross the blood–brain barrier and might be a preferred TKI in this setting. Data from patients transplanted in CP suggest that TKI therapy after transplantation may prolong relapse-free survival, and continuation of TKI posttransplantation should be strongly considered for patients transplanted in AP or BP, particularly for those who underwent reduced-intensity conditioning. III. CHRONIC LYMPHOCYTIC LEUKEMIA A. Epidemiology. CLL is the most common form of leukemia in adults, accounting for approximately 30% of adult leukemias in the United States. According to the Surveillance, Epidemiology, and End Results (SEER) cancer database, approximately 20,700 new cases are diagnosed and 3,900 deaths are attributed to CLL each year in the United States (2019 estimates). The estimated prevalence in 2016 was approximately 178,000. The median age at diagnosis from 2012 to 2016 was 70, with approximately 11% of patients diagnosed at age 55 or younger. Monoclonal B lymphocytosis (MBL), defined as the presence of circulating monoclonal B lymphocytes with a typical CLL immunophenotype numbering less than or equal to 5,000/µL, can be detected in approximately 3.5% of normal healthy control subjects, with prevalence increasing with age. It is now generally accepted that MBL precedes the development of CLL, but only a minority of individuals with MBL eventually develop the disease. The Veteran’s Administration (VA) classifies CLL as an Agent Orange presumptive disease indicating a strong epidemiologic association between Agent Orange exposure and development of CLL. Other environmental and occupational risk factors have thus far not been reliably demonstrated and patients who are exposed to radiation do not appear to have an increased risk. Interestingly, the incidence of CLL is much lower (10% of that of Western countries) in Asian countries such as China and Japan, which is attributed to genetic rather than environmental factors. CLL, MBL, and other lymphoproliferative disorders occur at a higher than predicted frequency among first-degree relatives of patients with CLL, suggesting a subset of patients have inherited risk factors. Studies

of familial cohorts with CLL are ongoing and identification of genes involved in familial CLL may provide insights into the pathogenesis of this disease. B. Pathogenesis. CLL is a clonal lymphoproliferative disorder characterized by the accumulation of neoplastic, functionally incompetent B lymphocytes in the blood, bone marrow, lymph nodes, spleen, or other organs. After encountering antigen, a normal B cell enters the germinal center and proliferates where the B-cell receptor genes undergo somatic hypermutation. This process allows for B-cell receptor affinity maturation and selection of B-cell clones with high affinity for the antigen. Despite their uniform morphologic appearance and immunophenotype, there appears to be significant heterogeneity in CLL clones with regard to the mutational status of the immunoglobulin (Ig) heavy chain variable region (IGHV), which usually indicates whether the B cell has experienced somatic hypermutation in the germinal center. In CLL, approximately half of patients have a mutated IGHV (M-IGHV) indicative of a post-germinal center B cell, whereas other patients have an unmutated IGHV (UM-IGHV), a finding that has prognostic significance. The precise normal counterpart(s) of CLL cells during B-cell development has not been definitively identified. However, the CLL immunophenotype is similar to that of mature, antigenexperienced, activated B cells. Recent gene expression array experiments indicate that both M-IGHV and UM-IGHV CLL cells resemble memory B cells more than any other identified normal B-cell subset. The B-cell receptors of CLL cells are also characterized by a limited Ig repertoire with preferential usage of a subset of available heavy and light chain variable regions, suggesting a role for antigen exposure in the pathogenesis of this disease. Further advances in defining the relationship between CLL cells and normal B-cell development may yield novel therapeutic targets in CLL. Unlike many hematologic malignancies, CLL cells do not contain balanced chromosomal translocations detectable using traditional cytogenetic techniques. However, FISH technology has identified recurrent chromosomal abnormalities in approximately 80% of CLL cases. The most common cytogenetic abnormalities in CLL are del(13q14), del(11q), trisomy 12, and del(17p), which influence prognosis (Table 33-3). The gene(s) involved in 13q14 deletion have not been definitively identified. Two micro-RNAs (miR-15, miR-16) have been mapped to the 13q locus and are potential candidates for mediating the effects of this deletion in CLL. Del(11q22-23) encompasses the ataxia telangiectasia mutated (ATM) gene locus, and mutations in the ATM gene have been observed in CLL, suggesting that ATM is the target of this deletion. Similarly, del(17p) encompasses the TP53 tumor suppressor gene, and point mutations or deletions of TP53 are also present in CLL patients with poor prognosis, suggesting TP53 is the target gene in del(17p) CLL patients. The gene(s) important for trisomy 12 effects have not been identified. Approximately

95% of CLL clones demonstrate increased expression of the anti-apoptotic Bcl-2 oncogene, and 70% have expression levels equivalent to follicular lymphoma cells harboring t(14;18). CLL cells use other mechanisms to increase Bcl-2 expression, and do not typically contain the classic t(14;18) present in follicular lymphoma. Recent genome sequencing studies have defined recurrent somatic mutations in CLL patients. These genes affect common pathways including DNA damage and cellcycle control (ATM, TP53), Notch signaling (NOTCH1, FBXW7), RNA splicing (SF3B1, DDX3X), and cytokine/toll-like receptor signaling (MYD88, MAPK1). Of these, TP53 mutations affect about 10%, NOTCH1 mutations affect about 10%, and SF3B1 mutations affect 10% to 15% of CLL patients, and all confer an independent poor prognosis. Furthermore, substantial clonal heterogeneity exists in CLL patients, and ongoing research is studying how CLL subclonal architecture affects, and is in turn influenced by, anti-CLL therapy. TABLE 33-3

Prognostic Factors in Chronic Lymphocytic Leukemia

Favorable

Unfavorable

Low Rai or Binet clinical stage

High Rai or Binet clinical stage

Lymphocyte doubling time >12 mo

Lymphocyte doubling time 10

30

I

LN

9

35

II

Splenomegaly

7

25

III

Anemia

5

7

IV

Thrombocytopenia

5

3

A

Lymphocytosis, 10

65

B

Lymphocytosis, >3 areas of LN

7

30

C

Anemia, thrombocytopenia, or both

5

5

Rai

Binet

LN, lymph node enlargement.

Certain cytogenetic abnormalities also have prognostic significance in CLL. Del(13q) is considered a favorable prognostic finding whereas del(11q) and del(17p) indicate a poorer prognosis (N Engl J Med 2000;343:1910). The 17p region harbors the TP53 gene, and patients whose clones demonstrate TP53 mutations have been shown to have similarly poor responses to conventional chemoimmunotherapy as those with del(17p). Nevertheless, the poor prognosis associated with del(17p) and TP53 mutations may be partially offset by use of newer molecular targeted therapies. Next generation sequencing has identified additional mutations that may inform prognosis including NOTCH1 and SF3B1, but testing for these aberrations has not yet been incorporated into standard clinical practice. Composite prognostic indices, such as the German CLL Study Group prognostic score and the CLL-International Prognostic Index (IPI), have also been proposed and incorporate factors including cytogenetics, β2-microglobulin levels, IGHV mutation status, age, and Eastern Cooperative Oncology Group (ECOG) score to predict OS. Recently, measurement of MRD by flow cytometry has emerged as an important prognosticator of PFS and OS both during and at completion of therapy (Table 33-3). E. Complications associated with CLL 1. Richter syndrome. Richter syndrome (RS) refers to the development of an aggressive lymphoma in a patient with prior or concomitant diagnosis of CLL/SLL. RS occurs in 2% to 8% of CLL patients. The histology of the aggressive lymphoma resembles diffuse large B-cell lymphoma (DLBCL) in the majority of cases. The molecular pathogenesis of RS remains poorly understood.

Importantly, the DLBCL RS variant is characterized by a spectrum of genetic lesions distinct from those commonly seen in de novo DLBCL and CLL, with high frequency of defects in TP53, NOTCH1, MYC, and CDKN2A. Furthermore, although expression of programed cell death protein 1 (PD-1) is uncommon in CLL and de novo DLBCL, up to 80% of DLBCL-variant RS clones express this protein. The malignant clone in RS develops through transformation of the original CLL clone in approximately 80% of cases, whereas it arises as an independent neoplasm in approximately 20%. This distinction is clinically important, because patients with clonally unrelated RS/DLBCL have a superior prognosis relative to patients in whom RS/DLBCL arises from transformation of the underlying CLL (median OS of 62.5 months for clonally unrelated cases vs. 14.2 months for clonally related cases in one retrospective series). RS is suspected clinically in patients with CLL/SLL with rapidly enlarging lymph node groups, rapidly progressive splenomegaly or hepatomegaly, elevated LDH, new B symptoms, or a sudden decline in performance status. Patients with suspected RS should have a tissue biopsy to confirm the diagnosis. Positron emission tomography–computed tomography (PET-CT; with threshold SUV ≥5) is relatively sensitive (~90%) and specific (~80%) for detection of RS and can be used to guide biopsy site. The clonal relationship to the underlying CLL should be determined when possible. Given the relatively poor prognosis of clonally related RS, patients should be considered for clinical trials when available. In the absence of clinical trials, treatment usually involves aggressive combination chemotherapy as used in de novo DLBCL. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) yielded a response rate of 67%, a median PFS of 10 months, and a median OS of 21 months in one phase II study. For responding patients, autologous or reduced-intensity allogeneic stem cell transplant in first complete remission (CR) is preferred. Targeted therapies including ibrutinib, venetoclax, pembrolizumab, and nivolumab have also shown efficacy in early phase studies and warrant further investigation. 2. Autoimmune complications. Autoimmune phenomena are common in CLL and include autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), autoimmune neutropenia, and pure red cell aplasia (PRCA). There is also some evidence that AIHA and less commonly ITP can be triggered by treatment with purine analogs, though other reports have not validated this finding. In CLL patients with isolated anemia, testing should include review of peripheral smear, DAT testing, LDH, haptoglobin, and reticulocyte count, with consideration for other studies including iron panel and bone marrow biopsy if initial testing is unrevealing. Notably, a significant proportion of cases of CLL-associated AIHA

may have a negative direct antiglobulin test. The differential diagnosis of thrombocytopenia in CLL includes bone marrow infiltration, splenic sequestration, and treatment effects as well as secondary ITP. First-line treatment of AIHA and ITP in CLL patients is similar to the approach in non-CLL patients, typically with steroids and/or intravenous immunoglobulin (IVIG). If the autoimmune complication is not responsive to initial therapy, treatment of the underlying CLL may prove effective. 3. Infectious complications. The immune deficiency associated with CLL is multifactorial, and includes hypogammaglobulinemia, T and natural killer (NK) cell dysfunction, and decreased phagocytic function. Infectious complications are frequent and respond to appropriate antimicrobial therapy. For CLL patients with hypogammaglobulinemia (IgG 70 g/L) to stratify patients into low-, intermediate-, and high-risk groups. Low-risk patients are less than 65 with zero or one risk factor, and have an 87% 5-year survival. Intermediate-risk patients are older than 65 or those with two risk factors. High-risk patients have more than two risk factors. Five-year OS for intermediate- and high-risk patients are 68% and 38%, respectively. D. Therapy. The goal of treatment is to limit symptoms and prevent end-organ damage. Treatment is directed at reducing serum viscosity and treating the underlying lymphoma. Notably, severe neurologic symptoms or intractable bleeding because of hyperviscosity is an oncologic emergency, requiring urgent plasmapheresis and chemotherapy to reduce circulating IgM levels. Rituximab may cause an initial IgM flare, and patients with high IgM levels (>5 g/dL) should be cytoreduced with chemotherapy before rituximab is added to the regimen. Such regimens could be bortezomib-based or bendamustine-based regimens, which may be limited to a set number of cycles once disease is controlled. Ibrutinib, a Bruton tyrosine kinase

(BTK) inhibitor, is now approved as monotherapy or in combination with rituximab with efficacy upfront and in the relapsed setting, especially those with the MYD88 mutation with wild-type CXCR4. Ibrutinib is generally continued until disease progression or unacceptable toxicity. Nucleoside analogs (fludarabine, pentostatin, and cladribine) and alkylator-based regimens have activity, but may promote myelodysplasia or transformation to an aggressive lymphoma. Autologous stem cell transplantation is an option for eligible patients who have relapsed and refractory disease. Alkylating agents should be avoided in those in whom stem cell transplantation may be considered. V. POEMS SYNDROME (POLYNEUROPATHY, ORGANOMEGALY, ENDOCRINOPATHY, M PROTEIN, AND SKIN CHANGES) POEMS syndrome is a rare disorder with variable symptoms. Patients most often present in the fifth to sixth decade of life with stocking-glove numbness, paresthesias, weakness, fatigue, or other nonspecific symptoms. Diagnosis is based on the Mayo clinic criteria, requiring the presence of a monoclonal protein (virtually always λ restricted) and a polyneuropathy, which often begins as sensory and progresses to a motor chronic inflammatory demyelinating polyneuropathy; however, autonomic neuropathy does usually occur in POEMS. In addition to these necessary features, diagnosis depends on the presence of at least one major and one minor criterion. Major criteria include Castleman disease, osteosclerotic bone lesions, and elevated serum vascular endothelial growth factor (VEGF) levels (3 to 4 times the upper limit of normal). Minor criteria include organomegaly, endocrinopathy, skin changes, papilledema, thrombocytosis, polycythemia, or volume overload. Osteosclerotic bone lesions are the most common major criteria, occurring in 97% of cases, and diagnosis should proceed cautiously in their absence. Diabetes mellitus and gonadal dysfunction are the most frequent endocrinopathies in POEMS syndrome. Skin changes may include hyperpigmentation, hemangiomas, hair changes, or acrocyanosis. BM biopsy generally demonstrates less than 5% plasma cells. Radiation may be utilized for the treatment of limited disease, whereas more widespread involvement usually requires systemic treatment with myeloma-like regimens. Peripheral blood stem cell transplant following high-dose therapy has been successfully used and should be reserved for young patients with extensive disease or rapidly progressive neuropathy. The course of POEMS syndrome is indolent, with median survival of almost 14 years. SUGGESTED READINGS Bolli N, Biancon G, Moarii M, et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia 2018;32:2604–2616. Dispenzieri A. POEMS syndrome: 2019 update on diagnosis, risk-stratification, and management. Am J Hematol 2019;94:812–827. Dispenzieri A, Stewart AK, Chanan-Khan A, et al. Smoldering multiple myeloma requiring treatment: time for a new

definition? Blood 2013;122:4172–4181. Fakhri B, Vij R. Clonal evolution in multiple myeloma. Clin Lymphoma Myeloma Leuk 2016;16:S130–S134. Fermand J-P, Bridoux F, Dispenzieri A, et al. Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications. Blood 2018;132:1478–1485. Gertz MA. Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2018. Blood Cancer J 2018;8:44. Gertz MA. Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management. Am J Hematol 2019;94:266–276. Hillengass J, Usmani S, Rajkumar SV, et al. International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders. Lancet Oncol 2019;20:e302–e312. Kyle RA, Larson DR, Therneau TM, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med 2018;378:241–249. Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol 2020;38:1126–1137. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol 2015;33:2863–2869. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood 2016;127:2955–2962.

GENERAL CARE OF THE PATIENT WITH HIV AND CANCER I.

GENERAL Approximately 1.1 million people in the United States are living with human immunodeficiency virus (HIV) infection. Without treatment, HIV infection causes acquired immunodeficiency syndrome (AIDS). Cancer is 50% more common among HIV-infected individuals than the general public. A malignancy develops in about 20% of patients with HIV during their lifetime and is often the first clinical evidence of HIV infection. It is also responsible for 28% of AIDS patients’ deaths. The most common malignancies in this patient population are non-Hodgkin lymphoma (NHL) and Kaposi sarcoma (KS; AIDS-defining cancers in addition to cervical cancer), and lung cancer and anal carcinoma (non–AIDS-defining cancers). The incidence of other malignancies is also increased in HIV-infected patients, including Hodgkin lymphoma (HL), multiple myeloma, testicular tumors, hepatocellular carcinomas (HCCs), and childhood sarcomas. The frequency of non–AIDS-defining cancers has increased significantly over the last 15 years and has been attributed to expansion of the HIV-infected population and aging. Most of these malignancies are associated with oncogenic viruses, including Epstein– Barr virus (EBV), human herpesvirus-8 (HHV8), and human papilloma viruses (HPV). When CD4 cell counts drop below 200 cell/mL, HIV-infected patients tend to experience greater toxicity with chemotherapy. Dose modifications and dose delays are common in this setting. Often, personalized dose modifications in lower performance status patients may be chosen by treating physicians. Providers need to be cognizant of any drug–drug interactions of highly active antiretroviral therapy (HAART) with antitumor therapies as well as supportive medications. Regular discussions between medical oncologists, infectious disease specialists, and radiation and surgical oncologists are essential.

Maximizing nutritional status can assist in minimizing toxicity and accelerating recovery from therapy. Social work assistance is invaluable for these patients, who often have other financial, social, and personality difficulties. II. DIAGNOSTIC STUDIES FOR HIV INFECTION should be considered in patients who are not known to be HIV infected, but who develop a malignancy that occurs at increased frequency with HIV infection. Approximately one out of seven patients with HIV infection is unaware of the risk factors or denies their existence. HIV testing is recommended for all individuals presenting with aggressive B-cell lymphomas, KS, or anogenital carcinomas, as well as individuals with any malignancy who have higher than average risk for HIV (i.e., IV drug abusers, homosexuals or bisexuals, individuals with large numbers of sexual partners, and individuals from countries in Africa, Southeast Asia, or parts of the Caribbean where HIV is especially prevalent). The Centers for Disease Control and Prevention (CDC) recommends that all patients diagnosed with cancer who do not opt out should be tested for HIV if not already known to have documented HIV infection. Appropriate pre- and posttesting counseling services should be available for these individuals. The screening HIV test is an enzyme-linked immunosorbent assay (ELISA), which, if positive, is confirmed by Western blot or plasma HIV RNA assay. The rapid, point-of-care, HIV antibody tests are an acceptable alternative to the ELISA and are in wide use. If HIV is diagnosed concurrently with such a malignancy, additional clinical evaluation of their HIV infection may be indicated. Plasma HIV RNA and CD4 should be determined during the evaluation of HIVassociated malignancies. However, it is important to recognize that chemotherapy can cause wide fluctuations of the CD4 count that may not be an accurate measurement of the immune status. III. HAART will usually be recommended as concurrent therapy for the malignancy and, in some cases, prophylaxis for opportunistic infections (OIs). Although issues of drug interactions and excessive toxicity must be considered, there is now considerable evidence supporting the concurrent use of HAART in all HIV-1-infected individuals.> A. HAART regimens include the use of at least two or three antiretroviral agents with nucleoside- or nucleotide-reverse transcriptase inhibitors (zidovudine, lamivudine, abacavir, tenofovir, and emtricitabine) combined with non-nucleoside reverse transcriptase inhibitors (nevirapine, efavirenz, rilpivirine, doravirine, etravirine), protease inhibitors (PIs; ritonavir, saquinavir, amprenavir, lopinavir plus ritonavir, atazanavir, tipranavir, fosamprenavir, and darunavir), fusion or postfusion inhibitors (enfuvirtide, maraviroc, ibalizumab), or integrase inhibitors (raltegravir, dolutegravir, bictegravir, elvitegravir). Several nucleoside combination pills are available. A triple nucleoside regimen without a non-nucleoside or PI or integrase inhibitor or entry inhibitor is not appropriate. An undetectable viral load is the goal.

B. Benefits of HAART include a lower incidence of development of HIV-associated malignancies, especially primary central nervous system (CNS) lymphoma and KS. Moreover, with HAART the onset of malignancies in individuals is at a higher level of CD4, there is improved tolerance of full-dose chemotherapy, improved response rates and duration of responses, and improved survival during treatment of their malignancy. Pharmacokinetic studies have suggested that metabolism and clearance of several cytotoxic chemotherapeutic agents is not affected by HAART, but caution is still recommended when high doses of chemotherapy are utilized, for example, during stem cell transplantation studies. Several antivirals are inducers and/or inhibitors of cytochrome Cyp3A4, including PIs, cobicistat (boosts elvitegravir levels), and, to a lesser extent, non-nucleoside reverse transcriptase inhibitors. Thus, adverse interactions may occur with targeted chemotherapeutic agents that are Cyp3A4 substrates (e.g., dasatinib, imatinib, nilotinib, erlotinib, gefitinib, everolimus, sunitinib, sorafenib, and pazopanib). C. Specific recommendations for combining HAART with chemotherapy include avoiding the nucleoside analog zidovudine, in light of excessive neutropenia and anemia. Moreover, the PI atazanavir, which causes hyperbilirubinemia in almost onethird of patients, can also be problematic when anthracyclines or vinca alkaloids are utilized. Some authors have also suggested that HAART regimens, including PIs, may be associated with more myelosuppression when combined with chemotherapy than those lacking PIs, although this remains controversial. PIs commonly cause gastrointestinal (GI) toxicities. It should also be recognized that nucleoside inhibitors may cause lactic acidosis, abacavir may cause a multisystem hypersensitivity reaction, emtricitabine occasionally causes hyperpigmentation of the palms and soles, etravirine causes a rash, nevirapine may cause liver toxicity, and efavirenz is frequently associated with central nervous side effects. Tenofovir alafenamide is associated with less renal and bone toxicity compared with tenofovir disoproxil fumarate because it achieves lower tenofovir concentrations. Atazanavir, ritonavirboosted lopinavir, and saquinavir are associated with prolongation of the QT interval, as are anthracyclines, arsenic trioxide, dasatinib, lapatinib, nilotinib, sunitinib, lenvatinib, ivosidenib, vandetanib, selpercatinib, and tamoxifen. Therefore, because of the potential for sudden death, these combinations should be avoided. A welltolerated regimen for a HAART-naïve patient who will receive chemotherapy would be Biktarvy (bictegravir, tenofovir alafenamide, emtricitabine). D. Initiation of HAART therapy should be accompanied by liver function tests, amylase, and lipase as baseline values because several antiretrovirals can cause pancreatitis, an HIV genotype test to identify drug-resistant mutations, fasting glucose and lipid profile because PIs may cause dyslipidemias and glucose intolerance, serologic tests for syphilis, hepatitis A, B, and C viruses, toxoplasmosis,

cytomegalovirus (CMV), glucose-6-phosphate dehydrogenase testing in case dapsone will be needed, cervical Papanicolaou smear, ophthalmology examination, and anal and cervical screening for HPV if available, and tuberculin skin test, chest radiography, and an electrocardiogram because HIV may be associated with cardiomyopathy. Vaccinations for influenza, hepatitis A and B viruses, Streptococcus pneumoniae, and HPV (up to age 26) should also be considered. E. Optimal care of the HIV-infected patient should be done in collaboration with an infectious disease specialist. During active treatment, repeat HIV RNA levels should be assessed, and after completion of therapy, both HIV RNA and CD4 counts should be obtained. IV. PROPHYLAXIS FOR OIs is also indicated in individuals with depressed CD4 count. Because chemotherapy can also transiently affect the CD4 count, it has been suggested that OI prophylaxis recommendations be expanded in individuals receiving chemotherapy. Thus, if it is anticipated that the CD4 count will decline below 200/mm3, prophylaxis for Pneumocystis jiroveci pneumonia (PJP) is recommended with bactrim thrice weekly, or in allergic patients, dapsone or atovaquone. Prophylactic antivirals are recommended for individuals with a history of oral or anogenital herpes simplex virus infection. Antifungal prophylaxis is recommended for individuals with a history of mucosal candidiasis when CD4 count is less than 100/mm3. Mycobacterium aviumintracellulare (MAI) prophylaxis is no longer recommended for individuals with low CD4 counts who are receiving HAART. In individuals with prior OI, who have a CD4 count above these cutoff values and have discontinued prophylactic antibiotics, resumption of prophylactic antibiotics concurrent with chemotherapy may be indicated. Quinolone prophylaxis is recommended after aggressive chemotherapy in individuals with CD4 less than 100/mm3. Special attention is also recommended in evaluating possible clinical signs of OI in the HIV-positive patient receiving chemotherapy as follows: (1) any CD4 count: oral and esophageal candidiasis, mycobacteria including tuberculosis, bacterial pneumonias, histoplasmosis, or coccidioidomycosis, (2) CD4 less than 100: MAI, Toxoplasma encephalitis, and (3) CD4 less than 50: CMV retinitis, pneumonitis, or colitis, or progressive multifocal leukoencephalopathy. V. EVALUATION OF ANEMIA IN HIV-POSITIVE PATIENTS For patients with a malignancy, one should consider causes other than chemotherapy or antiretrovirals, and should also include other causes of decreased erythropoiesis including (1) drugs (e.g., trimethoprim-sulfamethoxazole, ganciclovir, and dapsone); (2) nutritional deficiency of iron, folate, or vitamin B12; (3) effects of uncontrolled HIV on bone marrow stromal cells; (4) OIs (e.g., parvovirus, atypical or typical mycobacteria, or histoplasmosis); and (5) preexisting conditions (e.g., sickle cell disease or thalassemia). Alternatively, causes of erythrocyte loss should also be considered, including (1)

hemolysis caused by thrombotic thrombocytopenic purpura, glucose-6-phosphate dehydrogenase deficiency, autoimmune hemolytic anemia, or drug-induced hemolysis; (2) GI bleeding that may complicate lymphoma, KS, or enteric infections caused by CMV, Candida, or parasites; and (3) hypersplenism associated with infection, lymphoma, or cirrhosis that may complicate hepatitis B or C virus infections. VI. EVALUATION OF NEUTROPENIA IN HIV-POSITIVE PATIENTS For patients with a malignancy, one should consider causes other than chemotherapy or antiretrovirals. These include causes of decreased myelopoiesis from drugs (e.g., ganciclovir, trimethoprim-sulfamethoxazole, pentamidine, rifabutin, and dapsone), nutritional deficiencies (e.g., folate or vitamin B12 deficiency), infections (e.g., uncontrolled HIV, atypical or typical mycobacteria, histoplasma), or bone marrow involvement by the malignancy (e.g., lymphoma, multiple myeloma). Increased loss of neutrophils may occur with autoimmune neutropenia or hypersplenism. Granulocyte colony-stimulating factor (G-CSF) has been shown to be safe and effective in HIVinfected patients, although there is controversy about the use of granulocyte–macrophage colony-stimulating factor (GM-CSF), which can potentiate HIV replication in macrophages. VII. EVALUATION OF THROMBOCYTOPENIA IN HIV-POSITIVE PATIENTS For patients with a malignancy, one should consider causes other than chemotherapy or antiretrovirals. Causes of decreased thrombopoiesis include (1) drugs (e.g., trimethoprim-sulfamethoxazole, pyrimethamine, ganciclovir, fluconazole, and clarithromycin), (2) nutritional deficiency (e.g., folate or vitamin B12), (3) infection (e.g., uncontrolled HIV, mycobacteria, histoplasma, or Bartonella henselae), or (4) bone marrow involvement by lymphoma. Causes of decreased platelet survival include (1) immune thrombocytopenic purpura from HIV infection or autoimmune conditions, (2) thrombotic thrombocytopenic purpura, or (3) hypersplenism. VIII.CANCER SCREENING AND PREVENTION IN HIV-POSITIVE PATIENTS HIV-positive individuals should receive the same cancer screening procedures as HIVnegative individuals, including procedures for early detection of lung, prostate, breast, colon, and cervical cancers. However, it is noted that there is limited information on the sensitivity and specificity of these procedures in this population. Current studies are examining the role of low-dose computed tomography (CT) screening for HIV-positive individuals with significant tobacco use histories. HIV-positive individuals have a higher rate of tobacco use than HIV-negative individuals (50% vs. 20%, respectively), and should be strongly encouraged to participate in a smoking cessation program. Other studies are examining the role of high-resolution anoscopy in individuals who have anal intercourse.

AIDS-ASSOCIATED DIFFUSE LARGE B-CELL LYMPHOMAS (DLBCL) I.

CLINICAL PRESENTATION A. NHLs are 7- to 23-fold more frequent in HIV-positive individuals than the general population, and occur in 5% to 10% of HIV-infected individuals. HIV-DLBCL accounts for about 2% of all DLBCL cases in the United States. AIDS-associated lymphomas are generally aggressive B-cell malignancies that present at an advanced stage with extranodal involvement in more than two-thirds of individuals. DLBCL accounts for 75% of NHLs in HIV-positive individuals. B. Pertinent history should include performance status, duration of HIV infection, treatment of OIs, and current antiretroviral regimen. C. B symptoms, such as fever, night sweats, and weight loss in excess of 10% of the normal body weight, are very common, but should be attributed to AIDS-associated lymphoma only after the exclusion of OIs. Extreme fatigue from anemia caused by bone marrow involvement may be seen. D. Lymph node enlargement may be asymptomatic or associated with pain or obstructive symptoms. This should be differentiated from persistent generalized lymphadenopathy (PGL) because of HIV replication or other AIDS-related OIs. Splenomegaly is commonly present and may be related to the cause of lymphadenopathy. E. GI involvement causing anorexia, nausea, vomiting, hemorrhage, change in bowel habits, or obstruction occurs in 10% to 25% of patients. Jaundice and abdominal discomfort may be due to lymphomatous hepatic or pancreatic involvement. F. CNS or meningeal involvement resulting in seizures, altered mental status, and neurologic defects occurs in 10% to 30% of patients. Other causes of neurologic defects in this patient population should also be considered, such as HIV-associated encephalopathy. G. Pleural or pericardial effusions may cause dyspnea and chest discomfort. H. The physical examination should include careful examination and measurements of enlarged lymph nodes, spleen, and liver. Pulmonary and cardiac examinations may reveal pleural or pericardial effusions. A thorough neurologic examination should be done to determine the presence of meningismus or focal neurologic defects.

II. DIAGNOSTIC WORKUP AND STAGING A. Pathology. Definitive diagnosis of AIDS-associated NHL is made with the identification of lymphoma in lymph node biopsies or other tissues (bone marrow, cerebrospinal fluid [CSF], pleural fluid, and liver), in an HIV-infected individual. For lymph node biopsies, multiple core-needle biopsies or excisional biopsies are

preferred to allow for evaluation of the nodal architecture. DLBCL is characterized by large noncleaved cells with a diffuse growth pattern. They usually express cell surface pan-B-cell marker, CD20, and lymphocyte common antigen, CD45, but not CD3. The transcription factor BCL-6 is expressed in the centroblastic subtype but not the immunoblastic subtype. In contrast, the immunoblastic subtype is typically characterized by CD138 expression as well as EBV latent membrane protein-1 (LMP-1). Centroblastic DLBCL is thought to arise in the germinal center (GC), whereas immunoblastic DLBCL is a post-GC lymphoma. GC B-cell-like type DLBCL is considered when CD10 is expressed in more than 30% of the malignant tumor cells, or if cells are CD10−, BCL6+, and IRF4/MUM1−. All others are considered to be activated B-cell-like type or non-GC types, which have inferior prognoses. Cytogenetics or fluorescence in situ hybridization (FISH) should be performed for MYC, BCL-6, and BCL-2 translocations, because these variants have a poor outcome with chemoimmunotherapy. DLBCL with multiple translocations are now distinctly categorized by the 2016 World Health Organization (WHO) classification as “high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements” rather than “double-hit” or “triple-hit.” “Double-expresser” DLBCL lacks the translocations but has increased protein expression of MYC and BCL2protein measured by immunohistochemistry and is also associated with inferior outcomes relative to DLBCL with normal levels of expression. B. Laboratory tests. Complete blood counts (CBCs) may reveal anemia, leukopenia, or thrombocytopenia, even if there is no marrow involvement. Serum chemistries may show abnormalities in liver function tests, elevated lactate dehydrogenase (LDH), calcium, or uric acid. Electrolytes and creatinine should also be monitored during therapy. Screening for hepatitis B and C should also be performed. C. Radiology/procedures 1. Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scans are the standard imaging for aggressive lymphomas, which are usually highly FDG avid. They are helpful in distinguishing adenopathy due to lymphoma from that associated with PGL or OIs, which show less intense FDG uptake. Increased FDG uptake in the bone marrow may allow a patient to forego a bone marrow biopsy. PET/CTs are routinely used as interim scans during a treatment regimen to assess response as well as to detect residual or relapsed disease. Response is measured using the 5-point scale (Deauville criteria), regardless of the size of the residual mass. 2. CT scan of the chest, abdomen, and pelvis is often how lymphomas are initially discovered and are useful in aiding procedural planning, but have been supplanted by FDG-PET/CT as the standard for staging. 3. Magnetic resonance imaging (MRI) of the brain is necessary for the staging of

AIDS-related NHL given the relatively high incidence of CNS disease. 4. Bone marrow aspiration and biopsies reveal bone marrow involvement in approximately 20% of patients and may be associated with increased risk of CSF involvement. It may not be necessary if involvement is suggested by PET imaging. 5. Lumbar puncture should be performed and CSF sent for cytologic examination. Cell count and protein may be normal or elevated, whereas glucose may be low. Analysis of CSF by flow cytometry or for EBV DNA by polymerase chain reaction (PCR) may predict lymphomatous meningitis. 6. Cardiac ejection fraction either via transthoracic echocardiogram or multigated acquisition (MUGA) scan should be assessed prior to use of anthracyclines. D. Staging and prognostics. The Ann Arbor staging system and Lugano classification for NHL are both used for AIDS-related NHL. Prognostic factors correlating with poor survival in patients with AIDS-related NHL include stage IV disease, Karnofsky performance status less than 70%, CD4 count less than 100/mm3, elevated LDH, and history of OIs before lymphoma diagnosis. However, the International Prognostic Index (IPI) has greater prognostic value than the immune status. III. THERAPY A. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) was not significantly more effective than CHOP in AIDS-NHL (complete response [CR] rates of 58% and 47%, respectively) in one study, but was significantly more toxic (14% and 2% serious treatment-related toxicities). The increase in mortality with R-CHOP compared with CHOP, in this randomized study, was primarily due to infectious deaths, particularly in individuals with CD4 lymphocyte counts less than 50/mm3. However, subsequent trials using prophylactic quinolone antibiotics for individuals with less than 100 CD4 cells/mm3 obviated this complication. Moreover, a meta-analysis of trials using various different forms of chemotherapy with or without rituximab found a reduced risk of lymphoma recurrence and death from any cause with the addition of rituximab to combination chemotherapy (Blood 2013;122:3251). Some trials used decreased cyclophosphamide doses if CD4 is less than 100 to 200/mm3. Pharmacokinetic studies have shown no significant adverse interaction between R-CHOP and nucleoside (or nucleotide) and integrase inhibitors (without cobicistat). Concurrent use of G-CSF is advised. B. The infusional dose-adjusted (DA)-EPOCH-R regimen (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) with growth factor support resulted in complete remission in 74% of 39 patients, with 60% disease-free survival at 53 months. In this trial, antiretrovirals were withheld during chemotherapy, and after reinstitution of HAART, CD4 cells recovered by 12 months and viral load

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decreased below baseline by 3 months. Important features of this regimen are that it utilizes 5 days of oral prednisone (60 mg/m2/day), a 4-day infusion of etoposide (50 mg/m2/day), vincristine (0.4 mg/m2/day, not dose capped), and doxorubicin (10 mg/m2/day), and day 5 cyclophosphamide, followed by G-CSF or Neulasta. Cycle 1 cyclophosphamide dose is 375 mg/m2 for patients with CD4 less than 100 and 750 mg/m2 for patients with CD4 greater than or equal to 100. In subsequent cycles, the cyclophosphamide dose is increased by 187 mg/m2 each cycle up to a maximum of 750 mg/m2 if grade 3 or 4 neutropenia or thrombocytopenia has not occurred, and decreased by 187 mg/m2 each cycle if one of these complications has occurred. Thus, monitoring of the CBC at days 8, 10, and 12 of each cycle is necessary for guiding subsequent therapy. Concurrent use of rituximab plus EPOCH resulted in a 73% CR in one study, and 5-year progression-free survival (PFS) and overall survival (OS) of 84% and 68%, respectively, in another study. The above cited meta-analysis suggested that infusional regimens, such as DA-EPOCH, lead to improved response compared to R-CHOP. Short-course EPOCH-RR regimen includes rituximab given on days 1 and 5 of each cycle. To determine the number of cycles of therapy, all patients undergo restaging with CT and FDG-PET after the second treatment cycle, and each cycle until achieving CR or no further tumor shrinkage. The criteria for stopping therapy after a minimum of three cycles of therapy are that there is less than 25% reduction in bidimensional tumor products compared with the previous interim CT scan and the standardized uptake values on FDG-PET have decreased at least 50% compared with the pretreatment FDG-PET. With 5 years of follow-up, PFS and OS were 84% and 68%, respectively, and 79% of patients only required three treatment cycles. Other systemic regimens, such as mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), CDE (cyclophosphamide, doxorubicin, and etoposide), and ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisolone), are rarely used for initial therapy for DLBCL. Indications for CNS prophylaxis in AIDS-DLBCL are not well defined. Bone marrow involvement has been suggested as increasing the likelihood of CNS relapse, as well as paraspinal, paranasal, epidural, testicular, or widespread systemic involvement. Although the CNS IPI (based on age, performance status, LDH, number extranodal sites, stage and presence or absence of kidney or adrenal disease) has not been validated with HIV-lymphomas, it may provide guidance. When CNS prophylaxis is provided, the usual recommendation is four weekly treatments of either intrathecal cytarabine (50 mg) or methotrexate (12 mg). Lymphomatous meningitis should be treated with intrathecal cytarabine or methotrexate 2 to 3 times weekly via Ommaya reservoir until the CSF is clear of

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malignant cells, then weekly for 4 weeks, and then monthly. The duration of therapy remains poorly defined, but is often given for 6 to 12 months. In patients failing to respond to intraventricular chemotherapy, CSF flow studies can be performed after instilling radioisotope to identify possible blockade. A more common approach is to use high-dose methotrexate (see Primary CNS Lymphoma section). Radiotherapy may be given as palliation to bulky, rapidly enlarging, organ compressing, or CNS lesions or as consolidation to patients with localized lymphoma after chemotherapy. Duration of first-line therapy for AIDS-DLBCL should be three to eight cycles, with six cycles usually given, unless there is severe toxicity or lymphoma progression. This should include one to two cycles after obtaining a CR. For patients with stage I disease and good prognostic characteristics, three cycles of therapy followed by involved field radiation is appropriate therapy. Salvage chemotherapy regimens for AIDS-associated lymphomas are not highly effective (response rates of 20% to 80%) with most patients relapsing within months, as in the HIV-negative population. This includes the use of rituximab with etoposide and high-dose cytosine arabinoside and cisplatin (ESHAP), mitoguazone, or a combination of etoposide, mitoxantrone, and prednimustine. The use of rituximab with ifosfamide, carboplatin, and etoposide (R-ICE) is a reasonable choice for a salvage regimen, but trials in AIDS patients have not yet been reported. There is little reported experience with dexamethasone, cisplatin, cytarabine (DHAP), mesna, ifosfamide, mitoxantrone, etoposide (MINE), gemcitabine-oxaliplatin (GemOx), or carmustine, etoposide, cytarabine, melphalan (miniBEAM) regimens in this patient population. Autologous stem cell transplantation has also been utilized for refractory or relapsed AIDS-associated lymphomas, particularly in the HAART era, in individuals who respond to salvage chemotherapy. In individuals with a good performance status, lacking severe immune compromise, stem cell collections were successful in 80% to 100% of cases, and graft failure was rare. Long-term survivors have been reported from such studies, but the number of patients in each series remains low. In one study of 68 patients from 20 institutions, including 16 patients in first CR and 44 patients in CR more than one, partial remission, or chemotherapy-sensitive relapse, and 8 patients with chemotherapy-resistant disease, nonrelapse mortality was 30% at 24 months. Only anecdotal and small clinical trial reports have appeared thus far for the use of allogeneic transplants in HIV-infected individuals. Chimeric antigen receptor (CAR) T-cell therapy studies in relapsed and refractory lymphoma have generally excluded HIV-positive patients. Case reports have described successful use in such patients.

IV. COMPLICATIONS A. Complications of disease. Rapidly enlarging tumors may compromise airways and other vital organs. Significant hepatic dysfunction, hypercalcemia, and CNS relapse may occur. OIs and other AIDS-related illnesses are causes for morbidity and mortality in patients with AIDS-NHL; thus, PCP prophylaxis should be continued during active lymphoma therapy, if indicated. B. Complications of therapy 1. Lymphocytotoxic chemotherapy may cause depletion of CD4 and total lymphocyte counts, increasing the risk of severe myelosuppression and infections. Potential interactions with chemotherapy and HAART may produce substantial and unexpected toxicity that may require dose delay or reduction, possibly compromising optimal antilymphoma therapy. 2. Intrathecal chemotherapy may cause chemical arachnoiditis that is relatively acute, subacute neurologic deficits occurring within days to weeks, or chronic encephalopathy occurring over weeks to months. Spinal CSF leak may predispose to the development of subdural hematomas or cerebral hypotension. 3. Cardiomyopathy may occur after the use of doxorubicin, particularly in individuals receiving cumulative doses of more than 550 mg/m2, but may occur at lower cumulative doses in individuals who received chest radiotherapy, or have other cardiac disorders, such as HIV-associated cardiomyopathy. 4. Virus reactivation is a potential complication of rituximab-based therapies, particularly hepatitis B virus (HBV), hepatitis C virus (HCV), and John Cunningham virus (JCV). Monitoring HBV and HCV levels during therapy is indicated in individuals with chronic persistent infections. Antiviral therapy is recommended for high-risk HBV-positive patients. V. FOLLOW-UP During treatment, intervening history, physical examination, CBC, chemistries, and LDH should be obtained prior to the initiation of each cycle of therapy and as clinically indicated. Interim FDG-PET scans are usually performed once or twice after two to four cycles, although it remains unclear if they should guide treatment changes. However, the interim PET scan is useful to detect progression of disease. With DA-EPOCH-R, more frequent measurements of CBC are required to guide the dose level for the subsequent cycle (twice each week through nadir). Six to eight weeks after completion of therapy, follow-up PET/CT scans are performed. If bone marrow involvement was present initially, and there is no other indicator of disease after therapy, repeat bone marrow examination should be performed. After completion of therapy, for patients in complete remission, follow-up visits and laboratory studies are required approximately every 3 months for 1 year, every 3 to 4 months during the second year, and then every 4 to 6

months during years 3 to 5 posttherapy completion. CT and PET scans are only performed if clinically indicated. It is important to remember that these patients are at risk for relapse of their AIDS-NHL or development of a second AIDS-NHL. VI. CURRENT FOCUS OF RESEARCH Current studies of AIDS-DLBCL are evaluating (1) genomics of AIDS-DLBCL; (2) the combination of ibrutinib or acalabrutinib with DA-EPOCH-R chemotherapy for first-line therapy; (3) programmed cell death protein 1 (PD-1) antibody immune checkpoint inhibitors in relapsed, refractory disease, (4) safety and efficacy of CAR-T cell therapy, (5) gene therapy in patients undergoing stem cell transplantation; and (6) CHOP versus oral chemotherapy in a resource-limited setting. AIDS-ASSOCIATED BURKITT-LIKE LYMPHOMAS I.

BACKGROUND AIDS-Burkitt-like lymphoma (BL) is associated with EBV infection in 25% to 40% of cases. However, the pattern of latency differs from that of AIDS-DLBCL, with expression of EBNA-1 but not LMP1 or EBNA2. As in BL not associated with HIV, translocations between immunoglobulin genes and MYC are uniformly present. TCF3, a transcription factor involved in controlling GC proliferation, and its inhibitor ID3 are often mutated in conjunction with MYC overexpression. Mutational inactivation of tumor suppressor protein p53 is also prevalent. BL accounts for 15% to 40% of AIDS-NHL cases. AIDS-BL accounts for about 20% of all BL cases in the United States. The clinical presentations of AIDS-BL patients are similar to those of HIV-negative patients in terms of histology, disease stage, and proportion with bone marrow and CNS involvement.

II. DIAGNOSTIC WORKUP AND STAGING The pathology of AIDS-BL is characterized by a population of small- or medium-sized noncleaved lymphocytes, often vacuolated, typically exhibiting a “starry sky” appearance and a cohesive growth pattern, but atypical variants are noted with plasmacytoid differentiation, granulomatous reaction, or nuclear pleomorphism. The tumor cells are generally CD10- and CD20-positive and usually express proliferation antigen Ki67 on almost 100% of malignant cells, transcription factor Bcl-6, and, uncommonly, antiapoptosis protein Bcl-2. These tumors are classified as high-grade lymphomas. Molecular diagnostic or cytogenetic studies should be used to confirm the presence of the 8;14 translocation or the variant location 2;8 or 8;22, all of which involve a translocation of MYC with an immunoglobulin locus. It is rare for BL to have “doublehit” and “triple-hit” translocations involving MYC, BCL6, and/or BCL2, and such cases should be classified as “high-grade lymphoma with MYC and BCL6 and/or BCL2

translocations.” Mutations in TCF3 and ID3 have been found to synergize with MYC translocations and drive proliferation. Other aggressive lymphomas (e.g., lymphoblastic lymphoma, blastoid variant of mantle cell lymphoma), although not increased in HIVpositive individuals, should be excluded. III. THERAPY A. CHOP therapy was used for AIDS-associated BL, prior to the development of HAART, and responses were similar to those of AIDS-associated DLBCL. However, with HAART therapy, AIDS-BL may have a worse prognosis than AIDS-DLBCL when treated in the same fashion, suggesting a need for more aggressive therapy in this setting. B. R-hyper-CVAD is a regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, and rituximab given in alternating cycles with high doses of both cytosine arabinoside and methotrexate, followed by leucovorin for a total of eight cycles. Antibiotic prophylaxis is provided with a quinolone, fluconazole, and valganciclovir, together with standard prophylactic regimens for PCP, MAI, and CMV, where indicated. In a single-center study, 9 of 11 patients achieved CR, and 1 patient partial response (PR). Grade 3 or 4 myelosuppression occurred in all patients, and fever or infection during 35% of chemotherapy cycles. Six of seven patients given HAART concurrently with chemotherapy remained in CR for a median of 29 months (Adv Hematol 2012;735392). C. R-CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) was used for the treatment of 14 HIV-positive patients, of whom 63% had CRs, with a 2-year diseasefree survival of 60%. Grade 3 or 4 toxicities included anemia (100%), neutropenia (88%), thrombocytopenia (75%), mucositis (75%), neutropenic fever (63%), sepsis (38%), neuropathy (38%), and nephrotoxicity (24%). In a study of 34 AIDS-BL patients with R-CODOX-M/IVAC, 1-year OS was 83% (Blood 2015;126:160). D. DA-EPOCH-R was utilized in 30 subjects with BL, including 13 individuals with AIDS-BL who received three to six cycles of therapy, including one cycle after obtaining complete remission, resulting in PFS and OS in 12 of these 13 subjects at a median of 36 months of follow-up (N Engl J Med 2013;369:1915). A confirmatory study reported event-free survivals at almost 5 years of 100% and 82% in low and high-risk patients, respectively, with no significant differences between HIV-positive and -negative individuals (J Clin Oncol 2020;38:2519).This regimen is generally better tolerated than R-hyper-CVAD or R-CODOX-M/IVAC and is currently the most commonly used regimen for initial therapy. E. Prephase treatment may be utilized for individuals who cannot receive all components of the regimen during the first cycle because of hyperbilirubinemia or

patients at high risk of tumor lysis syndrome. This therapy consists of cyclophosphamide (200 mg/m2 × 5 days) with 100 mg/m2 of prednisone for 7 days. F. Prophylactic intrathecal chemotherapy with methotrexate or cytosine arabinoside should be given to all AIDS-BL patients, generally four to six weekly doses of therapy in patients who do not have positive CSF cytology. G. Salvage regimens for individuals who fail to achieve complete remission are listed above under the DLBCL section, but the majority of patients fail to achieve a response. Thus, clinical trial enrollment is encouraged for relapsed, refractory BL. IV. COMPLICATIONS The risks of myelosuppression, tumor lysis syndrome, and neurotoxicity are higher for AIDS-BL patients given more intensive therapies, such as R-hyper-CVAD or RCODOX-M/IVAC, than for AIDS-DLBCL patients given R-CHOP. V. FOLLOW-UP is as described for AIDS-DLBCL patients. VI. CURRENT FOCUS OF RESEARCH A trial of varlilumab (an antibody against the CD27 costimulator protein) in combination with nivolumab includes HIV-positive subjects. AIDS-ASSOCIATED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMAS I.

BACKGROUND AIDS-Primary Central Nervous System Lymphoma (PCNSL) occurs in 2% to 11% of HIV-infected patients, representing a 3,600-fold higher incidence of this disease, compared with that of the general population. Latent EBV-infected cells develop into malignant clones in the relatively immune-privileged CNS, secondary to decreased immunosurveillance resulting from HIV-related T-cell depletion. Efforts to induce lytic EBV replication with zidovudine and ganciclovir have been considered. PCNSL usually presents in severely immunocompromised individuals with CD4 counts less than 50/mm3. AIDS-PCNSL accounts for about 13% of all PCNSL cases in the United States. With widespread use of HAART, the incidence of AIDS-associated PCNSL has declined significantly. Typical presentations are with confusion, memory loss, lethargy, or focal neurologic signs. Patients may also present with seizures, headaches, memory loss, or dementia. The physical examination should include a testicular exam, in addition to the features described above for DLBCL.

II. DIAGNOSTIC WORKUP AND STAGING A. Differential diagnosis includes systemic lymphomas with CNS involvement, toxoplasmosis, HIV encephalopathy, progressive multifocal leukoencephalopathy,

B.

C.

D.

E.

F.

G. H.

and other infections associated with viral, fungal, mycobacterial, or parasitic infections. Some investigators have suggested that in patients with serologic evidence of prior toxoplasma exposure, a 14-day course of anti-toxoplasmosis therapy may be indicated to assess response. However, given the other diagnostic modalities available, this approach is rarely utilized now, and the delay in therapy resulting from this approach is potentially risky. Diagnostic workup should include full-body FDG-PET/CT in order to exclude systemic disease. If these scans are negative, it is unclear whether or not bone marrow biopsy is needed, because the yield of positive results in this setting may be very low. Patients should undergo slit-lamp ophthalmologic exam to exclude concurrent intraocular lymphoma. Men should undergo a testicular ultrasound. Lumbar puncture should be performed to determine if leptomeningeal disease is present, unless a contraindication exists (e.g., thrombocytopenia, increased intracranial pressure, spinal abscess). Brain MRI or CT scan typically shows multifocal disease. However, lesions are typically larger and fewer than those associated with Toxoplasma encephalitis. Lesions may be ring enhancing and are often associated with edema and shift of normal brain structures, and may be found at any location in the brain. Brain PET or single-photon emission computed tomography (SPECT) is helpful in distinguishing PCNSL from other HIV-associated brain lesions, such as toxoplasmosis, which exhibit less uptake of FDG. Brain biopsy is the gold standard for diagnosis, but tumor location and other factors may preclude this procedure. CT-guided stereotactic brain biopsies can produce diagnostic rates with acceptable morbidity, comparable to that of open brain biopsy. CSF EBV PCR is a sensitive (80%) and specific (99%) test for AIDS-associated PCNSL, because EBV infection is uniformly associated with this condition. For patients with positive CSF EBV PCR and PET or SPECT scans showing intense uptake in the brain lesion, biopsy may be obviated. Pathology is typically a DLBCL, usually of the activated B cell–like subtype, with angiocentric distribution. BCL6 expression is common, as is PD-L1 overexpression. The International Extranodal Lymphoma prognostic scoring system is more relevant than the Ann Arbor or IPI systems with five adverse prognostic factors: age greater than 60, ECOG PS more than 1, elevated serum LDH, elevated CSF protein concentration, involvement of deep region of the brain.

III. THERAPY for PCNSL should also include HAART, which significantly improves survival. A. Whole brain radiotherapy alone was used in the pre-HAART era, because the median survival of patients presenting with PCNSL was only 1 to 3 months as a

B.

C.

D.

E.

F.

result of OIs. Typically, 4,000 cGy is used in fractions of 267 cGy each. Cranial irradiation alone results in a 53% rate of tumor regression and slightly improved survival compared with untreated individuals. Because of the multifocal nature of AIDS-PCNSL, radiation should be directed to the whole brain and meningeal fields to the level of the second cervical vertebra without spinal irradiation. In patients with poor performance status, who are severely immune compromised, and/or patients with multidrug-resistant HIV infection, this may be the most appropriate therapy. Autopsy studies showed that patients who did not receive radiotherapy died of lymphoma progression, whereas those who did receive radiotherapy died of OIs. High-dose methotrexate (2.5 to 3.5 g/m2 every 14 days) with leucovorin rescue was reported to produce a CR of 50%, a median OS of 10 months, and improved quality of life. For patients with a good performance status, who are not severely immunocompromised and are responding to HAART therapy, a chemotherapy regimen including high-dose methotrexate may be appropriate, followed by cranial irradiation, as in the HIV-negative PCNSL population. However, recent studies have questioned the need for cranial irradiation in those individuals who achieve complete remission with chemotherapy. High-dose methotrexate therapy requires careful monitoring of methotrexate levels and adjustment of leucovorin doses if delayed methotrexate clearance is found. It is unclear whether higher doses of methotrexate (e.g., 8 g/m2) are more effective. Methotrexate should not be used in individuals with a third space fluid collection or creatinine clearance less than 30 mL/minute. High-dose cytosine arabinoside added to high-dose methotrexate has been reported in a small randomized phase 2 trial to improve response rates in HIV-negative PCNSL, although there were higher rates of myelosuppression and neutropenic infections. Steroids are used to limit edema, but the impact on survival is unclear. Glucocorticoid therapy is generally avoided, because it can delay diagnosis, and exacerbate immunosuppression. Rituximab has been reported to play a role in CNS lymphomas not associated with AIDS, when given systemically, but there are only anecdotal reports of its use for AIDS-PCNSL. Intrathecal rituximab remains investigational. Other agents (e.g., temozolomide, topotecan, procarbazine, vincristine, etoposide, carmustine, thiotepa, pemetrexed, ifosfamide, ibrutinib, temsirolimus, and lenalidomide) and stem cell transplantation remain to be evaluated in AIDSassociated PCNSL.

IV. COMPLICATIONS A. Complications of PCNSL include ocular lymphoma that may involve the vitreous, uvea, or retina, and is usually bilateral. Bilateral ocular irradiation, or high-dose

cytarabine or methotrexate, which penetrate the vitreous, may be given. Leptomeningeal lymphoma can be treated with intrathecal methotrexate or cytarabine via Ommaya reservoir. B. Complications of therapy of AIDS-associated PCNSL are coincident OIs and neurologic toxicity from whole brain radiotherapy. V. FOLLOW-UP should be performed every 3 months in the first two years after completion of therapy, with MRI brain scans and less often thereafter. AIDS-ASSOCIATED PRIMARY EFFUSION AND PLASMABLASTIC LYMPHOMAS I.

BACKGROUND AIDS-associated primary effusion lymphomas (PELs) are uniformly associated with HHV8 infection and frequent coinfection with EBV. It is unclear why PEL arises in body cavities, but there is evidence that viral Bcl-2 is activated by hypoxia, which may contribute to lymphoma development. Current research is examining the role of daratumumab (anti-CD38 antibody) for these lymphomas. Other studies (e.g., varlilumab plus nivolumab, see HIV-BL section) also include PEL and plasmablastic lymphomas. Anecdotal reports on the use of bortezomib, lenalidomide, or tocilizumab have not yet been followed up in larger clinical studies. PELs account for 1% to 5% of HIV-NHL. PEL presents 200-fold less commonly in HIV-negative patients, including elderly individuals or organ transplant recipients. Plasmablastic lymphomas account for about 2% of HIV-NHL, but less than 0.1% of NHL in the HIV-negative population. These lymphomas are uniformly EBV positive. A. Classical presentations of PEL are ascites, pleural effusion, or pericardial effusions without infiltrative growth patterns or tumor masses. Some cases of PEL extend into tissues underlying serous cavities, including the nodes, omentum, mediastinum, and lung. Other cases of HHV8-positive solid lymphomas are extracavitary variants of PEL. Plasmablastic lymphomas typically present in the oral cavity, but other presentations (e.g., skin or GI tract) have also been described. B. PEL occurs primarily in homosexual men and late stages of HIV infection (mean CD4 count 98/mm3). In one study, 64% of patients had previous manifestations of AIDS. PEL commonly occurs in patients with previous manifestations of HHV8 infection, such as KS or Castleman disease.

II. DIAGNOSTIC WORKUP AND STAGING A. Diagnostic thoracentesis, pericardiocentesis, or paracentesis is usually required to diagnose a patient with PEL. B. PEL is classified as a stage IV NHL.

C. Pathology of PEL usually demonstrates plasma cell differentiation as shown by expression of CD138 or syndecan-1. The cells typically express leukocyte common antigen, CD45, EMA, and activation antigens, HLA-DR, CD23, CD25, CD30, CD38, CD70, and CD77. However, they are usually negative for T- and B-cell markers, including CD20, although clonal immunoglobulin gene rearrangements are present. Although the large, pleomorphic malignant cells may resemble Reed– Sternberg (RS) cells, they are CD15 negative. Plasmablastic lymphomas are also CD20 negative, but express CD79a, IRF-4/MUM-1, BLIMP-1, CD38, CD138, and other markers of plasmacytic differentiation. Plasmablastic lymphomas may be associated with MYC or ALK rearrangements. III. THERAPY A. CHOP therapy was generally ineffective in the pre-HAART era (Nador Blood 1996;88:645). However, now that HAART is available, the CHOP regimen is an appropriate choice of therapy for these patients, if they have adequate performance and immune status. Rituximab is not recommended for use in these lymphomas, which are typically CD20 negative. There are also anecdotal reports of use of other combination chemotherapy regimens for PEL, as described for DLBCL. B. HAART alone has been reported to be effective for AIDS-PEL, according to anecdotal reports. C. DA-EPOCH is commonly used for the treatment of PEL and plasmablastic lymphomas. Some recommend the addition of bortezomib to DA-EPOCH (with or without removal of vincristine to reduce neurotoxicity) given the plasmacytic differentiation (Blood 2015;125:2323). Others utilize alternative regimens for aggressive lymphomas, such as hyper-CVAD or CODOX-M/IVAC. The role of hematopoietic stem cell transplantation for these lymphomas is not defined. D. Major prognostic factors for response are good performance status and preexisting use of HAART therapy. In a study using a variety of treatment regimens, of which CHOP was the most common, OS was greater than 3 years in 32% of patients. In a retrospective study of patients treated in the HAART era, a 1-year survival rate of 67% was reported for patients with plasmablastic lymphoma treated with combination chemotherapy (Leuk Lymphoma 2016;57:1731). IV. FOLLOW-UP Follow-up should include PET or PET/CT, 6 to 8 weeks after completion of therapy, repeat bone marrow if positive at diagnosis. If patients are in complete remission, follow-up usually occurs every 3 months during the first year, every 3 to 6 months in the second year, and then every 6 months, with history, physical examination, CBC, chemistries, and LDH. There is no role for routine imaging during these visits unless

indicated by clinical issues. HIV-ASSOCIATED HL I.

BACKGROUND EBV has been identified in 80% to 100% of HIV-HL cases compared with about 50% in the HIV-negative population. The RS cells of HL from HIV-negative patients are generally derived from GC B cells, whereas those of HIV-HL patients are derived from post-GC B cells. The incidence of HL is 5- to 20-fold higher in the HIV-positive population compared with the HIV-negative population. Approximately 4% of HL patients are infected with HIV. A. At diagnosis, 74% to 92% of HIV-HL patients present with advanced disease, with frequent extranodal involvement, including the bone marrow, liver, and spleen, but mediastinal involvement is uncommon. Moreover, 70% to 96% of patients have B symptoms. Bone marrow involvement is present in 40% to 50% of patients, and is the first indicator of disease in 20% of cases. Bone marrow only HIV-HL is found occasionally. In contrast to the HIV-negative population, noncontiguous nodal spread of lymphoma is common; for example, liver without splenic involvement or lung without mediastinal node involvement. B. Median CD4 count at presentation is in the range of 150 to 300/mm3, but HL is increased in the HIV-positive population at all CD4 levels.

II. DIAGNOSTIC WORKUP AND STAGING A. Lymph node enlargement may be due to HIV or HL, and PET scans may be helpful in distinguishing the etiology. Other coincident causes of lymph node enlargement should also be excluded, such as mycobacterial or CMV infection or NHL. B. Pathology shows the mixed cellularity subtype as the most common variant in HIVinfected individuals, as well as an increased frequency of the lymphocyte-depleted subtype compared with HIV-negative HL. LMP-1 is expressed in almost all cases in the RS cells. RS cells are typically CD15+CD30+CD45−. C. Staging evaluation is as described by AIDS-DLBCL except that brain MRI/CT scans and lumbar puncture may be omitted unless there are neurologic symptoms. Pulmonary function tests should be performed prior to the use of bleomycin. D. Fertility preservation strategies should be discussed at diagnosis prior to initiation of therapy. E. Smoking cessation should be highly encouraged because of the increased risk of potentially life-threatening pulmonary toxicity with bleomycin and smoking.

III. THERAPY A. Full-dose chemotherapy regimens are recommended, combined with HAART and G-CSF. However, it should be recognized that G-CSFs increase the likelihood of bleomycin pulmonary toxicity, and thus the fewest possible doses of CSFs should be utilized. B. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) given with G-CSF support is the most commonly used regimen, given at the same doses as in the HIVnegative population. In the pre-HAART era, this regimen resulted in a CR of 42%. In the post-HAART era, CR rates of 87% and 91% have been reported in separate studies. Recent studies show that HIV infection does not adversely affect the OS or event-free survival for individuals with HL treated with ABVD (J Clin Oncol 2012;30:4056). It is reasonable to discontinue bleomycin after two cycles in individuals who have symptoms or signs of pulmonary compromise. Patients with advanced HL and a negative interim PET scan after two cycles of ABVD may also have the bleomycin discontinued and continue with four more cycles of AVD (N Engl J Med 2016;374:2419). Prophylactic treatment with G-CSF is not required. C. EBVP (epirubicin, bleomycin, vinblastine, and prednisone) resulted in a CR rate of 74%, with grade 3 or 4 leukopenia in 32% of patients. D. The Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone) resulted in a complete remission rate of 81%, 3-year OS of 51%, and disease-free survival of 68%. This regimen maintains or increases the dose intensity of individual drugs, but reduces the cumulative doses of bleomycin and doxorubicin compared with ABVD, and may reduce the incidence of pulmonary or cardiac dysfunction. E. The BEACOPP regimen (cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisone, bleomycin, and vincristine) resulted in CR in all 12 treated patients and 83% 2-year survival, but grade 3 or 4 leukopenia in 75% of cases. F. The BV-AVD regimen (brentuximab, doxorubicin, vinblastine, dacarbazine) given with G-CSF support is safe in the absence of strong Cyp3A/4 inhibitor concomitant medications. Results from the phase 2 portion of this study are pending (NCT01771107). HIV infection was an exclusion criterion in the pivotal ECHELON1 study. G. Risk-adapted therapy was utilized in a study of HIV-associated HL. Subjects with early-stage favorable disease received two to four cycles of ABVD plus involved field radiation, whereas patients with early-stage unfavorable disease received four cycles of BEACOPP or a combination of four cycles of ABVD, followed by involved radiotherapy if disease was greater than 5 cm or residual disease greater than 2 cm. Patients with advanced disease received 8 cycles of BEACOPP. CRs occurred in 96% of subjects, and 2-year PFS was 92%, and 2-year OS was 91% ( J

Clin Oncol 2012;30:4117). H. Stage I favorable prognosis patients (nonbulky disease, ESR less than 30, no B symptoms, normal LDH) with HIV-HL are generally treated similar to HIV-negative HL subjects, although there is limited clinical trial information for this subset. These individuals generally received two to four cycles of ABVD with or without involvedsite radiation. Other stage I and II HIV-HL subjects are generally treated like advanced disease subjects. I. Salvage therapy studies have not been reported in AIDS patients. However, patients relapsing more than 12 months after obtaining an initial complete remission may be candidates for treatment with one of the first-line regimens described earlier. Patients relapsing in a shorter period of time may be candidates for similar salvage approaches as described for AIDS-DLBCL patients, but without use of rituximab. The role of brentuximab and nivolumab, an anti-PD-1 monoclonal antibody, in salvage therapy remains to be defined in HIV-associated HL, although there are care reports of their successful use. If response is seen, hematopoietic stem cell transplantation is generally recommended. PD-1 inhibitors are approved therapies for relapse after autologous stem cell transplantation and/or multiple lines of therapy. IV. COMPLICATIONS of the disease or treatment are as described for AIDS-DLBCL with the addition of possible pulmonary fibrosis resulting from use of bleomycin. This complication, characterized by acute pneumonitis with fever, congestion, cough, and dyspnea, occurs most commonly after cumulative doses of more than 200 to 400 U/m2, but may occur at lower doses when chest radiotherapy is also utilized. Peripheral neuropathy may also result from HIV infection as well as the use of vinblastine or brentuximab. V. FOLLOW-UP should be as described for AIDS-associated DLBCLs. VI. CURRENT FOCUS OF RESEARCH Current research is examining the safety and efficacy of nivolumab with or without ipilimumab in relapsed or refractory HIV-HL. Other research is examining the use of allogeneic hematopoietic cell transplantation for relapsed and refractory HIV-HL. HIV-ASSOCIATED ANAL CARCINOMAS I.

BACKGROUND Anogenital squamous cell carcinomas are uniformly associated with HPV infection, particularly high-risk strains 16, 18, 31, and 35. The HPV E6 protein binds tumor suppressor protein p53 and promotes its degradation, abrogating its cell cycle arrest and apoptosis functions. The HPV E7 protein binds retinoblastoma family proteins, p105,

p107, and p130, and promotes cell cycle transition into the S phase. HIV-infected individuals have a 25- to 35-fold higher rate of anal carcinoma than HIV-negative individuals. These squamous cell carcinomas result from high-risk HPV infections. These malignancies are not clearly associated with immune suppression, occur in individuals with a wide range of CD4 counts, and are not considered AIDSdefining illnesses. The incidence of anal cancers appears to have increased since the introduction of HAART, although clinical features and OS have not changed. The most common clinical presentations are pain or bleeding. However, larger tumors may interfere with anal sphincter function and lead to incontinence. A. Clinical examination will identify a mass, and the size and position within the anal canal or anal margin should be documented. Rectal examination may detect enlarged perirectal lymph nodes. B. Enlarged inguinal nodes, identified on physical examination, should be considered for fine needle aspiration. C. Proctosigmoidoscopy should be done in all of these patients. D. A thorough gynecologic examination should be done in women, especially if the tumor is situated in the anterior anal canal or if the perineum is involved. Evidence of vaginal mucosal involvement suggests that rectovaginal fistula might develop during treatment. If pelvic examination cannot be performed because of pain, this examination should be done under anesthesia. II. DIAGNOSTIC WORKUP AND STAGING A. Screening strategies for anal or cervical dysplasia are based on CD4 count and the local expertise. B. Pathology shows that distal anal tumors tend to be keratinized, whereas more proximal tumors are nonkeratinized and referred to as cloacogenic or basaloid. However, the clinical behavior of both types of tumors is similar. C. Differential diagnosis includes other rare tumors arising in the anal canal that need to be distinguished from squamous cell carcinoma including adenocarcinomas of the anal ducts or glands, melanomas, clear cell sarcomas, and neuroendocrine tumors. D. Staging evaluations should include endoanal ultrasonography, CT, MRI, or PET. E. Prognosis depends on sex, tumor stage, nodal status, and response to chemoradiation. Patients with well-differentiated tumors have a more favorable outcome than those with poorly differentiated cancers. III. THERAPY is generally with concurrent chemotherapy with radiotherapy. A. Chemotherapy options may include fluorouracil and mitomycin, as in the HIVnegative patient population, fluorouracil alone, or fluorouracil with cisplatin. Capecitabine may be substituted for fluorouracil. Local control rates are 80% to 90%

for tumors less than 4 cm, and 70% to 85% for larger tumors. The addition of mitomycin to fluorouracil improves local control and disease-free survival. HIVinfected patients with CD4 counts greater than 200/mm3 generally tolerate therapy similar to that of the HIV-negative patient population, although the rate of local skin/mucous membrane toxicity and bone marrow suppression may be higher in HIV-positive than in HIV-negative individuals. Individuals with CD4 counts less than 200/mm3 may tolerate chemotherapy less well, and consideration should be given for withholding or reducing the dose of mitomycin. B. Recurrent or residual disease is associated with substantial morbidity, poor wound healing, and wound infections or sinuses. Salvage therapy for recurrent local disease in selected cases may include inguinofemoral lymph node dissection, pelvic exenteration, or additional radiotherapy if the region has not received the maximum tolerated doses. C. Distant metastatic disease is managed with palliative intent, and active chemotherapy agents include carboplatin and paclitaxel, or cisplatin and fluorouracil, second-line taxane or immune checkpoint inhibitor therapy. Resection of isolated metastases in the liver or lung may be considered in select cases. In select cases of limited metastatic disease (e.g., paraaortic nodes only), curative therapy with chemoradiotherapy may be considered. IV. COMPLICATIONS Late complications of chemoradiotherapy occur in 3% to 16% of patients after 3 to 10 years, and include necrosis of the anus, especially with more than 60 Gy external radiotherapy or after interstitial implants. Other complications include neurogenic bladder, urethral stenosis, small bowel damage, cytopenia, intractable diarrhea, and radiation-induced sarcoma. These complications are more common in patients with CD4 less than 200/mm3 (J Clin Oncol 2008;26:2550). V. FOLLOW-UP of treated patients involves digital rectal examination, inguinal lymph node palpation, and anoscopy every 3 to 6 months for 3 years, and every 6 to12 months for the subsequent 2 years. Chest CT plus MRI of the abdomen and pelvis is recommended annually for individuals with initial lymph node positive disease. If persistent thickening is present after 3 months, follow-up CT or MRI examinations and/or biopsies may be indicated. However, it is important to recognize that abnormalities may continue to regress over 6 months. VI. CURRENT FOCUS OF RESEARCH is examining the efficacy of vaccines in preventing acquisition of high-risk HPV strains. Moreover, vaccines expressing epitopes of HPV E6 or E7 are also being examined as therapeutic vaccines. Studies are also underway examining the efficacy of adjuvant PD-1 antibody therapy in high-risk

localized anal carcinoma (stage IIB or III), the efficacy of lower doses of radiation therapy in early-stage anal carcinoma, the role of high-dose brachytherapy with chemotherapy for residual localized disease, and the activity of combined immune checkpoint inhibitor therapy in metastatic disease. The Anchor Study is a phase 3 randomized multicenter study examining topical (imiquimod or fluorouracil) or ablative treatment (infrared photocoagulation therapy) versus monitoring in preventing anal cancer in patients with HIV and anal high-grade squamous intraepithelial lesions. AIDS-ASSOCIATED KS I.

BACKGROUND A. KS develops in HIV-negative individuals, including older men primarily of Eastern European, Mediterranean, and/or Jewish descent, individuals undergoing immunosuppression (e.g., associated with bone marrow or organ transplantation), and young males in equatorial Africa, as well as in HIV-infected individuals. AIDSassociated KS occurs in individuals who are homosexual or bisexual and very rarely, if at all, in other HIV risk groups. The incidence of AIDS-KS has decreased significantly with the use of HAART in the United States. However, in other parts of the world with limited access to HAART, KS incidence continues to increase. B. Pathogenesis of KS is thought to involve expression by the spindle cells of cytokines such as interleukin-6, basic fibroblast growth factor, vascular endothelial growth factor (VEGF), matrix metalloproteinases, tumor necrosis factor-α, oncostatin M, platelet-derived growth factor, and interferon-γ. C. HHV8, also designated KS herpes virus (KSHV), is thought to be the etiologic agent of this disorder, with primarily latently infected cells contributing to the development of this disorder. A small proportion of cells with lytic HHV8 replication may also contribute to disease pathogenesis. HHV8 is present in AIDS-KS, as well as KS developing in HIV-negative populations. Several viral genes implicated in the pathogenesis of KS include those encoding homologs of antiapoptosis proteins Bcl-2 and an inhibitor of Fas-mediated apoptosis, interleukin-6, cyclin D, interferonregulatory factors, chemokines, and G protein–coupled receptors. Serologic tests for HHV8 are not yet routinely available. The median time for KS development in HHV8-positive, HIV-1-infected individuals is estimated to be about 10 years. HHV8 is thought to be transmitted through saliva. Blood-borne transmission is thought to occur, but inefficiently. Mother-to-child transmission also occurs, which is primarily through saliva.

II. CLINICAL PRESENTATION A. KS occurs 500-fold more commonly in HIV-positive individuals than in the general population. Although occurring more commonly in patients with less than 200 CD4 3

lymphocytes/mm3, the CD4 count at presentation can be quite variable, and KS may be the first manifestation of AIDS. B. Clinical presentation depends on the site and degree of KS involvement. Manifestations of disease may range from asymptomatic innocuous cutaneous macules to life-threatening visceral lesions. The clinical course of KS is also highly variable, with rapid increase in the number and size of lesions in some patients over the course of weeks to months, or indolent lesions gradually shrinking over years. C. Pertinent history should include a description of all areas of initial KS involvement, lesion duration and rates of progression, oral lesions, GI and pulmonary lesions, presence of KS-associated edema, and other KS-associated symptoms, AIDSdefining illnesses, other sexually transmitted diseases, OIs, and past and current antiretroviral treatment. D. Physical examination includes evaluation of performance status, complete evaluation of the skin, oral cavity, and lymph nodes, with assessment of the chest, abdomen, and neurologic assessment, and genital and rectal examinations. Baseline measurements of at least five indicator lesions, description of whether lesions are flat or raised, and determination of the number of lesions per area (e.g., left leg, torso, head, and neck) are necessary for later assessment of rate of progression and response to therapy. Photographs or drawings of sites of KS involvement are helpful for follow-up evaluations. 1. Cutaneous manifestations. Typically, KS presents with skin lesions, from a few millimeters to several centimeters in size, that may be flat or raised, with a pink to purple or brown color. These lesions tend to be painless and nonpruritic, although bleeding and superficial infection or cellulitis may occur. Visceral KS can occur without skin manifestations. a. Facial KS typically involves the nasal, periorbital, or conjunctival areas. These may be cosmetically unappealing and cause anxiety and social stigmatization. b. Oral KS occurs in 30% of patients, and often involves the hard and soft palates, and occasionally the gums, tongue, tonsils, and pharynx. The lesions may be macular, nodular, or exophytic, causing dysphagia, odynophagia, or speech difficulties. c. Genital KS is characterized by irregular erythematous patches on the foreskin or shaft of the penis. d. KS of the feet may cause pain and ambulation difficulties. e. Lymphedema may occur because of dermal and lymphatic involvement of KS, resulting in a nonpitting, sometimes woodlike edema of the lower extremities and genitals, sometimes disproportionally more severe than the degree of KS involvement. Skin breakdown may cause weeping, ulceration,

and subsequent superimposed bacterial infections. 2. Nodal KS may present with painless lymph node enlargement, caused by focal or total replacement with KS. This should be differentiated from lymphoma, mycobacterial or HIV lymphadenitis. 3. Visceral manifestations most often affect the lungs and GI tract. a. Pulmonary KS affects 40% of KS patients and is usually associated with dyspnea without fever, cough, or hemoptysis. This may be progressive, debilitating, and rapidly fatal if left untreated. b. GI KS occurs anywhere in the GI tract in 40% of patients at diagnosis, and is generally asymptomatic, although bleeding, obstruction, or enteropathy can occur. c. Other visceral organs, such as spleen, bone marrow, liver, heart, and pericardium, may be involved with KS. However, CNS involvement with KS is highly unusual. III. DIAGNOSTIC WORKUP AND STAGING A. Diagnosis of KS should be confirmed in all patients by biopsy on at least one occasion. Differential diagnosis of skin lesions in HIV-infected patients includes ecchymosis, nevi, melanoma, Bartonella henselae–associated skin lesions, and dermatofibromas. B. Clinical evaluations 1. Evaluation of cutaneous disease includes counting the number of lesions if less than 50, or the number of lesions on a single portion of the body, measurement of biperpendicular diameters of five lesions, description of the color of the lesions, and whether they are raised or flat, whether there is tumor-associated edema, and photographic documentation of the lesions. 2. Evaluation of mucosal lesions should include description of the size of the lesions and their site of involvement. 3. Evaluation of visceral disease should be directed primarily at assessing pulmonary and GI tract lesions. Patients should have a baseline and at least annual chest radiograph, or, if indicated, chest CT. If GI bleeding, vomiting, pain, or other abdominal symptoms are present, upper or lower endoscopy should be strongly considered. C. Pathology. The diagnosis of KS is made by biopsy and histologic examination of cutaneous lesions, enlarged lymph nodes, or visceral tissues. Typical pathology shows a proliferation of spindle cells that may express endothelial markers such as PECAM-1 (CD31), CD34, LYVE1, podoplanin (D2-40), and FLI1 and KSHV (HHV8) markers such as LANA, mixed with endothelial cells, fibroblasts, inflammatory cells, and extravasated erythrocytes. Similar histologic findings are

D.

E.

F.

G.

H.

present in non–AIDS-related KS. Radiology and endoscopic procedures 1. A baseline chest radiograph is done for all patients with KS to exclude pulmonary KS and other cardiopulmonary disorders associated with HIV infection. Localized or diffuse interstitial reticulonodular infiltrates with mediastinal prominence may be seen in patients with pulmonary KS and should be differentiated from lymphoma or PCP and other typical (i.e., bacterial) and atypical pneumonias (i.e., mycobacterial, CMV, or histoplasma pneumonias). KS may also present with alveolar infiltrates, pleural effusion, or isolated pulmonary nodules. KS lesions are generally thallium or PET positive and gallium negative, in contrast to pulmonary infections. 2. Bronchoscopy may reveal endobronchial erythematous KS-like lesions even with radiologically normal studies. Because transbronchial biopsies have poor histologic yield, a presumptive diagnosis of pulmonary KS can be made on the basis of dyspnea without fever, chest radiograph, and bronchoscopic findings after exclusion of other disease processes. Staging of KS utilizes the AIDS Clinical Trials Group (ACTG) classification system, which characterizes patients as good risk or poor risk, on the basis of their tumor burden (T), immune function (I), and presence of systemic illness (S). T0 denotes good-risk KS confined to skin and/or lymph nodes and/or minimal oral disease, whereas T1 poor-risk lesions are associated with symptomatic lymphedema, tumor ulceration, extensive oral disease, and/or visceral involvement. Immune function is categorized according to whether the CD4 count is less than or greater than or equal to 150/mm3. S0 is defined as no history of OIs, B symptoms, other HIV-related illness, and Karnofsky score of at least 70%. Good-risk KS patients are T0I0S0. Prognosis in the HAART era is largely determined by the T and S stages, whereas in the era of HAART use, CD4 count does not have a significant impact on survival. The 3-year OS is 88% for individuals with T0S0, 81% for T0S1 patients, 80% for T1S0 patients, and 53% for T1S1 patients. Morbidity from KS is associated with painful lesions in the mouth or on the soles of the feet, lymphedema, symptoms associated with visceral KS, or psychological disturbances resulting from the cosmetic effects of KS lesions. Mortality from KS is associated primarily with pulmonary KS and less commonly with hemorrhage from GI lesions.

IV. THERAPY A. Patients with good-risk or asymptomatic and stable poor-risk KS may be offered local or systemic therapy.

1. Local therapies include electron beam radiotherapy, topical 9-cis retinoic acid (Panretin Gel) or imiquimod (5% cream), intralesional injections or iontophoresis of vinblastine (0.1 mL of 0.2 mg/mL) or 3% sodium tetradodecyl sulfate (0.1 to 0.3 mL), cryotherapy, laser coagulation therapy, or surgical excision. Despite the effectiveness of these procedures, there are several possible complications. Radiotherapy may result in chronic residual lymphedema, postirradiation telangiectasias, woody skin changes, and reappearance of KS after treatment. It is more toxic for mucosal than skin lesions. Panretin gel can cause local inflammation and lightening of the skin, resulting in inadequate cosmetic results. Photodynamic therapies can result in moderate pain and photosensitivity for a number of weeks after treatment. Intralesional injections cause necrosis or sclerosis of mucocutaneous lesions, which may be quite painful. Cryotherapy can result in hypopigmented areas, particularly troublesome for dark-skinned individuals. Surgical excision is not optimal for large lesions because of reappearance of KS at the margins. 2. HAART therapy alone produces a response rate of about 80% in patients with T0 lesions, but responses are unusual in patients with T1 lesions. This approach is more likely to be effective in patients naïve to HAART who have previously poorly controlled HIV and who will be compliant with subsequent use of HAART. The time to response is 3 to 9 months. PI-based and non-nucleoside reverse transcriptase inhibitor–based HAART regimens have been verified to be similarly effective. It should be noted that progressive KS may also develop in patients who have recently initiated HAART, attributed to an immune reconstitution syndrome (IRIS). 3. Thalidomide has been reported to produce responses in 30% to 50% of patients, at doses of 100 to 1,000 mg/day (200 mg/day is the usual maximal tolerated dose), but is complicated by fatigue, constipation, neuropathy, xerostomia, neutropenia, orthostatic hypotension, risk of birth defects, and, less commonly, hyper- or hypoglycemia, hypothyroidism, tremor, elevated serum transaminases, or thrombosis. Lenalidomide (25 mg/day on days 1 to 21 of 28 day cycle) and pomalidomide (4 mg/day) also have significant activity. 4. Interferon-` produces responses in about 30% of patients, when used in high doses, greater than 20 mU/m2 3 times per week, but fewer responses at lower doses when used alone, although responses at low doses are improved when combined with PIs. Interferon-α can result in neutropenia, flulike symptoms, and depression. The use of pegylated interferon for KS has not been reported. B. Patients with poor-risk symptomatic visceral KS or rapidly progressive KS should be treated with HAART combined with chemotherapy or investigational agents. Pharmacologic doses of systemic corticosteroids should be avoided, because

this can cause marked acceleration of KS. Therapy is usually continued until there is a plateau in the response, or two cycles beyond complete remission. 1. Liposomal anthracyclines are the most appropriate initial therapy, and liposomal doxorubicin (Doxil, 20 mg/m2 IV every 2 to 3 weeks) results in response rates of 50% to 70%. Grade 3 or 4 adverse effects include myelosuppression (36%), nausea and vomiting (15%), anemia (10%), and handfoot syndrome. The incidence of extravasation injury, mucositis, nausea, alopecia, and cardiomyopathy with liposomal anthracyclines is lower than that with nonliposomal anthracyclines. 2. Paclitaxel 100 mg/m2 q2 to 3 weeks is generally considered the most effective and best-tolerated second-line agent, although some oncologists recommend it as first-line therapy for life-threatening KS. Response rates of 59% to 71% have been reported, with a median duration of response of more than 10 months. Myelosuppression (grade 3 or 4 in 35%), alopecia, neuropathy, and hypersensitivity reaction are the major toxicities. Liposomal paclitaxel (Xyotax) has not been studied in AIDS-KS. 3. Oral etoposide may be useful as a third-line agent, given at a dose of 50 mg/day for 7 days of each 14-day cycle. In a trial of 36 patients, the response rate was 36%, with a median duration of response of 25 weeks. This therapy was complicated by grade 3 or 4 neutropenia in 36% of the patients. 4. Vinorelbine has a 43% response rate in patients with one or more prior systemic therapies for KS, but is associated with myelosuppression. 5. Alternative chemotherapy regimens that may be considered include bleomycin, docetaxel, nAb-paclitaxel, gemcitabine, or a combination of doxorubicin, bleomycin, and vincristine. 6. Duration of therapy depends on individual patients. Generally, chemotherapy is given until a plateau in the response has been achieved, and then doses of therapy can be discontinued or given less frequently. Chronic chemotherapy can be associated with limiting cumulative treatment-related toxicities. V. COMPLICATIONS A. Complications of AIDS-KS. Although visceral KS, especially GI and pulmonary KS, may prove fatal, AIDS-related immunosuppression and OIs remain the major cause of morbidity and mortality in patients with KS. Superimposed bacterial, fungal, and parasitic infections in ulcerated, weeping lesions are not uncommon. Severe dyspnea from pulmonary KS and hemorrhage from GI involvement of KS also may be seen. Inflammatory syndromes, characterized by fever and lymphadenopathy, associated with KS include the KS inflammatory cytokine syndrome (KICS), multicentric Castleman disease, and KS IRIS.

B. Complications of therapy. The use of HAART with systemic anti-KS therapy, such as paclitaxel, may potentially cause profound toxicity in some patients with AIDSKS. The metabolism of paclitaxel, docetaxel, and anti-HIV PIs involves cytochrome P450 3A4 isoform. It is important to recognize that immunosuppressants, including glucocorticoids and rituximab, may exacerbate KS. VI. FOLLOW-UP The frequency of follow-up may vary from every 2 weeks to every 6 months, depending on the stage of disease, rate of disease progression or regression, and the type of therapy. During follow-up visits, indicator lesions should be measured, the number of KS lesions in indicator regions should be counted, and the character of the lesions described. Repeat photographs and follow-up chest radiographs should be performed as clinically indicated. VII. CURRENT FOCUS OF RESEARCH A. Antiangiogenic agents have been extensively studied in AIDS-associated KS. This includes thalidomide, as well as several agents studied in phase 1 and 2 trials, including fumagillin analog TNP-470, a VEGF receptor inhibitor SU5416, antiangiogenic dipeptide IM862, bevacizumab, lenalidomide, and ephrin and Notch pathway inhibitors. The matrix metalloproteinase inhibitor, COL-3, a tetracycline analog, resulted in a 44% response rate for a median duration of more than 25 weeks in a cohort of 17 patients. This therapy was complicated by headache, photosensitivity, or rash. Interleukin 12 has also been shown to be a potent inhibitor of angiogenesis, perhaps through induction of inducible protein 10, and reactivation of KSHV. An antisense oligonucleotide to VEGF mRNA will also be studied in AIDS-KS. A clinical trial of soluble ephrin B4 is currently underway. There is also evidence that antiretroviral PIs may function as angiogenesis inhibitors, and a clinical trial of high-dose nelfinavir is currently underway. B. Inhibitors of growth factor receptor signaling were studied, including imatinib, as an inhibitor of platelet-derived growth factor and c-kit receptors. In a trial of 10 individuals given 600 mg/day, five exhibited a PR, but grade 3 or 4 diarrhea, depression, or neutropenia occurred in eight patients. Other studies are based on the mediators of signaling pathways, including phosphatidylinositol 3-kinase, serinethreonine kinase Akt, extracellular receptor kinase Erk, nuclear factor kappa B, target of rapamycin (TOR), and cyclin D. C. Cell-differentiating retinoids have also been used systemically in AIDS-KS patients. Oral 9-cis-retinoic acid (alitretinoin or Panretin) resulted in a 37% response rate, but almost half of the patients discontinued treatment because of headache or skin toxicity. Hypertriglyceridemia and subclinical pancreatitis have also been

reported with retinoids, including alitretinoin. There are no reports of the use of bexarotene for AIDS-KS. D. Anti-HHV8 therapy with cidofovir or foscarnet has been reported in anecdotal or retrospective studies. For example, time to KS progression was prolonged in patients treated with foscarnet compared with patients treated with ganciclovir (211 vs. 22 days). Histone deacetylase inhibitors, such as butyrate and valproic acid, and nuclear factor kappa B inhibitors (e.g., proteasome inhibitors bortezomib and ixazomib), which have been shown to induce lytic gene expression of HHV8, are being evaluated in clinical trials. E. Immunotherapy with PD-1 and CTLA-4 inhibitors are currently under investigation for KS. Although anecdotal responses have been reported, a few serious adverse events have also been noted. These included the induction of multicentric Castleman disease in one patient, and KICS in another. OTHER HIV-ASSOCIATED MALIGNANCIES Although a number of other malignancies may be more frequent among HIV-positive than among HIV-negative individuals, treatment approaches are generally similar, especially if virus load is well controlled and CD4 is not profoundly depressed. I.

HCC is about 5-fold more common in HIV-positive individuals than in the general population, primarily because of a higher rate of persistent hepatitis B and C virus infection. However, higher rates of alcohol abuse, nonalcoholic steatohepatitis, and diabetes may contribute to HCC development in HIV-positive individuals. Screening for active HBV and HCV infection is recommended for all HIV-positive individuals. Hepatitis B vaccine should be provided to all individuals who are not immune to HBV. Antiviral treatment is recommended for individuals with persistent infection and evidence of liver disease. Screening for HCC in patients with cirrhosis is recommended every 6 months with ultrasound. Treatment of HCC in HIV-positive patients, with transplantation, TACE, or sorafenib (depending upon the stage), is similar to that in HIVnegative individuals. However, outcomes of transplantation for HCC may be worse in HIV-positive individuals, in terms of HCV and HCC recurrence. Results of other therapeutic agents (e.g., lenvatinib, cabozantinib, ramucirumab, and checkpoint inhibitor therapy) have not been reported for HIV-associated HCC.

II. LUNG CANCERS occur 2.5- to 5-fold more commonly in HIV-positive individuals than in the general population, and are the most frequently diagnosed non–AIDSdefining malignancy in this population. Lung cancer risk is unrelated to level of HIVinduced immunosuppression. III. LIP CANCERS occur 3.1-fold more commonly in HIV-infected patients than in the

general population. Some of these cancers may be HPV related. IV. CERVICAL CANCERS occur 3- to 5-fold more commonly in HIV-infected women than in the general population. Although cervical cancer accounts for only 1% of cancers in U.S. HIV-positive patients, it is one of the most common HIV-associated cancers in resource-limited settings. Pap smears are recommended at the time HIV is diagnosed, and repeated at least once within 6 months if normal. If the initial or follow-up Pap smear shows severe inflammation, a repeat study should be performed in 3 months. If a Pap smear shows squamous intraepithelial lesions or atypical squamous cells of undetermined significance, colposcopic examination and, if indicated, biopsies should be performed. High-risk HPV infections are found more commonly in sexually active HIVinfected women than in women not infected with HIV. When cervical cancer presents in an HIV-infected woman with CD4 less than 500/mm3, it appears at a younger age and with more advanced disease, and it is associated with a worse outcome than in women without HIV infection. The incidence and therapeutic response of cervical cancer, however, appear unchanged by HAART therapy. The use of radiation therapy combined with chemotherapy may also be less well tolerated in HIV-infected women than in women lacking HIV. As for HIV-negative patients, early-stage, nonbulky cervical tumors respond well to surgical intervention, and for more advanced tumors, the standard of care is concomitant chemoradiotherapy with cisplatin. V. VULVAR AND PENILE CANCERS occur 9- and 5-fold, respectively, more commonly in HIV-positive individuals than in the general population. VI. OTHER Higher rates of testicular seminomas, multiple myeloma, multicentric Castleman disease, nonmelanotic and melanotic skin cancer, conjunctival tumors (in sub-Saharan Africa), and leukemia have also been described in HIV-infected individuals than in the general population. SUGGESTED READINGS Alvarans JC, Zaia JA, Forman SJ. How I treat patients with HIV-related hematological malignancies using hematopoietic cell transplantation. Blood 2017;130:1976–1984. Barta SK, Xue X, Wang D, et al. Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients. Blood 2013;122:3251–3262. Bower M, Palfreeman A, Alfa-Wali M, et al. British HIV Association guidelines for HIV-associated malignancies 2014. HIV Med 2014;15:1–92. Dittmer DP, Damania B. Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 2016;126:3165–3175. Dunelavy K, Pittaluga S, Shovin M, et al. Low-intensity therapy in adults with Burkitt’s lymphoma. New Engl J Med 2013;369:1915–1925. Dunleavy K, Wilson WH. How I treat HIV-associated lymphoma. Blood 2012;119:3245–3255. Lurain K, Polizzotto MN, Aleman K, et al. Viral, immunologic, and clinical features of primary effusion lymphoma. Blood

2019;133:1753–1761. Ratner L, Lee J, Tang S, et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 2001;19:2171–2178. Rudek MA, Flexner C, Ambinder RF. Use of antineoplastic agents in patients with cancer who have HIV/AIDS. Lancet Oncol 2011;12:905–912. Uldrick TS, Little RF. How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. Blood 2015;126:1226–1235. Yarchoan R, Uldrick TS. HIV-associated cancers and related disease. N Engl J Med 2018:378:1029–1041.

I.

INTRODUCTION Cancer is a disease of aging; the incidence of most malignancies increases with age. Over half of new cancer diagnoses and nearly 70% of cancer deaths occur in patients over the age of 65. With the aging of the population, the number of older adults with cancer is estimated to increase by 67% by 2030. There are significant differences in cancer-specific death rates between older and younger individuals. These age-related disparities likely differ in cause among different malignancies, but contributory factors include differences in screening, more advanced stage at presentation, differences in biology of disease across the age spectrum, and less aggressive treatment in older adults. Knowledge gaps in the treatment of older adults with cancer: Contributing to differences in treatment between older and younger adults are the increased vulnerability of older adults to toxicity of therapy and the underrepresentation of older adults in clinical trials. Older adults are less likely to be enrolled in clinical trials owing to restrictive exclusion criteria based on organ function or comorbidities. In addition, clinicians are less likely to propose participation in a clinical trial, although, if asked, older adults are as likely as younger adults to agree to participate. This underrepresentation of older adults in clinical trials has resulted in substantial gaps in the knowledge about the safety and efficacy of cancer therapies when applied to older adults. With the growth in the number of older adults with cancer, increasing attention is now being directed to the need to increase our knowledge base on treating older adults with cancer.

II. BIOLOGY OF CANCER IN OLDER ADULTS There is a commonly held perception that, overall, cancer in older adults is less aggressive than in younger adults. Breast cancer is one example, being more likely to be

hormone receptor positive. Overall, however, most cancers do not exhibit substantial age-related differences in biology. In some cases, older age is actually associated with more aggressive, treatment-resistant biology, as in acute myeloid leukemia and diffuse large B-cell lymphoma. Thus, in older adults, variations in treatment decisions are largely not driven by biology of disease, but rather by the patient’s individual health status. III. COMPREHENSIVE GERIATRIC ASSESSMENT Increasing chronologic age is associated with an increasing prevalence of comorbidities and functional or cognitive impairment. A comprehensive geriatric assessment (CGA) is a multidimensional assessment of geriatric domains (Table 36-1). Although the screening tools used are often referred to as “CGA,” in geriatrics, CGA refers to the multidisciplinary assessment, interpretation of screening tools, and recommended tailored interventions. TABLE 36-1

Domains of a Comprehensive Geriatric Assessment

Domain

Commonly Used Scales/Measures

Comorbidities

• • • •

Physical performance

• Timed Up and Go • Short physical performance battery

Functional status

• Activities of daily living • Bathing • Continence • Dressing • Toileting • Transferring • Feeding • Instrumental activities of daily living • Using telephone • Getting to places out of walking distance • Shopping for groceries • Preparing meals • Doing housework • Doing laundry • Taking medications • Managing finances • Performance status

Cognition

• Short blessed test • Montreal Cognitive Assessment (MoCA) (http://www.mocatest.o

Charlson comorbidity index Cumulative illness rating scale—geriatrics Adult comorbidity evaluation-27 (ACE-27) Hematopoietic cell transplantation comorbidity index (HCT-CI)

rg) • Mini-Mental Status Examination Depression

• Geriatric Depression Scale (GDS) • Patient Health Questionnaire-9 (PHQ-9)

Polypharmacy and inappropriate medications

• Beers Criteria for potentially inappropriate medications in the elderly • STOPP/START criteria

Geriatric syndromes are extremely common in older adults with cancer and are inadequately described in a routine oncology assessment. Coexisting medical conditions are present in more than 80% of cancer patients over the age of 80. Functional decline or disability refers to the greater need for assistance with daily activities owing to physical or cognitive decline. Cognitive impairment is common among older adults with cancer, with 15% to 25% of patients in the outpatient setting and 40% to 50% of patients in the inpatient setting screening positive. Additionally, up to two-thirds of patients over the age of 75 with hematologic malignancies have been reported as potentially being cognitively impaired. Older adults with cancer are also at high risk for polypharmacy. A review of 248 community-dwelling older adults with cancer found 84% to be on 5 or more medications and 43% on 10 or more medications (J Clin Oncol 2015:33:1453). A meta-analysis found that polypharmacy (defined as five or more medications) was associated with postoperative complications, chemotherapy toxicities, and physical and functional decline (Oncologist 2019;24:1). Falls are also a common, costly, and serious adverse event in the lives of older adults with cancer. Functional dependence, self-reported slowing, depression, use of selective serotonin reuptake inhibitors, benzodiazepines or proton pump inhibitors, polypharmacy, impaired physical performance on the Timed Up and Go test, and impaired renal function have been shown to be risk factors for falls (Support Care Cancer 2018;26:3563). Evaluating only performance status (PS) significantly underestimates the level of impairment in an older individual. Comorbidities and functional status are entirely independent. Among older adults with cancer who had an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1, 10% were dependent in one or more activities of daily living (ADLs), nearly 40% were dependent in one or more instrumental activities of daily living (IADLs), nearly 30% were cognitively impaired, and 30% were depressed. Thus, PS is an inadequate measure of the heterogeneous health statuses of older adults. IV. TREATMENT OF CANCER IN OLDER ADULTS A. Surgery. Surgical management of cancers does not differ between older and younger

patients overall. Studies that appropriately control for confounders (such as comorbidities, advanced cancer stage, and functional impairment) demonstrate similar outcomes in older and younger patients undergoing cancer surgery. That said, some older adults are at greater risk for postoperative complications. In the Preoperative Assessment of Cancer in the Elderly (PACE) study, dependence in IADLs, self-reported fatigue, and an ECOG PS of two or more were associated with increased risk of complications of surgery (Crit Rev Oncol Hematol 2008;65:156). Similarly, dependence in ADLs, IADLs, and poor PS were associated with longer length of stay. Age was not associated with increased 30-day mortality, though male gender, advanced cancer stage, and extent of surgery were. Thus, age alone should not be a primary consideration in decisions regarding cancer surgery; decisions are better made in the context of evaluation of the patient’s individual functional status. B. Radiation. Similarly, age alone is generally not a primary consideration in decisionmaking regarding radiation therapy (RT) for cancer. Some studies have demonstrated greater acute functional decline during chemotherapy in older adults undergoing RT, but similar longer-term outcomes in patients undergoing curative-intent RT. Thus, among patients being treated with curative intent, the initial toxicity may be warranted given the longer-term outcomes. Conversely, among older adults treated with palliative intent, the risk of toxicity and functional decline must be balanced with the potential benefit of therapy. Among patients with glioblastoma, older age is associated with greater toxicity and cognitive impairment related to radiation with concurrent temozolomide. Little is known about predictors of toxicity of RT in older adults with cancer. In a small study of older adults with rectal cancer, comorbidities were associated with greater risk of acute toxicity. The role for evaluation with geriatric assessment in older adults undergoing RT remains to be examined. C. Systemic therapy. Age-related physiologic changes may increase the risk of toxicity of chemotherapy among older adults; these include reduced gastrointestinal motility, decreased splanchnic blood flow, changes in body composition resulting in altered volume of distribution, decreased hepatic blood flow, polypharmacy and drug interactions, and declining renal function (J Clin Oncol 2007;25:1832). 1. Chemotherapy. A comprehensive discussion of age-related differences in toxicity of individual chemotherapeutic agents is beyond the scope of this chapter. However, some important themes merit discussion. a. Hematologic toxicity. Older adults are at greater risk for myelosuppression than younger adults, particularly with exposure to the alkylating agents, because of age-related decreases in hematopoietic stem cell reserve. b. Mucositis. Older adults are at greater risk for mucositis with fluoropyrimidines, the liposomal anthracyclines, and high-dose melphalan, likely because of decreased ability to respond to mucosal damage.

c. Dose adjustments for renal insufficiency. Renal function declines with age. Serum creatinine levels alone are an inadequate reflection of renal function, which is better estimated with an equation, such as the Cockcroft–Gault or Modification of Diet in Renal Disease (MDRD) equation, or measured with a 24-hour urine collection. Many chemotherapeutic agents have not been thoroughly studied in patients with renal insufficiency. 2. Targeted agents. A large number of targeted agents have been brought from the bench to clinical trial and into the clinics in the past 15 years. The underenrollment of older adults in clinical trials has resulted in a paucity of data on most of these targeted agents in older adults, particularly older adults with comorbidities. A number of agents, including erlotinib, sorafenib, bevacizumab, imatinib, bortezomib, and lenalidomide, have been shown to have greater toxicity in older adults (Crit Rev Oncol Hematol 2011;78:227). Trastuzumab also appears to have an increased risk of cardiac toxicity in older adults. Overall toxicities in older patients treated with anti–programmed cell death (PD-1) or anti– programmed cell death ligand (PD-L1) therapy appear similar to younger patients. Additionally, there is early evidence to suggest that geriatric assessment–based risk prediction tools may help identify older patients who may be at increased risk of immunotherapy-related toxicities. In other cases, subgroup analyses of patients fit enough to participate in clinical trials may demonstrate similar efficacy and toxicity, only to be found to have increased toxicity and decreased effectiveness when applied in “real-world” settings, among patients with comorbidities and functional impairment. Caution must be used in using targeted agents in older adults, with attention to emerging postmarketing/phase IV data. V. PREDICTING TOXICITY OF CHEMOTHERAPY IN OLDER ADULTS With the increased vulnerability to toxicity and lack of data on treating older adults with cancer, clinicians are left to make decisions by combining clinical trial data and clinical judgment. Several instruments are being evaluated to aid in risk stratification and decision-making for older adults considering chemotherapy. In the Cancer and Aging Research Group study, over 750 patients underwent CGA prior to initiation of chemotherapy. Factors predictive of chemotherapy toxicity were age >73 years, anemia, renal insufficiency, recent falls, hearing impairment, limited ability to walk one block, decreased social activities, and requiring assistance with medications (J Clin Oncol 2011;29:3457; J Clin Oncol 2016;34:2366). In the Chemotherapy Risk Assessment for High Age Patients (CRASH) trial, diastolic blood pressure, dependence in IADLs, elevated lactate dehydrogenase (LDH), and the intensity of chemotherapy were associated with hematologic toxicity of chemotherapy, whereas ECOG PS, cognitive

impairment, nutritional compromise, and intensity of chemotherapy were associated with nonhematologic toxicity (Cancer 2012;118:3377). VI. PRACTICAL GUIDE TO ADDRESSING GERIATRIC SYNDROMES IN OLDER ADULTS WITH CANCER Consensus guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend routine use of the geriatric assessment in cancer patients aged greater than 65. Although more randomized trials are needed to examine the effectiveness of the geriatric assessment in older adults with cancer, several studies have suggested that benefits of its use may include predicting functional decline and side effects from treatment, estimating survival, detecting problems not found by routine evaluation, and improved pain control. Additionally, a randomized trial of more than 500 patients showed that when oncologists were provided with a summary and recommendations from a patient’s geriatric assessment, there was an increase in the number and quality of discussions about age-related concerns and an improvement in patient satisfaction (J Clin Oncol 2018;36, Suppl). Table 36-2 lists some potential interventions for geriatric syndromes identified in older adults. TABLE 36-2

Interventions for Geriatric Syndromes

Domain

Intervention

Comorbidities

Comanagement with primary care physician

Functional decline

Physical therapy consult Occupational therapy consult

Falls

Physical therapy consult Occupational therapy consult for home safety evaluation Screen for neuropathy Medication review

Nutritional risk

Consultation with dietitian Social work consult for resource assistance (meals-on-wheels, cancer foundation support for nutritional supplements)

Polypharmacy and inappropriate medications

Medication reconciliation and review Home health nursing for medication setup Consultation with pharmacist

Lack of social support

Consultation with social worker

VII. SURVIVORSHIP IN OLDER ADULTS With the coming increase in the number of older adults with cancer, there will be a consequent increase in the number of older adult cancer survivors. Older adult cancer survivors are at greater risk for developing geriatric syndromes. In a study of over 12,000 older adults, cancer survivors were more likely to report hearing impairment, incontinence, depression, falls, and osteoporosis. Even after completion of cancer therapy, older adults will remain increasingly vulnerable and will require attention to long-term effects of their cancer therapy. VIII.SUMMARY The population is aging, and with the increased incidence of cancer with age, the number of older adults with cancer will increase significantly over the coming years. Older adults may be at increased risk for chemotherapy toxicity, but tools to better predict toxicity are being validated. CGA is a tool that holds promise to aid in individualizing cancer treatment for older adults. SUGGESTED READINGS Audisio RA, Pope D, Ramesh HS, et al. Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help: a SIOG surgical task force prospective study. Crit Rev Oncol Hematol 2008;65:156–163. Exterman M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the chemotherapy risk assessment scale for high-age patients (CRASH) score. Cancer 2012;118:3377–3786. Gonsalves W, Ganti AK. Targeted anti-cancer therapy in the elderly. Crit Rev Oncol Hematol 2011;78:227–242. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 2011;29:3457–3465. Mohile SG, Dale W, Somerfield M, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guidelines for geriatric oncology. J Clin Oncol 2018;36:2326–2347.

I.

INTRODUCTION Cancer patients have a 5- to 7-fold increased risk of developing venous thromboembolism (VTE) compared with noncancer patients ( JAMA 2005;293:715), with cancer-associated VTE accounting for 20% to 30% of all VTEs ( J Thromb Haemost 2007;5:692). Patients with cancer-associated VTE had decreased survival compared with those without VTE matched by cancer type and stage. When treated with anticoagulation, cancer patients have higher rates of major bleeding events compared to patients with VTE without cancer (Blood 2002;100:3484).

II. PATHOPHYSIOLOGY AND RISK FACTORS The pathophysiology of cancer-associated VTE is multifactorial and complex. In response to cancer-induced inflammatory cytokines, tissue factor (TF) or cancer procoagulants are aberrantly expressed on the surface of cancer cells, monocytes, and endothelial cells, promoting a hypercoagulable state, angiogenesis, and tumor metastasis. Second, decreased patient activity because of the disease or therapy leads to increased venous stasis. In addition, vascular injury from surgery, chemotherapy, radiation, and central venous catheters (CVCs) are major risk factors for VTE, completing Virchow’s triad. Thus, cancer is a heterogeneous disease with varying VTE risk based on cancer subtype and stage, patient-associated factors, and cancer-specific therapy. A. Type of cancer. Cancers associated with the highest risk of VTE include lung, pancreas, brain, ovary, and hematologic malignancies (myeloma, lymphoma, leukemia) (JAMA 2005;293:715). B. Stage of cancer. More advanced stage is associated with higher risk. C. Timing related to cancer diagnosis. Patients are at highest risk for VTE in the period immediately following cancer diagnosis. This is hypothesized to be due to the

presence of the largest disease burden. In addition, this period correlates with initiation of therapy (i.e., chemotherapy/surgery). D. Patient-associated risk factors. These are similar to those in noncancer patients and include age, race, obesity, presence of medical comorbidities, surgery, history of VTE, presence of hereditary thrombophilia, and leukocytosis and/or thrombocytosis. E. Cancer treatment. Recent surgery is a well-documented risk factor for VTE in both cancer and noncancer patients. Pathophysiology is attributed to direct vascular damage, prolonged immobility, and the presence of an inflammatory state. Patients receiving chemotherapy or hormonal therapy are at increased risk of VTE. Plausible mechanisms for this prothrombotic state include decreased activity of physiologic anticoagulants, release of procoagulants from apoptotic cancer cells, and druginduced injury to endothelial cells. Some of the specific therapies that have been associated with increased risk of VTE in randomized, prospective trials include cisplatin, hormonal therapy, antiangiogenic agents, erythrocyte-stimulating agents (ESAs), and immunomodulatory agents (i.e., lenalidomide and thalidomide). Knowledge of these potential risk factors for VTE in cancer patients can guide clinicians to identify patients with increased risk of VTE and target therapy accordingly. Several risk prediction models are available to identify cancer patients at greatest risk of developing VTE. The 2019 American Society of Clinical Oncology (ASCO) VTE guidelines recommend the use of the model proposed by Khorana et al., given that it has been validated in a large population of cancer patients (Blood 2008;111:4902; J Clin Oncol 2020;38:496). In a model using a cohort of 4,066 ambulatory cancer patients initiated on chemotherapy, several important risk factors for VTE were identified in multivariate analysis including site of cancer, prechemotherapy platelet and leukocyte counts, hemoglobin or use of red cell growth factors, and body mass index (BMI). Using a point system for each risk factor, they divided patients into three risk groups: high (3 points), intermediate (1 to 2 points), and low (0 points) risk, with VTE rates of 6.7%, 2%, and 0.3%, respectively, over 2.5 months. The Khorana score has been externally validated in multiple large studies. The clinical utility of such models was recently assessed in two large randomized controlled trials (RCTs) assessing the safety and efficacy of thromboprophylaxis with direct oral anticoagulants (DOACs) in ambulatory cancer patients at high risk of VTE (defined as Khorana score ≥2). III. UNPROVOKED VTE AND OCCULT CANCER About 20% to 30% of all newly diagnosed VTE are cancer associated. The majority of these cases will present with thrombosis after an established diagnosis of cancer. However, a percentage of patients with seemingly unprovoked VTE will subsequently be diagnosed with cancer. This association has raised the question of the clinical benefit of cancer screening in patients who present with idiopathic VTE.

In a study by Prandoni et al. (N Engl J Med 1992;327:1128), 260 consecutive outpatients with objectively diagnosed deep vein thrombosis (DVT) were followed for 2 years. Development of cancer in patients was compared between the idiopathic (n = 153) and secondary DVT (n = 107) groups. History, physical, and routine laboratory testing were performed at VTE diagnosis in each group, identifying 3.3% (n = 5) of patients with an underlying malignancy in the idiopathic group (two lung cancers, one multiple myeloma, one osteosarcoma, and one chronic lymphocytic leukemia) compared to no patients in the secondary DVT group. During the 2-year follow-up in the remaining patients, symptomatic malignancies were diagnosed in 11 of 145 patients (7.6%) with idiopathic DVT compared to 2 of 105 patients (1.9%) with secondary DVT. The majority of malignancies (77%) were diagnosed in the first 12 months of follow-up, with all cases diagnosed by 18 months. Given the association, oncologists may be asked to evaluate patients with idiopathic VTE for occult cancer. Several trials have assessed the role of screening for occult malignancy in patients with unprovoked VTE. In the SOME trial, 854 patients with a first, unprovoked VTE were randomly assigned to undergo limited screening (history and physical, routine blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited screening combined with computed tomography (CT) (N Engl J Med 2015;373:697). Over the 12-month study period, 14 patients in the limited screening and 19 patients in the limited screening combined with CT received a diagnosis of cancer (p = 0.28). Within these groups, limited screening missed 4 of the 14 diagnoses, whereas limited screening plus CT missed 5 of 19 diagnoses (p = 1.0). In addition, there was no significant difference between time to cancer diagnosis (p = 0.88), overall mortality (p = 1.0), or cancer-related mortality (p = 0.75) between the two groups. A meta-analysis assessed the prevalence of occult cancer in patients with unprovoked VTE in different subgroups, including patients undergoing limited versus extensive screening strategies (Ann Intern Med 2017;167:410). The overall prevalence of cancer within 12 months of VTE diagnosis was 5.2% (95% confidence interval [CI] 4.1 to 6.5). Extensive screening was associated with a 2-fold increased probability of an occult cancer diagnosis at screening (p = 0.01) compared to limited screening, with no difference in probability at 12 months. Of the cases diagnosed with extensive screening, 66% of the diagnoses were found through limited screening procedures (i.e., history and physical). In summary, 20% to 30% of all newly diagnosed VTEs are cancer associated. Although a significant proportion of cancers are known at the time of VTE diagnosis, the majority of the remaining cases will be established between presentation and 12 months. Aggressive screening for occult cancers in asymptomatic patients with unprovoked VTEs has not been associated with improved survival and is not recommended. However, evaluation with history, physical, routine labs, and age/gender-appropriate

cancer screening is an appropriate strategy. IV. PREVENTION OF VTE IN PATIENTS WITH CANCER As stated previously, cancer patients have a 7-fold increased risk of VTE compared to those without cancer, with risk highest in the first 3 months after cancer diagnosis (53fold increased risk) (JAMA 2005;293:715). VTE can lead to significant morbidity and mortality, hospitalizations, delay in cancer therapy, and more. Therefore, effective VTE prevention strategies are crucial in the care of these high-risk patients. A. VTE prophylaxis in cancer patients in the perioperative setting. The incidence of VTE after cancer surgery may be as high as 50% without prophylaxis. Although mechanical prophylaxis can reduce postoperative VTE by approximately 50%, it is inferior to anticoagulant prophylaxis. Prospective studies comparing prophylacticdosed low-molecular-weight heparin (LMWH) to unfractionated heparin (UFH) for 7 to 10 days postoperatively in cancer patients have shown similar efficacy and safety, with VTE rates around 15% and major bleeding incidents around 4%. These findings formed the basis for recommendations that cancer patients should receive postoperative VTE prophylaxis for 7 to 10 days following major surgery. There are compelling data to support extended DVT prophylaxis beyond 10 days following some types of cancer surgery (i.e., abdominal and pelvic). In the ENOXACAN II study, patients undergoing curative, open surgery for abdominal or pelvic malignancies were randomized to receive prophylactic enoxaparin for 6 to 10 days (routine prophylaxis) versus 25 to 31 days (extended prophylaxis) (N Engl J Med 2002;346:975). The incidence of DVT was significantly different: 12% for routine and 4% for extended prophylaxis, whereas bleeding complications were comparable (3.6% and 4.7%, respectively). On the basis of this, the 2012 American College of Chest Physicians (ACCP) guidelines recommend extended DVT prophylaxis with LMWH for patients undergoing abdominal/pelvic open surgery for cancer (Chest 2012;141:e227S). There is limited consensus on prophylactic regimens following minor or less invasive surgeries. Patients undergoing laparoscopic colorectal, urologic, and gynecologic cancer surgeries have documented increased risk for VTE complications. Thus, 7 to 10 days of postoperative DVT prophylaxis with UFH or LMWH is reasonable until future studies determine the ideal prophylaxis schedule for this population. Lastly, patients who undergo surgery for central nervous system neoplasms have one of the highest rates of postoperative VTE and lowest tolerance for bleeding complications. Several prospective randomized trials have validated the safety and efficacy of VTE prophylaxis with UFH and LMWH starting approximately 24 hours after surgery (Br J Haematol 2004;128:291). These findings are supported in the ACCP guidelines recommending pharmacologic prophylaxis following craniotomy

in cancer patients (Chest 2012;141:e227S). B. VTE prophylaxis in hospitalized cancer patients. Major guidelines have recommended all hospitalized oncology patients admitted for management of acute medical conditions or cancer therapy should be considered for mechanical or pharmacologic VTE prophylaxis. Unfortunately, there is a lack of data supporting these recommendations, which are primarily based on studies in general hospitalized, acutely ill medical patients. Several prospective, randomized VTE prevention studies have confirmed the efficacy and safety of LMWH and UFH prophylaxis in acutely ill medical patients; however, cancer patients comprised only 5% to 14% of these populations. A subset analysis of cancer patients in the MEDENOX (N Engl J Med 1999;341:793) study detected a 50% reduction in VTE risk in patients receiving enoxaparin versus placebo. Based on the available data, the 2012 ACCP guidelines recommend UFH or LMWH for VTE prophylaxis in hospitalized cancer patients (Chest 2012;141:e227S). Temporary risk factors for bleeding complications, including invasive procedures or thrombocytopenia, may require interruption of anticoagulant prophylaxis. In patients with high risk of bleeding or active bleeding, mechanical prophylaxis can be pursued, but UFH or LMWH should be resumed when bleeding risk resolves. Ambulation should also be conscientiously encouraged during hospitalization. C. VTE prophylaxis in ambulatory cancer patients. Given the high risk of developing VTE in cancer patients, numerous investigators have assessed the efficacy of thromboprophylaxis. A meta-analysis of studies evaluating LMWH prophylaxis in unselected ambulatory cancer patients found a significant reduction in the rate of VTE (relative risk [RR] 0.54; 95% CI 0.38 to 0.75) and no increase in the risk of major bleeding (RR 1.44; 95% CI 0.98 to 2.11) (Cochrane Database Syst Rev 2016;12). However, the low overall rate of VTE in the placebo arms, the morbidity and cost of daily injections, and the potential for bleeding prevented routine adoption of prophylaxis. The subsequent development of validated risk prediction models as well as the availability of oral prophylaxis with DOACs prompted two large RCTs to assess the safety and efficacy of DOACs for prevention of VTE in high-risk ambulatory cancer patients. The AVERT study assessed the efficacy and safety of apixaban 2.5 mg twice daily versus placebo for the prevention of VTE in ambulatory cancer patients with Khorana score of ≥2 points (N Engl J Med 2019;380:711). The primary efficacy outcome was objectively confirmed proximal DVT or pulmonary embolism (PE) at 180 days. Apixaban was associated with a significant reduction in the risk of VTE compared to placebo (4.2% vs. 10.2%, hazard ratio [HR] 0.41; p < 0.001), albeit with a higher risk of major bleeding (3.5% vs. 1.8%, hr 2.00; p = 0.046). When limiting the analysis to the on-treatment period (only accounting events occurred while on

study medications or within 3 days of being off study medications), there was no significant difference in major bleeding between the two arms (2.1% vs. 1.1%, HR 1.89; 95% CI 0.39 to 9.24). On the other hand, the CASSINI trial assessed the efficacy of rivaroxaban 10 mg daily for the prevention of VTE in a double-blind, placebo-controlled, randomized trial in a similar patient population (ambulatory cancer patients with Khorana score of ≥2 initiating a new line of chemotherapy) (N Engl J Med 2019;380:720). Screening ultrasound of bilateral lower extremities was employed at enrollment, 8, 16, and 24 weeks, and screen-detected DVTs were included in the primary outcome. The primary composite endpoint included (1) objectively documented proximal lower extremity DVT or PE, (2) symptomatic DVT in the upper extremity or distal lower extremity, and (3) death attributed to VTE over 180 days. The rate of the primary endpoint was numerically lower, but not statistically significant, with rivaroxaban compared to placebo (6.0 % vs. 8.8%, HR 0.66; p = 0.10). On-treatment analysis showed a significant reduction in the primary endpoint with rivaroxaban (2.6% vs. 6.4%, HR 0.40; 95% CI 0.20 to 0.80) compared to placebo. Major bleeding occurred in 2.0% of patients on rivaroxaban, compared to 1.0% on placebo (HR 1.96; 95% CI 0.59 to 6.49). Given the above findings, the ASCO 2019 guidelines as well as the International Society of Thrombosis and Haemostasis (ISTH) guidelines both recommend consideration of prophylaxis with apixaban, LMWH, or rivaroxaban in high-risk ambulatory cancer patients (Khorana score of ≥2) starting a new line of chemotherapy, provided the patient does not have major risk factors for bleeding or alternate contraindications to therapy. V. CVC AND THROMBOSIS Percutaneously inserted CVCs and port-a-catheters provide reliable venous access for blood collection, administration of chemotherapy, medications, and blood components to cancer patients. However, they are associated with several complications, one of which is thrombosis (including occluded catheter lumen, external catheter fibrin sheath, and partial or occlusive VTE). The reported frequency of symptomatic upper extremity DVT associated with CVC in cancer patients not using prophylactic anticoagulants decreased from approximately 38% (Ann Intern Med 1990;112:423) in the 1990s to around 4% in more recent years ( J Clin Oncol 2005;23:4057), most likely reflecting refinements in catheter materials and insertion techniques. Although earlier RCTs have demonstrated a significant reduction in venography-confirmed upper extremity DVTs with either warfarin 1.0 mg/day or dalteparin 2,500 IU/day, further RCTs have failed to show a significant reduction of asymptomatic or symptomatic CVC-associated DVTs with warfarin 1.0 mg/day, enoxaparin 40 mg/day, or dalteparin 5,000 IU/day compared with placebo. Based on the results of these contemporary studies, the 2012 ACCP guidelines

do not recommend routine prophylaxis for cancer patients with CVCs. Optimal treatment for symptomatic CVC-associated DVTs is controversial. Although the risk of symptomatic PE appears to be low, it remains a potentially fatal complication. Because of the lack of high-quality evidence, expert opinions guide current practice. The current recommendations are that the catheter can remain in place as long as it is still needed, functional, and with no other compelling reason for removal such as infections; however, it should be removed whenever it is not needed or not functional. It is recommended to continue anticoagulation as long as the catheter is present or until 3 months after removal of the catheter. Current studies are underway to investigate whether shorter duration of anticoagulation (4 to 6 weeks) is appropriate after catheter removal. VI. TREATMENT OF VTE IN CANCER PATIENTS A. Therapy of VTE in patients with cancer 1. Special issues in patients with cancer. Three important issues related to treatment of cancer-associated VTE are the safety, type, and duration of anticoagulation therapy. The only absolute contraindication to therapeutic anticoagulation is active bleeding that cannot be rapidly or reliably controlled. However, bleeding risk can be difficult to predict in a quantitative manner for each individual patient. Treatment of VTEs in patients with primary or metastatic brain tumors is challenging, because of the potentially devastating complications of intracranial hemorrhage associated with anticoagulation, the high risk of recurrent VTE, and the limited evidence to guide management. Therapeutic anticoagulation is considered by some providers to be an absolute contraindication in patients with highly vascular brain metastases or recent craniotomies. For patients in whom the benefit of anticoagulation is judged to outweigh the risk, one approach involves cautious initiation of continuous infusion of UFH and, if tolerated, switch to long-term anticoagulation therapy such as LMWH. Thrombocytopenia, either cancer related or secondary to chemotherapy, complicates anticoagulation. Although data to define an evidencebased, safe, minimal platelet count are not available, expert opinions and anecdotal clinical experiences support the safety of therapeutic anticoagulation when the platelet count is >50,000/μL. When the platelet count drops below this level, lower intensity or interruption should be considered. 2. Role of inferior vena cava (IVC) filters. IVC filters are used to prevent development of a PE in patients with acute, lower extremity DVT when anticoagulation cannot be safely administered. However, IVC filters are thrombogenic and have been shown to increase the risk of lower extremity DVT over time. Therefore, careful evaluation for the need of IVC filter is strongly

recommended prior to insertion; if it’s deemed needed, a retrievable filter should be used, with reinitiation of anticoagulation and removal of the filter as soon as possible, when the risk of acute bleeding has resolved. 3. Initial treatment of VTE. Options for initial anticoagulation in cancer patients include continuous UFH, LMWH, fondaparinux, and rivaroxaban. Subgroup analyses of cancer patients initially treated with LMWH versus UFH for acute VTE showed similar efficacy for VTE recurrence. LMWH became preferred over UFH in cancer patients because of the ease of administration, ability to use in the outpatient setting, elimination of need for therapeutic monitoring, and lower risk of heparin-induced thrombocytopenia (HIT). In a study comparing twice-daily (1 mg/kg) versus once-daily (1.5 mg/kg) dosing of enoxaparin for acute VTE, the cancer patient subgroup had a nonsignificant higher VTE recurrence rate with once-daily dosing (12.2%) compared with twice-daily dosing (6.4%) (Ann Intern Med 2001;134:191). Limited data exist on the use of fondaparinux in cancer patients. Limitations include its long half-life (17 to 21 hours), 100% renal clearance, and inability to reverse. However, small studies have shown the safety of fondaparinux in patients with HIT. Recently, the Select-D study is a pilot study comparing the efficacy of rivaroxaban to LMWH for treatment of acute VTE in patients with active malignancy. Results of this trial are discussed in “long-term anticoagulation for VTE in patients with cancer.” Based on available evidence, the 2019 ASCO guidelines recommend LMWH, UFH, fondaparinux, or rivaroxaban as initial anticoagulation for patients with cancer-associated VTE. 4. Long-term anticoagulation for VTE in patients with cancer. Historically, oral vitamin K antagonists (VKAs) were used as the standard for treatment and secondary prevention of VTE in cancer patients. However, cancer patients have more thrombotic recurrences (4-fold higher) and bleeding complications (2-fold higher) than patients without cancer during long-term VKA therapy. This translates into cumulative recurrent VTE and bleeding incidences of 20% and 12%, respectively, after 1 year of anticoagulation therapy (Blood 2002;100:3484). Additionally, VKAs require frequent therapeutic monitoring, have a slow onset and offset of action, and have numerous food and medication interactions. Several prospective, randomized, open-label studies have shown that LMWH is superior to VKAs in long-term management of VTE in cancer patients. The pivotal study, the CLOT trial, randomized patients with active malignancy to VKA versus dalteparin (LMWH) for 6 months following diagnosis of a first symptomatic VTE (N Engl J Med 2003;349:146). Patients receiving LMWH had a 52% reduction in VTE recurrence and no significant difference in major bleeding compared to those receiving VKA. A meta-analysis supported these findings when combing the results of eight RCTs, reporting an overall 53%

reduction in risk of recurrent VTE with LMWH compared to VKA therapy (HR 0.47; 95% CI 0.32 to 0.71) (Cochrane Database Syst Rev 2008:CD006650). The same meta-analysis found no difference in rates of bleeding or overall mortality between the two groups. Based on the aforementioned evidence, the 2012 ACCP, 2013 ASCO, and the National Comprehensive Cancer Network all recommend chronic anticoagulation with LMWH when possible for treatment of DVT or PE in cancer patients for the past decade. In recent years, the approval of DOACs for the treatment of VTE in the general population provides effective, safe, and convenient alternative oral anticoagulants. DOACs represent an attractive treatment option in the cancer population, with their oral formulation, no need of monitoring, and less interactions with drug and diet. Recently, four prospective RCTs provide evidence on the role of DOACs in patients with cancer. Hokusai VTE Cancer study randomized 1,050 cancer patients to edoxaban (after at least 5 days of LMWH) versus dalteparin (N Engl J Med 2018;378:615) during 12 months of follow-up. The primary composite outcome, recurrent VTE or major bleeding, showed edoxaban was noninferior to dalteparin (12.8% vs. 13.5%, HR 0.97: p = 0.006 for noninferiority). There was a statistically higher rate of major bleeding with edoxaban compared to dalteparin (6.9% vs. 4.0%, HR 1.77; 95% CI 1.03 to 3.04). This increased bleeding risk was particularly noted as upper gastrointestinal (GI) bleeding in patients with GI cancer (p = 0.02 for interaction). The pilot Select-D trial compared rivaroxaban (15 mg twice daily for 21 days followed by 20 mg once daily) versus dalteparin for the treatment of cancer-associated VTE ( J Clin Oncol 2018;36:2017) in 406 patients over 6 months. VTE recurrence was 4% with rivaroxaban compared to 11% with dalteparin (HR 0.43; 95% CI 0.19 to 0.99). Major bleeding occurred in 6% on rivaroxaban compared to 4% on dalteparin (HR 1.83; 95% CI 0.69 to 4.96). Again, the trend for major bleeding on rivaroxaban was higher for those with GI cancers. A recent smaller RCT evaluating apixaban (N = 300) (10 mg twice daily for 7 days followed by 5 mg twice daily) versus dalteparin has been published ( J Thromb Haemost 2020;18:411). There was no difference in the primary outcome of major bleeding for apixaban (0%) versus LMWH (1.4%) (p = 0.14). Apixaban significantly decreased the risk of recurrent VTE compared to LMWH (0.75 vs. 6.3%; p = 0.028). The Caravaggio trial randomized 1,155 cancer patients to apixaban versus dalteparin (N Engl J Med 2020;382:1599) during 6 months of follow-up. The primary outcome was objectively confirmed recurrent VTE, with major bleeding as the primary safety outcome. The results found that apixaban was noninferior to dalteparin (5.6% vs. 7.9%, HR 0.63: p < 0.001 for noninferiority). in addition, there was no significant difference in the risk of major bleeding with apixaban compared to dalteparin (3.8% vs. 4.0%, hr 0.82: p = 0.60). Based on the current data, the ASCO clinical guidelines ( J Clin Oncol

2020;38:496) and the ISTH ( J Thromb Haemost 2018;16:1246) recommend LMWH, edoxaban, or rivaroxaban as long-term anticoagulation for patients with cancer and VTE. 5. Duration of anticoagulation in cancer patients with VTE. The duration of anticoagulation in cancer patients should be individualized. In general, anticoagulation is recommended to be continued until cancer is in remission and cancer therapies have been stopped. In the setting of ongoing active malignancy, the risk of recurrence is much higher, and long-term anticoagulation is appropriate and commonly used. 6. Treatment of incidental VTE. Incidental VTEs (VTE found incidentally on imaging studies without symptoms) are common in the cancer population, given the baseline high risk of thrombosis and the frequency of imaging studies for cancer staging. Several retrospective studies showed that 35% to 50% of DVTs and PEs were incidentally discovered in cancer patients. The need of treatment for incidental VTEs has been questioned, given the lack of symptoms. However, many studies have revealed that rates of VTE recurrence, bleeding, and mortality are similar in cancer patients with incidental VTE compared to those with symptomatic VTE. Therefore, expert consensus recommends the same treatment for incidental VTE as compared with symptomatic VTE. 7. Thrombosis despite anticoagulation. Cancer patients commonly have recurrent VTE despite anticoagulation. Approximately 10% to 17% of cancer patients on warfarin and 6% to 9% on LMWH will have recurrent VTE (N Engl J Med 2003;349:146). There is no standard therapy for patients with recurrent VTE despite anticoagulation, because no high-quality evidence is available. In this setting, it is important to first confirm compliance and rule out HIT. In the case of true failure of therapeutic anticoagulation, various treatment strategies have been employed, including switching anticoagulation from warfarin to LMWH (if the patient were to be on warfarin at the time of VTE recurrence), switching to a different type of LMWH (if the patient were to be on LMWH at the time of VTE recurrence), increasing the dose of LMWH, addition of antiplatelet agents such as aspirin, or a combination of these methods. Recent data showed improved efficacy of DOAC compared to LMWH in VTE prevention in the cancer population, so changing to DOAC would be a reasonable alternative. Studies are needed for optimal management of this group of challenging patients. SUGGESTED READINGS Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020;382:1599–1607. Agnelli G, George DJ, Kakkar AK, et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012;366:601–609.

Agnelli G, Gussoni G, Bianchini C, et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, doubleblind study. Lancet Oncol 2009;10:943–949. Blom JW, Doggen CJ, Osanto S, et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715–722. Carrier M, Lazo-Langner A, Shivakumar S, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med 2015;373:697–704. den Exter PL, Hooijer J, Dekkers OM, et al. Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. J Clin Oncol 2011;29:2405–2409. Di Niso M, Porreca E, Candeloro M, et al. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev 2016;12:CD008500. Falanga A. Thrombophilia in cancer. Semin Thromb Hemost 2005;31:104–110. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S–400S. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020;38:496–520. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapyassociated thrombosis. Blood 2008;111:4902–4907. Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost 2018;16:1891–1894. Lee AY. Management of thrombosis in cancer: primary prevention and secondary prophylaxis. Br J Haematol 2004;128:291–302. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–153. McBane RD, Wysokinski WE, Le-Rademacher JG, et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost 2020;18:411–421. Piccioli A, Lensing AW, Prins MH, et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost 2004;2:884–889. Prandoni P, Lensing AW, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327:1128–1133. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484–3488. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615–624. Van Es N, Le Gal G, Otten HM, et al. Screening for occult cancer in patients with unprovoked venous thromboembolism: a systematic review and meta-analysis of individual patient data. Ann Intern Med 2017;167:410–417. Young AM, Marshall A, Thirwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018;36:2017–2023.

I.

METABOLIC EMERGENCIES A. Hypercalcemia 1. Pathophysiology. Hypercalcemia is common with advanced malignancies and is associated with poor prognosis. The most common cancers associated with hypercalcemia are breast, lung, and multiple myeloma. Hypercalcemia of malignancy results from three main mechanisms: (1) secretion of parathyroid hormone-related protein (PTHrP), (2) local osteolytic activity, and (3) abnormal production of 1,25-dihydroxyvitamin D (Calcitriol). Humoral secretion of PTHrP accounts for more than 70% of hypercalcemia of malignancy and is seen in a variety of cancers including squamous cell cancer, renal, ovarian, endometrial, non-Hodgkin lymphoma (NHL), and breast cancer. Malignant hypercalcemia because of osteolytic activity is seen in approximately 20% and is a complex interplay between receptor activator of nuclear factor κB ligand and receptor activator of nuclear factor κB (RANKL and RANK) interaction/activation and cytokine production (e.g., interleukin [IL]1, IL6, and tumor necrosis factor [TNF]-alpha) that stimulates differentiation of macrophages to osteoclasts. It usually develops in patients with extensive skeletal metastases (e.g., breast cancer, lung cancer, prostate cancer, or multiple myeloma). In Hodgkin lymphoma and a few NHLs, malignant lymphocytes secrete the active form of vitamin D (1, 25-dihydroxyvitamin D), resulting in increased osteoclastic bone resorption and intestinal absorption of calcium leading to hypercalcemia. 2. Signs and symptoms. Patients with mild hypercalcemia (6 mEq/L or with electrocardiogram [ECG] changes) may be treated immediately with 50 mL of 50% glucose solution with 15 U of regular insulin IV over an hour. Indications for hemodialysis include volume overload, serum uric acid greater than 10 mg/dL, or rapidly increasing phosphorus levels and uncontrolled hyperkalemia. Renal failure caused by TLS is usually reversible, and even patients requiring hemodialysis often regain normal kidney function as the TLS subsides. B. Syndrome of inappropriate antidiuretic hormone (SIADH) 1. Pathophysiology. SIADH is a syndrome of excessive inappropriate secretion of antidiuretic hormone (ADH), resulting in water retention and hyponatremia. This causes increased urine osmolality and increased sodium loss, resulting in concentrated urine. Small cell lung cancer (SCLC) is the most common cancer causing SIADH, with over 15% of patients with SCLC developing SIADH at some point during the course of the illness. Head and neck cancers (squamous cell carcinoma), olfactory neuroblastomas, and extrapulmonary small cell

carcinomas are less common causes of SIADH. 2. Signs and symptoms. Patients initially present with headache and fatigue and, if left untreated, may rapidly progress to confusion, seizure, coma, and death. A low plasma osmolality with elevated urine osmolality (>100 mOsm/kg) and urine sodium more than 40 mEq/L are suggestive of SIADH. 3. Management. The treatment of SIADH varies with the severity of hyponatremia and presence of symptoms. Fluid restriction is the initial step of management for patients with mild-to-moderate SIADH. In patients with acute (48 hours), the goal of correction is to increase serum sodium 1 mEq/L per hour for 3 to 4 hours. When the serum Na levels reach 120 mEq/L, then the 3% saline should be stopped and fluid restriction instituted. For patients with no symptoms or mild symptoms, initial treatment with fluid restriction with PO salt tablets is recommended (Table 38-3). TABLE 38-3

Treatment of Symptomatic and Asymptomatic Hyponatremia from SIADH

Severity of Hyponatremia

Symptoms

Treatment

Comment

Serum sodium 1 hour) in patients with an absolute neutrophil count less than 500/μL (or 10 days) and profound neutropenia (ANC < 100/μl), age older than 65 years, uncontrolled primary disease, pneumonia, hypotension, and multiorgan dysfunction (sepsis syndrome), invasive fungal infection, or development of fever during hospitalization. Dose-dense/dose-intense regimens. CSF-supported dose-dense/dose-intense regimens should only be used within appropriately designed clinical trials or if supported by efficacy data. Dose-dense/dose-intense regimens with CSF support have been shown to increase disease-free and overall survival in the adjuvant treatment of high-risk breast cancer and with high-dose methotrexate, vinblastine, doxorubicin, and cisplatin (HD-M-VAC) in urothelial cancer. Trials of dosedense chemotherapy in lymphoma, lung cancer, ovarian cancer, osteosarcoma, and sarcoma have been negative (J Clin Oncol 2015;33:3199). Bone marrow transplant. CSFs may be used alongside chemotherapy, after, or in conjunction with plerixafor (a CXCR4 receptor antagonist) to mobilize peripheral stem cells. CSFs are recommended following autologous stem cell transplant, and may be administered after allogeneic stem cell transplant to reduce duration of severe neutropenia. Acute myeloid leukemia. The administration of CSFs following induction chemotherapy for AML can decrease the duration of neutropenia when begun shortly after chemotherapy; however, studies have not consistently shown a positive impact on the duration of hospitalization and incidence of severe infections. CSFs following induction chemotherapy in AML are considered reasonable and may have the most benefit in patients older than 55 years. In the setting of consolidative therapy for AML, CSFs are recommended following chemotherapy, because CSFs have convincingly been shown to decrease the incidence of infection and decrease hospitalization rates. There is also a more pronounced shortening of the duration of neutropenia following consolidative chemotherapy when compared with induction chemotherapy. There are currently no data surrounding the use of pegylated CSFs in patients with myeloid leukemias, and so their use in this setting is not recommended at this time. The use of CSFs for priming of leukemia cells is also not recommended. Acute lymphoid leukemia (ALL). CSFs are recommended following the completion of induction or first postremission course of therapy because this has been shown to shorten the duration of neutropenia (100 mg/day), has been associated with prolongation of QT interval and cardiac arrhythmia. The marked variability in elimination half-life, complex and often significant drug–drug interactions, and the concern for QT prolongation limits the clinical utility of methadone. Methadone can be given through oral, rectal, or IV routes (local tissue reaction may complicate repeated subcutaneous or IM administration) with high bioavailability. Oxymorphone (parenterally) is approximately 10 times more potent than is parenteral morphine, but due to modest oral bioavailability, oral oxymorphone is only 3 times more potent than is oral morphine. Elimination half-life of oxymorphone is 1.3 ± 0.7 hours, with active and inactive oxymorphone metabolites excreted in the urine. Hepatic and/or renal insufficiency greatly influences oxymorphone pharmacokinetics. Oxymorphone is available for oral, parenteral, and rectal administration. Codeine, a prodrug, provides almost no pain relief directly; rather, it undergoes cytochrome P450-2D6 metabolism into active metabolites (morphine and morphine-6-glucuronide) to provide codeine-derived analgesic effect. Approximately 8% Caucasians lack sufficient enzyme activity to derive significant codeine analgesic effect. Conversely, 1% to 10% Caucasians and 3% to 28% of African Americans are ultrarapid metabolizers at risk for relative opioid overdose from overproduction of active metabolites. This P450-2D6 polymorphism results in such marked variability in codeine analgesic potency that codeine is rarely used in clinical practice and is contraindicated in patients younger than 18 years and in breastfeeding mothers. Codeine may have greater risk of nausea than does hydrocodone or oxycodone. Codeine is available for oral, IM, or subcutaneous administration (IV administration should be avoided because of the risk of histamine release and subsequent cardiovascular instability). Hydrocodone, a derivative of codeine, is a direct-acting opioid and is metabolized by cytochrome P-450 into hydromorphone, which may also mediate some hydrocodone effects. Hydrocodone is primarily available in oral preparations combined with nonopioid analgesics, but plain hydrocodone long-acting preparations are available. With chronic, high-dose hydrocodone, there may be concern for rare but nonreversible sensorineural hearing loss, with most cases reported in the context of opioid abuse. Buprenorphine, a mixed agonist–antagonist at mu-, delta-, and kappa-opioid receptors, is a semisynthetic opioid available in sublingual, transdermal, and injectable formulations for management of pain and/or opioid addiction. It is predominately metabolized in the liver using cytochrome P450-3A4 enzymes

and excreted through bile, with little effect from renal impairment; the active metabolite norbuprenorphine is a potent analgesic. Long buprenorphine halflife of 20 to 70 hours, ceiling effect for both analgesic and euphoric effects, and good safety profile make buprenorphine an alternative to conventional long-acting opioids in chronic and cancer pain. Buprenorphine administration to persons chronically receiving other opioids potentially can precipitate opioid withdrawal symptoms. j. Tramadol (50 to 100 mg PO q.i.d., maximum 400 mg/day) has modest analgesic efficacy because of weak affinity for mu-opioid receptors. Dose is limited to a maximum of 400 mg/day, because of risk of seizures with higher doses. Tramadol is also a norepinephrine, serotonin reuptake inhibitor, similar to some antidepressant medications: It should not be used in individuals receiving full doses of antidepressants, to avoid toxicity (serotonin syndrome). In the United States, it is only available for oral administration. k. Tapentadol is a synthetic, centrally acting opioid with moderate affinity to mu-opioid receptors that also inhibits synaptic norepinephrine reuptake. Immediate- and extended-release dosing is limited to total 600 mg daily. Tapentadol decreases seizure threshold and raises intracranial pressure, so it is contraindicated in patients with seizures and intracranial pathologies. Caution should be exercised with concomitant use of serotonergic agents because of the potential risk of serotonin syndrome. Doses should be reduced in moderate hepatic insufficiency, and tapentadol is contraindicated in severe hepatic insufficiency. l. Meperidine has no utility in pain management. It is metabolized to normeperidine, which accumulates because of a long half-life, and is associated with excitatory effects including tremulousness and seizures. Severe reactions, after even a single dose of meperidine, may occur in patients being treated with monoamine oxidase (MAO) inhibitors, including excitation, delirium, hyperpyrexia, convulsions, and death. 5. Opioid rotation involves intentionally switching from one opioid analgesic to another, using appropriate guidelines for equianalgesic dosing, to improve pain control and reduce opioid adverse effects. Although individuals tolerant to one opioid will have cross-tolerance to other opioids, the cross-tolerance may be incomplete, such that the effective analgesic dose of the new opioid may be 50% (or less) of the anticipated equianalgesic dose depending on the prior opioid requirement. Opioid rotation must be undertaken with caution to avoid overdosing or underdosing, potentially resulting in excess adverse effects, inadequate pain control, or other problems. Although the data are limited to case reports and case series, opioid rotation is widely utilized in clinical practice

especially to manage adverse effects related to a specific opioid. E. Adjuvant analgesics (Table 40-5) TABLE 40-5

Adjuvant Analgesics Usual, Single Oral Dose (mg)

Maximum Daily Dose (mg)

Half-life (h)

Gabapentin

100–1,200

3,600

5–9

Lamotrigine

50–250

500

15–30

Levetiracetam

250–1,000

3,000

6–8

Pregabalin

50–300

600

10–12

Amitriptyline

25–300

300

16–30

Bupropion

50–150

450

14

Citalopram

10–40

40

30–36

Doxepin

25–300

300

16–30

Duloxetine

30–120

60–120

10–14

Milnacipran

25–100

100–200

8–10

Fluoxetine

10–80

80

100

Sertraline

50–200

200

24–60

Trazodone

25–400

400

8

Venlafaxine

25–100

375

5–11

Anticonvulsants

Antidepressants

1. Anticonvulsants are variably effective analgesics in neuropathic pain. Gabapentin (300 to 1,200 mg PO t.i.d.) or pregabalin (100 to 600 mg daily divided into two or three doses per day) is the most widely used anticonvulsants for neuropathic pain, with some analgesic efficacy for acute postoperative pain. Other anticonvulsants (i.e., topiramate, levetiracetam, lamotrigine, and oxcarbazepine) should be considered upon failure of/intolerance to gabapentin and pregabalin, but care must be taken to avoid potentially significant drug–drug interactions with these agents. Dosing of anticonvulsants must be adjusted in renal and/or hepatic insufficiency. 2. Antidepressants, especially tricyclic antidepressants (TCAs), have analgesic efficacy in chronic neuropathic pain, as do duloxetine, venlafaxine, and milnacipran. Other antidepressants (e.g., citalopram, fluoxetine, paroxetine, and

sertraline) may be less effective analgesics than are TCAs for pain control, but may be better tolerated. If one antidepressant is poorly tolerated or provides ineffective analgesia, a different antidepressant should be tried. 3. Miscellaneous agents a. Muscle relaxants have not been studied in cancer pain, but are commonly used for musculoskeletal pain. Sedation is a common adverse effect. Baclofen (10 to 20 mg PO, 3 times daily) is widely used for control of spasticity, but also has limited analgesic efficacy in neuropathic pain. To avoid potentially serious withdrawal, chronic baclofen therapy must be tapered over several days, rather than abruptly discontinued. Tizanidine (2 to 8 mg PO, 3 to 4 times daily) is an effective agent for spasticity also, with limited efficacy in chronic pain. Potential adverse effects include hypotension and hepatotoxicity (periodically monitor liver function, especially during drug initiation). Renally cleared, tizanidine dosing must be reduced in renal insufficiency. Other muscle relaxants (methocarbamol, cyclobenzaprine, and metaxalone) have only a limited role in management of cancer-related musculoskeletal pain. b. Local anesthetics. Lidocaine IV infusion (1 to 1.5 mg/kg lean body mass/hour) may be effective for intractable neuropathic pain resistant to systemic opioid. Systemic lidocaine may accumulate with infusion and patients must be monitored for signs of systemic lidocaine toxicity. Depending on overall goals of care, it may be appropriate to check systemic lidocaine levels as often as every 24 hours. Oral mexiletine (10 mg/kg/day, divided into three doses daily) has modest efficacy in neuropathic pain. Lidocaine patches (4% or 5%) provide pain relief through topical anesthetic action and are especially indicated in neuropathic pain associated with markedly increased skin sensitivity (cutaneous mechano-allodynia). Lidocaine patch has little systemic absorption, but the water-based adhesive may cause dermatitis if left in place for more than 12 hours daily. c. Systemic corticosteroids are used in patients with cancer to provide analgesia, improve appetite, prevent nausea and malaise, and improve quality of life. Corticosteroids may be particularly useful for at least short-term relief of acute pain because of bony metastases, tumor infiltration, or compression of neural structures; increased intracranial pressure (headache); obstruction of a hollow viscus or organ capsule distention; or spinal cord compression. Long-term use of steroids may lead to gastrointestinal ulceration, so the use of gastroprotective agents is advised. IV. SPECIAL TECHNIQUES FOR THE MANAGEMENT OF RESISTANT CANCER

PAIN A. Psychological and behavior medicine techniques. Cancer pain is a complex emotional experience, and emotional distress, anxiety, and depression increase pain and suffering. Pharmacologic and nonpharmacologic therapies for the treatment of psychological and psychiatric comorbidities are essential to cancer pain management. Cognitive behavioral therapies (CBTs) are the most frequently used psychological modalities in chronic pain management. Through CBT, patients learn to control the thoughts, emotions, and behaviors that modulate pain experience. CBT includes hypnosis, relaxation techniques (including progressive muscle relaxation, meditation, and guided imagery), biofeedback, coping skills training, music therapy, cognitive restructuring, supportive and group therapy, and stress management techniques. B. Physical and occupational therapies are essential to optimize functional status, especially with prolonged medical illness or following surgical intervention. Therapeutic and conditioning exercise programs are essential to successful chronic pain management. Specific therapies such as orthotic bracing and assistive devices may improve pain control and/or function. C. Complementary and alternative (CAM) therapies are widely used, alone or in conjunction with conventional therapies, for pain control by persons with cancer. Patients should be routinely asked about CAM therapies, if only to allow screening for potential adverse interactions between CAM and conventional therapies. Alternative therapies such as acupuncture, massage, healing touch, and many herbal therapies have shown benefits in controlling pain and other symptoms, but comparative trials with other analgesic therapies are lacking. D. Interventional techniques for severe cancer pain are important components of comprehensive care for severe cancer pain and should not be relegated to treatments of last resort. Interventional pain therapies should be considered if pain is not adequately controlled with systemic analgesics, or if use of such analgesics is associated with adverse effect (e.g., sedation, constipation, and/or nausea). Interventional pain therapies can potentially improve quality of life by (1) providing more effective pain control and (2) allowing reduction in analgesic dose and/or analgesic adverse effects. Improved pain control and reduced analgesic adverse effects through appropriate use of interventional pain therapies may improve life expectancy in patients with terminal disease. 1. Spinal analgesic administration delivers medication to the spinal cord to enhance analgesic efficacy and potentially minimize systemic (brain) adverse effects of analgesics. Spinal analgesics (opioids, local anesthetics, clonidine, and/or baclofen) are used alone or in combination for intrathecal or epidural administration. Spinal administration of combined opioid, local anesthetic, and

clonidine is an especially potent analgesic therapy. Spinal analgesics may be administered by percutaneous epidural or intrathecal (subarachnoid) catheters, but an implanted pump (for intrathecal infusion) is most commonly used. a. Spinal opioids (especially morphine and hydromorphone) have significantly increased potency: 100 mg/day parenteral morphine is roughly equivalent to 10 mg/day epidural morphine, which is roughly equivalent to 1 mg/day intrathecal morphine; however, actual doses must be titrated to effect. Fentanyl, because of its high lipid solubility, has rapid systemic absorption after spinal administration; therefore, spinal administration of fentanyl may have little advantage over systemic administration. Spinal opioid adverse effects include sedation, respiratory depression (onset may be delayed for several hours), constipation, nausea, pruritus, peripheral edema, and urinary retention. Exceptionally high doses of spinal opioids may result in myoclonic jerks or even diffuse muscle rigidity. b. Spinal local anesthetics (bupivacaine) may markedly decrease pain without sedation or some of the other potential adverse effects associated with opioid analgesics and low doses of spinal local anesthetic may provide pain relief without significant extremity weakness or numbness. Potential adverse effects include hypotension (especially orthostatic hypotension), extremity weakness, and urinary retention. c. Spinal clonidine has analgesic efficacy after epidural or intrathecal administration, through action at spinal alpha-2 adrenergic receptors. Potential adverse effects include hypotension (especially orthostatic hypotension), bradycardia, congestive heart failure, and sedation. E. Interventional technique for severe cancer pain 1. Electrical stimulation neuromodulation, including spinal cord stimulation (SCS), dorsal root ganglion (DRG), and peripheral nerve stimulation (PNS), involve implanted medical devices that apply electrical current near neural structures to modulate pain neural transmission. Best used for primarily neuropathic pain, these stimulation therapies may be helpful in treating intractable pain in cancer patients and survivors. Generally, these approaches include a trial, percutaneous placement of stimulating electrode arrays to determine the likely success of a subsequently implanted device. These stimulation trial and implant procedures are minimally invasive, generally performed as an outpatient, and the devices can be removed if necessary. 2. SCS may be particularly helpful in managing peripheral neuropathic pain of the extremities resulting from complex regional pain syndrome, postlaminectomy syndrome, peripheral vascular disease, and/or other pain conditions originating from nerve involvement (e.g., chemotherapy-induced peripheral neuropathy

[CIPN]). Previously, SCS devices were incompatible with magnetic resonance imaging (MRI), but conditionally MRI-compatible devices are now available, expanding utility to those patients likely to need MRI. 3. DRG stimulation involves percutaneous placement of electrode leads into the epidural space and out of individual neural foramina to rest on the superior aspect of the DRG. DRG stimulation may be especially effective in neuropathic pain in a dermatomal distribution involving the chest, lower body, or lower extremities. 4. PNS may be more beneficial when pain is limited to a focal nerve distribution, because electrodes are implanted near a peripheral nerve. PNS is helpful in treating painful conditions, such as hemiplegic shoulder pain, complex regional pain syndrome, brachial plexus injuries, postamputation pain, postherpetic neuralgia, or some cases of poststroke pain. F. Vertebral augmentation (vertebroplasty, kyphoplasty, and tumor-ablative vertebroplasty) is a range of procedures for the percutaneous injection of bone cement (polymethyl methacrylate—PMMA) into vertebral bodies affected by compression fractures because of metastatic tumor, destructive vertebral hemangiomas, or osteoporosis. Kyphoplasty differs from vertebroplasty in that bone cement is injected after a balloon has been used to create a cavity in the vertebral body, in an attempt to restore vertebral body height. Vertebroplasty/kyphoplasty can be highly effective in control of pain from vertebral compression fractures because of osteoporosis and/or tumor. Thorough radiographic evaluation is essential before vertebroplasty/kyphoplasty. Potential adverse effects include spread of unhardened PMMA beyond the vertebral body, through direct spread to the spinal canal or through vascular embolization. In tumor-ablative vertebral augmentation, plasmamediated radiofrequency energy is used to ablate metastatic vertebral disease to create cavitation within the vertebral body before injection of PMMA, to potentially decrease tumor burden. Vertebroplasty/kyphoplasty need not delay treatment of spinal metastases with radiation therapy, but may provide rapid onset of pain relief, which may facilitate the use of such antitumor therapies. G. Neurolytic neural blockade should be considered for patients with terminal disease in whom pain is poorly controlled with less-invasive therapies and pain is localized to a suitable region of the body. If pain recurs after several months, neurolytic blockade may be repeated, but repeated blockade is generally not necessary. 1. Neurolytic celiac plexus block (NCPB), the most commonly performed neurolytic technique for cancer pain, is indicated for upper abdominal visceral pain from pancreatic or other upper abdominal malignancy. Up to 85% of appropriately selected patients report good-to-excellent pain relief after NCPB. The side effects of orthostatic hypotension and increased frequency of bowel movements (diarrhea) transiently affect most persons after NCPB, but only 1% to

2% require long-term medical management of these symptoms. The risk of significant nerve damage or paralysis (0.1% to 0.2%) may cause some patients with cancer to decide against NCPB, but to most, the potential for good-toexcellent pain relief (75% to 85%) with potential improvements in constipation, nausea, and an improved sense of well-being outweighs procedural risk. 2. Neurolytic hypogastric plexus block may be effective for visceral pain from pelvic malignancy. Its use is not significantly associated with extremity weakness, but ejaculatory failure/inorgasmia is a potential adverse effect. Neurolytic hypogastric plexus block is not likely to provide good pain control if there is tumor invasion of somatic or neural structures. H. Neurosurgical techniques for pain control, such as cordotomy or cingulotomy, are rarely used but potentially powerful tools for the management of otherwise intractable pain. Especially for unilateral lower body or lower extremity pain, in the setting of terminal illness, cordotomy (percutaneous or open surgical approach) may provide remarkable control of previously intractable pain. I. Management of refractory pain and/or other symptoms of terminal illness. In the last hours to days of life, some dying people develop intractable symptoms such as intractable pain, dyspnea, delirium, and/or emesis. If such symptoms are intolerable to the dying patient, but would be refractory to further palliative therapy, consideration should be given to alleviation of distress through administration of sedatives. Terminal, palliative sedation should be considered only for those who have requested not to be resuscitated (“no code”) in the event of cardiac/respiratory arrest. Midazolam is the most commonly used drug for palliative sedation (1 to 2 mg IV, IM, or subcutaneously q 1 hour, p.r.n.; or loading dose of 1 to 2 mg IV with infusion 0.5 to 2 mg/hour) but other benzodiazepines (diazepam, 5 to 10 mg PO, 2 mg IV q 2 hours, p.r.n.) can be used instead. Benzodiazepines may worsen agitation in some persons, and they may be better treated other agents (propofol, dexmedetomidine, phenobarbital, or opioid) titrated to effect to ease suffering from otherwise intractable symptoms. The use of palliative terminal sedation to provide a dying person relief from intractable, intolerable suffering is firmly within the realm of good, supportive palliative care and should not be confused with euthanasia. V. SPECIFIC PAIN SYNDROMES A. Mucositis is one of the most debilitating, refractory adverse effects following chemotherapy and/or radiotherapy damage to tissues of the alimentary canal. Mucositis is associated with pain and increased risk of infection, malnutrition, and dehydration. Traditional management of oral mucositis has involved patient education for avoidance of dehydration, oral rinses (saline, hydrogen peroxide diluted 1:1 with saline), topical lidocaine solution, systemic analgesics, nutritional

support, and prevention/management of infection. B. Bone pain from cancer, often related to bony metastases, is a common problem. Bone pain management may require various modalities including analgesics, corticosteroids, bisphosphonates, radiation therapy, hormonal and/or chemotherapy, and/or orthopedic surgical intervention. 1. Bisphosphonates inhibit osteoclast-mediated bone resorption and have been shown to relieve pain, reduce the number of metastases, prevent osteolysis, and decrease the frequency of fractures. All bisphosphonates can induce gastrointestinal upset, renal damage, and mandibular osteonecrosis. Dose should be adjusted on the basis of renal function. 2. Denosumab, a monoclonal antibody against RANKL (receptor activator of nuclear factor kappa-beta ligand), blocks osteoclast activation and thereby reduces bone resorption and lessens skeletal-related events in osseous metastasis of solid tumors and multiple myeloma. 3. Abiraterone, an androgen biosynthesis inhibitor acting through selective cytochrome P450 17A1 inhibition, improves survival and bone pain in castration-resistant prostate cancer. 4. Radioisotopes, through parenteral administration, provide systemic radiation to diminish multifocal painful skeletal metastasis. 89Sr and 153Sm have shown selectivity for bone metastasis and have been found to be effective in reducing pain. High-cost, delayed pain relief, and hematologic toxicity limit use. 5. External beam radiation is used in relieving local tumor-related bone pain. Focal lesion can be managed by localized external beam irradiation (also known as involved-field irradiation). Multiple painful sites can be managed by widefield external beam irradiation (e.g., hemibody irradiation). Side effects include bone marrow suppression and radiation tissue damage. C. Neuropathic pain from tumor invasion of major nerve plexus. Neuropathic pain may be relatively less responsive to opioid analgesics than to nociceptive pain, especially when tumor directly invades a major nerve or plexus. Clinical situations such as tumor invasion of brachial plexus (Pancoast tumor), or retroperitoneal sarcoma invading the lumbosacral plexus, require aggressive pain therapies early in the course of disease. Adjuvant, nonopioid analgesic (anticonvulsants, antidepressant) therapies should be optimized. Although rarely needed, severe neuropathic pain not responding to systemic analgesics is a relatively common indication for spinal analgesics or neurosurgical intervention. D. Cancer treatment–related pain syndromes/cancer survivors and pain. Advances in cancer treatment have improved cancer survival, but also increased the prevalence of patients living with chronic, cancer-related pain. It is estimated that chronic posttreatment pain is present in 30% of cancer survivors. Pain in cancer survivors

can be the result of tissue damage from the cancer itself or from cancer treatments: chemotherapy, radiation, hormonal therapy, long-term steroid use, and/or surgery. Graft-versus-host disease is another potential source of persistent pain. Chronic pain management in cancer survivors frequently requires a multidisciplinary approach. The goals of treatment should focus on functional improvement and management strategies rather than complete elimination of pain. Multimodal analgesia combines analgesics with different mechanisms to provide improved pain relief with fewer medication-related adverse effects. There is increasing concern for potential adverse effects of chronic opioid use, including tolerance/hyperalgesia, hypogonadism, and immunosuppression, in addition to the well-known adverse effects of sedation, respiratory depression, constipation, nausea, and so on. Nonopioid and adjuvant analgesics (antidepressants and anticonvulsants) and interventional pain therapies may be utilized to limit opioid use and improve symptom control. Physical and rehabilitation therapies, especially when combined with psychological/behavioral medicine therapies, potentially play an important role in functional restoration. 1. Chemotherapy-induced peripheral neuropathy is frequently a treatmentlimiting and potentially disabling complication of some chemotherapy protocols. CIPN most commonly affects large sensory neurons, and therefore may present as a purely sensory disturbance; however, pure motor disturbance or as a mixed sensory-motor disturbance presentation is not uncommon. Typically, paresthesias or dysesthetic sensations follow chemotherapy from a wide range of agents including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (e.g., thalidomide-like agents). With no specific treatment for CIPN, effort has been focused on prevention, but with limited success. These strategies include selection of less toxic agents, chemotherapy dose modifications, interruption of dosing (i.e., “stop and go” protocols). Neuroprotective agents that have been used in an attempt to prevent CIPN but without proven efficacy. Various antineuropathic pain medications (gabapentin, pregabalin, duloxetine, and perhaps other antidepressants) and/or opioids may be useful analgesics. Acupuncture and SCS have been used in the management of CIPN with varied success. 2. Radiation neuropathy following radiation therapy is of variable incidence, appears to be dose dependent, and most commonly involves the brachial plexus (after radiation therapy for breast cancer, lung cancer, or Hodgkin lymphoma) or lumbosacral nerves (after radiation for pelvic and abdominal malignancies). Peripheral neuropathy is also seen, but usually is self-limited and less symptomatic. Injury can occur to any nerve in the beam of the radiation therapy device. The common complaints include paresthesias, dysesthesias, allodynia,

hyperalgesia, and hyperpathia in the area of nerve injury. Most of these neuropathies present weeks after radiation therapy. Treatment includes anticonvulsants, opioids, NSAIDs, TCAs, and local and topical anesthetics. In very severe cases, SCS or spinal analgesic administration should be considered. Psychological and physical therapy modalities should be utilized as a part of a multidisciplinary pain management program. 3. Postsurgical pain syndromes a. Postmastectomy pain syndrome, involving persistent pain in the anterior chest, axilla, and medial and posterior portions of the arm, occurs after 4% to 30% of surgical procedures involving the breast and occurs 2 weeks to 6 months after surgery. The pain is variable, but it is usually a combination of somatic and neuropathic pain. Treatment includes anticonvulsants, antidepressants, topical agents (lidocaine patch), physical therapy, and CBT. Persistent pain may require other therapies (opioid, spinal stimulation). b. Postradical neck dissection pain syndrome is a combination neuropathic and myofascial pain condition that occurs in as many as 50% of postsurgical patients, typically involving one or more branches of the superficial cervical plexus (SCP). It is usually described as spontaneous, continuous burning pain, shooting pain, or allodynia. Treatment is similar to that for other postsurgical neuropathic pain syndromes, but myofascial trigger point injections using local anesthetic and/or botulinum toxin may be of benefit. c. Postthoracotomy pain syndrome (PTPS) is persistent pain in the area of the thoracotomy incision scar reflecting intercostal neuralgia. Typically occurring in a small percentage of patients, PTPS can persist indefinitely. Care must be taken not to confuse PTPS with tumor reoccurrence pain. The pain is described as numbness, tingling, burning, itching, or shooting. There is quite often hyperesthesia in the involved dermatome. Treatments include physical therapy, opioids, anticonvulsants, lidocaine patch, transcutaneous electrical nerve stimulation, SCS, or DRG stimulation. E. Postherpetic neuralgia 1. Herpes zoster (HZ), resulting from reactivation of varicella zoster (VZ) infection, is characterized by painful, vesicular cutaneous lesions in a dermatomal pattern. Pain may precede visible lesions by 2 to 3 days. HZ is typically self-limited in normal hosts, but in immunocompromised patients may cause cutaneous dissemination or even potentially fatal systemic and/or CNS infection. Acute HZ pain (acute herpetic neuralgia) typically resolves with healing of cutaneous lesions; however, the risk of persistent postherpetic neuralgia (PHN) increases with age. Even with aggressive therapy, up to 30% of individuals older than 60 years presenting with HZ will experience PHN, and up

to 50% of persons with PHN may have pain lasting indefinitely. Prevention of PHN. The incidence and/or duration of PHN is reduced with the use of oral antiviral agents during acute HZ in adults older than 50 years, if therapy is started within 72 hours of onset of rash. Acyclovir (800 mg every 4 hours, five doses daily, for 7 to 10 days) speeds healing of lesions, decreases pain from acute HZ, and may decrease the incidence of PHN. Newer antivirals famciclovir (500 mg every 8 hours for 7 days) and valacyclovir (1,000 mg every 8 hours for 7 days) have been shown to decrease the incidence of PHN with less frequent dosing, which may improve compliance. The addition of systemic corticosteroid to antiviral therapy does not further reduce the risk of PHN, but adding TCA (amitriptyline 25 mg orally at bedtime) may be of benefit. Sympathetic nerve blocks and epidural steroid injections provide excellent pain relief in acute HZ and may reduce PHN. High-potency VZ vaccine has been shown to decrease the incidence of HZ and the severity of PHN in adults 60 years of age and older and should be routinely used to prevent PHN. Treatment of established PHN is based on the use of systemic analgesics and may include TCAs and anticonvulsants. Topical lidocaine 5% patch may be of benefit in PHN associated with cutaneous extra sensitivity (mechanoallodynia). Persistent, severe PHN may respond to stimulation therapies (SCS, DRG). F. Opioid toxicity syndrome (OTS) consists of diffuse hyperalgesia, myoclonus, and altered mental status (agitation/delirium or sedation/confusion). Although rare, it is most often seen when patients are on very high doses of opioid (often >100 mg morphine/hour or equivalent), yet inadequate pain control requires further rapid opioid dose escalation. In such settings, increasing opioid dose may not result in improved pain control, but instead worsened pain (hyperalgesia) and deterioration of mental status. In extreme cases, myoclonus may be nearly continuous and resemble seizure-like activity, but patients are generally conscious and conversant (although often delirious). Dehydration and/or renal insufficiency may increase the risk of OTS. OTS has been most frequently described with systemic morphine, but has been reported with other systemic opioids and with spinal opioid. Opioid-induced facilitation of pain signal transmission (opioid-induced hyperalgesia) appears to be one of the principal factors contributing to OTS. Management of OTS requires switching to another opioid (opioid rotation), typically using less than the fully equivalent dose. In extreme cases of OTS, it may be necessary to completely discontinue opioid analgesics temporarily, and rely on nonopioid analgesics (e.g., anticonvulsants or IV lidocaine infusion) for pain control. Once OTS symptoms improve, patients may be managed with relatively lower doses of another opioid.

VI. PAIN MANAGEMENT IN SPECIFIC POPULATIONS A. Cancer pain management in the noncompliant patient. Pain management therapies are less likely to be successful if not used appropriately and consistently. To manage apparent noncompliance, treating healthcare professionals must identify and manage contributing factors such as (1) cognitive impairment (because of underlying disease(s), treatments, and other factors); (2) psychological/psychiatric disorders (depression/anxiety and personality disorders); (3) substance abuse or dependence; and (4) lack of ability to obtain, store, and access prescribed treatments. In chronic illness and/or malignancy, patients often develop tolerance (increasing dose requirement) and physical dependence (withdrawal symptoms with abrupt discontinuation), but rarely develop new substance dependence or addiction. In the context of chronic pain in oncology practice, “drug-seeking” behavior likely reflects inadequate pain control. “Substance dependence” or “addiction” is best characterized by compulsive, continued drug use despite harm, and/or drug craving. Substance abuse/dependence is rarely newly diagnosed in patients with terminal disease, but can significantly complicate pain management therapies. It is essential to obtain the patient’s cooperation to get a thorough substance abuse history and find optimal management strategies. Patients with cancer pain and active substance abuse/dependence will require very close monitoring and multidisciplinary care. 1. Involve psychiatrist and addictionologist, especially if substance abuse is recent, ongoing. Encourage participation in a 12-step recovery program (Alcoholics Anonymous, Narcotics Anonymous) if feasible. 2. Analgesics filled by only one prescriber. 3. Use one opioid analgesic, preferably a long-acting formulation, given on a regular schedule. As far as possible, limit the use of short-acting or “as-needed” doses of opioid. 4. Optimize the use of nonopioid and nonpharmacologic pain therapies. 5. Utilize pill counts and urine toxicology screens to help with monitoring of compliance with prescribed therapies and avoidance of other abuse substances. 6. Limit quantity of controlled substances to weekly supply, if compliance is poor. (In extreme cases, it may be necessary for medication to be dispensed daily by a home health nurse or even through a substance abuse program.) 7. Utilization of written opioid analgesic guidelines may help patients understand what is expected regarding appropriate use of analgesic therapies. SUGGESTED READINGS Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–587. Bannister K, Dickenson AH. Opioid hyperalgesia. Curr Opin Support Palliat Care 2010;4:1–5. Brennan MJ. The effect of therapy on endocrine function. Am J Med 2013;126:S12–S18.

Cherny NI. Cancer pain assessment and syndromes. In: McMahon SB, Loltzenburg M, Tracey I, et al, eds. Wall and Melzack’s Textbook of Pain, 6th ed. Philadelphia, PA: Elsevier-Saunders, 2013:1039–1060. Deer TR, Pope JE, Hayek SM, et al. The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines. Neuromodulation 2017;20:96–132. Estfan B, LeGrand SB, Walsh D, et al. Opioid rotation in cancer patients: pros and cons. Oncology 2005;19:511–516. Grandhi RK, Lee S, Abd-Elsayed A. Does opioid use cause angiogenesis and metastasis? Pain Med 2017;18:140–151. Ibrahim EY, Ehrlich BE. Prevention of chemotherapy-induced peripheral neuropathy: a review of recent findings. Crit Rev Oncol Hematol 2020;145:102831. Khosrow-Khavar F, Kurteva S, Cui Y, et al. Opioids and the risk of infection: a critical appraisal of the pharmacologic and clinical evidence. Expert Opin Drug Metab Toxicol 2019;15:565–575. Krakauer EL, Thomas EQ. Sedation and palliative medicine. In: Hanks G, Cherny NI, Christakis NA, et al, eds. Oxford Textbook of Palliative Medicine, 4th ed. Oxford, UK: Oxford University Press, 2009. Levy MH, Adolph MD, Back A, et al. Palliative care. J Natl Compr Canc Netw 2012;10:1284–1309. Lo B, Rubenfeld G. Palliative sedation in dying patients: “we turn to it when everything else hasn’t worked.” JAMA 2005;294:1810–1816. Park N, Patel NK. The role of surgical neuroablation for pain control. In: Hanks G, Cherny NI, Christakis NA, et al, eds. Oxford Textbook of Palliative Medicine, 4th ed. Oxford, UK: Oxford University Press, 2009. Penson RT, Nunn C, Younger J, et al. Trust violated: analgesics for addicts. Oncologist 2003;8:199–209. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 2002;20:4040–4049. Sorensen ST, Kirkegaard AO, Carreon L, et al. Vertebroplasty or kyphoplasty as palliative treatment for cancer-related vertebral compression fractures: a systematic review. Spine J 2019;19:1067–1075. Swarm RA, Karanikolas M, Rao L, et al. Interventional approaches for chronic pain. In: Cherny NI, Fallon M, Kaasa S, et al, eds. Oxford Textbook of Palliative Medicine, 5th ed. Oxford, UK: Oxford University Press, 2013. Swarm RA, Youngwerth JM, Anghelescu DL, et al. NCCN guidelines for adult cancer pain. NCCN clinical practice guidelines in oncology. http://www.NCCN.org. Accessed April 12, 2020. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patient with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733–742. Wareham D. Postherpetic neuralgia. Clin Evid 2005;15:1–9. World Health Organization. Cancer Pain Relief and Palliative Care: Report of a WHO Expert Committee. Geneva, Switzerland: World Health Organization, 1990:804.

“The best care possible does not stop with excellent disease treatments; it includes concern for a person’s physical comfort, emotions and spiritual well-being.” Ira Byock, The Best Care Possible I.

INTRODUCTION The focus of palliative care (PC) is to achieve the best possible quality of life (QOL) for patients and their caregivers at any stage of serious illness. Its hallmark is a comprehensive, team-based interdisciplinary approach, emphasizing collaboration and coordination of care with other providers and across settings. The National Hospice and Palliative Care Organization defines PC as “patient and family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering. Palliative care throughout the continuum of illness involves addressing physical, intellectual, emotional, social, and spiritual needs and facilitating patient autonomy, access to information, and choice.”

II. PC CORE PRINCIPLES The following features characterize PC philosophy and delivery: A. Care is provided and services are coordinated by an interdisciplinary team consisting of physicians, nurses, social workers, and chaplains. The team may also include pharmacists, psychologists, physical therapists, nutritionists, and other professionals in order to address patient and family physical, psychosocial, and spiritual needs. B. Patients, families, and all providers communicate and collaborate about care needs. C. Services may be provided concurrently or independently of disease-directed care. D. Patients’ and families’ hopes for peace and dignity are supported throughout the

entire course of illness, including the dying process, and even after death. Both hospice and PC aim to relieve suffering and improve QOL. In the United States, hospice care is limited to patients who have an expected survival of less than 6 months. However, PC is applicable to a much broader patient population, including patients living with progressive, chronic conditions (e.g., cardiovascular diseases, dementia, neurodegenerative conditions, renal or kidney dysfunction, liver disease, pulmonary disease, and advanced malignancy), and acute, life-threatening illnesses or injuries (e.g., severe trauma, intensive care unit [ICU] admission, or acute leukemia) where the disease itself or its treatments pose significant challenges to the QOL and well-being of the patient and family. III. HISTORY OF PC The wider concept of PC began with the modern hospice movement in the middle of the 20th century. The term “hospice” (from the same linguistic root as “hospitality”) can be traced back to medieval times when it referred to a place of shelter and rest for weary or ill travelers, some of whom were making pilgrimages in the hope of a miraculous cure. The word was first applied to specialized care for dying patients by social worker and physician Dame Cicely Saunders, who began her work with the terminally ill in 1948 and eventually established the St. Christopher’s Hospice in London in 1967 (Lancet 2018;391:1391). The first American hospice opened in 1974 in New Haven, Connecticut. In 1979, the National Hospice Organization was formed in the United States, and in 1982, the Health Care Finance Administration established the Medicare Hospice Benefit (MHB). At its inception, hospice care was most often provided at specialized facilities; however, most hospice care in the United States today is delivered at home. Hospice care is also available in homelike hospice residences, nursing homes, assisted living facilities, veterans’ facilities, hospitals, and prisons. Unfortunately, availability of hospice care may be limited by its capitated payment structure and by its eligibility criteria, which generally do not allow patients to receive hospice care and disease-directed treatment at the same time. The first U.S. hospital-based PC programs began in the late 1980s at a handful of institutions such as the Cleveland Clinic and Medical College of Wisconsin. Since then, there has been a marked increase in hospital-based PC programs, now numbering over 1,800, as well as recent developments in home-based PC and establishment of outpatient centers. In 2001, with the support of the Robert Wood Johnson Foundation, PC leaders from across the United States met to discuss the standardization of PC across settings with the goal of improving quality. A task force called the National Consensus Project (NCP) grew out of this meeting and currently includes members of the American Academy of Hospice and Palliative Medicine (AAHPM), the Center to Advance

Palliative Care (CAPC), the Hospice and Palliative Nurses Association (HPNA), and the National Palliative Care Research Center (NPCRC). The NCP’s fourth edition of the Clinical Practice Guidelines for Quality Palliative Care was released in 2018 and provides best-practice standards and supporting evidence for all clinicians caring for seriously ill patients. Certification of specialized physician expertise and training in palliative and hospice care initially was administered by the AAHPM; the American Board of Medical Specialties (ABMS) approved the creation of Hospice and Palliative Medicine (HPM) as a subspecialty of 10 participating boards in 2006. Since 2014, physicians wishing to achieve board certification in HPM must complete a 1-year fellowship program to be eligible for the examination. In addition to specialty certification for physicians, there are also nationally recognized advanced PC certification processes for nurses, nurse practitioners, social workers, chaplains, and counselors. Advanced Palliative Care Certification for hospitals was first offered by the Joint Commission in 2011, to promote high standards in quality and adherence to published guidelines. There are currently 137 HPM fellowship programs in the United States with 370 fellows in training in 2018 to 2019, and the specialty is rapidly growing. Despite this growth, many sources project severe shortages of HPM physicians in the coming years, with a projected shortage of 18,000 HPM physicians, emphasizing the need for wider education of other specialists, including oncologists, primary care physicians, and midlevel providers, in primary PC skills (Lancet 2018;391:1391; N Engl J Med 2013;368:1173). IV. RATIONALE FOR INTEGRATION OF PC INTO ONCOLOGY CARE Despite rapid and ongoing advances in cancer treatment, patients and caregivers still shoulder significant physical, psychological, spiritual, and financial burdens. Adequate symptom management remains a challenge, even for patients with early-stage malignancies and cancer survivors. A seminal research published in a study of 3,123 ambulatory patients with breast, colorectal, lung, or prostate cancer revealed that 33% received inadequate analgesic treatments (J Clin Oncol 2012;30:1980). In addition, many patients are troubled by “symptom clusters” or multiple symptoms at any given time. Family caregivers of patients with advanced cancer also experience significant morbidity as a result of their role. The team approach of PC and the focus on supporting the patient and the caregivers can reduce family and caregiver distress and improve QOL. PC teams can also help bridge the communication gap surrounding prognostic information and patient’s wishes in the face of disease progression. Although the majority of advanced cancer patients and their family members report they desire realistic and timely information if their disease is incurable, available data suggest that

many people do not receive this information until very late in the illness trajectory (J Clin Oncol 2010;28:4364). A lack of time and formal clinician training, prognostic uncertainty, and the perception that discussing a poor prognosis will have a negative effect on patients and families can all contribute to a delay in having these discussions. Unfortunately, this lack of communication can lead to increased cost and resource utilization at the end of life (EOL), and decreased quality time spent with family and friends (JAMA 2008;299:2667). Patients with advanced cancer who report recent discussions of prognosis and life expectancy with their oncologists have a better understanding of the terminal nature of their illnesses (J Clin Oncol 2016;34:2398). In addition, clear communication about prognosis has been associated with improvements in patient and family QOL and in patient–physician relationships. True integration of oncology and PC benefits patients, families, and care teams by combining aggressive cancer-directed treatment with focused attention directed toward the patient and family experience. Randomized clinical trials evaluating integrated oncology–PC delivery models have shown improvements in symptom management, patient and family satisfaction and QOL, and efficient use of healthcare resources (JAMA 2016;316:2104). Integrating PC into oncology has also been associated with consistent improvements in advance care planning and, importantly, has not been associated with increased mortality or shortened length of life. Rugno and colleagues found that gynecologic oncology patients who received early PC reported better QOL and less depression, received less chemotherapy within the last 6 weeks of life, and survived longer (Gynecol Oncol 2014;135:249). V. INTEGRATED PALLIATIVE CANCER CARE MODELS A. Inpatient consultation service. Investigators from the MD Anderson Cancer Center described clinical characteristics and outcomes of mobile interdisciplinary palliative consultation team in the setting of a comprehensive cancer center (J Palliat Med 2007;10:948). They demonstrated that 28% of patients evaluated by a consult team showed symptom improvement within 24 hours and 38% within 72 hours after initial consultation. The consult team found an average of eight symptoms per patient, most commonly pain, delirium, and opioid side effects, such as excessive sedation, confusion, and constipation. In a randomized multicenter controlled trial of inpatient PC team consultation versus usual hospital care for patients admitted with lifelimiting illness including 27% of patients with cancer, there were decreased ICU stays, decreased hospital readmissions, and increased number of patients who completed advance directives (ADs) in the PC group, although there were no differences in symptoms or QOL measures (J Palliat Med 2008;11:180). In a 2015 systematic review, Khandelwal and colleagues found that PC interventions and advance care planning decreased ICU admissions and reduced ICU length of stay

(Crit Care Med 2015;43:1102). A retrospective cohort study of oncology patients found that inpatient PC consultation was associated with increased hospice utilization and a decreased 30-day readmission when the patient was discharged to hospice (J Palliat Med 2018;21:62). B. Outpatient education and support interventions. The projects ENABLE and ENABLE II (Educate, Nurture, Advise, Before Life Ends) investigated a nurse-led educational and support intervention in patients with advanced cancer in a rural National Cancer Institute (NCI)-designated comprehensive cancer center. Both demonstration project and subsequent randomized controlled trial added in-person sessions and telephone-based follow-up to usual oncology care (Palliat Support Care 2009;7:75). Advance practice nurses assessed patients using the National Comprehensive Cancer Network (NCCN) distress thermometer and provided targeted and problem-solving resources based on identified areas of distress. In addition, with participant permission, nurses contacted their clinical team about issues requiring immediate attention. Patients in the usual care group were allowed to have unrestricted access to all oncology and supportive services available at the institution. Patients receiving intervention had higher scores for QOL (p = 0.02) and fewer incidence of depression (p = 0.02). Symptom intensity did not change significantly, although a trend toward lower intensity was noted (p = 0.06). The intervention did not affect hospitalizations, emergency room visits, or ICU days. Limitations of the study included lack of in-person contact and relatively low baseline symptom intensity reported in both groups of patients. A randomized trial of an innovative educational intervention, COPE (Creativity, Optimism, Planning, and Expert information), administered to patients simultaneously enrolled in phase I, II, and III therapeutic oncology clinical trials, and their caregivers was conducted at the City of Hope (J Palliat Med 2011;14:465). Similar to the ENABLE model, this intervention focused on coaching and guided problem-solving around common sources of distress, including physical, psychological, social, and spiritual. Patients and caregivers in the intervention arm participated together in three educational sessions, led by trained instructors, during their first month of clinical trial enrollment, followed by a 6-month follow-up period. Patients in the control arm received usual oncology care. The primary outcome measure was self-assessed, global QOL for patients and caregivers. Results indicated significantly slower rate of QOL decline for caregivers in the intervention arm, but no difference in QOL measures for patients. Limitations of this study included the group-based nature of the intervention, rather than individual patient and caregiver visits. It was also not specifically mentioned how the information gained from the intervention was communicated to the patient’s primary oncology team. An unblinded parallel assignment randomized trial of outpatient advanced cancer

patients tested the effects of usual care with CALM (managing Cancer and Living Meaningfully), a novel and brief psychotherapeutic intervention (J Clin Oncol 2018;36:2422). Patients were stratified by Patient Health Questionnaire-9 (PHQ-9) scores. Patients in the intervention arm received three to six CALM psychotherapy sessions from therapists, with CALM therapy focusing on symptom management and communication with healthcare providers, changes in self and relations with close others, spiritual well-being and the sense of meaning and purpose, and mortality and future-oriented concerns. The control arm was usual care without CALM. The primary caregiver was invited to one or more sessions when acceptable to the patient and the therapist. The primary outcome measure was change in PHQ-9 at 3 months. Results indicated fewer depressive symptoms with CALM compared to usual care at 3 and 6 months, as well as significant improvement in preparation for EOL in the intervention group. Limitations included a patient population that was largely white and well educated. C. Palliative home care. Provision of PC in the home setting is another promising pattern for integration of PC and oncology care. Palliative home care interventions are typically modeled on the interdisciplinary hospice care approach, but do not require patients to forego disease-directed therapy. The Veteran’s Affairs Medical Centers (VAMC) are currently testing “concurrent care models,” in which veterans with advanced cancer can receive hospice care concurrently with cancer-directed treatments. A recent qualitative study of the project concluded that these programs improve care education and coordination and are valued as a bridge to hospice care (Support Care Cancer 2019;27:1263). They remain underused, however, because of the heterogeneity of the interventions across different VAMC sites, as well as provider concerns about Medicare compliance. Interventions outside of the VAMC also point to improvements in care coordination, patient satisfaction, and cost, but financial sustainability has limited their spread. D. Early integrated outpatient PC clinic. Temel and colleagues conducted a groundbreaking randomized trial (1:1 randomization) of early PC integrated into standard oncology care versus standard oncology care alone in patients with metastatic non–small cell lung cancer (N Engl J Med 2010;363:733). Patients were enrolled within 8 weeks from diagnosis, and were evaluated by the PC team within 3 weeks of enrollment and at least monthly thereafter. Intention to treat analysis included 74 patients in the usual care arm and 77 patients in the early PC arm. Patients in the control arm could be referred to the PC team at the discretion of the treating oncologist, but did not cross over to the integrated PC group. The PC team consisted of board-certified physicians and specially trained advance practice nurses. The care was provided according to National Consensus Project for Quality Palliative Care guidelines and included symptom assessment and management,

discussions about patient and family coping with the disease, and illness understanding and education. All patients were ambulatory and had Eastern Cooperative Oncology Group performance status 0-2 at the start of the study. The primary outcome was change in the QOL at 12 weeks determined by the Functional Assessment of Cancer Therapy-Lung scale. Investigators also collected data on changes in mood, type of EOL care received (chemotherapy within 14 days of death, and use and timing of hospice care). Patients receiving early PC had significantly better QOL (p = 0.03), lower depression scores (p = 0.01), were less likely to receive aggressive EOL care (p = 0.05), and had longer median hospice stay (p = 0.09, 11 vs. 4 days) compared with the standard oncology care group. In addition, more patients in the early PC arm had their resuscitation preferences documented in the ambulatory medical record (p = 0.05). In a post hoc analysis, median overall survival was significantly longer for those in the concurrent care arm (11.6 vs. 8.9 months, p = 0.02), despite fewer patients receiving aggressive EOL care. It is important to note that the study was not powered to determine a survival benefit. Also, although PC consultation was allowed in a control group at the discretion of the oncologist, only a small minority of patients (14%) in that group had any contact with the PC team. Additional analysis of the data revealed that there was no significant difference between the groups with respect to the total number of regimens and time to the administration of second- or third-line chemotherapy. However, patients in the PC group were less likely to receive intravenous (IV) chemotherapy in the last 2 months of life, and any chemotherapy in the last 14 days (J Clin Oncol 2012;30:394). On the basis of this study and other randomized clinical trials, the American Society of Clinical Oncology published “Provisional Clinical Opinion: The Integration of Palliative Care into Standard Oncology Care” in February 2012 (J Clin Oncol 2012;30:880). It states: “it is the Panel’s expert consensus that combined standard oncology care and palliative care should be considered early in the course of illness for any patient with metastatic cancer and/or high symptom burden.” In 2016, an international consensus proposed 11 major and 36 minor criteria to guide appropriate referral to outpatient PC specialists (Lancet Oncol 2016;17:e552). VI. PRIMARY VERSUS SPECIALTY PC As the recognition of PC needs is increasing, so is the controversy over who should be managing those needs. Multiple models of specialized PC have been shown to improve outcomes, but it may not be practical or necessary for every patient with advanced cancer to see a PC specialist in addition to their oncology team. Several authors have suggested that “primary palliative care,” including primary management of pain, nausea, other symptoms, as well as fundamental communication and prognostication skills, should be delivered by oncology teams. Other more complex skills requiring specialized training, such as negotiating a difficult family meeting, addressing persistent distress, or

managing refractory symptoms, may be better suited for consultation or comanagement with a PC specialist/team. VII. BARRIERS TO PC INTEGRATION INTO ONCOLOGY PRACTICE Despite significant advances in PC research and practice over the last decade, significant barriers remain for integration of PC and cancer care. Many unanswered questions exist with regard to the feasibility of different models, availability of primary and specialized PC, standardization of the interventions, patient selection for inpatient and outpatient PC consultations, and financial models. Additional barriers include physician perceptions that PC is the same as hospice care, and that current models of cancer care already provide adequate EOL care (Lancet Oncol 2018;19:e588). VIII.HOSPICE A. Eligibility criteria. Under Medicare, Medicaid, and most private insurance plans, a patient is eligible for hospice if his/her physician and the hospice medical director certify that he/she is terminal and has 6 months or less to live. The patient and caregivers must agree to the philosophy of hospice: care will be focused on managing symptoms without the use of life-prolonging measures. The patient needs to have a 24-hour caregiver or be willing to come up with a plan with the hospice team for 24-hour care when such care becomes necessary. Such a plan could include the hiring of 24-hour private-duty nursing care, entrance into a long-term care facility, making arrangements to live with a family member, or for friends or family to take shifts in the patient’s own home. Patients do not have to sign a Do Not Resuscitate (DNR) order to be on hospice; however, most patients decide to change their code status after initiating hospice. To be eligible for hospice care through Medicare, patients with a diagnosis of cancer must have distant metastatic disease at presentation or disease that has progressed from an earlier stage to metastatic disease. Patients with small cell lung cancer, brain cancer, and pancreatic cancer, however, may be eligible for hospice care even without distant metastatic disease. In most cases, patients must also be willing to forego further disease-directed treatment. Patients may remain on hospice beyond 180 days (6 months) as long as criteria for hospice care are still met and a face-to-face encounter with a physician or nurse practitioner is performed to document this. B. Funding. Hospice is covered by a specific MHB. Most private insurance companies and Medicaid offer a similar benefit. Patients who sign for their MHB have elected to have their Medicare Part A (hospital benefit) assigned to a Medicare-certified hospice (“Medicare-Certified Agency” or “MCA”). The hospice is then responsible for the patient’s plan of care and bills for services through the insurance policy. The MCA receives a per diem rate from Medicare that covers all medications for pain and

symptom management, durable medical equipment and supplies, nursing care, social services, chaplain visits, and other needed services. The 2019 per diem rate for routine home care is about $190 a day. The MHB does not cover private-duty nursing or the cost of room and board at a nursing facility. If the patient is dually eligible for Medicare and Medicaid, hospice care will be funded by Medicare and room and board will be covered by Medicaid. If the patient is eligible only for Medicare, the family must pay privately for room and board in a nursing facility. C. The MHB provides four levels of care for hospice patients: 1. Routine home care. Hospice services provided in the patient’s home or a nursing facility. 2. Inpatient respite care. Short-term inpatient admission (usually limited to 5 days) to promote caregiver well-being. Owing to the physical and psychological stress and strain experienced by the 24-hour care of the family member, respite care is essential. It may be for a few days or the patient may be transferred to a facility from the hospital setting. 3. Inpatient symptom management. Inpatient admission is sometimes required for intensive management of issues that are difficult to manage outside of the hospital setting. Such issues may include, but are not limited to, severe pain, intractable seizures, uncontrolled bleeding, and intractable nausea/vomiting because of gastrointestinal obstruction. Before admission, the hospice medical director, admitting care team, patient, and family discuss the purpose of the hospitalization. The hospice agency remains responsible for the plan of care and must be involved daily and at all levels of decision-making in collaboration with the inpatient staff. The MHB limits what sorts of treatment a patient can receive and still be on hospice. When considering more invasive treatment options, the patient’s hospital care team should discuss with the hospice program what types of services may be provided without disqualifying a patient from hospice. Some measures, such as intravenous hydration, blood transfusions, tube feedings, paracentesis, and thoracentesis, may be appropriate for palliation, but must be approved on a case-by-case basis by the hospice medical director. 4. Bereavement care. Bereavement care is a required component of the MHB and is provided by specially trained hospice staff for at least 1 year after the patient’s death. Depending on the hospice, this service may be provided by the nurse, social worker, chaplain, or specially trained volunteers. Bereavement care can include periodic mailings, phone calls, and home visits. Some hospices offer bereavement support groups, and some host annual memorial services. If the family requires additional counseling services, the hospice may choose to provide extended services or refer them to other resources in the community.

IX. PRACTICAL SUGGESTIONS FOR IMPROVED COMMUNICATION AND SYMPTOM MANAGEMENT A. Estimation of prognosis. Progression of disease in advanced cancer is characterized by worsening symptoms and functional status. Physicians may miss opportunities to explore patient wishes regarding EOL care unless discussions of prognosis and the uncertainty surrounding it begin early in the course of therapy, but many struggle with the timing of these discussions. Several risk-profiling scores have been developed to improve physician estimates of prognosis; even so, it remains difficult to predict the disease trajectory for many patients with advanced cancer. Seminal events, such as unplanned hospitalizations, delirium, and venous thromboembolism, may provide additional predictors of mortality. Adding to the complexity, many patients with advanced cancer have multiple other comorbidities. Under these circumstances, determining prognosis can be difficult for oncologists and PC and hospice practitioners alike. The heterogeneous data surrounding prognostic scales make it difficult to recommend a single scale as the definitive best. Multiple studies, however, have concluded that clinician estimates alone tend to be overly optimistic, and that complementing clinician estimates with more objective tools improves accuracy. One remarkably effective approach to complex prognostic uncertainty in advanced disease involves inverting the usual question of “how long does this person have to live?” and asking instead, “would I be surprised if this person were to die in the next 6 months?” A 2017 review of this “surprise question” found it to be accurate almost 75% of the time (BMC Med 2017;15:139). B. Communication around prognosis. Physicians may feel reluctant to address the possibility of dying with their patients, but patients and their caregivers frequently find such information helpful. Discordance between patients’ and clinicians’ perspective of intended purpose of cancer-directed treatment is common. Clinicians tend to confuse the matter further by steering the conversation toward treatment, describing PC as “doing nothing,” and failing to check patient and family understanding of the treatment goals. Communication about prognosis and preferences regarding EOL care should be viewed as an ongoing process. Initial discussions may be quite brief, but as the disease progresses, more in-depth conversations will become necessary. To communicate effectively in these difficult situations, it is important to assess what the patient knows and wants to know about the disease and its prognosis. Cognitive impairment is common among advanced cancer patients; if appropriate, clinicians should offer to include caregivers in the discussion. One simple but effective model for “bad news” conversations is “ask-tell-ask.” The clinician starts by asking about the patient’s understanding, then tells information, and finally asks for feedback from the patient. Eliciting questions and establishing a common understanding require

careful attention not just to the words spoken but also to the emotions displayed. The extent of discussion will depend on the readiness of the patient and the family to hear and accept what the clinician is saying. In the event that a patient is reluctant to address EOL issues, the clinician may conclude the discussion by asking permission to raise the topic again at a future visit. C. Advanced care planning. An Advance Directive (AD) is a legal document that provides guidance about a person’s wishes for medical care. ADs frequently also designate a “durable power of attorney for healthcare” or surrogate decision-maker. These documents go into effect only if a person becomes unable to speak for himself. In addition, good patient–physician communication around advanced care planning improves patient satisfaction with their medical care. PC consultation has been shown to increase preparedness, planning, and use of ADs among patients and families. The idea that one should “hope for the best and prepare for the worst” will be recognized by most people. This concept may be used to communicate the clinician’s desire to support the patient in their quest for life-prolonging therapy in the face of a life-limiting illness. Focusing conversations about patient preferences for EOL care on “big picture goals” and values, instead of specific treatment decisions, may prove helpful in guiding future care. D. Symptom management. Patients with end-stage cancer suffer from a significant burden of symptoms, because of both the pathophysiology of cancer and the common comorbidities, such as arthritis and sleep-disordered breathing. Although comorbid conditions must be addressed, aggressive and effective cancer-directed treatment is the first line of symptom management in advanced cancer. Common symptoms reported by patients with advanced cancer include pain, dyspnea, fatigue, anorexia and dysgeusia, depression, and anxiety. Pain. Pain is a common and debilitating symptom in patients with cancer. Cancer pain may result from the underlying pathophysiology of cancer itself or it may be associated with frequently occurring comorbidities, including degenerative arthritis, anxiety, and depression. General principles of pain management can be applied to the treatment of pain in cancer patients. However, special attention must be paid to drug selection and dosing, and therapeutic effectiveness must be frequently reassessed. Opioids remain the mainstay of cancer pain treatment, and recent studies have demonstrated that they work best in the context of a holistic treatment plan that addresses the psychological, emotional, and existential, in addition to physical, aspects of pain. Dyspnea. Although the mechanisms are not fully understood, low-dose opioids may provide relief in refractory dyspnea. Oxygen supplementation is frequently used to treat dyspnea, particularly in hypoxemic patients. Even patients without significant hypoxemia may derive benefit. However, it is not clear whether this is due to the

oxygen itself or to the sensation of air flow. Benzodiazepines may also be used as a second-line therapy, particularly for anxiety associated with dyspnea at EOL. Fatigue. Many end-stage cancer patients struggle with fatigue, which may be associated with inflammation. Several studies have now documented links between markers of inflammation and fatigue before, during, and particularly after treatment. Screening and treatment for potentially reversible underlying causes of fatigue, such as pain, sleep disturbances, anemia, or hypothyroidism, can improve patients’ QOL. A number of pharmacologic treatments have been evaluated for cancer-related fatigue. Methylphenidate and dexamethasone provide significant improvements in fatigue and QOL for patients with advanced stage cancer, and hematopoietic growth factors improve fatigue for patients with chemotherapy-induced anemia (J Pain Symptom Manage 2011;41:761). In addition, a variety of interventions have shown benefit in randomized clinical trials, including graded aerobic exercise programs, cognitive behavioral therapy, acupuncture, mindfulness meditation, yoga, and biofield therapy. Depression and anxiety. Patients with advanced cancer face uncertainty about the future and loss of independence. Depression is common, as are spiritual distress and demoralization, but these may be difficult to recognize, as they frequently mimic some of the symptoms of disease progression. In addition, depression is a major factor in predicting poor QOL for cancer patients. Supportive counseling may be beneficial, as may some complementary and alternative medicine interventions, such as mindfulness-based stress reduction and dignity therapy. For those patients who require pharmacologic treatment, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, benzodiazepines, and psychostimulants, such as methylphenidate, have all shown some benefit in the treatment of depression, particularly when used in conjunction with counseling. Benzodiazepines should be used with caution in the elderly because of the potential adverse effects of sedation and confusion. Psychostimulants may be a better option in patients for whom a rapid response is important, although patients may experience worsening anxiety or agitation. Anorexia, cachexia, and dysgeusia. Weight loss and anorexia in advanced cancer patients are thought to be related to the neurohormonal effects of cancer itself. A number of pharmacologic treatments exist for anorexia and cachexia in cancer patients, but none of them are disease modifying. Potentially treatable underlying causes, therefore, must be addressed, including hypothyroidism, depression, and uncontrolled pain. Appetite stimulants, such as megestrol acetate and cannabinoids, may be helpful in cancer-related anorexia but can cause side effects that may outweigh the benefits. Discussions about the reasons for anorexia and weight loss in advanced cancer may allow patients and families to focus less on the quantity of food

consumed and more on the quality of the experience. Encouraging smaller servings of favorite foods and liberalizing dietary restrictions when appropriate can benefit the patient with end-stage cancer. Dysgeusia is common in advanced cancer, and may be related to inflammation, chemo- or radiation therapy, or alterations in the gut microbiota. In addition to maintaining good oral hygiene, zinc supplementation may be useful, especially for patients whose nutritional status may be compromised by their dysgeusia. SUGGESTED READINGS Braiteh F, El Osta B, Palmer JO, et al. Characteristics, findings, and outcomes of palliative care inpatient consultations at a comprehensive cancer center. J Palliat Med 2007;10:948–955. Gade G, Venohr I, Conner D, et al. Impact of an inpatient palliative care team: a randomized controlled trial. J Palliat Med 2008;11:180–190. Kaasa S, Loge JH, Aapro M, et al. Integration of oncology and palliative care: a Lancet Oncology Commission. Lancet Oncol 2018;19:e588–e653. Kavalieratos D, Corbelli J, Zhang D, et al. Association between palliative care and patient and caregiver outcomes. JAMA 2016;316:2104–2114. Quill TE, Abernethy AP. Generalist plus specialist palliative care—creating a more sustainable model. N Engl J Med 2013;368:1173–1175. Smith TJ, Temin S, Alesi ER, 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.

I.

INTRODUCTION Antineoplastic-induced nausea and vomiting (AINV) are common side effects of many cancer treatments and often most feared by patients and their families. If not prevented or treated, it is estimated that 60% to 80% of patients experience AINV when receiving chemotherapy. AINV can be detrimental not only because it affects patients’ quality of life but can also lead to delay or refusal of treatment.

II. CLASSIFICATION AINV can be categorized into five different groups: acute, delayed, breakthrough, refractory, and anticipatory. Acute chemotherapy-induced emesis occurs within the first 24 hours and usually peaks 5 to 6 hours after chemotherapy administration. Delayedonset emesis develops more than 24 hours after chemotherapy administration, reaches a peak of intensity usually 48 to 72 hours after chemotherapy, and may last up to 7 days. Breakthrough emesis occurs when nausea and vomiting (N/V) occur despite adequate prophylactic treatment. Refractory N/V occurs in subsequent cycles. Anticipatory N/V occurs after a patient experiences AINV and then sensory stimuli, such as smells, sounds, tastes, or sights, trigger episodes of nausea or vomiting prior to receiving chemotherapy. Pathophysiology. There are different mechanisms and neurotransmitters in the central nervous system (CNS) and peripheral nervous system (PNS) that are responsible for acute and delayed AINV. In acute AINV, effects of the chemotherapy stimulate the enterochromaffin cells in the gastrointestinal (GI) tract, leading to the release of serotonin (5-HT). 5-HT then binds to 5-HT3 receptors on intestinal vagal afferent nerves,

which activates the nucleus of the solitary tract (NTS) and the area postrema (also known as the chemoreceptor trigger zone [CTZ]) in the CNS, both of which trigger the vomiting reflex. This pathway may also be involved in delayed AINV, although it is not the main mechanism. In delayed AINV, chemotherapy triggers the release of the neurotransmitter substance P from neurons in both the CNS and the PNS. Substance P binds to neurokinin-1 (NK1) receptors in the NTS and CTZ, which leads to vomiting. Dopamine is another neurotransmitter that plays a role in AINV. There are dopamine D2 receptors located in the CTZ that are also targets of antiemetic therapy and appear to be more effective for acute AINV. Unlike 5-HT, substance P, and dopamine, whose actions promote emesis, other neurotransmitters such as cannabinoids may have antiemetic effects, although much less is known about their actions at receptors in the CNS and their role in treating AINV. Risk factors. Risk factors for AINV can be categorized as patient or treatment related. Patient-related risk factors include age 250 mg/m2) Cisplatin Cyclophosphamide (≥1,500 mg/m2) Dacarbazine Doxorubicin (≥60 mg/m2) Epirubicin (>90 mg/m2) Ifosfamide (>2 g/m2) Mechlorethamine Streptozotocin

Moderate (30%–90%)

Aldesleukin (>12–15 million IU/m2) Amifostine (>300 mg/m2) Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin (AUC 1 × ULN

Ziv-afilbercept

Not studied

>3 × ULN

>1.5 × ULN

>1.5 × ULN

Child–Pugh class C >2 mg/dL

AST > ULN

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; ULN, upper limit of normal.

Index Note: Locators followed by the letter ‘f’ and‘t’ refers to figures and tables A Abemaciclib regimen, 107–108 Abiraterone regimen, 337–339, 673 ABO incompatibility, 465 ABVD regimen, 476, 481, 598 Accelerated fractionation, 53 Acetaminophen, 658 Acinic cell carcinomas, 202 Acral lentiginous melanoma (ALM), 412 Actinic keratosis, 425–426 Active surveillance (AS), 332 Activities of daily living (ADLs), 613 instrumental, 613, 615 Acute airway compromise, 643–644 Acute graft-versus-host disease (aGVHD), 466 Acute leukemias, 504–527. See alsoindividual types complications and supportive care, 524–527 CNS involvement, 526–527 growth factors, 526 infection, 525 intravenous access, 526 transfusions, 524 tumor lysis syndrome, 526 epidemiology and risk factors, 504 follow-up, 527 HIV and, 507 presentation of, 505 therapy and prognosis, 510–524 acute lymphoblastic leukemia, 520–524 acute myeloid leukemia, 510–517 acute promyelocytic leukemia, 517–520 cytogenetics in, 510–511

workup and staging, 505–510 Acute lymphoblastic leukemia (ALL), 520–524 presentation of, 505 therapy and prognosis, 520–524 Acute lymphoblastic lymphoma, 498 Acute lymphocytic leukemia (ALL), 70 myeloid growth factors in, 651 Acute myeloid leukemia (AML), 504, 505, 511–513t, 517t, 650–651 Acute promyelocytic leukemia (APL), 505 associated coagulopathy, 517 Adamantinoma, 405 Adaptive system, 115 Adenocarcinomas, 202 of the cervix, 386 clear cell, 391 localized gastric, 277–280 metastatic gastric, 280–281 papillary serous adenocarcinoma of the peritoneal cavity, 449 Adenoid cystic carcinoma, 202 ADIC regimen, 402 Adjuvant analgesics, 667–669 Adjuvant chemotherapy, 59 for bone sarcoma, 407 for soft-tissue sarcoma, 399 for testicular seminoma, 348 Adjuvant Navelbine International Trialists Association (ANITA), 218 Adjuvant radiation therapy, for soft-tissue sarcoma, 399 Adjuvant therapy with post-operative radiation and concurrent chemotherapy (POACRT) for squamous cell cancer of the head and neck, 188 Adjuvant therapy with post-operative radiation (POART) for squamous cell cancer of the head and neck, 188 Adoptive cell therapies, 131 Ado-trastuzumab emtansine regimen, 101 AD regimen, 402 Adrenal tumors, 436–439 definition of, 436 diagnosis of, 437

epidemiology of, 436 presentation of, 436 treatment for, 437–439 workup for, 437 Adrenocortical carcinoma (ACC), 436 Advanced Palliative Care Certification, 681 Adverse events, 156–159 monitoring and response assessment, 159–160 Afatinib regimen, 76 Afebrile neutropenia, 650 Aggressive lymphomas, 487, 494–495 AIDS-associated malignancies, 585–591 Aging-related clonal hematopoiesis (ARCH), 538 AIDS-associated carcinomas, 600–602 AIDS-associated malignancies, 585–609 anal carcinomas, 600–602 Burkitt-like lymphomas, 591–593 diffuse large B-cell lymphoma, 585–591 Hodgkin lymphomas, 597–599 Kaposi sarcoma, 602–608 non-Hodgkin lymphoma, 585–591 other, 608–609 primary central nervous system AIDS-associated malignancies lymphomas, 593–595 primary effusion lymphomas, 595–597 AJCC Cancer Staging Manual 8th edition, 331 AJCC TNM staging criteria, 272 Alemtuzumab regimen, 90–91 Allogeneic bone marrow transplantation (BMT), 549 Allogeneic hematopoietic cell transplantation (allo-HCT), 453 Alpelisib regimen, 98 Alpha-fetoprotein (AFP), 344, 345 Alternative hypothesis, 166 American Academy of Hospice and Palliative Medicine (AAHPM), 680 American Association for the Study of Liver Diseases (AASLD), 299 American Board of Medical Specialties (ABMS), 680 American Joint Committee on Cancer (AJCC), 272, 346, 398t, 406t, 412

American Society for Colposcopy and Cervical Pathology (ASCCP), 380–381 American Society of Clinical Oncology (ASCO), 65, 310 Amyloidosis (AL), 576–578 Anal cancer, 296–297 Anaplastic lymphoma kinase (ALK) fusion targeting, 73–75 Anaplastic thyroid carcinoma, 434 Androgen deprivation therapy (ADT), 328, 334 Anemia, 584 Angiogenesis, 1 Angiosarcoma, 397 Ann Arbor staging system for Hodgkin lymphoma (HL), 475t, 587 Antibody-based therapies, 117–129 Antibody-dependent cellular cytotoxicity (ADCC), 68 Anti-CD30 antibody, 480 Anticonvulsants, 667 Anti-CTLA-4 (CD152) antibodies, 123 Antigen-presenting cells (APC), 115 Anti-human herpes virus-8 (HHV8), 608 Antineoplastic agents, 4, 63–65 Antineoplastic-induced nausea and vomiting (AINV), 690–702 antiemetic prophylaxis, principles of, 695 classification, 690–691 defined, 690 emetic potential, 691, 695 general principles, 691 pathophysiology, 690–691, 692–695t, 692–700t risk factors, 691 therapeutic drug classes, 691 Anti-PD-1 (CD279)/PD-L1 (CD274) antibodies, 123–125 Apoptosis, 5–6 Arsenic trioxide regimen, 517 Aspirin and nonacetylated salicylates, 658 Astrocytomas, 174 Atezolizumab regimen, 93–94 Atypical chronic myeloid leukemia (aCML), 535t Atypical glandular cells of undetermined significance (AGUS), 370 Atypical squamous cells of undetermined significance (ASCUS), 381

Atypical squamous cells that cannot exclude HSIL (ASC-H), 381 Autologous stem cell transplantation, 589 Avelumab regimen, 94 Axicabtagene Ciloleucel, 146, 155 Axillary lymph node dissection (ALND), 233–234 Axitinib regimen, 81, 318 B Bacillus Calmette-Guerin (BCG), 322 Barrett esophagus (BE), 270–271 Basal cell carcinoma (BCC), 411, 426–428 Base excision repair (BER), 6 “Bayesian” statistics, 163 BCR-ABL tyrosine kinase inhibition, 70–73, 541 BEACOPP (increased dose) regimen, 478, 598 BEP regimen, 349, 351 Bereavement care, 686 Bevacizumab regimen, 83–84, 178, 288, 318, 360, 362–363, 386, 614 Bias, defined, 162 Bicalutamide regimen, 335 Bilateral orchiectomy, 335 Bilateral pelvic lymphadenectomy, 391 Biliary obstruction, 31 Biostatistics, as applied to oncology, 162–169 data, 162–163 making inferences about, 166 viewing, 165–166 measurement with error, 164–165 modeling relations, 167–168 probabilities, 163–164 Birt-Hoggs-Dubé syndrome, 313 Bispecific antibodies, 127 Bispecific T cell Engagers (BiTES), 153 Bisphosphonates, 572, 629, 632, 673 Bivariate scatter plots, 165 Bladder cancer, 321–326 background of, 321

bladder-sparing/ approaches to, 323 clinical presentation of, 321 epidemiology of, 321 metastatic disease, 324–326 muscle-invasive disease, 323–324 non-muscle-invasive disease, 322–323 risk factors of, 321 workup and staging, 321–322 Blastic bone metastases and elevated PSA, men with, 449 Blinatumomab (Amgen), 153–154 B lymphocytes, 115 Body surface area (BSA) calculations, 63–64 Bone marrow aspiration and biopsies, 587 as source of HSCs in transplantation, 459–461 transplant, 650 Bone pain, 673 Bone sarcoma, 403–408 chondrosarcoma, therapy for, 408 Ewing sarcoma, therapy for, 408 history of, 403 laboratory features of, 404 local therapy, general principles of, 405–407 metastatic disease, management of, 407 osteosarcoma therapy, 407 pathology of, 404–405 physical examination, 403 radiographic imaging of, 404 staging of, 405, 406t treatment for, 405–408 “Bootstrap,” 165 Bortezomib regimen, 103, 568, 614 Bosutinib regimen, 71, 547 Bowel obstruction, 30 Bowel perforation, 29–30 B-progenitor ALL, 520–521 Brachytherapy, 35, 333, 400

BRAF inhibitors, 414, 417–418, 422–423, 433 Brain biopsy, 594 Brain metastases, 211–212, 422–423 BRCA1 and BRCA2 genes, 225, 356 Breast cancer, 224–251 ductal carcinoma in situ (DCIS), 231–232 early-stage invasive breast cancer (stages I to III), 233–243 adjuvant chemotherapy and radiation therapy, sequence of, 240–241 adjuvant radiation therapy, 232 chemotherapy, 234 HER2 therapy, 237–240 neoadjuvant chemotherapy, 237–241, 239–240t neoadjuvant systemic therapy, 234, 235 surgery, 233–234 systemic treatment, 232–233 trastuzumab therapy, 238 epidemiology of, 224 follow-up, 242 histopathology of, 226 lobular carcinoma in situ (LCIS), 232–233 locoregional recurrent, 243–244 metastatic, 244–251 bone metastasis, 251 chemotherapy, 246 duration of chemotherapy treatment, 250–251 follow-up while on treatment, 249–250 HER2-targeted therapy, 246–249 hormone therapy, 245–246 immunotherapy, 249 PARP inhibitor, 249 radiation therapy, 244–245 regimens, 247–248t surgery, 244 postmastectomy pain syndrome, 674–675 presentation of, 227–228 risk factors, identifiable, 224–226 screening, 227

workup and staging of, 228–231 Breast-conserving therapy (BCT), 232 Breast reconstruction techniques, 234 Brentuximab vedotin regimen, 101–102, 480 Breslow thickness, 411–412 Bridging therapy, 155 Bronchoscopy, 433 Bruton tyrosine kinase inhibitor, 89–90 Burkitt lymphoma (BL), 498 AIDS-associated, 591–593 C Cabazitaxel/prednisone regimen, 339 Cabozantinib, 434 Calcitonin, 629 Calvert formula, 64 Cancer and Leukemia Group B (CALGB), 268 Cancer immunotherapy, 114–135 definition of, 114 immune-related response criteria, 134–135 immune system, 115–116 therapeutic modalities, 116–134 Cancer of unknown primary site, 443–452 background, 443 diagnosis of, 443–444 presentation of, 443 therapy and prognosis, 448–451 workup, 444–448 electron microscopy, 446 endoscopy, 444 genetics, 447–448 imaging, 444 immunohistochemistry, 445–446 light microscopy, 444 tumor markers, 447 Cancer-related fatigue (CRF), 709 Cancer survivorship, 704–713

care plan, 705 coordination of care, 704–705 effects of cancer and treatment, 707–713 anxiety, depression, and distress, 710 bone health, 710–711 cardiac toxicity, 707 cognitive impairment, 709–710 fatigue, 709 hormone-related issues, 711–712 lymphedema, 707–708 peripheral neuropathy, 708–709 reproductive health, 712–713 overview, 704 preventive health, 705–706 screening, 704 surveillance of recurrence, 704 Cancer vaccines, 129–133 Capecitabine/oxaliplatin regimen, 287 Capecitabine regimen, 441 Carboplatin dose calculation, 64 Carboplatin/paclitaxel regimen, 260, 359, 372 Carcinoembryonic antigen (CEA), 302 Carcinogen, 410 Carcinoma ex-pleomorphic adenoma, 202 Carcinoma in situ (CIS), 322, 344 Carcinoma of unknown primary (CUP), 443–452 background, 443 defined, 443 diagnosis of, 443–444 presentation of, 443 therapy and prognosis, 448–451 workup, 444–448 Cardiac tamponade, 641–642 Cardiomyopathy, 590 Carfilzomib regimen, 103–104, 568 Categorization, 165 Catheterization, 26

CD8+ (cytotoxic) T cells, 115 CDE regimen, 588 CD4+ (helper) T cells, 115 CDKN2A tumor suppressor gene, 410 Cell cycle, 4 Cell differentiating retinoid, 608 Cell infusion, 155–156 Cemiplimab regimen, 94 Center to Advance Palliative Care (CAPC), 680 Central venous catheterization, 26 Hickman catheters/Broviac catheters, 26 implantable catheters (Portacath, Infusaport), 26 Central venous catheters, 618 Cervical cancer, 384–387 background of, 384 complications of, 386–387 follow-up of, 387 presentation of, 384 therapy and prognosis of, 386 workup and staging, 384 Cervical cytology screening (Pap test), 380 Cervical intraepithelial neoplasia (CIN), 380 Cervical intraepithelial neoplasia 1 (CIN 1), 381, 384 Cervical intraepithelial neoplasia 2 (CIN 2), 380, 384 Cervical intraepithelial neoplasia 3 (CIN 3), 382, 384 Cervix adenocarcinoma of, 388 cancer, in AIDS patients, 609 preinvasive lesions of, 380–384 Cetuximab regimen, 78, 189, 288, 426 Chemoradiation for head and neck cancers, 188–189 Chemotherapy, 310, 338, 372 adjuvant, 324 for cervical cancer, 386 cytotoxic. See Cytotoxic chemotherapy dose adjustments, 721–739

for hepatic failure, 730–739 for renal failure, 722–729 for elderly patients with cancer, 614 for endometrial cancer, 372 for gestational trophoblastic disease, 377–378 for head and neck cancer, 188–189, 192–193 intrathecal, 590, 595 irradiation and, 59 lymphocytotoxic, 590 in metastatic prostate cancer, 338 neoadjuvant, 323–324 for thymic carcinoma, 266 toxicity in older adults, prediction of, 615 Chemotherapy-induced peripheral neuropathy (CIPN), 674 Chemotherapy Risk Assessment for High Age Patients (CRASH) trial, 615 Child-Pugh score, 299 Chimeric antigen receptor therapies (CAR-T), 138–139, 142–147, 143f manufacturing of, 155 Cholangiocarcinoma, 303–306 epidemiology of, 303 management of, 304–306 presentation of, 303 treatment for, adjuvant therapy, 305 workup and staging, 304 Chondrosarcoma, 405, 408 CHOP regimen, 587, 592, 596 Choriocarcinoma, 344, 345, 376 Chromatin modifiers, 8 Chronic graft-versus-host disease (cGVHD), 459, 461, 469–470 Chronic leukemias, 541–562. See alsoindividual types defined, 541 Chronic lymphocytic leukemia (CLL), 550–562 clinical presentation, laboratory features, and diagnosis, 553 complications, 556–557 epidemiology of, 550–551 pathogenesis of, 551–553 prognostic factors, 552t

staging and prognosis, 554–556, 555t stem cell transplantation, 561–562 treatment initiating, 557–558 of relapsed and refractory CLL, 560–561 of small lymphocytic leukemia, 560–561 Chronic myeloid leukemia (CML), 68, 541–550 clinical and laboratory features of, 542 epidemiology of, 541 history of, natural, 542 initial workup, 544–545 pathogenesis of, 541–542 treatment: transplant options allogeneic bone marrow transplantation, 549 treatment: tyrosine kinase inhibitors bosutinib, 547 chemotherapy, 549 dasatinib, 546–547 imatinib, 545–546 nilotinib, 547 ponatinib, 547–548 therapy, 548–549 Chronic myelomonocytic leukemia (CMML), 536t Cisplatin and 5-FU (PF) regimen, 190, 198 Cisplatin/etoposide/bleomycin regimen, 349 Cisplatin/paclitaxel regimen, 360, 386 Cisplatin regimen, 323–325, 386, 438 for adrenocortical carcinoma, 438 for metastatic SCCHN, 191 Clear cell adenocarcinomas, 391 Clinically palpable tumors, 38 Clinical target volume (CTV), 54 Clonal cytopenia of undetermined significance (CCUS), 538 Clonal hematopoiesis, 538 Clonal hematopoiesis of indeterminate potential (CHIP), 538 Clonidine, spinal, 670 CMV regimen, 323

Cockcroft-Gault equation, 614 Codeine, 666 Cognitive behavioral therapies (CBT), 669 Cold coagulation, 383 “Cold” knife conization (CKC), 383 Colon cancer prognostic factors, 285–286 surgical principles, 283–284 treatment by stage, 286–293 metastatic CRC therapy, 288–292 second-line and subsequent therapy, metastatic CRC, 290–291 stage I colon cancer (T1-T2, N0 M0), 286 stage II colon cancer (T3-T4, N0 M0), 286–287 stage III colon cancer (any T, N1-N2, M0), 287–288 workup and staging, 283–286 Colorectal cancer (CRC), 283–297. See also Colon cancer; Rectal cancer chromosomal instability, 295 complications, 293–294 epidemiology, 294–295 follow-up, 294 hypermethylation phenotype, 295 microsatellite instability, 286 presentation, 283 risk factors, 295 screening, 294–295 treatment, 286–293 Colposcopy, 381–382, 388 Comparative genomic hybridization (CGH), 412 Complementarity determining regions (CDR), 69 Complementary and alternative therapies, 669–670 Complement-mediated lysis, 69 complications, 500–501 Comprehensive geriatric assessment (CGA) domains of, 612t for elderly patients with cancer, 611–613 Computed tomography (CT) for adrenocortical carcinoma, 437

for bone sarcoma, 404 for cervical cancer, 384 for esophageal cancer, 271 for gestational trophoblastic disease, 377 for Hodgkin lymphoma (HL), 474, 475–476 for malignant melanoma, 413 for non-small cell lung cancer, 215–216 for prostate cancer, 330 for renal cell carcinoma, 314 for small cell lung cancer, 208 for soft-tissue sarcoma, 395 for testicular cancer, 344, 351 for thyroid carcinoma, 433 Concomitant chemoradiotherapy, 651 Concurrent chemotherapy and radiation (CRT), 188 Confounding, defined, 168 Conjugated monoclonal antibodies, 101–102 CONKO-001, 309 Continuous random variables, 164 Conventional fractionation, 41 Copanlisib regimen, 98–99 COPE (Creativity, Optimism, Planning, and Expert information), 683 COPP/ABVD chemotherapy, 481 Core needle biopsy, 16 Corticosteroids, for aGVHD, 468 Covariates, choice of, 168 Crizotinib regimen, 75 Cryoablation, 316 Cryotherapy, 28 for basal cell carcinoma (BCC), 427 hypopigmented areas caused by, 605 for prostate cancer, 334 CSF cytology, 183 CSF EBV PCR test, 594 CTLA-4 (cytotoxic T lymphocyte antigen-4), 95–97, 116–117 C-type lectin receptors, 115 Cushing disease, 438

Cutaneous melanomas. See Primary cutaneous melanomas Cutaneous punch biopsy, 17 C-VAD (Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone), 571 CVD (cyclophosphamide, vincristine and dacarbazine), for adrenocortical carcinoma, 438 CXCL12, 460 CXCR4, 460 Cyclophosphamide, 152 Cytogenetics, 504 Cytokine release syndrome (CRS), 145, 148, 156 Cytokines, 116–117 Cytomegalovirus (CMV), stem cell transplantation and, 459, 468 Cytotoxic chemotherapy dose calculations, 63–65 for amputees, 64 for elderly patients, 65 formulas, 63–64 for hepatic dysfunction, 65 manipulation of, 64 for obese patients, 65 for renal dysfunction, 65 for endometrial cancer, 372–374, 375 special considerations in, 63–65 D Dabrafenib regimen, 87, 417, 418 Dacarbazine regimen, 123 Dactinomycin regimen, 379 DA-EPOCH-R regimen, 592, 597 Daratumumab regimen, 111–112 Dasatinib regimen, 71–72, 546–547 D-CEP (Dexamethasone, cyclophosphamide, etoposide, and cisplatin), 571 ddMVAC regimen, 324–325 Deep shave (Saucerization) biopsy, 411 Deep vein thrombosis (DVT), 328 Dendritic cells (DC), 114 Denosumab regimen, 339, 673 Dexamethasone regimen, 568

DHAP regimen, 497 Diagnostic procedures, 15–16 core needle biopsy, 16 cutaneous punch biopsy, 16 fine needle aspiration cytology (FNA), 16 Differentiated thyroid cancer, 433 Differentiation syndrome, 521 Digital rectal examination (DRE), 328 Dimethyl sulfoxide (DMSO), 463 Direct repair, 6 Discrete random variables, 164 DNA alterations, types of, 4–6 damage, sources of, 1–4 human papillomavirus (HPV), 381 methylation, 7–8 repair, 6–7 Docetaxel regimen, 189, 191, 212, 337–338 Donor lymphocyte infusions (DLIs), 139, 141–142, 466, 469 Do Not Resuscitate (DNR) order, 685 Dopamine regimen, 690 Dose-dense/dose-intense regimens, 650 Dose-volume histograms (DVHs), 55 Dot plots, 165 Doxorubicin/cisplatin regimen, 372 Doxorubicin regimen, 323, 376, 402, 435, 438 DT-PACE (Dexamethasone, Thalidomide, cisplatin, Doxorubicin, cyclophosphamide, and etoposide), 571 Dual affinity retargeting proteins (DARTS), 139 Dual-targeting cell engagers, 139–154 DuBois and DuBois formula, 63 Ductal carcinoma in situ (DCIS), 225, 231–232 Durvalumab regimen, 94 Duvelisib regimen, 99 E Eastern Cooperative Oncology Group (ECOG) trial, 267

Effective sample size, 164 Elderly patients with cancer, care of, 611–617 biology of, 611 chemotherapy toxicity, prediction of, 615 comprehensive geriatric assessment for, 611–613 geriatric syndromes, practical guide to addressing, 615–616 survivorship, 616 treatment for, 613–615 Electrical stimulation neuromodulation, 670–671 Electron microscopy, 446 Elotuzumab regimen, 112 Eltrombopag (Promacta«), 654 Embryonal carcinomas, 345 Embryonal rhabdomyosarcomas, 345 Embryonal tumors, 182 Emergencies hematologic, 639–641 oncologic. See Oncologic emergencies palliative procedures for, 29t ENABLE model, 683 Enasidenib, 519 Endocervical curettage (ECC), 381, 384 Endocrine malignancies, 432–442 adrenal tumors, 436–439 parathyroid carcinoma, 435–436 thyroid carcinoma, 432–435 Endodermal sinus tumors, 391 Endogenous erythropoietin (EPO), 651 Endogenous G-CSF, 647 Endogenous GM-CSF, 648 Endogenous TPO, 654 Endometrial cancer, 369–374 background of, 369–370 complications of, 374 follow-up of, 374 presentation of, 370 stages of, 372–374

therapy and prognosis of, 370–374, 373t workup and staging, 370 Endometrial stromal sarcoma (ESS), 374 Endometrium, premalignant disease of, 367–369 Endoscopic retrograde cholangiopancreaticography (ERCP), 302 Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), 302 Endoscopy, 433, 444 End points, primary, 162 Engraftment, 464–465 Entrectinib regimen, 96 Enzalutamide regimen, 337–339 Ependymoma, 180–181 Epidermal growth factor receptor (EGFR) expression of, in SCCHN, 186 targeting, 75–77 Epidural spinal cord compression, 637–638 Epigenetic modifications, analysis of, 13 Epigenetic regulators, 7 Epithelial ovarian cancer, 356–364 EPOCH regimen, dose-adjusted, 588 EPOCH-R regimen, 496, 498 EPOCH-RR regimen, 588 EP regimen, 349, 351 Epstein-Barr virus (EBV), 186, 581 Erdafitinib regimen, 97–98 Erectile dysfunction (ED), 327 Erlotinib regimen, 76–77, 310, 614 Erythroid growth factors, 651–654 Erythroleukoplakia, 194 Erythropoietin (EPO), 572, 651–653 escBEACOPP regimen, 479–480 ESHAP regimen, 497 Esophageal cancer, 270–275 complications of, 275 course of, 275 epidemiology of, 270–271 localized, therapy for, 272–274

metastatic, therapy for, 274–275 staging, 272 workup, 271–272 Esophagogastroduodenoscopy (EGD), 271 Established postherpetic neuralgia, treatment of, 676 Esthesioneuroblastoma, 203 Etoposide/cisplatin regimen, 349, 352 Etoposide regimen, 438 European Organization for Research and Treatment of Cancer (EORTC), 211, 232, 267, 323 European Study of Pancreatic Cancer (ESPAC)-3, 309 Everolimus regimen, 88–89 Ewing sarcoma, 405 therapy for, 408 Excisional biopsy, 17, 411 External beam pelvic radiation therapy (EBRT), 372 External beam radiation, 324, 333, 434, 673 Extragonadal germ cell tumor (EGGCT), 344, 354 Extramedullary plasmacytomas, 575–576 Extrapleural pneumonectomy (EPP), 262 Extremity sarcoma, 394–395, 399 F Facial Kaposi sarcoma, 603 Fallopian tube carcinoma, 364 False-positive/negative, 166 Febrile neutropenia, 650 Fecal occult blood tests (FOBT), 294 Federation of Gynecologists and Obstetricians (FIGO) surgical staging of cervical cancer, 384, 385t of endometrial cancer, 370, 374 of ovarian cancer, 357, 358t of uterine sarcomas, 375t of vaginal cancer, 391t of vulvar cancer, 388, 389t Fedratinib regimen, 110–111 Feet, Kaposi sarcoma of, 603 Fentanyl, 665

Fertility issues, 348 Field cancerization, 194 Fine needle aspiration (FNA), 16, 203–204, 414 5-Fluorouracil (5-FU), 286, 302, 309, 390 for metastatic SCCHN, 191 5-Fluorouracil/leucovorin regimen, 286 Fludarabine, 152, 560 Fluorescence in situ hybridization (FISH), 11, 412, 465 Fluorodeoxyglucose positron emission tomography (FDG PET) for non-small cell lung cancer, 216 for parathyroid carcinoma, 435 for thyroid carcinoma, 433 Fluoropyrimidines regiment, 293, 614 Flutamide regimen, 335 FOLFIRI regimen, 288–289 FOLFIRNIOX, 310 FOLFOX4 regimen, 287 Follicular Lymphoma International Prognostic Index (FLIPI), 493 Formalin-fixed paraffin-embedded (FFPE) tissue, 12 French-American-British (FAB) classification, 507 Frequentist, 163 Functional Assessment of Cancer Therapy-Lung scale, 684 Fungating tumors, 191 G Gallbladder cancer, 301–303 management of, 302–303 presentation of, 302 workup and staging, 302 Gastric cancer, 275–281 complications of, 281 course of, 281 epidemiology of, 275–276 localized gastric adenocarcinoma, 277–280 metastatic gastric adenocarcinoma, 280–281 pathology of, 276 workup, 277

Gastrointestinal Kaposi sarcoma, 603 Gastrointestinal stromal tumor (GIST), 397 therapy for, 401 Gastrostomy tubes (G-tubes), 27 GC regimen, 325 Gehan and George formula, 64 Gemcitabine/docetaxel regimen, 376 Gemcitabine regimen, 191, 311–312 Gemtuzumab/ozogamicin regimen, 517 Generalized linear models, 168 Genital Kaposisarcoma, 603 Geriatric syndromes interventions for, 616t in older adults, practical guide to addressing, 615–616 German Hodgkin Study Group, 478 Germ cell ovarian cancers, 365 Germ cell tumor (GCT), testicular, 343–354 Gestational trophoblastic disease (GTD), 376–380 background of, 376 complications of, 378 current focus of, 379–380 follow-up of, 379 presentation of, 377 therapy and prognosis of, 377–378 workup and staging, 377 Gestational trophoblastic neoplasia (GTN), 377, 378–379t Giant cell tumor of bone, 405 Gilteritinib regimen, 106–107 Glasdegib regimen, 92 Gleason score, 330 Glioblastoma multiforme (GBM), 171 Gliomas, 171–181 astrocytomas, 174 ependymoma, 180–181 glioblastoma multiforme, 171 oligoastrocytomas, mixed, 174 oligodendrogliomas, 174

pilocytic astrocytomas, 180 Glomerular filtration rate (GFR), 63 Gonadotropin-releasing hormone (GnRH) agonists, 335 Goodness-of-fit, 168 Goserelin (Zoladex) regimen, 336 Graft failure, 466 Graft-versus-host disease (GVHD), 461 prophylaxis, 466–468 Graft-versus-leukemia (GvL) effect, 454 Graft-versus-tumor (GvT) effect, 454 Granulocyte colony-stimulating factor (G-CSF), 460, 647 Granulocyte-macrophage colony stimulating factor (GM-CSF), 460, 648–649 Granulocytes, 115 Gross tumor volume (GTV), 54 Growth factors epidermal, 5 erythroid, 651–654 hematopoietic, 647–654 megakaryocytic, 653–654 myeloid, 647–651 vascular endothelial, 81–85, 316 Gynecology Oncology Group (GOG), 359, 360, 362, 369, 372, 374, 378 Gynecomastia, 343 H Haploidentical donor transplants, HLA matching of, 459 HBV surface antigen (HBsAg), 130 Head and neck cancer, 186–204 approach to patient, 186 background of, 186 larynx and hypopharynx, 197–199 lip and oral cavity, 193–194 locally recurrent disease, 190 metastatic disease, 190–191 nasal cavity and paranasal sinus tumors, 203 nasopharyngeal cancer, 200–202 oropharynx, 195–196

platinum-refractory SCCHN, 191 salivary gland cancers, 202–203 therapy for, overview of, 186–193 unknown primary, neck management and, 203–204 Health Care Finance Administration, 680 Heavy-chain deposition disease, 574 Hematologic emergencies, 639–641 Hematologic toxicity, of chemotherapy, 614 Hematopoietic cell transplantation (HCT), 453–471, 482 conditioning regimens, 461–463 donor selection, 459 infusions, stem cell, 463 late complications of allogeneic transplantation, 470–471 patient selection, 454–458 posttransplant care and complications, 464–469 acute graft-versus-host disease, 466–467 hematopoietic, 464–466 infections, 468–469 relapsed disease, 469 veno-occlusive disease of the liver, 469 sources of hematopoietic stem cells, 459–461 bone marrow, 459–460 peripheral blood stem cells, 460–461 umbilical cord blood, 461 types of, 453–454 Hematopoietic growth factors, 647–651 erythroid, 651–654 myeloid, 647–651 platelet and megakaryocytic, 653–654 Hematuria, 314, 321–322 Hemodialysis, 572 Hemorrhage, 31 Hemostasis, 388 Heparin, 620 Hepatic artery infusion (HAI) catheters, 26 Hepatitis B virus (HBV), 129–130 vaccine, 130

Hepatocellular carcinoma (HCC), 298–301 epidemiology of, 301–302 management of, 300–301 presentation of, 298 workup and staging, 298–299 Hereditary diffuse gastric cancer syndrome (HDGC), 226 Hereditary nonpolyposis colorectal cancer (HNPCC), 295 Herpes simplex virus (HSV), 468 Herpes zoster (HZ), 675–676 HER2 targeting, 78–81 High-dose cytarabine (HDAC), 515 High-dose-rate (HDR) brachytherapy, 333 High grade squamous intraepithelial lesions (HSILs), 381 Highly active antiretroviral therapy (HAART), 582–583, 597, 605–606 High risk metastatic disease, 378 Hirschsprung disease, 432 Histograms, 165 Histone deacetylase inhibition, 104–106 HIV (human immunodeficiency virus), 581–609 acute leukemia and, 507 AIDS-associated malignancies and, 608–609 anemia, evaluation of, 584 diagnostic studies for HIV infection, 581–582 highly active antiretroviral therapy for, 582–583 Hodgkin lymphoma and, 473 Kaposisarcoma and, 394, 397 neutropenia, evaluation of, 584 non-Hodgkin lymphoma, 486, 498 occurrence, rate of, 581–582 opportunistic infections, prophylaxis for, 582 thrombocytopenia, evaluation of, 585 HLA alleles, 459 matching of unrelated donor transplants, 459 typing, 459 Hodgkin and Reed-Sternberg cells (HRS), 473 Hodgkin lymphoma (HL), 473–484

AIDS-associated, 597–599 background of, 473 chemotherapeutic regimens for, 477t complications, 484 epidemiology and risk factors, 473 follow-up, 483–484 genetics, 473 molecular biology, 473 presentation of, 473–474 therapy and prognosis, 476–483 nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), 481–482 recurrent Hodgkin lymphoma, 482–483 stage I/II classical Hodgkin disease: favorable risk, 476–479 stage I/II classical Hodgkin disease: unfavorable, 479–480 stage III/IV classical HL, 480–481 workup and staging, 474–476 Hormonal therapy for adrenocortical carcinoma, 438 for neuroendocrine tumors, 441 for thyroid carcinoma, 434–435 Hormone replacement therapy (HRT), breast cancer and, 226 Hormone-sensitive disease, 335–336 Hospice, 679, 685–686 bereavement care, 686 eligibility criteria for, 686 funding for, 687 inpatient respite care, 686 inpatient symptom management, 686 routine home care, 686 Hospice and Palliative Medicine (HPM), 679–680 Hospice and Palliative Nurses Association (HPNA), 680 Human antimouse antibodies (HAMAs), 69 Human chorionic gonadotropin (hCG), 344, 345, 377 Human herpes virus-8 (HHV8), 608 Human leukocyte antigen (HLA) typing, 507 Human papillomavirus (HPV), 130–131, 186, 380, 384 Human placental lactogen (HPL), 376

Hurthle cell pathology, for thyroid carcinoma, 432 Hydrocodone, 666 Hydromorphone, 665 Hypercalcemia, 628–632 Hyperfractionation, 53 Hyperparathyroidism, 432 Hyperplasias, 367–369, 382 atypical, 369 simple and complex, 368–369 Hyperviscosity syndrome, 640–641 Hypofractionation, 53 Hypotheses, 162, 163 alternative, 166 null, 166 Hysterectomy, 371 I Ibritumomab Tiuxetan regimen, 102–103 Ibrutinib regimen, 90 ICE regimen, 497 Idelalisib regimen, 99, 494 Idiopathic cytopenia of undetermined significance (ICUS), 538 Idiopathic dysplasia of unknown significance (IDUS), 538 Ifosfamide/MESNA/cisplatin regimen, 376 Ifosfamide/MESNA regimen, 376 Ifosfamide regimen, 191, 376 Image-guided radiation therapy (IGRT), 53, 56–58 Imatinib regimen, 72, 545–548, 614 IMCgp100 (Immunocore), 154 I-Metaiodobenzylguanidine (MIBG) scintigraphy, 437, 438 Imiquimod regimen, 390 Immune Checkpoint Blockade, 117–123 Immune mobilizing mTCR Against Cancer (ImmTACs), 154 Immune-related response criteria, 134–135 Immune system, 115–116 Immunohistochemistry (IHC), 445–446 IMPACT B2 Study, 286

Implantable catheters (Portacath, Infusaport), 26 Imputation, 162 Incisional biopsy, 16–17, 411 Indolent lymphomas, 487 Induction chemotherapy, for squamous cell cancer of the head and neck, 189–190 Infectious emergencies, 644–645 Inferior vena cava (IVC) filters, 624 Inflammatory bowel disease, 294 Influential points, 168 Infusaport catheters, 26 Innate system, 115 Inpatient consultation service, 682 Inpatient symptom management, 686 Insertions, 5 Instrumental activities of daily living (IADLs), 615 Intensely-modulated radiation therapy (IMRT), 40, 55–56 Intensity-modulated radiation therapy (IMRT), 333 Interaction, 168 Intercalary resection, 407 Intercellular adhesion molecule 1 (ICAM-1), 564 Interferon, type-1, 115 Interferon Alpha, 116, 606 Interferon Alpha 2a regimen, 116 Interferon Alpha 2b regimen, 116 Interferon Alpha n3 regimen, 116 Interferon Beta, 116 Interferon Gamma, 116 Interleukin 1b (IL-1b), 115 Interleukin 2 (IL-2), 116–117, 132 Interleukin 7 (IL-7), 117 Interleukin 12 (IL-12), 115, 117 Interleukin 15 (IL-15), 117 Interleukin 21 (IL-21), 117 International Adjuvant Lung Cancer Trial (IALT), 28 International Bladder Cancer Group, 322 International Germ Cell Cancer Consensus Group (IGCCCG) classification system, 347, 351 International Mesothelioma Interest Group (IMIG), 262

International Society of Gynecological Pathologists, 367 International Staging System (ISS), 565 International System for Cytogenetic Nomenclature (ISCN), 10 International Union Against Cancer (UICC), 272 Interstitial XRT with seed implants (brachytherapy), 333 Intracranial mass lesion, 170–171 evaluation, 170 presentation, 170 treatment, 170–171 Intrathecal chemotherapy, 590, 595 Intravenous oxytocin, 377 Inversions, 5–6 Involved node radiotherapy (INRT), 478 Ionizing radiation, 4 Ipilimumab/nivoloumab regimen, 420 Ipilimumab regimen, 96, 123, 416, 423–424 Ipsilateral thyroid lobectomy, for thyroid carcinoma, 435 IPSS-R, 530, 533t Irinotecan regimen, 293, 312 Irreversible electroporation (IRE), 28 Isolated axillary adenopathy, women with, 448–449 Isolated inguinal lymphadenopathy from squamous cell carcinoma (SCC), 449–450 Ivosidenib, 519, 586 J Japanese Gynecologic Oncology Group (JGOG), 361 Jejunostomy tubes (J-tubes), 27 Juvenile myelomonocytic leukemia (JMML), 537t K Kaposisarcoma (KS) AIDS-associated, 602–608 soft-tissue sarcoma and, 397 Karyotype analysis, traditional, 10 Keyes punch biopsy, 388 Kidney cancer. See Renal cell carcinoma (RCC) Kinase therapy, for thyroid carcinoma, 434

KIT mutations, 423–424 Klatskin tumors, 304 Kyphoplasty, 671 L Lactate dehydrogenase (LDH), 344, 414 Laparoscopic radical prostatectomy (LRP), 333 Laparoscopy, for staging, 18 Laparotomy, for staging, 18 Lapatinib regimen, 79 Larotrectinib regimen, 96–97 Laryngoscopy, 433 Larynx and hypopharynx, cancers of, 197–199 Latissimus dorsi flap, 234 Leiomyosarcoma (LMS), 374, 397 Lenalidomide regimen, 494, 568, 614 Lentigo maligna melanoma (LMM), 412 Leukemias acute, 504–537 acute lymphoblastic, 520–524 acute lymphocytic, 70 acute myeloid, 504, 505, 650–651 acute promyelocytic, 505 in AIDS patients, 609 chronic, 541–562 chronic lymphocytic, 550–562 chronic myeloid, 68, 541–550 plasma cell, 575 Leukoplakia, 194 Leukostasis, 505, 639–640 Leuprolide acetate (Lupron), 336 Leydig cell tumors, 345 Lidocaine, 669 Li-Fraumeni syndrome, 226 Ligands, 7 Light-chain deposition disease, 574 Light microscopy, 444

Likelihood, 163 function, 163 ratio tests, 168 Linear modeling, 168 Linear-quadratic equation, 38–41 Lip and oral cavity cancer, 193–194 in AIDS patients, 609 Liposarcoma, 396 Liposomal anthracyclines regimen, 606, 614 Lobular carcinoma in situ (LCIS), 225, 232–233 Local anesthetics, 669 spinal, 670 Localized gastric adenocarcinoma, 277–280 Locally weighted regression, 165 Loop electrosurgical excisional procedure (LEEP), 383 Lower Anogenital Squamous Terminology (LAST), 381 Low grade neuroendocrine carcinoma, 450 Low grade squamous intraepithelial lesions (LSILs), 381 Low risk metastatic GTN, 378 Lumbar puncture, 587 Lung cancer, 206–213 in AIDS patients, 609 non-small cell. See Non-small cell lung cancer (NSCLC) small cell. See Small cell lung cancer (SCLC) smoking, 213 Luspatercept, 535t, 537t Luteinizing hormone (LH), 346 Lutetium-177 Dotatate, 441 Lymphadenectomy, 316, 371 for staging, 18 Lymphangiosarcomas, 394 Lymphedema, 603 Lymphocytic leukemia (ALL), 70 Lymphocytotoxic chemotherapy, 590 Lymphomatous meningitis, 589 Lymphovascular space invasion (LVSI), 386 Lynch syndrome, 295

M Macrophages, 115 Magnetic resonance angiography (MRA), for renal cell carcinoma, 314 Magnetic resonance cholangiopancreatography (MRCP), 302 Magnetic resonance imaging (MRI), 299, 302 for bone sarcoma, 404 for cervical cancer, 384 for CNS tumors, 174–175 in AIDS patients, 594 for ependymoma, 180 for glioblastoma multiforme, 174–175 for malignant melanoma, 414 for medulloblastoma, 183 for meningioma, 181 for neuroendocrine tumors, 440 for non-small cell lung cancer, 216 for prostate cancer, 330 for renal cell carcinoma, 314 for small cell lung cancer, 208 for soft-tissue sarcoma, 395 for testicular cancer, 344 MAID regimen, 403 Major histocompatibility complex (MHC), 459 Malignant melanoma, 410–430 background of, 410–411 epidemiology of, 410 localized disease, treatment of, 414–415 primary cutaneous melanomas, 411–423 risk factors of, 410 special considerations, 423 Mantle cell lymphoma (MCL), 495–496 Masaoka staging system for thymoma, 255t Mast cells, 115 Matched sibling donors, 454 Matched unrelated donors (MUD), 454, 516 Mature B-cell ALL, 521 mBACOD regimen, 588

MDRD equation, 614 Measures of information, 168 Mediastinoscopy for non-small cell lung cancer, 216 for staging, 18 Medicaid, 686 Medicare, Part A (hospital benefit), 686 Medicare-Certified Agency (MCA), 686 Medicare Hospice Benefit (MHB), 680, 686 Medroxyprogesterone, 368 Medullary thyroid carcinomas (MTC), 432 Medulloblastoma, 182–184 Megakaryocytic growth factors, 653–654 MEK inhibitors, 417, 424 Melanomas acral lentiginous, 412 lentigo maligna, 412 malignant, 410–430 metastatic, 417–418 mucosal, 423–424 nodular, 412 primary cutaneous, 411–423 superficial spreading, 412 of unknown primary, 423 uveal, 424 Melphalan regimen, 614 Memorial Sloan Kettering Cancer Center (MSKCC) model, 315 MEN2A syndrome, 432 MEN2B syndrome, 432 Meningioma, 181–182 Meperidine, 667 Merkel cell carcinoma (MCC), 428–430 Merkel cell polyomavirus (MCPyV), 428 MESNA regimen, 402 Mesothelioma, 260–268 background of, 252 presentation of, 260

prognosis of, 267–268 treatment for, 262–267 workup and staging, 261–262 Meta-analyses, 167 Metastases, surgery for, 22 Metastatic gastric adenocarcinoma, 280–281 Metastatic melanoma, 417–418 Methadone regimen, 665 Methotrexate regimen, 191, 323, 378, 594–595 Mexiletine regimen, 669 MGD006 (Macrogenics), 154 MGMT gene, 175 Microarray-based gene expression profiling, 12–13 Microarray technology molecular testing and, 12–13 Microscopic tumor, 38 Microwave ablation, 28 Midostaurin regimen, 107 Minimal residual disease (MRD), 516 Mismatched related donors, 454 Mismatch repair (MMR), 6–7 Missing data, 162 Mitomycin regimen, 322 Mitotane regimen, 438 Modeling relations, 167–168 Mogamulizumab regimen, 91–92 Molecular diagnosis, 1–21 DNA alterations, types of, 4–6 damage, sources of, 1–2 repair, 6–7 genomic alterations, in cancer epigenetic regulators, 7–8 genomics alterations in cancer, 1–8, 2–3t hallmarks of cancer, 1 mutations, targets of genes, 5–6

tumor suppressor genes, 5 Molecularly targeted therapy ALK fusion targeting, 73–75 BCR-ABL tyrosine kinase inhibition, 70–73 Bruton tyrosine kinase inhibitor, 89–90 CD38 target, 111–112 conjugated monoclonal antibodies, 101–102 CTLA-4 target, 95–97 cyclin-dependent kinase inhibitors, 107–108 EGFR targeting, 75–77 epidermal growth factor receptor (EGFR) targeting, 75–77 FLT3 inhibition, 106–107 HER2 targeting, 78–81 histone deacetylase inhibition, 104–106 monoclonal antibodies (mAbs), 68–69 mTOR targeting, 88–89 PARP inhibitors, 109–111 proteasome inhibition, 102–103 radioimmunoconjugates, 102–104 Raf tyrosine kinase inhibition, 85–86 tyrosine kinase inhibitors, 67–68 unconjugated monoclonal antibodies, 90–91 VEGF targeting, 81–85 Molecular testing, 8–14 description, 8 emerging techniques, 13–14 hybridization tissue in situ, 11 microarray-based gene expression profiling, 12–13 polymerase chain reaction, 11 Monoclonal antibodies (mAbs), 68–69 Monoclonal gammopathy of undetermined significance (MGUS), 574 Monomethyl auristatin E (MMAE), 480 “Monte Carlo” simulation, 165 Morphine, 664–665 MOSAIC study, 286 Mosteller formula, 64

MP (Melphalan and Prednisone), 569 MPR (Melphalan, Prednisone, and Lenalidomide), 569 MPT (Melphalan, Prednisone, and Thalidomide), 569 mTOR targeting, 88–89 M2 (vincristine, carmustine, cyclophosphamide, and melphalan), 571 Mucoepidermoid cancers, 202 Mucosal melanoma, 423–424 Mucositis, 614, 672–673 Multicentric Castleman disease in AIDS patients, 609 Multiple endocrine neoplasia syndromes, 432 Multiple-gated acquisition (MUGA) scan, 507 Multiple myeloma (MM), 564–573 Multiple testing, effect of, 167 Muscle-invasive bladder cancer, 323–324 Muscle relaxants, 667–668 Muscularis propria, 322 M-VAC regimen, 324–325 Myeloablative conditioning, 461–463 Myelodysplastic syndromes, 527–537, 651 complications and supportive care, 537 epidemiology and risk factors, 527–528 pathogenesis, 532 presentation, 528 therapy and prognosis, 533–537 treatment algorithm for, 533t workup and staging, 528–531 Myelodysplastic syndrome/myeloproliferative neoplasms-unclassified (MDS/MPN-U), 536t Myeloid growth factors, 647–651 Myeloma in AIDS patients, 609 N Nab-paclitaxel regimen, 311 Narcotics, 187 Nasal cavity and paranasal sinuses, tumors of, 203 Nasopharyngeal cancer, 200–202 National Consensus Project for Quality Palliative Care, 680, 684 National Hospice Organization, 680

National Institutes of Health (NIH) system, 377 National Marrow Donor Program (NMDP), 459 National Palliative Care Research Center (NPCRC), 682 National Surgical Adjuvant Breast and Bowel Project (NSABP), 232 Natural killer (NK) cells, 114, 139 therapies, 152–153 Nausea and vomiting. See also Antineoplastic-induced nausea and vomiting (AINV) anticipatory, treatment of, 702 breakthrough, treatment of, 702 radiotherapy-induced, 702 Neck cancer. See Head and neck cancer Neoadjuvant chemotherapy, 59, 239–240t, 407 Neoadjuvant radiotherapy, 400, 401 Nephrectomy cytoreductive, 317 radical, 316 Neuroendocrime tumors, 439–442 defined, 439–442 diagnosis, 440 epidemiology, 439 presentation, 439–440 treatment, 440–442 workup, 440 Neurofibromatosis-1 (NF1), 180 Neurofibromatosis-2 (NF2), 181–182 Neurolytic celiac plexus block, 672 Neurolytic hypogastric plexus block, 672 Neurolytic neural blockade, 671–672 Neuropathic pain from tumor invasion of major nerve plexus, 673 Neurotoxicity or Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS), 156 Neutropenia, 584 Neutropenic enterocolitis (typhlitis), 30–31, 526 Neutropenic fever, 644–645 Next-generation sequencing (NGS), 11–12 Nicotine replacement therapy (NRT), 715, 717 NIH scoring system, 470 Nilotinib regimen, 72, 547

Nilutamide regimen, 335 99mTc-Sestamibi scintigraphy, for parathyroid carcinoma, 435 Niraparib regimen, 109 Nivolumab regimen, 95, 124, 319 Nodal Kaposisarcoma, 603 NOD-like receptors (NLRs), 115 Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), 481–482 Nodular melanoma (NM), 412 Noncompliant patient, pain management in, 676 Non-germ cell tumors (non-GCT), 345 Non-Hodgkin lymphoma (NHL), 486–501 epidemiology and risk factors, 486 follow-up, 501 molecular biology, 486–487 pathogenesis, 487 presentation of, 487–488 therapy and prognosis, 492–500 Burkitt lymphomas, 498 HIV-associated, 498 lymphoblastic lymphoma, 498 mantle cell lymphoma, 498 WHO classification of, 488–490t workup and staging, 488–492 Nonhomologous enjoining, 7 Nonlinear modeling, 168 Nonopioid analgesics, 657–658 Nonparametric methods, 165 Non-receptor tyrosine kinases, 68 Nonseminoma, testicular, 345 Non-small cell lung cancer (NSCLC) ALK gene rearrangements and, 220–221 background, 214 EGFR mutations and, 220 follow-up, 221 KRAS mutations and, 221 pathologic diagnosis, 216 pathology, 216

presentation, 214–215 radiotherapy in, 214 risk factors, 214 ROS1 gene rearrangements and, 221 staging, 217 theory and prognosis, 217–222 therapy and prognosis stage I and II, 217–218 stage III, 218–219 stage IV, 219–222 workup and staging, 215–216 Nonsteroidal anti-inflammatory drugs (NSAIDs), 658–659 NSABP C-07 trial, 287 NSABP-07 trial, 287 Nucleotide excision repair (NER), 6 Null hypothesis, 166 O Oat cell, 386 Obinutuzumab regimen, 99–100 Objectives, 162 Occult cancer, 619–620 Occult testicular tumor presenting as carcinoma of unknown primary, 345–346 Ofatumumab regimen, 100 Olaparib regimen, 109, 362–363 Older adults with cancer biology of, 611 chemotherapy toxicity, prediction of, 615 comprehensive geriatric assessment for, 611–613 geriatric syndromes, practical guide to addressing, 615–616 survivorship, 616 treatment for, 613–615 Oligoastrocytomas, mixed, 174 Oligodendrogliomas, 174 Oncogenes, 5–6 Oncologic emergencies, 628–645 cardiac, 641–643

cardiac tamponade, 641–642 superior vena cava syndrome, 642–643 hematologic, leukostasis, 639–640 hyperviscosity syndrome, 639–640 infectious, 644–645 metabolic, 628–637 hypercalcemia, 628–632 syndrome of inappropriate antidiuretic hormone, 635–637 tumor lysis syndrome, 632–635 neurologic, spinal cord compression, 637–638 respiratory, 643–644 surgical intervention for, 28–32 biliary obstruction, 31 bowel obstruction, 30 bowel perforation, 29 hemorrhage, 31 neutropenic enterocolitis (typhlitis), 30–31 pericardial tamponade, 31 spinal cord compression, 32 superior vena cava syndrome, 31–32 One-tailed test, 166 Opioid analgesics, 667 general principles for use of, 659–661 limitations of use in cancer pain management, 663–664 opioid rotation, 667 specific opioid analgesics, 664–667 spinal, 670 Opioid toxicity syndrome (OTS), 676 Opportunistic infections (OIs), prophylaxis for, 582 Oral combined contraceptives (OCP), 225 Oral etoposide, 606 Oral Kaposisarcoma, 603 Orchiectomy, 346, 349, 351 Oropharynx, cancer of, 195–196 Osteoarticular resection, 407 Osteoblastic (bone-forming) lesions, 404 Osteolytic (bone-destroying) lesions, 404

Osteosarcoma therapy, 407 Outliers, 165, 168 Outpatient education and support interventions, 682 Ovarian cancer, 356–365 epithelial, 356–364 fallopian tube carcinoma, 364 germ cell, 365 stromal tumors of the ovary, 365 Oxaliplatin regimen, 293, 309 Oxycodone, 665 Oxymorphone, 665–666 P Paclitaxel/doxorubicin/cisplatin regimen, 372 Paclitaxel/ifosfamide/cisplatin regimen, 352 Paclitaxel regimen, 191, 435, 606 Paget disease of the nipple, 226 Pain assessment, comprehensive, 655–657 Pain assessment scales, 655 Pain management, 655–677 analgesics, systemic, 657–669 adjuvant analgesics, 667–669 nonopioid analgesics, 657–658 nonsteroidal anti-inflammatory drugs, 658–659 opioid analgesics, 659–667 WHO ladder, 657 barriers to, 656t pain assessment, comprehensive, 655–657 pain syndromes, specific, 672–676 bone pain, 673 mucositis, 672–673 neuropathic pain from tumor invasion of major nerve plexus, 673 noncompliant patient, pain management in, 676 opioid toxicity syndrome, 676 postherpetic neuralgia, 675–676 tumor treatment-related neuropathic pain syndromes, 673–675 resistant cancer pain, special techniques for management of, 669–672

neurosurgical techniques, 672 psychological and behavior medicine techniques, 669 refractory pain and/or other symptoms of terminal illness, 672 severe pain, interventional electrical stimulation neuromodulation, 670–671 neurolytic neural blockade, 671–672 spinal administration of analgesics, 670 techniques, 670 vertebral augmentation, 671 vertebroplasty and kyphoplasty, 671 Palbociclib regimen, 108 Palliative care, 679–689 communication and symptom management, suggestions for, 687–689 core principles of, 679–680 definition of, 679 history of, 680–681 home care, 683 hospice care, 685–686 integration into oncology practice, barriers to, 685 primary vs. specialty, 685 rationale for, 681–682 Pancreatic cancer, 308–312 epidemiology of, 308 management of, 309–312 metastatic, 310–312 presentation of, 308 workup and staging, 308–309 Panitumumab regimen, 78, 289 Papillary serous adenocarcinoma of the peritoneal cavity, women with, 448–449 Pap test (cervical cytology screening), 380 PARADIGM trial, 190 Parameters, 164 Parametric, 164 Paraneoplastic syndromes, 192, 206, 207–208t, 253t Parathyroid carcinoma, 435–436 defined, 435 diagnosis of, 435

epidemiology of, 435 presentation of, 435 treatment for, 435–436 workup for, 435 Pathogen-associated molecular pattern (PAMP), 115 Pattern recognition receptors (PRR), 115 PAX8-PPAR gamma, and thyroid carcinoma, 433 Pazopanib regimen, 82–83, 318, 441 PCP prophylaxis, 469 PCV regimen, 179 PD-1 (program death-1), 117 Pelvic examination, 380 Pelvic lymphadenectomy, 331, 333 Pelvic lymph node dissection, 323 Pembrolizumab regimen, 95 Pemetrexed regimen, 191 Penile cancer, AIDS and, 609 Pericardial tamponade, 31 Peripheral blood stem cell (PBSC) harvesting, 460–461 as source of HSCs in transplantation, 460–461 transplants, 459 Peripheral T-cell lymphoma, 499 Permutation tests, 165 Pertuzumab regimen, 79 Pexa-Vec (JX-594), 133 Pharmacogenetics, 13 Pheochromocytoma, 432, 438 Physical and occupational therapies, 669 Pilocytic astrocytomas, 180 Planning target volume (PTV), 54 Plasma cell dyscrasias, 564–580 amyloidosis, 576–578 extramedullary plasmacytomas, 575–576 heavy-chain deposition disease, 574 light-chain deposition disease, 574 monoclonal gammopathy of undetermined significance, 574

multiple myeloma, 564–573 plasma cell leukemia, 575 POEMS syndrome, 579–580 smoldering myeloma, 574–575 solitary plasmacytomas of bone, 575 Waldenström macroglobulinemia, 578–579 Plasma cell leukemia, 575 Platinum-refractory SCCHN, 191 Plerixafor, 460 Pleurectomy with decortication (P/D), 262 Pleurodesis, 262 POEMS syndrome, 579–580 Poly (ADP-ribose) polymerase (PARP), 361 Polycyclic aromatic hydrocarbons, 4 Polymerase chain reaction (PCR), 11 Polymerase slippage hypothesis, 7 Pomalidomide regimen, 571 Ponatinib regimen, 73, 547–548 Poorly differentiated carcinoma of midline distribution, men with, 449 Port-A-Cath catheters, 26 Positron emission tomography (PET), 349 for adrenocortical carcinoma, 437 for cervical cancer, 384 for CNS tumors in AIDS patients, 594 for esophageal cancer, 271 fluorodeoxyglucose for non-small cell lung cancer, 216 for thyroid carcinoma, 433 for HIV, 587 for Hodgkin lymphoma, 475, 476 for renal cell carcinoma, 314 for small cell lung cancer, 208 for soft-tissue sarcoma, 395 for testicular cancer, 351 for thyroid carcinoma, 433 Positron emission tomography with computed tomography (PET-CT), for malignant

melanoma, 414 Postchemotherapy masses, 352 Posterior probability distribution, 163 Postherpetic neuralgia, 675–676 prevention of, 675 Post hoc power calculation, 167 Postmastectomy pain syndrome, 674–675 Postoperative irradiation, 58 Postradical neck dissection pain syndrome, 675 Postsurgical pain syndromes, 674–675 Postthoracotomy pain syndrome (PTPS), 675 Prednisone regimen, 337–339 Preinvasive lesions of the cervix, 380–384 background of, 380 complications of, 383–384 follow-up of, 384 presentation of, 380 screening of, 380 terminology of, 381 therapy and prognosis of, 382–383 workup, 381–382 Premalignant disease of the endometrium, 367–369 background of, 367 complications of, 369 follow-up of, 369 presentation of, 367 therapy and prognosis of, 368–369 workup and staging, 367–368 Preoperative Assessment of Cancer in the Elderly (PACE), 613 Preoperative radiation therapy, 58 Primary central nervous system lymphoma (PCNSL) AIDS-associated, 593 Primary chemotherapy, 59 Primary cutaneous melanomas, 411–423 biopsy, 411 diagnostic dilemmas, 411 histologic reporting and classification, 411–412

physical examination of, 411 Primary effusion lymphomas (PEL), AIDS-associated, 595–597 Primary endpoints, 162 Primary melanoma, 412 Prior (probability) distribution, 163 Probability distribution, 163 Procarbazine, 179 Proctosigmoidoscopy, 600 Prophylactic cancer vaccines, 129–130 Prophylactic cranial irradiation (PCI), 210 Prophylactic surgery, 23t Prophylactic thyroidectomy, MEN2A/MEN2B syndrome, 432 Prostate cancer, 327–340 background of, 327 complications, 340–341 of bisphosphonate therapy and RANK ligand inhibitor therapy, 341 of chemotherapy, 341 of hormone deprivation therapy and antiandrogens, 340–341 of surgery, 340 of XRT, 340 presentation of, 327–329 treatment for, 332–339 localized disease (T1 to T3 N0 M0), 332–334 locally advanced disease (T3 N0), 334–335 metastatic disease, 335–337 workup and staging, 329–332 Prostate-specific antigen (PSA), laboratory testing, 329–330 Prostate-specific antigen (PSA) era, 327 Proteasome inhibition, 102–103 Proteomics, 14 Proto-oncogenes, 5 Pseudoprogression, 177 Pulmonary Kaposisarcoma, 603 p-value, 166 Q Quality Assurance Committee, 61

Quality of life (QOL), 327, 337, 340 QUantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC), 41 Quantitative PCR. See Real-time PCR QUASAR study, 286 R Radiation neuropathy, 674 Radiation oncology, 33–61 combination of therapeutic modalities, 58–60 defined, 33 follow-up, 60 goals of, 36–37 prescription of, basis for, 37 quality assurance, 60–61 radiobiologic principles, 37–54 dose-time factors, 41, 53 effects of radiation on normal tissue, 38–41 linear-quadratic equation, 38–41 treatment time, tumor control, and morbidity, 54 tumor control, probability of, 37–38 treatment planning, 54–58 intensity-modulated radiation therapy, 55–56 introduction to, 54 three-dimensional treatment planning, 55–56 types of radiation used in, 33–36, 35f Radiation therapy (RT), 310, 333, 386 for adrenocortical carcinoma, 438 for bone sarcoma, 407 for elderly patients with cancer, 614 for non-small cell lung cancer, 214 for small cell lung cancer, 209 for testicular cancer, 348 for thymic carcinoma, 266 Radiation toxicity, acute, 192 Radical cystectomy, 323–324 Radical hysterectomy, 391 Radical prostatectomy (RP), 330, 332–333

Radical retropubic prostatectomy, 332–333 Radical vulvectomy with inguinofemoral lymphadenectomy, 388 Radioactive iodine (RAI), 434 Radiofrequency ablation (RFA), 28, 300, 316 Radioimmunoconjugates, 102–104 Radioisotopes, 673 Raf tyrosine kinase inhibition, 85–86 Random error, 164 Random sample, 163 Random variable (RV), 164 continuous, 164 discrete, 164 RAS mutations, and thyroid carcinoma, 433 R-CHOP regimen, 493, 588 R-CODOX-M/IVAC regimen, 592 Reactive oxygen species (ROS), 4 Real-time PCR, 12 Receptor activator of nuclear factor kB ligand (RANKL), 564 Receptors, 5 Receptor tyrosine kinases, 67–68 Recombinant human erythropoietin (rHuEPO), 651–652 Recombinant human granulocyte colony-stimulating factor (rHuG-CSF), 647 Recombinant preparations (rHuG-CSF), 647 Recombinant thyroglobulin (ThyrogenTM), 433 Recombinatorial repair, 7 Reconstruction, functional and cosmetic, 22 Rectal cancer, 292–293 chromosomal instability, 295 epidemiology, 294–295 microsatellite instability, 295 risk factors, 295 Recurrent disease, 22, 362–364 after initial therapy, 352–354 Recurrent locoregional disease, in head and neck cancer, 190 Reduced intensity conditioning (RIC), 463 Refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), 537t Regorafenib regimen, 85–86

Regression, locally weighted, 165 Relapsed disease, 469 Related haploidentical donors, 454 Renal cell carcinoma (RCC), 313–319 background of, 313 cytoreductive nephrectomy, 317 epidemiology of, 313 evaluation of renal mass, 314 metastatic disease, 317–319 pathology of, 314–315 presentation of, 313–314 risk factors of, 313 systemic therapy, role of, 317 immunotherapy, 317 targeted therapy, role of, 317–319 VEGF-targeted therapies, 318 treatment for localized disease, 316–317 locally advanced disease, 316–317 treatment of non-clear, 319 workup and staging, 315–316 Renal insufficiency, dose adjustments for, 614 Replication, 164 technical, 164 Replication competent lentivirus or retrovirus, 146 Resampling, 165 Residuals, 168 Respiratory emergencies, 643–644 Respite care, 686 Retinoic acid-inducible gene-1 (RIG-1) receptors, 115 Retinoic acid syndrome (RAS), 517, 519 RET-PTC rearrangements, and thyroid carcinoma, 433 Retroperitoneal lymph node dissection (RPLND), 346, 351 Retroperitoneal sarcomas, 395, 400–401 Rhabdomyosarcomas, 391, 397 embryonals, 345 Rh immune globulin (RhoGAM), 377

R-hyper-CVAD regimen, 592 Ribociclib regimen, 108–109 Richter syndrome (RS), 556 Rimethoprim-sulfamethoxazole, 177 Rituximab regimen, 100–101, 493, 595 RNA interference (RNAi), 8 analysis of, 8 Robert Wood Johnson Foundation, 680 Robust methods, 165 smoothing, 166 Romidepsin regimen, 105–106 Romiplostim regimen, 654 Rotational slice-by-slice IMRT, 56 Rucaparib regimen, 110 Ruxolitinib regimen, 111 S Salivary gland cancers, 202–203 Salmon calcitonin, 629 Salvage regimens, 592, 599 Sample size, 163 effective, 164 Sarcoma, 374–376, 393–408 angiosarcoma, 397 approach to patient, 393 background of, 374 bone, 403–408 chondrosarcoma, 405, 408 embryonal rhabdomyosarcomas, 345 endometrial stromal, 374 epidemiology of, 393 Ewing, 405, 408 extremity, 394–395, 399 grading of, 396t Kaposi, 397, 602–608 leiomyosarcoma, 374, 397 liposarcoma, 396

lymphangiosarcomas, 394 molecular biology, 394 presentation of, 374 retroperitoneal, 395, 400–401 rhabdomyosarcomas, 391, 397 risk factors of, 393–394 soft-tissue. See Soft-tissue sarcoma synovial, 397 therapy, stage-directed approach to, 399–403 early stage disease (stage I to III), 399–402 local recurrence, treatment of, 402 metastatic soft-tissue sarcomas, treatment of, 402 therapy and prognosis of, 374–376 visceral, 395, 401–402 workup and staging, 374 Schistosoma haematobium, 321 Seizures, 170 Selumetinib, 424 Seminoma, testicular, 344–345, 348–351 in AIDS patients, 609 Semiparametric methods, 165 Sentinel lymph node biopsy (SLNB), 412–413 for staging, 18 Sentinel lymph node biopsy (SLN) biopsy, for breast cancer, 233 Sertoli cell tumors, 345 Serum mesothelin-related protein (SMRP), 262 Serum tumor markers, 346 Sex cord stroma tumors, 345 Significance level, 166 Single base pair (bp) substitutions, 4 Single photon emission computed tomography (SPECT), 594 Sinonasal undifferentiated carcinomas (SNUCs), 203 Sipuleucel-T regimen, 131, 338 Skin cancer, in AIDS patients, 609 Small cell lung cancer (SCLC), 206–213 background, 206 background of, 206

chemotherapeutic regimens for, 209 maintenance chemotherapy for, 211 presentation of, 206–208 prognosis, 212–213 relapsed, 212 therapy for, 209–210 workup and staging, 208–209 Small round blue cell tumors, 405 Smoking bladder cancer and, 321 cessation counseling/behavioral modification for, 716–717 medications to aid, 715 practice guidelines for, 715–716 kidney cancer and, 313 lung cancer and, 213 Smoldering myeloma, 574–575 Smooth muscle tumor of uncertain malignant potential (STUMP), 374 Soft-tissue sarcoma diagnosis of, 395–398 pathology, 395–398 radiographic imaging, 395 staging, 397, 398t history of, 394–395 Kaposisarcoma (KS) and, 397 overview of, 394 physical examination for, 395 Solitary plasmacytomas of bone, 575 Sonidegib regimen, 92–93 Sorafenib regimen, 86, 317–318, 614 Southwest Oncology Group (SWOG), 323 Sperm banking, 348 Spinal administration of analgesics, 670 Spinal clonidine, 670 Spinal cord compression, 32 epidural, 637–638 Spinal local anesthetics, 670

Splines, 165 Spontaneous chemical reactions, 2, 4 Squamous cell cancer of the head and neck (SCCHN), 186–204 approach to patient, 186 background of, 186 larynx and hypopharynx, 197–199 lip and oral cavity, 193–194 locally recurrent disease, 190 metastatic disease, 190–191 nasal cavity and paranasal sinus tumors, 203 nasopharyngeal cancer, 200–202 oropharynx, 195–196 platinum-refractory SCCHN, 191 salivary gland cancers, 202–203 therapy for, overview of, 186–193 unknown primary, neck management and, 203–204 Squamous cell carcinoma (SCC), 390 of cervical lymph nodes, 449 isolated inguinal lymphadenopathy from, 449–450 of the skin, 424–426 Staging, 18. See also under specific cancers American Joint Committee on Cancer (AJCC), 272, 346, 398t, 406t, 412 Ann Arbor system for Hodgkin lymphoma (HL), 475t, 587 FIGO of cervical cancer, 384 of endometrial cancer, 371t, 374 of ovarian cancer, 357, 358t of vaginal cancer, 391t of vulvar cancer, 388 Gleason score, 331 laparoscopy, 18 laparotomy, 18 lymphadenectomy, 18 mediastinoscopy, 18 recurrent disease after initial therapy, 352–354 sentinel lymph node biopsy, 17–18 tumor, node, metastases system, 272, 331

Stanford V regimen, 598 Stauffer syndrome, 313 Stem-and-leaf plots, 165 Stem cell mobilization, 460 Stem cell transplantation, chronic lymphocytic leukemia and, 561–562 Stereotactic body radiation therapy, 41 Stereotactic radiation therapy, 56–58 Stereotactic radiosurgery (SRS), 57 Steroids, 595 Stromal tumors of the ovary, 365 Study power, 167 Subclinical disease, 38 Sublethal damage repair (SLDR), 38 Sunitinib regimen, 83, 318, 441 Superficial spreading melanoma (SSM), 412 Superior vena cava syndrome (SVC), 31–32, 206, 642–643 Surgery for adrenocortical carcinoma, 437–438 diagnostic procedures, 15–17 for elderly patients with cancer, 613 for head and neck cancer, 188 salvage, 189–190 irradiation and, 58 metastases and recurrent disease, 22 oncologic emergencies, 28–32 oncologist’s role, 15 for parathyroid carcinoma, 435 reconstruction, 22 staging, 18 for thyroid carcinoma, 433–434 treatment, surgical, 19–25 vascular access, 26 Surrogate, 162 Surveillance, Epidemiology, and End Results Program (SEER), 410 Syndrome of inappropriate antidiuretic hormone secretion (SIADH), 192, 635–637 Syngeneic transplantation, 453 Synovial sarcoma, 397

Systematic data loss, 162 Systematic error, 164 Systemic corticosteroids, 669 Systemic therapy for adrenocortical carcinoma, 438 for elderly patients with cancer, 614–615 for neuroendocrine tumors, 441 for parathyroid carcinoma, 435 for thyroid carcinoma, 434 T Taking ratios, 165 Talazoparib regimen, 110 Talimogene laherparepvec (T-VEC), 133 Tapentadol, 667 TAP regimen, 372–373 Targeted therapy, 317–319 Target population, 163 Taxanes, 189 TAX 324 trial, 189 T-cell ALL, 521 T cell depletion, 467–468 T cell receptors (TCR), 115 gene therapy, 147–149 T cell therapies, 151–152 TCR-Ts, 138, 147–149 Technical replication, 164 Temozolomide regimen, 175 Temsirolimus regimen, 89 Teratomas, 345 Testicular cancer, 343–354 background of, 343 EGGCT, 354 epidemiology of, 343 presentation of, 343 surveillance, 348–349 therapy for, 348–354

workup and staging, 344–348 Testicular intraepithelial neoplasm (TIN), 344 Testicular intratubular germ cell neoplasia carcinoma (TIGCN), 344 Thalidomide, 568, 606 Therapeutic cancer vaccines, 131–133 Therapeutic ratio, 40 Therapy Oncology Group (RTOG) study, 310 Three-dimensional conformal radiation therapy (3D-CRT), 40, 55–56 Thrombocytopenia, 585 Thrombopoietin (TPO), 653–654 Thrombosis. See Venous thromboembolic events (VTEs) Thymic carcinoma, 260 Thymic epithelial neoplasms, 254 Thymoma, 252–260 background of, 252 masaoka staging system for, 255t therapy and prognosis, 256–259, 258–259t thymic carcinoma, 260 WHO classification, 255t workup and staging, 253–255 Thyroid carcinoma, 432–435 defined, 432 diagnosis of, 433 epidemiology of, 432–433 presentation of, 433 treatment for, 433–435 workup for, 435 Thyroid-stimulating hormone (TSH), 433 Time-to-event modeling, 168 TIP regimen, 352 Tisagenlecleucel, 140t, 146, 155, 526 Tissue in situ hybridization, 11 Tizanidine, 668 T lymphocytes, 115 Tobacco use, in cancer patients and survivors, 719 Toll-like receptors (TLRs), 115 Total thyroidectomy, for thyroid carcinoma, 433–434

TPF regimen, 189–190 Tracheoesophageal puncture (TEP), 192 Tramadol regimen, 666 Trametinib regimen, 87–88, 417, 418 Transformation, 165 Transfusion therapy, support in HSCT, 465 Transhepatic chemoembolization (TACE), 305 Transitional cell carcinoma of the bladder, 322 Transurethral resection of bladder tumor (TURBT), 322 Transverse rectus abdominis myocutaneous (TRAM) flap, 234 Trastuzumab regimen, 79–80 Trellis plot, 166 Tremelimumab regimen, 123 Tumor, node, metastases (TNM) staging system, 272, 331, 346 Tumor-induced edema, 170 Tumor infiltrating lymphocytes (TIL), 132–133, 149–150 Tumor lysis syndrome (TLS), 505, 526, 632–635, 634t Tumor markers, 447 Tumor necrosis factor-a (TNF-a), 115 Tumor suppressor genes, 5 Tumor treatment-related neuropathic pain syndromes, 673–675 Two-tailed test, 166 Type I/II error, 166 Typhlitis (neutropenic enterocolitis), 30–31, 526 Tyrosine kinase inhibitors, 67–68 U Ultrasonography (USN), of liver, 299 Ultraviolet radiation (UV light), 4 Umbilical cord blood, as source of HSCs in transplantation, 461 Unconjugated monoclonal antibodies, 90–91 United Kingdom RAPID trial, 478 United States Adopted Names (USAN) Council, 69 Uterine cervix neoplasia, 380–387 preinvasive lesions of the cervix, 380–384 Uterine neoplasia, 367–380 cervix. See Uterine cervix neoplasia

endometrial cancer, 369–374 gestational trophoblastic disease (GTD), 376–380 premalignant disease of the endometrium, 367–369 sarcomas, 374–376 Uveal melanoma, 424 V Vaginal brachytherapy (VB), 372 for endometrial cancer, 372 Vaginal cancer, 390–392 background of, 390 complications of, 391–392 follow-up of, 392 presentation of, 390 therapy and prognosis of, 390–391 workup and staging, 390 Vaginal intraepithelial neoplasia (VAIN), 390 Vaginectomy, 391 Vandetanib, 434 Van Nuys prognostic index system (VNPI), 231, 231t Varenicline, and smoking cessation, 717 Varicella zoster virus (VZV), 469 Vascular access, 26 Vascular adhesion molecule 1 (VCAM-1), 564 Vascular endothelial growth factor, 81–85, 318 VCd (Bortezomib, Cyclophosphamide, and Dexamethasone), 568 VeIP regimen, 352 Vemurafenib regimen, 88, 418 Venetoclax regimen, 91 Veno-occlusive disease (VOD) of the liver, 469 Venous thromboembolic events (VTEs), 618–626 anticoagulation for VTE in cancer patients, duration of, 626 central venous catheters and, 618 diagnosis of, 620 heparin, role of, 620 inferior vena cava filters, role of, 624 occult cancer and, 619–620

pathophysiology of, 618–619 prevention of, in patients with cancer, 620–622 special issues in cancer patients, 623 thrombolytic therapy, role of, 623–626 Vertebral augmentation, 671 Vertebroplasty, 671 Veterans Administration (VA) Larynx Trial, 198 Video-Assisted Thoracoscopic Surgery (VATS), 18 for non-small cell lung cancer, 216 ViewRay system, 57 Vinblastine/ifosfamide/cisplatin regimen, 352 Vinblastine regimen, 323 Vincristine regimen, 179 Vinorelbine regimen, 606 Viral cytotoxic T lymphocytes (CTLs), 150–151 Visceral sarcomas, 395, 401–402 Vismodegib, 427 Vismodegib regimen, 93 VMP (Bortezomib, Melphalan, Prednisone), 569 Von Hippel-Lindau (VHL) gene, 313 Vorinostat regimen, 106 VRd (Bortezomib, Lenalidomide, and Dexamethasone), 568 Vulvar cancer, 387–390 background of, 387 complications of, 388 follow-up of, 389–390 presentation of, 387–388 therapy and prognosis of, 388 workup and staging, 388 W Waldenström macroglobulinemia, 578–579 Whole brain radiotherapy (WBRT), 498, 595 World Health Organization (WHO) for non-Hodgkin lymphoma, 488–490t pain management ladder, 657 thymic epithelial neoplasms, classification for, 254

X Xerostomia, 192 Y Yolk sac tumors, 344 Z Ziv-aflibercept regimen, 84–85 Zoledronic acid regimen, 339