Radiation Therapy of Benign Diseases (Medical Radiology) 3031355164, 9783031355165

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Medical Radiology · Radiation Oncology Series Editors: Nancy Y. Lee · Jiade J. Lu

David Roberge Sarah S. Donaldson  Editors

Radiation Therapy of Benign Diseases Third Edition

Medical Radiology

Radiation Oncology Series Editors Nancy Y. Lee Jiade J. Lu

Medical Radiology - Radiation Oncology is a unique series that aims to document the most innovative technologies in all fields within radiology, thereby informing the physician in practice of the latest advances in diagnostic and treatment techniques. The contents range from contemporary statements relating to management for various disease sites to explanations of the newest techniques for tumor identification and of mechanisms for the enhancement of radiation effects, with the emphasis on maximizing cure and minimizing complications. Each volume is a comprehensive reference book on a topical theme, and the editors are always experts of high international standing. Contributions are included from both clinicians and researchers, ensuring wide appeal.

David Roberge  •  Sarah S. Donaldson Editors

Radiation Therapy of Benign Diseases Third Edition

Editors David Roberge Department of Radiation Oncology Centre Hospitalier de l’Université de Montréal Montreal, QC, Canada

Sarah S. Donaldson Department of Radiation Oncology Stanford Medicine Palo Alto, CA, USA

ISSN 0942-5373            ISSN 2197-4187 (electronic) Medical Radiology ISSN 2731-4715             ISSN 2731-4723 (electronic) Radiation Oncology ISBN 978-3-031-35516-5    ISBN 978-3-031-35517-2 (eBook) https://doi.org/10.1007/978-3-031-35517-2 © Springer Nature Switzerland AG 1990, 2003, 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Prologue

In the mid-1980s, with the expansion of the use of ionizing radiation in the treatment of oncologic and nononcologic disorders, the National Academy of Science promoted a project to investigate this practice; the project produced the first edition of Radiation Therapy of Benign Diseases: A Clinical Guide edited by Stanley E Order and Sarah S Donaldson, and published in 1990. The text pointed to the beneficial uses of radiation in specific nonmalignant conditions, discussed the risk/benefit of such management, and offered caution about the inappropriate use of radiation therapy for certain benign diseases. At that time, with the development of high energy medical linear accelerators, standardization of units of radiation and nomenclature, and increased understanding of the biology and physics of radiation, the textbook on radiation therapy for benign disease became a functional addition to ones’ library and was widely referenced. In that era, the practice of radiation for rare diseases was, in large part, based upon individual clinicians’ experiences. The Inter-Society Council for Radiation Oncology (ISCRO), a multisocietal group representing leaders from the major American radiation oncologic societies, with sponsorship from the American College of Radiology, conducted a survey of 834 radiation oncologists with a goal to exchange information underlying the use of radiation for a host of nonmalignant conditions. Each benign disease in which radiation had been utilized for management that was published in the English literature was included in specific chapters of the textbook. The reader could easily reference a particular benign disorder, read a brief resume of the condition and tables summarizing the published data, and refer to citations of pertinent literature. The second edition of the book, published in 1998, expanded the conditions listed in the first edition. This benign disease text, intended to be a functional workbook, became an easily accessible text for the occasion when a practitioner was faced with the challenge of using radiation therapy for a rare, nononcologic disease, in which the risk/benefit ratio required careful analysis. A result from this major effort was a tabular consensus summarizing the clinical uses of radiation therapy for these rare and difficult diseases. The second edition of the book concluded with the statement “the text may never be complete as new techniques, disorders and the definition of risk become more clearly defined by clinical experience.” These words have proven to be

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true. Today, more than three decades later, with enhanced understanding of the biology of both benign and malignant disease, and with greatly expanded technical skills in the delivery of radiation, there is an even greater need to update and expand our practical and clinical experience in a third and revised edition of this clinical guide.

Prologue

Preface

Readers of previous editions of Radiation Therapy of Benign Diseases will notice changes in the format and substance of the work. Of course, as decades have passed, new and updated references have been added to indications which persisted in clinical use. The line between a malignant and a benign process can sometimes be blurry, and indications well documented in oncology textbooks and have been removed—low-grade astrocytoma as an example. These losses left room for new and often exciting topics—whether it be the treatment of refractory ventricular tachycardia or celiac pain. Although some indications defy classification, alphabetical ordering has been begrudgingly replaced by grouping in chapters by disease type. The entries remain concise and focused on summary reports of the use of radiation rather than attempting to educate the reader on the general aspects of a disease process or delving into protracted debates on the pertinence of radiation. Indications for which only isolated case reports could be found were typically not considered. We have chosen to no longer include surveys which may in the past have mislead readers as to the pertinence of radiotherapy in specific indications. Despite the longstanding history of radiotherapy in the management of nononcological disease, the evidence supporting most indications is weak. For many disease processes, it remains uncertain whether or not they are modified by radiation. Randomized trials are rare and most evidence is in the form of expert opinion based on small retrospective cohorts. In some cases, this may be because the outcome is subjective (the pain of a heel spur) in other cases because there are potential biases when assessment of the effect of radiation requires a comparison to the natural history of the disease (is the hemorrhage rate of a cavernoma reduced by radiation?). Even in those cases where the link between radiation and the biological outcome is not in doubt, that does not signify that the treatment improves the quantity or quality of life vs. observation—witness the heated debate over treatment of asymptomatic vascular malformations of the brain. In other cases, although radiotherapy might have the postulated biological effect and the benefits might outweigh the risks when compared to doing nothing, there is a preferred medical or surgical alternative. For example, hormonal manipulation can improve the life of women with hormone-sensitive breast cancer, but medication will be preferred over pituitary radiosurgery. The inclusion of a disease process in this textbook should not be interpreted as an endorsement of its treatment using ionizing radiation. In many vii

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cases, the reader might more appropriately view the inclusion as a historical curiosity or a cautionary tale. As scientists, we should view available evidence with skepticism and be supportive of prospective randomized trials— powerful tools to either limit ineffective radiotherapy or to improve accessibility to what may be underutilized and cost-effective treatments for serious disease processes. The final risk/benefit ratio in the treatment of an individual patient is determined by the physicians and the patient which must both often accept some measure of uncertainty when making their decision. In this process, one would be well advised to: 1. Determine the natural history of the benign disease. This may require some humility that the radiation oncologist cannot be up to date in all fields of medicine. 2. Have a clear vision of what would define success of a treatment—think in more specific terms than “improvement” or “slowing.” Ensure that expectations are in line with this definition of success. Some patients are desperate, and we must safeguard them against inappropriate treatments. 3. Use this text and other source material to evaluate the evidence that radiotherapy can lead to a successful outcome. When prospective comparative data is not available, be mindful of how results can be colored by biases, variability in the natural history of the disease process and the placebo effect. 4. Educate yourself on the alternate treatments. How effective are they? What evidence supports their efficacy? What are their associated risks and toxicities? Why were these not considered? 5. Determine the potential long-term risks of radiation treatment. Consider patient age, total dose, fractionation, the underlying organs at risk, as well as any underlying disease. Beware of bias when weighing an uncertain immediate benefit against future risks. As a thought exercise, allow me to share the following abstract: Background: Treatment of verrucae vulgares is sometimes difficult. Invasive methods should not be used for young children. Objective: Evaluation of a special X-ray therapy for treatment of verrucae vulgares in children. Methods: Nine children with warts on the hands and/or feet and in the face were treated with X-ray treatment. Results: Five children showed a complete remission of warts, 3 children a partial remission. For 1 child, there was no response. On average, 3 treatment sessions were needed for children showing a complete remission. Conclusion: This therapy offers an easy-to-perform, alternative treatment option. It is noninvasive and does not depend on special techniques. Now I must confess to having altered the abstract. In fact, the actual abstract described sham radiotherapy in the treatment of warts. After setting aside the morality of lying to children and the design of the trial (which certainly does not prove that sham radiotherapy is any more effective than sim-

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ple observation), take a moment to mentally replace warts with any other disease for which you might be considering radiation. Next imagine how you would receive a manuscript claiming results for sham radiotherapy equivalent to those published for actual ionizing radiation. The unaltered 2002 abstract describing treatment of verrucae vulgares is: Background: Treatment of verrucae vulgares is sometimes difficult. Invasive methods should not be used for young children. Objective: Evaluation of a special suggestion therapy for treatment of verrucae vulgares in children. Methods: Nine children with warts on the hands and/or feet and in the face were treated with a simulated X-ray treatment. Results: Five children showed a complete remission of warts, 3 children a partial remission. For 1 child, there was no response. On average, 3 treatment sessions were needed for children showing a complete remission. Conclusion: This therapy offers an easy-to-perform, alternative treatment option. It is noninvasive and does not depend on special psychological techniques for which training is required. I wish to thank Dr. Donaldson for her support and trust. I wish to thank my numerous collaborators for their diligence and patience. I wish to acknowledge wordsmiths of previous editions whose work survived to the present. I hope that this text, with its concise entries, will inform and intrigue the current generation of radiation oncologists as much as the prior edition captured my interest after a cashier at the McGill University bookstore failed to deter me from spending what seemed to her an inappropriately large sum on such a small book devoid of any color or illustrations. Reference • Meineke V, Reichrath J, Reinhold U, Tilgen W (2002) Verrucae vulgares in children: successful simulated X-ray treatment (a suggestion-based therapy). Dermatology 204(4):287–289. doi: 10.1159/000063360. Montreal, QC, Canada Palo Alto, CA, USA 

David Roberge Sarah S. Donaldson

Standard of Care

Physicians may have obligations related to their professional associations, licensing authorities, employers, and local legal frameworks. The following is a summary of important legal concepts in the physician-patient relationship from the viewpoint of a North American lawyer with more than 42 years of experience in the realm of healthcare.

Malpractice Appellate courts have defined malpractice as the failure of a practitioner to give and to exercise that degree of care as would be practiced by a reasonably competent practitioner under the same or similar circumstances. Simply stated, the appellate courts have recognized the existence of standards of care followed by competent specialists in the various fields. Thus, malpractice is found where a patient’s injury or death occurs as a result of a physician’s failure to use diagnostic and/or treatment methods which would be followed by the majority of competent physicians in the same field.

Informed Consent Informed consent is a well-recognized duty and legal obligation of the doctor in which he must disclose and provide adequate information to a patient for him to give a consent and take an informed decision regarding personal and life-changing health choices. An informed consent is a consent where the patient has the adequate information to make a decision on, for example, a treatment approach, surgery, medication, radiotherapy, etc. In fact, the informed consent of the patient touches every aspect of the medical relationship between the doctor and the patient. It implies a communication between the patient and the healthcare provider. It is a constant communication process in the medical relationship where the doctor has the duty to keep the patient informed of any changes or impressions that might change or affect the initial diagnosis, treatment offered, and thus affect the consent or decision of the patient.

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Moreover, it also touches the patient’s right to self-determination, to decide what is right or wrong for him, to decide in accordance with his beliefs, spirituality, and personal values. Even if the doctor considers a treatment to be the best choice or decision for a patient’s health and does highly recommend it, the right to accept or refuse a treatment remains a patient decision and must be respected. The doctor can recommend radiotherapy, but the patient can still refuse it. The right to auto determination of one’s personal body and choices is well recognized in society and in law. The patient has a right to know and to have the information to make an informed decision. Informed consent is also important to doctors regarding their legal liability. Lawsuits are common in that matter. Doctors have an obligation to exercise reasonable skill and judgment in treating patient, which is the standard of care. This standard of care includes the duty to disclose the adequate information so that the patient gives an informed consent.

Duty to Disclose In the decision of the Supreme Court of Canada, Ciarlariello v. Schacter1, the court establishes that the important element in the evaluation of medical liability of a doctor on the informed consent is to determine whether a reasonable person in the patient’s position would want to know of the risk2. In Hopp v. Lepp and in Reibl the Supreme Court of Canada establishes that: the relationship between doctor and patient gives rise to a duty to disclose all materials risks, as well as to answer any specific questions posed by the patient. Therefore, in a medical liability suit on the informed consent of a patient, the court will use an objective approach focusing on what a reasonable person in the patient’s position would want to know to give an informed consent3. Thus, experts will testify in front of the court on what risk should or should not be disclosed to the patient, on the material risks, and thus regarding the doctor breach on the duty of disclosure. The court has to look at the reasonable patient in a similar position, while taking into consideration the specific circumstances of the case. The court will then be able to respond to the question of whether a reasonable person in the patient’s position would want to know of the risk. Experts evidence regarding the risks that must be disclosed and on the alternative treatments that could have been proposed to the patient will certainly help the court to make a decision on the medical liability of the doctor but will not be the only elements that the court will look at to decide

Ciarlariello c. Schacter, [1993] 2 R.C.S. 119 Ciarlariello v. Schacter, [1993] 2 R.C.S. 119 3  Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007. 1  2 

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of the case issue4. The standard of disclosure is to inform the patient of the risk that a reasonable patient would want to know. It is established in the law that the doctors do not have to disclose every single risk to a patient. ¨Only the risks which are characterized as material, special, or unusual must be disclosed5¨. The court in Hopp v. Lepp also establishes that even if a certain risk is a mere possibility which ordinarily would not need be disclosed, yet if its occurrence carries serious consequences, as for example, paralysis or even death, it should be regarded as a material risk requiring disclosure6. The doctor must explain the material, special, or unusual risk and must explain the consequences if the risk were to materialize7. It is also important to note that in Hopp v. Lepp the court states that a doctor must answer any specific question of a patient regarding the risks involved of a proposed treatment8. In that sense, the question of the patient must be specific. The question of the patient requires a discussion with the doctor and a disclosure on some risks which normally would not need to be disclosed. The common risks associated with surgical treatments are considered by the court as risks that do not necessarily need to be disclosed. The test of reasonable person is used to determine what the patient would consider as a general and common risk, for example, the risk of dying of anesthesia during a surgery is considered as a common risk. However, the court will always evaluate the specific circumstances of a case and the specific situation of the patient, indeed a common risk for a given patient might be considered a specific risk for another patient with a health condition, predisposition, or physical or mental situation which increases the risk. Each case is different and must be evaluated from the objective point of view of the reasonable patient. The alternative treatments are part of the duty of disclosure of the doctor. Thus, the doctor should inform the patient of alternative treatments that may exist and explain the material, special, or unusual risks associated with the treatment proposed and with the alternative’s treatments. The doctor can explain and recommend one treatment over another and explain to the patient his medical opinion. This gives the patient an opportunity to make a choice knowing all the treatment possibilities and thus balancing the risks and benefits.

Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.133. 5  Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.135. 6  Hopp v. Lepp, [1980] 2 R.C.S. 192. Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007. 7  Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.149. 8  Hopp v. Lepp, [1980] 2 R.C.S. 192. Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.164. 4 

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 he Uncertainty of a Treatment Effectiveness Proposed by T the Doctor Medicine changes so fast; new treatments, medications, interventions, devices… those are only examples of how medicine is constantly evolving. A lot has changed in the medical field in the last years. This creates new challenges for doctors, regarding the uncertainty of a new treatment effectiveness and uncertainty of the benefits and risks of a treatment. For example, when a doctor pretends he did not know a risk that he should have disclosed normally and for that reason the risk was not disclosed, the court will have to determine if the doctor was negligent in not knowing of the risk. The court will apply the test of the reasonable doctor as to determine if a reasonable doctor in similar circumstances would probably have known of the risk. The law in general and the interpretation of the law by the court are not static. It is always adapting to new realities. New treatments for which the effectiveness is not yet determined in medical literature and for which doctors may be uncertain of the chances of success are part of the duty to disclose as discussed in this text. In that matter, doctors should disclose material, special, or unusual risks to the patient regarding a new treatment and they should inform the patient of the uncertainty regarding the effectiveness of the treatment proposed to allow the patient to balance the risks and benefits. In Nelson v. Patrick, a medical malpractice case, the patient alleged that the defendant failed to obtain the informed consent by not disclosing the risks of the radiation therapy9. The doctor recommended that the patient undergo adjuvant radiotherapy after a total abdominal hysterectomy to reduce the risk of cancer recurrence. Following the radiation treatments, the patient suffered from injury to her bowel. The court gave a decision in favor of the patient against the doctor.

Innovative Care New equipment, tools, techniques, or procedures impact the standard of care. Indeed, innovations in medicine imply the use of new technologies or treatments at first by some members of the medical field but not by all. In specific cases involving the use of innovative care: ¨the court must balance the desirability of promoting advances in medical technology against the need to caution against resorting too readily to novel and untested treatment10¨. A series of Alberta cases established that a doctor using a new technique or tool is subject to a higher standard of care11. In Cryderman and Zimmer cases against an obstetrician-gynecologist, the Alberta Court of Appeal emphasized that a higher standard of care is required where a technique is innovative or experiNelson v. Patrick, Court of Appeals of North Carolina, 1982. Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.244. 11  Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.247. 9 

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mental12. The Cryderman case was about the silver nitrate sterilization technique. The technique was invented and pioneered by the defendant in that case. The Court stated that a higher standard of care was required and the fact that the new technique was invented by the doctor elevated even more the standard of care for that particular doctor. In Zimmer, the Court stated that ¨the experimental nature of the procedure required that the patient receive careful and attentive after care as well as the fact that the patient must be informed that the procedure is innovative or experimental.¨13 In both cases, the doctor was considered not having met the standard of care.

Medical Research When it comes to medical research, the patient’s consent plays a heavy and very important role. ¨According to the Tri-Council Policy Statement, modern research ethics require a favorable harms-benefits balance that is that the foreseeable harms should not outweigh anticipated benefit14¨. A doctor who conducts a research that has unreasonable balance between the harms and benefits might be held liable for not meeting the standard of care, as of the research ethics committee of an institution that accepts the research might also be held responsible. In research and experimentation, a higher level of disclosure of the information must be met by doctors. In the Halushka v. University of Saskatchewan case a student participated in research for a test of a new anesthetic15. The student was told the test was safe and that he should not worry about anything. Thus, the student was not told that the research implied a new drug, and he was not told about the risks. Unfortunately, during the research he suffered from a cardiac arrest and had to be resuscitated. He subsequently sued the doctors. The Court stated that when it comes to medical research the participant is entitled to a full disclosure of the risks, probabilities, research information, and to the medical opinion that a reasonable person would want to know before giving consent. In the Weiss v. Solomon case, a patient underwent cataract surgery and agreed to participate in a research study involving the use of ophthalmic drops and fluorescein angiography16. When the angiography was performed, the patient experienced fatal ventricular fibrillation. The Court stated that even if the risk was low, that it should have been disclosed to the patient. The doctor and the hospital through the research committee were found to be negligent in not disclosing the risk. The Court stated that when it comes to the duty to inform in matters of scienLegal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.247. 13  Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.178 and 247. 14  Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.103é 15  Halushka v. University of Saskatchewan et  al.  53 D.L.R. (2d) 436 (Sask. C.A.) [Halushka] 1965. 16  Weiss v. Solomon, 1989, 48 C.C.L.T. 280 . Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.176. 12 

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tific research that all risks must be disclosed, even the risks that are rare, especially if there are serious consequences17.

Standard of Care The notion of standard of care refers to the conduct a doctor should have. Doctors have an obligation to exercise reasonable skill and judgment in treating patient. The criteria used by the court is to evaluate the conduct of a reasonable doctor in the same or similar circumstances. Would he have acted that way? This conduct must be analyzed taking into consideration all the circumstances. The court will evaluate the conduct of the doctor being sued by having experts’ opinions on the specific medical field in which the doctor practices. Thus, the court will evaluate if the doctor acted as a normal, prudent practitioner of his medical field. For example, a radiologist will be compared to other radiologists, to the conduct of a normal and prudent radiologist. The court will evaluate three elements in analyzing standard of care: the education, experience and qualifications of the doctor, the degree of risk involved in the procedure of treatment and the equipment, facilities, and resources available to the doctor. In Hazen v. Mullen, a judgment in favor of the plaintiff, it is a malpractice case in administering radiotherapy. The judgment was reversed in Court of appeal. The patient consulted the doctor for a tubercular adenitis and the doctor recommended radiotherapy. As a result of the treatments the patient developed telangiectasia18. In court it was determined that the defendant possessed the degree of skill and ability in their particular line of work, the X-ray treatment was an appropriate treatment for the condition of the patient, and the treatments were administered to the best of knowledge and skill of the doctor. In 1929, it was decided by the Court of appeal that telangiectasia may occur following radiotherapy and that there is no evidence that the doctor would have been negligent in administrating the X-ray treatment. The doctor was found to have exercised his best judgment and ability in treating the patient. In Carver v. United States19, the plaintiff alleged that the physicians at Letterman Army Medical Center (LAMC) negligently subjected him to radiotherapy and acted below the standard of care which caused him injury. In fact, the plaintiff alleged that the doctor administered radiotherapy without having sufficient evidence of brain metastases, not having located a primary tumor or had a biopsy performed of the lesions in the brain. As a result of the radiotherapy, the plaintiff suffered cognitive decline. Eventually a diagnosis of multiple sclerosis was suspected, and the patient was placed in a convalescent home. The Court concluded that the plaintiff failed to demonstrate that Legal liability of doctors and hospitals in Canada fourth edition, Ellen I. Picard & Gerald Robertson, 2007, p.176. 18  Hazen v. Mullen, Court of Appeals of the District of Columbia, 1929. 19  Carver v. United States, United States District Court California, 1984. 17 

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the physicians acted below the standard of care in administrating radiotherapy. In fact, the Court stated that the physicians balanced the risk of therapy versus the risk of inaction, and that had judged that a biopsy was not indicated and would be too risky.

Radiation Therapy Informed Consent Checklist The consent should be obtained using simple, lay terminology. 1. Inform the patient about the benign disease or tumor and the region of the body to be irradiated. Make certain that the patient understands the other options of treatment and the desired benefit of the radiation to be given. Do not assume that the patient has any prior understanding of the medical and/or surgical history of the disease or the reason for referral to the radiation oncologist. 2. Explain the desired goal of the planned radiation. 3. Explain the number of treatments contemplated. 4. Describe the dose to be administered and probable effect on the disease process as well as the effects of the treatment on the patient (i.e., nausea, diarrhea, hair loss, etc.) 5. Try to arrange a meeting with patient and spouse or patient and parent so that informed consent is understood by close family members. 6. Provide the opportunity for the patient to pose questions regarding the treatment to be given and the goals of such treatment. Specifically ask: Do you have any questions? 7. If the patient manifests uncertainty or confusion, strongly recommend a second opinion prior to starting treatment. 8. Send a letter after meeting with the patient to the referring physician, sending a copy to the patient as well. Legal counsel recommends outlining the treatment contemplated. 9. If the patient has past or present psychiatric history, obtain the patient’s permission to send a copy of the letter to the patient’s psychiatrist in addition to the referring physician. 10. Have a nurse, administrative assistant, or other witness present while the informed consent is obtained, and have that individual witness the consent form.

Acknowledgment

Stanley E. Order MD 1934–2013

We dedicate this third edition to Dr. Stanley E. Order, a true visionary and idea-man recognized for innovation in Radiation Oncology. Dr. Stanley (Stan) Order was born in Vienna, Austria, on November 1, 1934, and came to America as an infant when his parents migrated to avoid Nazi aggressions. The family settled in Philadelphia where Stanley’s father practiced medicine and where Stanley and his sister Sucha, also a physician and radiation oncologist, were educated. Stanley attended Albright College and Tufts Medical School. He began his medical training in pathology at the Brigham Hospital in Boston but was inspired to pursue training in radiation oncology at Yale, after fulfilling his military obligation. Stan was greatly influenced by early pioneers in US medicine, particularly Dr. Byron Waksman, who kindled his life-long interest in immunology, and powerful radiation oncology leaders, Dr. Morton Kligerman, his chairman at Yale, and Dr. Samuel Hellman, his chairman at the Harvard Joint Center for Radiation Oncology.

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In 1975, Dr. Order became the Chairman of the newly created Department of Radiation Oncology at Johns Hopkins, where he continued his research using radiolabeled antibodies for hepatoma and other challenging tumors. Stan was truly a leader in radioimmunotherapy and recognized for his innovative applications and novel administrations. In addition, he refined our understanding of radiation therapy for benign diseases as the prime mover of the first edition of the text Radiation Therapy of Benign Diseases, published in 1993. Stan was ASTRO President 1988-89 and enjoyed worldwide recognition. In 1991, he became head of the Institute for Systemic Therapy of Cooper Hospital University Medical Center in Camden, New Jersey, where he finished his active academic and clinical career. Dr. Stanley Order died on January 19, 2013. Stan was one of the most energetic and dedicated leaders of his time. He was witty and always a major focus in every gathering. His distinctive personality was reinforced by his enormous handlebar mustache. Stan had many interests beyond medicine, especially a love of fishing which he shared with many colleagues and friends. A gifted innovator, Stan was principled in the belief that “Technical excellence in radiation therapy is a standard, but compassion is what distinguishes a physician,” a quote he cited frequently. We remember Dr. Stanley Order for his immunologic and technical advances to radiation oncology, his compassion, and his drive to improve the outcome of his patients, particularly those with the most challenging oncologic problems. Sarah S. Donaldson

Acknowledgment

Contents

 Estimating the Risk of Radiation-­Induced Malignancy Following Radiotherapy for Benign Disease������������������������������������������   1 Jean L. Nakamura, Steve E. Braunstein, and Stephanie R. McKeown Understanding Radiation Units��������������������������������������������������������������  19 François De Blois Autoimmune Disorders����������������������������������������������������������������������������  27 Andrew Martella, Yushen Qian, and Rishabh Chaudhari Dermatologic Conditions������������������������������������������������������������������������  55 Khalil Sultanem Infectious Disease ������������������������������������������������������������������������������������  61 David Roberge Diseases of Inflammation������������������������������������������������������������������������  77 David Roberge Endocrinological Disorders��������������������������������������������������������������������  89 Tyler Safran and Daniel Juneau Musculoskeletal Disorders���������������������������������������������������������������������� 105 David Y. Mak and Philip Wong Neurological Disorders���������������������������������������������������������������������������� 181 Christian Iorio-Morin, Samuelle-­Arianne Villeneuve, Laurence Masson-Côté, and David Mathieu Benign Lymphoid Disorders ������������������������������������������������������������������ 191 Andrée-Anne Bernard Pain Disorders������������������������������������������������������������������������������������������ 199 Christian Iorio-Morin, Samuelle-­Arianne Villeneuve, Laurence Masson-Côté, and David Mathieu Psychiatric Disorders������������������������������������������������������������������������������ 211 M. Bret Schneider, Scott Soltys, and John R. Adler Jr Reproduction�������������������������������������������������������������������������������������������� 217 David Roberge

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Benign Tumors/Premalignant Conditions �������������������������������������������� 229 Houda Bahig and David Roberge Vascular Disorders���������������������������������������������������������������������������������� 295 Luis Souhami Other �������������������������������������������������������������������������������������������������������� 321 Dominique Mathieu and Bill Loo

Contents

Estimating the Risk of Radiation-­Induced Malignancy Following Radiotherapy for Benign Disease Jean L. Nakamura, Steve E. Braunstein, and Stephanie R. McKeown

Contents 1    Introduction 2    Evidence Used in Estimation of the Excess Risk of RIC Following MDRT 2.1  Mathematical Modeling and Phantom Studies 2.2  Epidemiological Studies 2.3  Second Malignant Neoplasms in Patients Exposed to HDRT for Cancer

1 Introduction  1

 2  3  3  4

3    Tissues at Risk of RIC Following MDRT for Benign Disease 3.1  Skin Cancer 3.2  Brain Cancer 3.3  Thyroid Cancer 3.4  Hematological Malignancies 3.5  Soft Tissue and Bone Cancer 3.6  Irradiation of the Chest Area

 5  5  6  7  8  9  10

4    Conclusions

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5    Guidelines for Clinicians

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References

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J. L. Nakamura (*) · S. E. Braunstein Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA e-mail: [email protected]; [email protected] S. R. McKeown Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK e-mail: [email protected]

Throughout this textbook there are descriptions of a wide range of diseases treated typically with moderate-dose radiotherapy (MDRT; conventionally fractionated dose range 5–40 Gy, mean ~20  Gy). These regimens may provide clinical benefit in many of these situations with, for the most part, minimal acute side effects (Taylor et al. 2015). The most important deterrent against the use of MDRT is often the acknowledged, if normally very small, risk of a radiation-induced cancer (RIC) many years after treatment (McKeown et al. 2015; Mazonakis and Damilakis 2017). However, the number of patients required to estimate the risk of an expected small/very small increase in RICs, occurring many years after exposure to MDRT to a confined radiation field, is large, yet (with a few exceptions) the numbers treated for these specific indications are small. Consequently, there have been very few directly relevant trials to identify the risk of a RIC following MDRT.  Indeed, due to the long latency time (LT) required, most of the studies discussed in this chapter relate to patients treated >30 years ago when RT treatment protocols were less sophisticated. The use of modern technology also modifies the extent and location of normal tissue exposure to ionizing radiation during RT (Lee et al. 2014; Liu et al. 2016). For example, the use of intensity-modulated RT (IMRT) to improve conformality may expose additional

Med Radiol Radiat Oncol (2022) https://doi.org/10.1007/174_2022_349, © The Author(s), under exclusive license to Springer Nature Switzerland AG Published Online: 29 September 2022

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healthy tissue to low doses of radiation because et al. 2020). The identification of genetic risk facof the increased number of angles used. This adds tors is multifaceted and further validation is another layer of complexity to the assessment of needed. In the future these approaches may allow RIC risk for current treatment approaches when identification of risk mediators for the developcomparing to data from historical cohorts ment of RIC. (Mazonakis and Damilakis 2017). The aim of this chapter is to present the eviIt is thought that individual radiosensitivity dence that is currently available to assist clinimay have a role in affecting the risk of a RIC in cians to make a judgement as to the benefits of normal tissue exposed to ionizing radiation. MDRT protocols, balanced against the risk of a However, even in patients exposed to high-dose subsequent RIC as it pertains to the individual RT (HDRT) required for cancer treatments this circumstances of their patient. has been very difficult to evaluate. In a recent consensus review of genetic testing to identify radiosensitivity profiles prior to HDRT, it was 2 Evidence Used in Estimation agreed that unless patients have a recognized of the Excess Risk of RIC radiosensitivity syndrome (e.g., ataxia-­ Following MDRT telangiectasia) or a recognized germline mutation, such as those involving the p53 (Braunstein This chapter updates previous reviews and Nakamura 2013; Sherborne et  al. 2017) or (Braunstein and Nakamura 2013; McKeown Rb genes (Kleinerman et al. 2019), the influence et al. 2015; Mazonakis and Damilakis 2017) and of genes on the radiosensitivity of normal tissues evaluates the currently available evidence of the in most patients was not currently a cause for likelihood of a SMN developing as a result of concern; however, they advised that further eval- exposure to radiation at doses pertinent to uations should occur now that modern profiling MDRT. In fact, there are only a very limited nummethodologies are available (Bergom et  al. ber of directly relevant studies that have evalu2019). Several recent studies suggest that this ated the risks of RIC in patients with benign may soon be possible. For example, when geno- disease especially when treated using modern typic and proteomic data were integrated, a group techniques. To some extent doses and treatment of eight plasma proteins combined with a VEGFA protocols in historical cohorts are similar but, in gene variant were found to predict for radiosensi- many situations, there are key differences, adding tivity (Drobin et  al. 2020). In patients treated to the uncertainty of risk estimates for current with RT to the chest area for Hodgkin’s lym- protocols. In addition, many of the previous studphoma (HL) several single-nucleotide polymor- ies have limitations, e.g., there is marked variphisms (SNPs) were associated with a higher risk ance in estimates of the received dose, dose of radiation-induced breast cancer (BCa) (Opstal-­ exposure between individuals, age on irradiation, van Winden et al. 2019). Genetic analysis may be and age at follow-up and often cohorts are small. particularly pertinent for children treated with Directly relevant information has come from theionizing radiation (Sherborne et  al. 2017). A oretical models, phantom studies, and a limited recent study of the Childhood Cancer Survivor number of clinical investigations, in which Study (CCSS) cohort has shown that survivors MDRT has been used for the treatment of specific with neurofibromatosis-1 (NF1) have a 2.4-fold benign diseases. However, most of the latter prohigher risk of a second malignant neoplasm tocols are no longer in use and involved treatment (SMN) (95% CI, 1.3–4.3; p  =  0.005); in one with antiquated equipment. Less direct evidence cohort, treatment with RT but not alkylating can also be obtained by analyzing cohorts agents further increased this risk (Bhatia et  al. exposed to low-dose environmental or medical 2019). Recently a germline MUTYH mutation in radiation and for those treated with HDRT for a pediatric cancer survivor has been implicated in cancer. The use of these information sources the subsequent development of a SMN (Lavergne requires extrapolation up or down, which has

Estimating the Risk of Radiation-Induced Malignancy Following Radiotherapy for Benign Disease

inherent flaws. In addition, these risk assessments have also been informed using data based on a range of methodologies that are subject to several important variables.

2.1 Mathematical Modeling and Phantom Studies It is possible to use mathematical modeling and phantom studies to provide more directly applicable evidence since they have been specifically designed to address the dose range pertinent to MDRT. However, mathematical models require a series of assumptions for which there may not be a consensus. In a recent review it was noted that many of the studies using radiobiology models in regular clinical use are abstract and empirical, and do not provide significant scope for mechanistic interpretations (McMahon and Prise 2019). Few relevant phantom studies have been described. However, a useful study of both male and female anthropomorphic phantoms has investigated the long-term risks of RIC in patients treated with relatively modern RT protocols for a range of benign diseases (heterotopic ossification, arthritis of the shoulder or knee joints, heel spurs, and hidradenitis suppurativa) (Jansen et al. 2005). They calculated the risk of RIC using the International Commission on Radiological Protection (ICRP) recommendation, which estimates the average carcinogenic risk resulting from ionizing radiation exposure to be 10%/Sv for high dose and high dose rate exposure (ICRP 1991a). The authors discussed in some detail the basis of the assumptions which indicated that when using MDRT to treat these conditions the effective dose range was 5–400 mSv, providing a prediction of an increase in RICs of 0.5–40 per 1000 patients treated. They acknowledged that this is a wide range, with age at exposure being a key risk modifier; body size and site of irradiation also influenced the risk. Consequently, it was advised that careful body positioning and shielding should be employed to optimize target volume coverage and reduce the effective dose to normal tissues to minimize the risk of a subsequent RIC.

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In a more recent phantom study, using similar methodology, the lifetime attributable risk (LAR) of a RIC following treatment with MDRT for vertebral hemangioma was compared to the lifetime intrinsic risk (LIR) in nonirradiated individuals (Mazonakis et al. 2016). The authors calculated the radiation exposure of a range of organs (both out-of-field and partially in-field) at risk following exposure to MDRT (34 Gy) to four different sites along the spine. The LAR for cancer development in organs excluded from the irradiated area was calculated to be trivial and considerably less than the LIRs. Although the risk was higher in organs that were partially irradiated during “treatment,” the risk was still very low and less than the LIRs for the same organs. It should be recognized that phantom studies require several assumptions making interpretation less certain, as highlighted in a recent review (Mazonakis and Damilakis 2017).

2.2 Epidemiological Studies Epidemiological studies of cohorts exposed to low-dose radiation (60 years, are the survivors of the atomic bombings in Japan; updates of the Lifespan Study (LSS) have been published regularly. These data show that the incidence of most solid tumors has an approximately linear increase in relation to exposed dose after a LT of about 10  years (Grant et  al. 2017). Not unsurprisingly, a big difference in risk is found depending on the age at exposure, with a tenfold difference between children and adults; in utero exposure has a similar level of risk to those exposed in infancy (Preston et  al. 2008; Ozasa et  al. 2019). The incidence of RIC has been

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quoted to decrease from about 15% per Sv of uniform whole-body irradiation for children 60 years (Kumar 2012). The data on hematological malignancies resulting from exposure to LDR are more varied, and the effects occur earlier (discussed further below). A recent report on women exposed to long-term low-dose environmental radiation (mean ~0.01 Gy) caused by contamination from the Chernobyl accident has also shown a small, but significant, increased risk of BCa in those exposed to higher doses (Rivkind et al. 2020). Recently studies have been published on two large groups of medical professionals exposed to very-low-dose ionizing radiation during their careers. One study of radiologic technologists (n > 146,000; >72% female), who had worked for at least 2  years between 1926 and 1982  in the USA, has shown an increased risk of BCa (Doody et al. 2006; Preston et al. 2016). Further analysis of the incidence of self-reported cancers and cancer mortality showed an approximately twofold increased risk of brain cancer mortality and modest elevations in the incidence but not mortality of melanoma and BCa. No other outcome evaluated showed significant excess incidence or mortality although some caution was advised in the interpretation of this data (Rajaraman et al. 2016). An increased risk of BCa has also been found in a large cohort of medical workers in South Korea (>94,000). However, the radiation-related risks identified were small and varied widely by sex and occupational group, but they were most significant for female radiologic technologists (Lee et al. 2018). Overall, these low-dose groups show that radiation exposure dose increases the incidence of RIC though the numbers affected are small and the LTs long.

2.3 Second Malignant Neoplasms in Patients Exposed to HDRT for Cancer The many sequelae of normal tissue exposure to HDRT during treatment of malignant tumors have been well documented and indeed they

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define the dose limits for HDRT exposure of specific organs (Hall and Giaccia 2018). It is now well accepted that cancer survivors have a higher risk of SMNs. Although this risk is small, it is accepted for patients with cancer due to the greater threat from poor control of their presenting pathology. However, as cancer treatments become more successful there are an increasing number of cancer survivors who are at greater risk of the development of a SMN.  Studies of these patients can inform as to the risk of RIC, albeit the data is from differing protocols and consequent on higher dose exposures (Kumar 2012; Braunstein and Nakamura 2013; Kamran et al. 2016; Schaapveld et al. 2015; Donin et al. 2016). A meta-analysis of >640,000 cancer patients identified from the “Surveillance, Epidemiology, and End Results” registries (SEER) in the USA has shown that, within 15 years of HDRT, there are 5 excess cancers per 1000 individuals; these data were acquired from 15 solid tumor types (Berrington de Gonzalez et al. 2011). In a further systematic review of 28 eligible studies, they identified 3434 patients who developed second cancers in 11 different organs known to receive >5 Gy. Most of the studies confirmed linear dose-­ response curves even up to ≥60  Gy; the main exception was thyroid cancer, which showed a downturn above 20 Gy. They also confirmed that the risk varied according to the tissue of origin of the second cancer (Berrington de Gonzalez et al. 2013). Often several tissues, with different risks of developing a RIC, are exposed to radiation ­during RT.  In a study of HDRT for cervical cancer (n  =  104,760) an increased risk for all second cancers was found that was particularly evident at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary, and genital sites) as compared to women in the general population. This persisted beyond 40 years of follow-up and was modified by age at treatment (Chaturvedi et  al. 2007). In a study of prostate cancer treatments, men receiving HDRT (n  >  50,000) showed that most SMNs occurred in organs close to the treatment field, e.g., bladder and rectum; however, 30% were induced in the lung which would have

Estimating the Risk of Radiation-Induced Malignancy Following Radiotherapy for Benign Disease

only received a scatter dose of about 0.6  Gy. Overall, there was a small but significant increase in risk of a RIC (6%), as compared to those treated by prostatectomy (n  >  70,000) and the relative risk (RR) increased in longer term survivors (Brenner et al. 2000). HDRT in childhood carries the greatest risk of a subsequent RIC since survival times are likely to be considerably longer and children are known to have an increased radiosensitivity (UNSCEAR 2013; Kutanzi et al. 2016). Consequently, current childhood cancer treatment protocols incorporate a specific aim to minimize the risk of RIC, by avoiding radiotherapy when possible, or alternatively minimizing dose (Kutanzi et  al. 2016; Turcotte et al. 2018). However, since some childhood cancers involve an underlying germline mutation, this may also contribute to the observed increase in the susceptibility to second malignancies (Zhang et al. 2015; Sherborne et al. 2017). The small size of pediatric patients further increases risk, since scatter radiation will affect more tissues (Hall 2006). Since most of the evidence confirms an approximately linear risk of RIC in relation to dose, the data obtained from cancer patients treated with HDRT can be used to give some guidance as to the expected lesser risks of RIC after exposure to MDRT.  However, treatment protocols/fractionation regimens will often be different so any extrapolation from HDRT must be interpreted with caution.

3 Tissues at Risk of RIC Following MDRT for Benign Disease As discussed in the remaining chapters of this book, MDRT can be used to treat a wide variety of benign diseases. Treatments involve many disparate parts of the body, a variety of RT protocols, and patients of all ages. Currently, most MDRT is used to treat older adults (aged >50), though for some conditions children and younger individuals might also be considered; in this latter group the risk of a RIC, although small, will be higher. Individual indications treated with

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MDRT have very different normal tissue exposure profiles and this should be factored in when considering the potential for a subsequent RIC. In the following sections, several key “at-risk” tissue types are considered in relation to some of the evidence available. However, none of the evidence is directly applicable since it comes from studies of HDRT and low-dose exposures. With this caveat, these studies can be used to estimate the risks of MDRT treatment for individual patients with specific benign diseases. Age is a particularly important risk modifier and should be factored in for all younger individuals. A selection of the more relevant studies was summarized previously (McKeown et  al. 2015) and the discussion below now includes some of the more recent evidence.

3.1 Skin Cancer Skin cancer is a potential risk for all patients receiving RT since there is, of necessity, almost always a concomitant skin exposure, with a LT normally >10  years. A small but quantifiable increase in non-melanoma skin cancer (NMSC) has been found following occupational exposure to ionizing radiation (Wang et  al. 2002; Azizova et  al. 2021) and RT for a range of benign indications, using relatively low doses (up to ~6  Gy but varying widely), e.g., tinea capitis (Shore et  al. 1984; Ron et  al. 1991; Boaventura et  al. 2012), acne, and other skin disorders (Lindelöf and Eklund 1986; Karagas et al. 1996). Most of these indications have not been treated with MDRT for many years. There is now considerable evidence that the risk of skin cancer is raised following many different radiation exposure scenarios, with BCCs being the predominant tumor type found (Li and Athar 2016). In the LSS cohort BCC showed a significant excess relative risk (ERR) of 15, 5.7, 1.3, and 0.9 that depended on age at exposure (0–9, 10–19, 20–39, >40 years, respectively); this risk increased 11% with each 1-year decrease in age at exposure. No significant dose responses were found for malignant melanoma or other skin cancers (Sugiyama et al. 2014).

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Modern HDRT protocols have resulted in longer survival times in individuals treated for childhood cancers. Consequently, a small but significant increase in NMSC has now become apparent in the CCSS cohort, which is likely to be associated with their exposure to RT and/or linked to a genetic predisposition (Armstrong et al. 2011). Later analysis has shown not only an increased incidence of BCCs (Watt et  al. 2012) but also an approximate 2.5-fold increase in the risk of melanoma (Pappo et al. 2013). Studies of adults with benign conditions exposed to above background radiation, such as tuberculosis patients exposed to multiple fluoroscopies (average 77) during treatment, have shown no marked increase in skin cancer risk (Davis et al. 1989). The extent of sun exposure was also thought to act synergistically with IR to cause skin damage (ICPR 1991b; Shore et  al. 2002); however, more recent studies have resulted in conflicting conclusions and the issue of interaction of effects in the low dose range is considered to be unresolved (ICRP 2015). In the dose range pertinent to some MDRT protocols there is more likely to be a synergistic effect. It should be noted that the lifetime risk of a radiation-induced BCC, based on 100 cm2 skin treated to a mean dose of 3 Gy, has been estimated to be ~0.006%, which is very much smaller than the spontaneous lifetime risk of >20% (Trott and Kamprad 2006). Overall, the data show a dose-dependent increase in the risk of NMSC, mostly BCCs that can, for the most part, be treated successfully, although it has been suggested that BCCs resulting from IR exposure are more aggressive and should ideally be excised with wider margins (Hassanpour et al. 2006). Long-term surveillance and reporting of suspicious changes in irradiated skin are advised, especially in individuals treated with RT as children.

3.2 Brain Cancer Exposure to radiation is a well-substantiated risk factor for cancers in the brain/central nervous system (CNS) with the evidence coming from a range of different studies (Ostrom et al.

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2019). In the LSS cohort a linear dose-dependent increase in the risk of RIC in the brain up to 2 Gy was found, which was inversely related to the age of exposure (Preston et al. 2007). In a recent analysis, the risk of brain cancer was found to be greater following childhood CT scanning compared to that obtained in the LSS cohort; however, several likely confounding factors were identified showing how complex these assessments are (Smoll et al. 2016). In a recent meta-­analysis of 6166 cases of meningioma, an increased risk was associated with repeated dental X-rays (pooled RR = 1.53 [CI 1.26–1.85]) although not for occasional exposure; no increase was found for gliomas (Memon et al. 2019). One well-recognized, if infrequent, outcome of exposure to MDRT or HDRT is the occurrence of meningiomas (Baldi et  al. 2018; Chowdhary et  al. 2012; Godlewski et  al. 2012). In a meta-­ analysis of 66 studies of RT for a wide range of conditions (mostly tumors) 143 patients were found to have developed meningiomas attributable to the RT (median age at RT was 12). The meningiomas presented at a younger age (80% at