Radiation Oncology Question Review, Second Edition – Radiation Oncology Board Review Guide by Expert Radiation Oncologists from Cleveland Clinic Taussig Cancer Institute, Book and Free eBook [2 ed.] 9780826135667, 9780826135674, 0826135668

Table of contents :
Cover
Title
Copyright
Contents
Contributors
Preface
Acknowledgments
Share Radiation Oncology Question Review, Second Edition
Chapter 1: Head and Neck Cancers
General Questions
Oropharyngeal Cancer
Oral Cavity
Paranasal Sinus
Nasopharynx
Larynx/Hypopharynx
Postoperative Radiotherapy
Salivary Gland Tumors
Melanoma
Merkel Cell Carcinoma
Unknown Primary
Non-Melanomatous Skin Cancer
Thyroid Cancer
Chapter 2: Central Nervous System
Brain Metastases
Glioblastoma
Low-Grade Gliomas
Craniopharyngioma
Anaplastic Gliomas
Prophylactic Cranial Irradiation
Spine Metastases
Primary CNS Lymphoma
Meningiomas
Trigeminal Neuralgia
Vestibular Schwannomas
Arteriovenous Malformations
Pituitary Tumors
Optic Gliomas
CNS Radiation Toxicities/Therapies for Toxicities
Spinal Cord Tumors
Chapter 3: Breast Cancer
Epidemiology and Cancer Risk
Imaging
Anatomy
Genetics
General Treatment Concepts
DCIS / LCIS
Chapter 4: Thoracic Cancers
Non–Small-Cell Lung Cancer—Early Stage
Non–Small-Cell Lung Cancer—Locally Advanced
Small-Cell Lung Cancer
Thymoma
Cardiac Tumors
Mesothelioma
Chapter 5: Gastrointestinal Cancers
Gastric Cancer
Hepatocellular Cancer
Biliary Tract Cancer
Pancreatic Cancer
Rectal Cancer
Anal Cancer
Chapter 6: Genitourinary Cancers
Prostate Cancer—General
Prostate Cancer—Low Risk
Prostate Cancer—Brachytherapy
Prostate Cancer—High Risk
Prostate Cancer—Adjuvant and Salvage Radiation
Node-Positive Prostate Cancer
Urethral Cancer
Penile Cancer
Renal Cell Carcinoma
Bladder Cancer
Testicular Cancer
Chapter 7: Gynecologic Cancers
Cervical Cancer
Uterine Cancer
Uterine Sarcoma
Vulvar Cancer
Vaginal Cancer
Brachytherapy
Gynecologic Oncology—General
Chapter 8: Lymphomas
Non-Hodgkin Lymphoma
Hodgkin Lymphoma
Multiple Myeloma
Chapter 9: Soft Tissue Sarcoma
Chapter 10: Pediatric Cancers
Retinoblastoma
Wilms
Neuroblastoma
Pediatric Leukemia
Hodgkin Lymphoma
Pediatric Gliomas
Soft Tissue Sarcoma
Langerhans Cell Histiocytosis
Liver Tumors in Children
Ewing Sarcoma
Rhabdomyosarcoma
Germ Cell Tumors (Non-CNS)
CNS Germ Cell Tumors
Medulloblastoma
Brainstem Glioma
Ependymoma
Osteosarcoma
Craniopharyngioma
Abbreviations
Index

Citation preview

Second Edition

Radiation Oncology Question Review efficiently tests and reinforces your knowledge of key concepts, critical studies, and major clinical guidelines, with the most important radiation oncology citations included. Organized by treatment site, detailed questions cover natural history, epidemiology, diagnosis, staging, treatment options, and treatment-related side effects all in a newly configured format. Each question tests your recall and sharpens your skills so that you can practice and feel confident in your ability to manage all disease site areas according to the standard guidelines and key literature in the field. Written by residents and expert radiation oncologists from the Cleveland Clinic Taussig Cancer Institute, this review is a comprehensive study guide for anyone preparing for the board exam, for practicing physicians reviewing a topic, or for preparing for MOC. Whether you are a few minutes between patients or are having a dedicated study session, this book is an invaluable resource that will strengthen your knowledge of the field. KEY FEATURES: • Updated and revised to reflect the new AJCC 8th Edition criteria, data guidelines for SBRT, hypofractionation for breast and prostate cancers, new advanced treatment planning and delivery techniques, and with a dedicated sarcomas section • Covers all clinical topics and disease site areas that are in the ABR clinical radiation oncology exam and MOC • Updated layout and organization of questions and answers • Includes access to the fully searchable downloadable eBook

Recommended Shelving Category: Oncology

RADIATION ONCOLOGY QUESTION REVIEW

MICHAEL A. WELLER, MD NIKHIL JOSHI, MD ANTHONY MASTROIANNI, JD, MBA, MD

WELLER JOSHI MASTROIANNI

RADIATION ONCOLOGY QUESTION REVIEW

Second Edition

ISBN 978-0-8261-3566-7 An Imprint of Springer Publishing

11 W. 42nd Street New York, NY 10036-8002 www.springerpub.com

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An Imprint of Springer Publishing

RADIATION ONCOLOGY QUESTION REVIEW Second Edition

MICHAEL A. WELLER NIKHIL JOSHI ANTHONY MASTROIANNI

An Imprint of Springer Publishing

9/13/18 12:39 PM

Radiation Oncology Question Review

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Radiation Oncology Question Review Second Edition Editors Michael A. Weller, MD Department of Radiation Oncology Cleveland Clinic Cleveland, Ohio Nikhil Joshi, MD Department of Radiation Oncology Cleveland Clinic Cleveland, Ohio Anthony Mastroianni, JD, MBA, MD Department of Radiation Oncology Cleveland Clinic Cleveland, Ohio

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Visit our website at www.springerpub.com ISBN: 9780826135667 ebook ISBN: 9780826135674 Acquisitions Editor: David D’Addona Compositor: diacriTech Copyright © 2019 Springer Publishing Company. Demos Medical Publishing is an imprint of Springer Publishing Company, LLC. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particular our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Library of Congress Cataloging-in-Publication Data Names: Weller, Michael A., editor. | Joshi, Nikhil, 1983- author. | Mastroianni, Anthony, editor. Title: Radiation oncology question review / editors, Michael A. Weller, Nikhil Joshi, Anthony Mastroianni. Other titles: Radiation oncology self-assessment guide Description: Second edition. | New York : Demos, [2018] | Preceded by Radiation oncology self-assessment guide / [edited by] John Suh. c2013. | Includes bibliographical references and index. Identifiers: LCCN 2018029124| ISBN 9780826135667 (alk. paper) | ISBN 9780826135674 (ebook) Subjects: | MESH: Neoplasms—radiotherapy | Examination Questions Classification: LCC RC271.R3 | NLM QZ 18.2 | DDC 616.99/40642—dc23 LC record available at https://lccn.loc.gov/2018029124

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Contents Contributors vii Preface ix Acknowledgments xi Share Radiation Oncology Question Review, Second Edition 1. Head and Neck Cancers 1 Nikhil Joshi, Shlomo A. Koyfman, and Monica E. Shukla 2. Central Nervous System 39 Aryavarta M. S. Kumar and Michael A. Weller 3. Breast Cancer 79 Betty Obi and Michael A. Weller 4. Thoracic Cancers 115 Monica E. Shukla and Matthew C. Ward 5. Gastrointestinal Cancers 157 Joycelin F. Canavan and Andrew Vassil 6. Genitourinary Cancers 221 Henry Blair and Michael A. Weller 7. Gynecologic Cancers 261 Eva Marie Suarez and Mihir Naik 8. Lymphomas Daesung Lee

305

9. Soft Tissue Sarcoma 331 Nikhil Joshi and Jacob Scott 10. Pediatric Cancers 339 Nikhil Joshi and Michael A. Weller Abbreviations Index 379

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Contributors Henry Blair, MD Staff Physician, Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, Ohio Joycelin F. Canavan, MD, FRCPC Clinical Assistant Professor, Department of Radiation Oncology, Cleveland Clinic Cancer Center, Mansfield, Ohio Nikhil Joshi, MD Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio Shlomo A. Koyfman, MD Assistant Professor of Medicine, Department of Radiation Oncology and Bioethics, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio Aryavarta M. S. Kumar, MD, PhD Radiation Oncologist, Department of Radiation Oncology, Louis Stokes VA Medical Center, Cleveland, Ohio Daesung Lee, MD Staff Physician, Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio Mihir Naik, DO Associate Staff, Department of Radiation Oncology, Cleveland Clinic Florida, Weston, Florida Betty Obi, MD Staff Physician, Department of Radiation Oncology, Cleveland Clinic Hillcrest Hospital, Mayfield Heights, Ohio Monica E. Shukla, MD Assistant Professor, Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin Jacob Scott, MD, DPhil Associate Staff, Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio Eva Marie Suarez, MD Associate Staff, Department of Radiation Oncology, Cleveland Clinic Florida, Weston, Florida Andrew Vassil, MD Staff Physician, Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio Pdf_Folio:vii

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CONTRIBUTORS

Matthew C. Ward, MD Radiation Oncologist, Department of Radiation Oncology, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina Michael A. Weller, MD Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio

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Preface We are proud to introduce the second edition of the Radiation Oncology SelfAssessment Guide, now titled Radiation Oncology Question Review. The first edition, edited by John Suh, MD, and published in 2012, provided a comprehensive overview of the field of radiation oncology in an easy-to-digest flashcard format. Based on the feedback we received from many individuals who purchased the first edition, we have updated the print format and design for a more rapid review. In an era when the doubling time of medical knowledge is estimated to be 73 days, it has become increasingly difficult for even the most diligent resident or practicing physician to stay current. Since the publication of the last edition, we have seen hypofractionation become the standard of care for many patients with breast and prostate cancer, new data guiding the use of stereotactic radiosurgery and stereotactic body radiation therapy across multiple disease sites, an increase in the utilization of advanced treatment planning and delivery techniques, and the rise of immunotherapy, just to name a few. Organized by treatment site, detailed question sets have been thoroughly revised to provide up-to-date information on the natural history, epidemiology, diagnosis, staging, treatment options, and treatment-related side effects for each cancer type. The format has been designed to efficiently test and reinforce knowledge of key concepts, critical studies, and major clinical guidelines, with the most important citations included. From trainees preparing for their board exams to practicing physicians looking for a review or preparing for the maintenance of certification exam, whether it be a few minutes between patients or a dedicated study session, we believe Radiation Oncology Question Review, Second Edition will continue to be an invaluable resource to the radiation oncology community. Michael A. Weller, MD Nikhil Joshi, MD Anthony Mastroianni, JD, MBA, MD

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Acknowledgments The editors would like to acknowledge the leadership of Dr. John Suh, as well as the many contributors to the first edition of the Radiation Oncology Self-Assessment Guide, including Dr. Shlomo Koyfman, Dr. Samuel T. Chao, Dr. Gaurav Marwaha, Dr. Rahul Tendulkar, Dr. Vincent Lee, Dr. Susan Guo, Dr. Andrew Vassil, Dr. Kevin L. Stephans, and Dr. Erin Murphy.

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Share Radiation Oncology Question Review, Second Edition

1 • • • • • • • • • • • • •

General Questions

Head and Neck Cancers

NIKHIL JOSHI, SHLOMO A. KOYFMAN, AND MONICA E. SHUKLA

Questions 1–12

Oropharyngeal Cancer Oral Cavity

Questions 13–19

Questions 20–23

Paranasal Sinus

Questions 24–29

Nasopharynx

Questions 30–38

Larynx/Hypopharynx

Questions 39–48

Postoperative Radiotherapy Salivary Gland Tumors Melanoma

Questions 49–52

Questions 53–61

Questions 62–65

Merkel Cell Carcinoma Unknown Primary

Questions 66–69 Questions 70–76

Non-Melanomatous Skin Cancer Thyroid Cancer

Questions 76.1–81

Questions 82–89

GENERAL QUESTIONS 1. Is there a benefit to radiation intensification with altered fractionation when treating locally advanced squamous cell cancer of the head and neck with radiation alone?

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A significant benefit in LC for HRT or ACB radiotherapy was shown in RTOG 90-03, a four-arm phase III randomized trial that demonstrated ~10% improvement for either HRT (81.6 Gy/68 fx at 1.2 Gy BID) or ACB

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(72 Gy/42 fx at 1.8 Gy QD with an additional 1.5 Gy fx in the PM for the last 12 treatment days) compared to either standard RT (70 Gy/35 fx) or split-course accelerated hyperfractionated radiotherapy (AHF-RT 67.2 Gy/42 fx at 1.6 Gy BID with a 2-week break after 38.4 Gy). LRC was ~55% in the former two groups compared to ~45% in the latter two groups. The MARCH meta-analysis also demonstrated a significant LRC advantage (7%) to both hyperfractionation and concomitant boost RT. While there was a modest survival advantage overall, hyperfractionated regimens produced an 8.1% OS advantage at 5 years and 3.9% at 10 years. Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 2000;48:7-16. 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(9): 1221-1237. doi:10.1016/S1470-2045(17)30458-8.

2. Is there a benefit to altered fractionation in the setting of concurrent chemotherapy?

No. The RTOG 0129 protocol randomized patients with locally advanced HNC to standard fractionation (70 Gy/35 fx) with three cycles of cisplatin (d 1, 22, 43) versus ACB radiotherapy (72 Gy in 42 fx) with two cycles of cisplatin (d 1, 22). There were no significant differences between the arms in terms of LRC or OS. Some hypothesize that a third cycle of cisplatin offers similar benefit to altered fractionation in this setting. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35. doi:10.1056/NEJMoa0912217.

3. Is there a benefit to treating locally advanced squamous cell cancer of the head and neck with 6 fx weekly rather than 5?

Yes. The phase III DAHANCA-6/7 trial randomized patients to 6 fx a week (either an extra fraction on Saturday/Sunday, or a BID fraction given on Thursday or Friday of weeks 2–6) versus 5 fx weekly, and demonstrated a LRC (70% vs. 60%) and DFS advantage to this regimen. This forms the basis for the current RTOG standard accelerated regimen of 70 Gy in 35 fx/6 weeks with a BID fraction delivered on Thursday/Friday of weeks 2 to 6 being used in the RTOG 1016 trial. Of note, the DAHANCA-6/7 trial treated to 66 to 68 Gy with concurrent nimorazole, and did not use concurrent chemotherapy. The IAEA-ACC also showed a 5-year LRC benefit to accelerated radiation (6 vs. 5 fx a week) of 42% versus 30%. No chemotherapy was used. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1016. Accessed October 25, 2011. Pdf_Folio:2

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Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet. 2003;362:933-940. doi:10.1016/S01406736(03)14361-9. Overgaard J, Mohanti BK, Begum N, et al. Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial. Lancet Oncol. 2010;11(6):553-560. doi:10.1016/S14702045(10)70072-3.

4. What are the indications to add systemic chemotherapy to definitive radiotherapy in head and neck cancer?

Chemotherapy is indicated in stage III/IV disease based on several prospective randomized trials that demonstrated LRC, DFS, and OS advantages with the addition of concurrent chemotherapy. This benefit was seen compared to standard fractionated RT (Adelstein) as well as hyperfractionated RT (Brizel). The MACH-NC meta-analysis also demonstrated a 4.5% 5-year OS advantage overall, with the highest advantage seen in the setting of concurrent chemotherapy. The absolute benefit was 6.5% at 5 years. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21:92-98. doi:10.1200/JCO.2003.01.008. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med. 1998;338:1798-1804. doi:10.1056/NEJM199806183382503. Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;2:4-14. doi:10.1016/j.radonc.2009.04.014.

5. What induction chemotherapy regimen produces superior results to conventional cisplatin and 5-fluorouracil (PF) chemotherapy?

The addition of docetaxel to the PF backbone was investigated in two phase III randomized studies and demonstrated improved LRC and OS (not DM), compared to PF alone. In the Vermorken study, patients were treated with TPF x four cycles followed by RT alone. In the Posner trial, patients were treated with similar induction chemotherapy (three cycles) followed by RT + concurrent weekly carboplatin. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357:1705-1715. doi:10.1056/NEJMoa070956. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357:1695-1704. doi:10.1056/NEJMoa071028.

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6. How is cetuximab dosed when used concurrently with radiotherapy, and what is the evidence supporting its use?

400 mg/m2 loading dose 1 week prior to RT and 250 mg/m2 weekly during RT. It was tested in a phase III study compared to RT alone and demonstrated superior outcomes, including 2-year LRC (50% vs. 41%) and 3-year OS (55% vs. 45%). There was no difference in rates of DM (16% vs. 17%). The 5-year OS was 45.6% in the cetuximab arm versus 36.4% in the radiotherapy alone group. Additionally, for the patients treated with cetuximab, OS was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34–0.72; p = .002). Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med. 2006;354:567-578. doi:10.1056/NEJMoa053422. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21-28. doi:10.1016/S1470-2045(09)70311-0.

7. What structures are removed in a radical neck dissection? Modified radical neck dissection? Selective neck dissection?

In these procedures, the following are removed:

• Radical neck dissection (RND)—removes levels I to V, sternocleidomastoid muscle (SCM), omohyoid muscle, IJV, EJV, CN XI, and submandibular gland.

• Modified RND—removes levels I to V, but does not remove at least one of the following structures: SCM, IJV, or CN XI.

• Selective neck dissection—does not remove all of levels I to V. There are several named subtypes of selective neck dissections, including the following: ■

Supraomohyoid neck dissection—removes levels I to III

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Lateral neck dissection—removes levels II to IV

Frank DK, Sessions RB. Management of the neck—surgery. In: Harrison LB, Sessions RB, Hong WK, eds. Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:185-189.

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8. In nonnasopharyngeal head and neck IMRT planning, what are the most important planning organs at risk? What constraints are used?

No more than 0.03 mL of the spinal cord planning risk volume (PRV) can receive greater than 50 Gy. No more than 0.03 mL of the brainstem PRV can receive greater than 52 Gy. The PRV cord = cord + 5 mm in each dimension. The PRV brainstem = brainstem + 3 mm in each dimension. These supercede PTV coverage. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1016. Accessed October 25, 2011.

9. In IMRT planning, what are the PTV coverage constraints generally mandated in RTOG studies?

>95% of the PTV should receive prescription dose; no more than 20% of PTV will receive ≥110% of prescription dose (V110 ≤20%); no more than 5% of PTV will receive ≥115% of prescription dose (V115 ≤5%) http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1016. Accessed October 25, 2011.

10. In IMRT planning, what are the three different target constraints for the parotid glands?

Mean dose to at least one gland (contralateral to disease) ≤26 Gy; or at least 50% of one gland to less than 30 Gy; or at least 20 mL of the combined volume of both parotid glands to less than 20 Gy. http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1016. Accessed October 25, 2011.

11. What is the main benefit to IMRT planning seen in randomized studies compared to 2D/3D-CRT?

IMRT has been studied in several phase III randomized trials and has been associated with reduced late grade ≥2 xerostomia (29%–40% for IMRT vs. 80%–83% for 2/3D). Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol. 2007;25:4873-4879. doi:10.1200/JCO.2007.11.5501. Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2011;12:127-136. doi:10.1016/S1470-2045(10)70290-4.

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12. What is the mechanism of action for amifostine and its primary side effects? Is it beneficial in preventing xerostomia in patients treated with RT for H&N cancer?

Amifostine is a free radical scavenger. It can cause nausea, vomiting, hypotension, and allergic reactions. The subcutaneous administration helps reduce these toxicities. It was tested in two phase III studies as an IV formulation. In the Brizel trial (RT vs. RT + amifostine at 200 mg/m2 15–30 minutes prior to RT), it significantly reduced the rate of acute (78% vs. 51%) and chronic (58% vs. 34%) grade ≥2 xerostomia. In the Beuntzel trial (RT + carboplatin + placebo vs. RT + carboplatin + amifostine), there was no advantage to its use. It is FDA approved as a radioprotectant, but is not routinely used in many centers. Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol. 2000;18:3339-3345. doi:10.1200/JCO.2000.18.19.3339. Buentzel J, Micke O, Adamietz IA, et al. Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebo-controlled phase III study. Int J Radiat Oncol Biol Phys. 2006;64:684-691. doi:10.1016/j.ijrobp.2005.08.005.

12.1. What are the changes to the ‘N’ staging for head and neck/skin cancers that are not p16 or EBV positive in the 8th AJCC Staging Manual?

In general, ENE or extranodal extension upstages the previous “pN” staging from AJCC 7th edition. For example, a single node less than 3 cm in size but with ENE on pathology is now pN2a (previously pN1). Multiple ipsilateral or bilateral nodes with ENE are now pN3b (previously pN2b/pN2c). Any clinical ENE in a lymph node is now categorized as cN3b. Lydiatt WM, Patel SG, Ridge JA, et al. Staging head and neck cancers. In: Amin MB, ed. AJCC Cancer Staging Manual. 8th ed. Chicago, IL: Springer Publishing; 2017:55-66.

12.2. What is the role of PET-CT for restaging patients treated with definitive chemoradiation?

A prospective, randomized, controlled trial reported recently studied this question. Head and neck cancer patients with SCC, N2/N3 disease treated with chemoradiation were randomized to PET-CT-guided surveillance (done at 12 weeks after the end of chemoradiation) with neck dissection only for incomplete or equivocal response or planned neck dissection. The primary end point was OS. Survival was similar across the two groups and PET-CT resulted in fewer operations, making it a more cost-effective approach.

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Mehanna H, Wong WL, McConkey CC, et al. PET-CT surveillance versus neck dissection in advanced head and neck cancer. N Engl J Med. 2016;374(15):1444-1454. doi:10.1056/NEJMoa1514493.

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12.3. How are patients selected for reirradiation? What are the outcomes?

A recent multi-institutional study looked at how to best select patients for modern IMRT-based reirradiation. It identified three prognostic subgroups with distinct OS: class I included patients greater than 2 years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients greater than 2 years with unresected tumors or those ≤2 years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%); and the remaining patients formed class III (2-year OS, 16.8%). The rates of grade ≥3, grade ≥4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade ≥3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. Ward MC, Riaz N, Caudell JJ, et al. Refining patient selection for reirradiation of head and neck squamous carcinoma in the IMRT era: a multi-institution cohort study by the MIRI collaborative. Int J Radiat Oncol Biol Phys. 2018;100:586594. doi:10.1016/j.ijrobp.2017.06.012.

OROPHARYNGEAL CANCER 13. What is the risk of ipsilateral and bilateral nodal disease for a BOT cancer?

About 70% of patients with BOT cancer have ipsilateral LN disease and 20% have contralateral nodal involvement at presentation. Hu KS, Choi WH, Culliney B, et al. Cancer of the oropharynx. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier/Saunders; 2010:549-550.

14. What is the risk of contralateral nodal involvement for a T1-2N0-1 welllateralized tonsil cancer?

The risk is below 5%. In a retrospective series from PMH in which patients with T1-2N0 tonsil cancers were treated with unilateral irradiation, the incidence of contralateral neck failure was 3.5% O’Sullivan B, Warde P, Grice B, et al. The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys. 2001;51:332343. doi:10.1016/S0360-3016(01)01613-3.

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15. What are the most common assays to stain for HPV and p16?

HPV is most often assessed using in situ hybridization techniques, which identify the HPV DNA, while the p16 protein is most reliably identified through immunohistochemistry. About 20% of tumors that are p16+ are high-risk HPV negative, making p16 a more sensitive assay. Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human papillomavirus. Summary of a National Cancer Institute State of the Science Meeting; November 9–10, 2008; Washington, DC. Head Neck. 2009;31:13931422. doi:10.1002/hed.21269. Allen CT, Lewis JS Jr, El-Mofty SK, et al. Human papillomavirus and oropharynx cancer: biology, detection and clinical implications. Laryngoscope. 2010;120:17561772. doi:10.1002/lary.20936.

16. Which subsite of the H&N is most associated with HPV/p16-related SCC, and what is its prognostic significance?

Oropharyngeal cancers are most heavily associated with HPV/p16+, with 60% to 70% of these tumors being HPV+ and/or p16+. Both HPV+ and p16+ status is a powerful prognostic marker, and has been shown on subset analysis of the RTOG 0129 trial to demonstrate the following improved outcomes: 3-y OS

3-y PFS

3-y LRF

3-y DM

2nd Primary

HPV+

82%

74%

14%

9%

6%

HPV−

57%

43%

35%

15%

15%

p-value

1 cm of the tongue) were excluded from RTOG 91–11 trials and are traditionally treated with TL + postop (C)RT. There are some published experiences with reasonably good outcomes for these patients with conservation approaches, but NCCN guidelines and ASCO consensus statement still recommend surgery as the primary mode of therapy. Pdf_Folio:20

Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:20912098. doi:10.1056/NEJMoa031317.

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47. What are indications to boost the tracheal stoma after a total laryngectomy?

The tracheal stoma should be boosted to 60 Gy if there is evidence of subglottic extension, tumor invasion into the soft tissues of the neck, positive tracheal margin, or an emergency tracheostomy through tumor. Cahlon O, Lee N, Le Q, et al. Cancer of the larynx. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:658.

48. Have organ preservation strategies been studied in hypopharyngeal cancer?

Yes. A prospective randomized trial following the same schema as the VA larynx trial was tested by the EORTC for stage II–IVB cancers of the pyriform sinus or AE fold. LRC and OS were similar between the two groups of patients. The organ preservation arm demonstrated significantly lower rates of distant failure (25% vs. 36%). The rate of functional larynx preservation at 5 years was 35%. The 10-year update showed a 10-year OS of 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year survival with a functional larynx was 8.7%. Lefebvre JL, Andry G, Chevalier D, et al. Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol. 2012;23(10):2708-2714. doi:10.1093/annonc/mds065. Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996;88:890-899. doi:10.1093/jnci/88.13.890.

POSTOPERATIVE RADIOTHERAPY 49. Is there evidence that supports the use of 60 Gy as the routine postoperative dose in head and neck cancer?

Yes. A phase III PRT (RTOG 73–03) compared 50 Gy preop RT to 60 Gy postop RT. This demonstrated a LRC advantage to the postop arm (58% vs. 70%) without impacting survival. There are also prospective data that confirmed that a dose of more than 57.6 Gy correlated to improved local control compared to lower doses. Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys. 1993;26:3-11. doi:10.1016/0360-3016(93)90167-T. Tupchong L, Scott CB, Blitzer PH, et al. Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: longterm follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys. 1991;20:2128. doi:10.1016/0360-3016(91)90133-O. Pdf_Folio:21

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50. What minimum postoperative dose is recommended for dissected LN with + ECE? Based on what evidence?

A randomized trial was conducted in the 1980s that randomized lowrisk patients (one risk factor) to 57.6 Gy (1.7 Gy/fx) versus 63 Gy and high-risk patients (>1 risk factor and/or ECE) to 63 Gy versus 68 Gy. There was no statistically significant improvement to dose escalation in general. However, patients with ECE that were treated with ≤57.6 Gy had inferior LC than those treated with ≥63 Gy (2-year LRC 52% vs. 74%, respectively). Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys. 1993;26:3-11. doi:10.1016/0360-3016(93)90167-T.

51. Is there a benefit to altered fractionation in the postoperative setting?

A multi-institutional randomized trial that compared 63 Gy in 7 weeks versus 63 Gy in 5 weeks using a concomitant boost RT technique did not show a significant LRC or DFS benefit to altered fractionation in the postoperative setting for patient with high-risk disease. Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;51:571-578. doi:10.1016/S0360-3016(01)01690-X.

52. What are the indications and evidence for the addition of concurrent chemotherapy to postoperative radiotherapy in head and neck cancer?

Two phase III trials were conducted comparing postop RT versus postop CRT. Chemotherapy was cisplatin 100 mg/m2 q3 week × 3. The EORTC 22931 trial demonstrated significantly improved LC (82% vs. 69%), PFS (47% vs. 36%), and OS (53% vs. 40%) at 5 years with CRT. RTOG 95– 01 demonstrated an LC (82% vs. 72%) and DFS advantage with no OS advantage at 2 years. Eligibility criteria differed between studies. While the RTOG study included only those patients with + ECE, + margins, or ≥2 LN+, the EORTC trial also included patients with other factors including T3/4, +PNI, +LVSI, or level IV/V nodes for oral cavity/oropharynx tumors. A pooled analysis of these two trials that compared RT alone to RT + cisplatin demonstrated that ECE and positive margins were the only two scenarios in which the addition of concurrent chemotherapy

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improved LC and OS. Long-term follow up confirmed improved locoregional control and DFS, but OS became borderline significant in favor of postop CRT (19.6% vs. 27.1%; p = .07). Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27:843-850. doi:10.1002/hed.20279. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945-1952. doi:10.1056/NEJMoa032641. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350:1937-1944. doi:10.1056/NEJMoa032646. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012;84(5):1198-1205. doi:10.1016/j.ijrobp.2012.05.008.

SALIVARY GLAND TUMORS 53. What is the most common type of benign salivary gland tumor? Where is it usually found?

Pleomorphic adenoma is the most common benign salivary gland tumor and comprises 75% of parotid tumors. Other benign tumors include Warthin’s tumor (papillary cystadenoma lymphomatosum), Godwin’s tumor (benign lymphoepithelial lesions associated with Sjögren’s syndrome), and oncocytomas. Chong LM, Armstrong JG. Tumors of the salivary glands. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:670.

54. What are the common malignant salivary gland tumor histologies?

Mucoepidermoid carcinoma is the most common malignant histology. It most commonly presents in the parotid gland. Other common malignant histologies include adenoid cystic carcinoma, salivary duct carcinoma, and adenocarcinoma. Acinic cell carcinoma is a common lowgrade malignant histology. Salivary gland tumors can be either low or high grade, which is a factor that significantly influences treatment approaches. While squamous cell carcinomas of the parotid is a recognized entity, these are more commonly found to be metastases from cutaneous SCC of the skin. Chong LM, Armstrong JG. Tumors of the salivary glands. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:670-673. Pdf_Folio:23

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55. What is the most common histologic subtype of cancer in the submandibular or minor salivary glands? What is unique about its pattern of spread and natural history?

Adenoid cystic carcinoma. It tends to infiltrate and spread along nerves. Perineural invasion is common, especially for higher-grade tumors, and is an indication to electively target involved cranial nerves up to the base of the skull. These tumors tend not to spread to lymph nodes, and do not require elective nodal irradiation. They are also notorious for late relapses (>10–20 years), most often in the form of lung metastases (40% lifetime risk). Chong LM, Armstrong JG. Tumors of the salivary glands. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:671-672.

56. What is the proportion of benign and malignant lesions found in parotid glands? Submandibular glands? Minor salivary glands?

In general, smaller the gland, the more likely a tumor within it is malignant. While only 25% of parotid lesions are malignant, about 50% of submandibular gland lesions, 75% of minor salivary gland lesions, and nearly all sublingual gland lesions are malignant. Chong LM, Armstrong JG. Tumors of the salivary glands. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:670-671.

57. When is sacrifice of the facial nerve indicated in resection of a malignant parotid gland cancer?

Preoperative weakness or paralysis of the facial nerve usually indicates tumor involvement, and in these instances, the main trunk or the involved nerve branches may have to be sacrificed. The nerve or its involved branches should also be sacrificed if there is intraoperative evidence of gross invasion or microscopic infiltration of the nerve by tumor, even in the presence of normal preoperative facial nerve function. If the nerve appears both clinically and intraoperatively uninvolved, it should be preserved even for tumors involving the deep lobe of the gland requiring a total parotidectomy. Adelstein DJ, Koyfman SA, El-Naggar AK, et al. The biology and management of salivary gland cancer. Semin Radiat Oncol. 2012;22(3):245253. doi:10.1016/j.semradonc.2012.03.009.

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58. What are the indications for postoperative radiotherapy in resected salivary gland tumors?

In general, postoperative RT is indicated for close or positive margins, lymph node metastases, locally advanced disease, bone or nerve involvement, recurrent disease, or a combination of other adverse features, such as high nuclear grade, perineural invasion, and lymphovascular space invasion. Chong LM, Armstrong JG. Tumors of the salivary glands. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:683.

59. What is the evidence for benefit to adjuvant radiotherapy in salivary gland cancer?

While there are no randomized data, several large institutional series have demonstrated 20% to 40% improvements in local control and DFS with the addition of RT to surgery alone. A match-pair analysis from MSKCC, for example, found that patients with stage III/IV disease, positive lymph nodes, or high-grade tumors had improved local control and, in some instances, improved survival with the addition of adjuvant radiotherapy, while those with low-grade or early-stage (I/II) disease did not appear to benefit. Experience from the Dutch group and a recent NCDB analysis also supports the role of adjuvant radiation for high-risk salivary gland cancers. Armstrong JG, Harrison LB, Thaler HT, et al. The indications for elective treatment of the neck in cancer of the major salivary glands. Cancer. 1992;69:615-619. doi:10.1002/1097-0142(19920201)69:33.0.CO;2-9. Bakst RL, Su W, Ozbek U, et al. Adjuvant radiation for salivary gland malignancies is associated with improved survival: a National Cancer Database analysis. Adv Radiat Oncol. 2017;2(2):159-166. doi:10.1016/j.adro.2017.03.008. Terhaard CH, Lubsen H, Rasch CR, et al. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys. 2005;61(1):103111. doi:10.1016/j.ijrobp.2004.03.018.

60. Is there any advantage to the use of fast neutron therapy in locally advanced/unresectable salivary gland tumors?

A randomized trial by the RTOG/MRC that compared photon/electron therapy versus fast neutron therapy demonstrated significantly improved local control (56% vs. 17%) in the fast neutron therapy arm, but distant metastases and overall survival in this arm had inferior outcomes. Severe late side effects were noted in long-term survivors. As such, it has fallen out of favor. However, dose escalation with proton and carbon ion therapies are still being investigated. Pdf_Folio:25

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Laramore GE, Krall JM, Griffin TW, et al. Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Int J Radiat Oncol Biol Phys. 1993;27:235-240. doi:10.1016/0360-3016(93)90233-L.

61. Are there discrete molecular phenotypes that are histology specific in salivary gland tumors? Does this impact treatment options?

Yes. The following table summarizes the molecular profiles of several common malignant histologies: Histology

EGFR

HER2

c-kit

VEGF

Androgen

Mucoepidermoid

40%

25%–35%

Rare

50%

Rare

Adenoca/salivary duct Carcinoma

30%–40%

20%–30%

Rare

65%

15%–40%

Adenoid cystic

20%

Rare

80%–90%

85%

Rare

Inhibitors of these various targets are currently being investigated in the metastatic setting, and some early reports suggest efficacy in a significant proportion of patients. Adelstein DJ, Koyfman SA, El-Naggar AK, et al. The biology and management of salivary gland cancer. Semin Radiat Oncol. 2012; 22(3):24553. doi:10.1016/j.semradonc.2012.03.009.

MELANOMA 62. Is there an advantage to hypofractionation in treating melanoma with radiotherapy?

It is unclear. In the definitive setting, large older retrospective series suggested doses of greater than 4 Gy/fx significantly improved complete response rates (59% vs. 33%). RTOG 8305 randomized patients with measurable melanoma to 50 Gy in 20 fx daily, versus 32 Gy in 4 weekly fractions of 8 Gy. Overall, there was no difference in response rates between the two regimens. In the postoperative setting, MDACC pioneered a regimen of 30 Gy in 5 fx given twice weekly, which yielded 5-year LRC of 88%. However, other retrospective series report equivalent efficacy with hypofractionated and conventionally fractionated regimens. Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys. 1994;30:795798. doi:10.1016/0360-3016(94)90351-4. Pdf_Folio:26

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Chang DT, Amdur RJ, Morris CG, et al. Adjuvant radiotherapy for cutaneous melanoma: comparing hypofractionation to conventional fractionation. Int J Radiat Oncol Biol Phys. 2006;66:1051-1055. doi:10.1016/j.ijrobp.2006.05.056. Overgaard J. The role of radiotherapy in recurrent and metastatic malignant melanoma: a clinical radiobiological study. Int J Radiat Oncol Biol Phys. 1986;12:867872. doi:10.1016/0360-3016(86)90378-0. Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys. 1991;20:429432. doi:10.1016/0360-3016(91)90053-7.

63. Is there randomized evidence supporting the use of adjuvant RT after resection of melanoma? What is the benefit of RT in this setting?

Based on a previous phase II study, the Trans-Tasman Radiation Oncology Group (TROG) performed a phase III randomized study comparing adjuvant nodal RT (48 Gy in 20 fx) versus observation in patients who had recurrent melanoma with ≥1 parotid, ≥2 cervical or axillary, or ≥3 groin palpable positive nodes; or extra nodal spread of tumor; or minimum metastatic node diameter of 3 cm (neck or axilla) or 4 cm (groin). There was a significant reduction in regional failure from 31% to 18%. OS were similar between arms. The 6-year update confirmed these findings: lymph node field relapse was 36% versus 21% favoring the radiation arm. Burmeister B, Henderson M, Thompson J, et al. Adjuvant radiotherapy improves regional (lymph node field) control in melanoma patients after lymphadenectomy: results of an intergroup randomised trial. Int J Radiat Oncol Biol Phys. 2009;66:S15. doi:10.1200/jco.2009.27.18_suppl.lba9084. Burmeister BH, Mark Smithers B, Burmeister E, et al. A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma—Trans Tasman Radiation Oncology Group (TROG) Study 96.06. Radiother Oncol. 2006;81:136-142. doi:10.1016/j.radonc.2006.10.001. Henderson MA, Burmeister BH, Ainslie J, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymphnode field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16(9):10491060. doi:10.1016/S1470-2045(15)00187-4.

64. What is the rate of grade 3 subcutaneous tissue fibrosis when radiating the axilla postoperatively for melanoma? What is the risk for the groin? How about grade 3 or higher lymphedema?

The 6-year update of the TROG study showed 5% grade 3 subcutaneous fibrosis in the axilla after radiation. The rate was 7% for the groin. The difference in the rate of grade 3 lymphedema between the two treatment groups was nonsignificant for both the axilla and groin. The rates were 24% (radiation) versus 14% (observation) for the axilla (p = .20) and 24% (radiation) versus 17% (observation) for the groin (p = .51). Pdf_Folio:27

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Henderson MA, Burmeister BH, Ainslie J, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymphnode field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16(9):10491060. doi:10.1016/S1470-2045(15)00187-4.

65. What is the role of SLNB in intermediate thickness melanoma (MLST-I trial)?

A phase III randomized controlled study compared SLNB + completion LND if SLN+ for intermediate thickness melanoma versus observation + complete LND at nodal relapse. 5-year DFS was significantly better with SLNB (78% vs. 73%), but no difference in OS. SLN+ was powerful predictor of outcome and its removal slowed progression of disease, but did not affect overall survival. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307-1317. doi:10.1056/NEJMoa060992.

65.1. What is the MLST II trial and what did it show?

The MLST II trial is a phase III randomized control trial, which assigned melanoma patients with sentinel lymph node positive metastases (by standard pathologic assessment or a multimarker molecular assay) to immediate completion lymph node dissection or nodal observation with ultrasonography. The primary end point was melanoma-specific survival. Immediate completion lymph node dissection increased the rate of regional disease control but did not increase melanoma-specific survival in melanoma patients with sentinel-node metastases. Interestingly, nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376:22112222. doi:10.1056/NEJMoa1613210.

MERKEL CELL CARCINOMA 66. What margin of resection is recommended for MCC? What is the role of SLNB?

Pdf_Folio:28

A wide margin of 2 cm is generally recommended as these tumors have a high rate of recurrence. A recent study found that SLNB was feasible and the rate of sentinel LN positivity was at least 15% to 20% in all groups of patients. SLN positivity was significantly associated with the clinical size of the lesion, greatest horizontal histologic dimension, tumor thickness,

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mitotic rate, and histologic growth pattern. SLNB is considered standard in MCC. Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol. 2011;29:1036-1041. doi:10.1200/ JCO.2010.33.4136.

67. What are the indications for adjuvant radiotherapy in MCC? What benefit does RT offer?

Indications for adjuvant RT include size greater than 1 cm, close/positive margins, LVSI, LN+ disease, LN not staged by SLNB or LND, or immunosuppressed. A large review found that nodal recurrence rates range between 40% and 50% in the unsampled primary echelon nodal basin. A recent SEER analysis demonstrated an overall survival advantage for adjuvant RT. For unresectable tumors, definitive RT is appropriate, as MCC is a radiosensitive tumor. Additionally, a recent NCDB analysis showed, adjuvant RT was associated with an improved OS for stage I-II MCC. Neither adjuvant RT nor chemotherapy was associated with improved OS in stage III MC. However, local control was not evaluated in this study. Allen PJ, Bowne WB, Jaques DP, et al. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol. 2005;23:23002309. doi:10.1200/JCO.2005.02.329. Bhatia S, Storer BE, Iyer JG, et al. Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: survival analyses of 6908 cases from the National Cancer Database. J Natl Cancer Inst. 2016;108(9):1-9. doi:10.1093/jnci/djw042. Mojica P, Smith D, Ellenhorn JD, et al. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol. 2007;25:10431047. doi:10.1200/JCO.2006.07.9319. National Comprehensive Cancer Network clinical practice guidelines: Merkel cell carcinoma. https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf. Version 1.2018.

68. What dose of RT is used for adjuvant radiotherapy to the tumor bed? To lymphatic region? For unresectable disease?

For the primary tumor bed, NCCN guidelines recommend a dose of 50 to 56 Gy for negative margins, 56 to 60 Gy for close/microscopically positive margins, and 60 to 66 Gy for grossly positive margins or unresectable disease. For uninvolved nodal basin, a dose of 46 to 50 Gy is recommended with higher doses used for gross nodal disease, or ECE. National Comprehensive Cancer Network clinical practice guidelines: Merkel cell carcinoma. https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf. Version 21.2018.

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69. Has adjuvant chemotherapy been investigated for MCC? What immunotherapy agents are active in MCC?

Yes. A phase II study (TROG 96–07) investigated adjuvant RT (50 Gy/25 fx) with concurrent carboplatin/etoposide for patients with one highrisk feature (recurrence after initial therapy, involved nodes, size >1 cm, gross residual disease, or occult primary with nodes). Three-year LF, DM, and OS were 25%, 24%, and 76%, respectively, and compared favorably to historical controls. Avelumab and pembrolizumab are PD1 directed immunotherapy agents that have shown activity in stage IV MCC. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapyrefractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374-1385. doi:10.1016/S1470-2045(16)30364-3. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016;374:2542-52. doi:10.1056/ NEJMoa1603702. Poulsen M, Rischin D, Walpole E, et al. High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study—TROG 96:07. J Clin Oncol. 2003;21:4371-4376. doi:10.1200/JCO.2003.03.154.

UNKNOWN PRIMARY 70. What is the workup for a patient that presents with a squamous cell carcinoma metastatic to a cervical LN, without evidence of an obvious primary?

First, an FNA of the cervical LN should be performed to confirm the diagnosis of SCC. Then either a CT neck with contrast, or a PET-CT should be done. While not universally accepted, PET-CT is commonly used in this situation. One study found that it detected a primary site in 25% of patients in whom a primary had not been identified. If imaging studies are unrevealing, an EUA with direct nasopharyngolaryngoscopy and directed biopsies are then performed. In the absence of any putative primary site, biopsies are taken of the nasopharynx, BOT, and pyriform sinuses. Generally, bilateral tonsillectomies are also performed. Importantly, an isolated SCV node most likely points to a primary originating below the clavicles (e.g., esophagus, lung) rather than a true head and neck primary and should be worked up as such including bronchoscopy, esophagoscopy, and CT chest, abdomen, and pelvis.

Pdf_Folio:30

Rusthoven KE, Koshy M, Paulino AC, et al. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer. 2004;101:2641-2649. doi:10.1002/cncr.20687. Strojan P, Ferlito A, Medina JE, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches. Head Neck. October 27, 2011;35(1):123-32. doi:10.1002/hed.21898.

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71. In what percentage of unknown primary H&N SCC is a primary site found? What is the most common site?

In about 50% to 60% of cases, a primary site will be identified after full workup. The base of tongue and tonsils account for ~80% of primary sites of unknown primary origin. Strojan P, Ferlito A, Medina JE, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches. Head Neck. October 27, 2011;35(1):123-132. doi:10.1002/hed.21898.

72. What pathologic stains can be done to help identify a primary tumor site?

For squamous histology, a positive EBV stain is highly suggestive of a NPC, while a positive HPV or p16 stain is highly suggestive of an oropharyngeal primary. With this information, fields can be modified to exclude the larynx/hypopharynx from the potential primary mucosal site targets, allowing for greater normal tissue sparing. For adenocarcinoma histology, calcitonin, CEA, and thyroglobulin stains can be used to help identify a thyroid primary site. National Comprehensive Cancer Network clinical practice guidelines: head and neck cancer. http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Version 2.2017.

73. What is the recommended adjuvant therapy for a patient with an unknown primary with a single 2.5-cm level II node, found to have no additional LNs on comprehensive neck dissection and no ECE?

Observation is generally recommended in such a situation. This situation accounts for about 25% of unknown primary cases. The rate of expected failure in the neck is less than 10%, with a 5% rate of a primary tumor manifestation in the future. For “all comers“ with unknown primary SCC-HN, the mucosal emergence rate is closer to 15% with radiation therapy. Coster JR, Foote RL, Olsen KD, et al. Cervical nodal metastasis of squamous cell carcinoma of unknown origin: indications for withholding radiation therapy. Int J Radiat Oncol Biol Phys. 1992;23:743-749. doi:10.1016/0360-3016(92)90647-Z. Grau C, Johansen LV, Jakobsen J, et al. Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology. Radiother Oncol. 2000;55:121-129. doi:10.1016/S0167-8140(00) 00172-9. Nieder C, Ang KK. Cervical lymph node metastases from occult squamous cell carcinoma. Curr Treat Options Oncol. 2002;3(1):33-40. doi:10.1007/s11864-002-0039-7.

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74. What areas are targeted in definitive radiation for an unknown primary with multiple left-sided level II and III LNs, the largest measuring 4.5 cm?

Management options include ipsilateral neck dissection, followed by comprehensive radiation versus definitive chemoRT. Typically, comprehensive radiation is used, which includes bilateral cervical nodes as well as putative primary sites (nasopharynx, orophayrnx, hypopharynx, and larynx). However, with a patient presenting with level II LN, there are mature data from the University of Florida in which the larynx/hypopharynx are not targeted, and spared with a traditional larynx block in an AP SCV field. With this approach, there are virtually no failures in either of those potential primary sites. Importantly, these data apply to a cohort of patients where HPV/p16 status was unknown. For patients presenting primarily with level III and/or IV LN, then the larynx and hypopharynx would be targeted as a putative mucosal site. Wallace A, Richards GM, Harari PM, et al. Head and neck squamous cell carcinoma from an unknown primary site. Am J Otolaryngol. 2011;32:286-290. doi:10.1016/ j.amjoto.2010.05.004.

75. Does unilateral radiation (for 0.1 mm diameter nerves), and tumor invasion beyond subcutaneous fat. ”T“ staging is as follows: T1—no risk factors; T2a—one risk factor; T2b—two to three risk factors; and T3—four risk factors or bone invasion. Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149(4):402-410. doi:10.1001/jamadermatol.2013.2456.

76.2. How do the outcomes of immunosuppressed patients with skin cancer compare with their immunocompetent counterparts?

Immunosuppressed patients have inferior outcomes compared with immunocompetent skin cancer patients. In a multi-institutional study reported recently, the locoregional recurrence-free and progression-free survival were significantly lower in immunosuppressed patients at 2 years compared to the immunocompetent patients. Manyam BV, Garsa AA, Chin RI, et al. A multi-institutional comparison of outcomes of immunosuppressed and immunocompetent patients treated with surgery and radiation therapy for cutaneous squamous cell carcinoma of the head and neck. Cancer. 2017;123:2054-2060. doi:10.1002/cncr.30601.

77. What are recommended dosing regimens for definitive radiation for cutaneous BCC or SCC?

Choice of dose/fractionation regimen depends on size and location of tumor as well and desired cosmetic outcome. Typically, the more protracted regimens yield improved long-term cosmesis. Select examples of curative radiation regimens include 60 to 70 Gy in 30 to 35 fx, 50 to 55 Gy in 17 to 20 fx, 40 to 44 Gy in 10 fx, 40 Gy in 5 fx (twice weekly), 30 Gy in 3 fx (once weekly), and 20 to 25 Gy in 1 fx. Koyfman SA, Cooper JS, Beitler JJ, et al. ACR Appropriateness Criteria® aggressive nonmelanomatous skin cancer of the head and neck. Head Neck. 2016;38(2):175-82. doi:10.1002/hed.24171.

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78. What radiation delivery techniques are commonly used for superficial skin cancer? What are their respective advantages/disadvantages?

Often superficial/orthovoltage therapy or electron beam therapy is used. Superficial (50–150 kV) and orthovoltage (150–500 kV) have D90 at 5 mm and 2 cm, respectively. Advantages over electrons include maximum dose at skin surface, ability to use smaller fields (less beam constriction at depth), and less penetration through eye shields. Electrons are typically prescribed to ensure the 90% IDL covers the deepest extent of the tumor. Wider margins (1–2 cm) are typically needed as high isodose lines constrict at depth. Advantages of electrons are widespread availability and sharper dose falloff. To minimize scatter into adjacent structures, a lead shield can be placed on patient’s skin. More sophisticated techniques include volumetric arc radiation therapy (VMAT) for homogenous dose distribution across complex curved surfaces and complex volumes (e.g., scalp cancer with treatment to adjacent nodal bed). This comes at the cost of sophisticated contouring, planning, treatment delivery, and cost. Advantages include ease of setup, better control over dose distribution, dose homogeneity, and conformal avoidance to organs at risk. 79. Is there any evidence that higher dose/fraction is associated with improved control rates?

Yes. Some retrospective series indicate that doses of greater than 2 Gy/fx are associated with improved outcomes for definitive RT, even with doses above 60 Gy. This does not apply to adjuvant RT. Locke J, Karimpour S, Young G, et al. Radiotherapy for epithelial skin cancer. Int J Radiat Oncol Biol Phys. 2001;51:748-755. doi:10.1016/S0360-3016(01)01656-X.

80. When is adjuvant RT indicated after MOHS resection of a BCC/SCC?

NCCN guidelines recommend adjuvant EBRT in cases with positive margins, extensive perineural or large nerve involvement, or recurrent disease. One large retrospective study showed that failure rates were significantly higher for patients treated with surgery and postop RT when there was clinical nerve involvement (symptomatic/radiographic) as opposed to only pathologic perineural involvement (5-year LC 57% vs. 90%). For the latter category, BCC seemed to do better than SCC (5-year OC 97% vs. 84%). As such, some advocate for adjuvant RT for pathologic PNI of SCC, while BCC with pathologic PNI only can be observed. Similarly, some argue that microscopic positive margins can be observed for Pdf_Folio:34

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BCC as the recurrence rate is only ~30% and usually highly salvageable with repeat surgery. Jackson JE, Dickie GJ, Wiltshire KL, et al. Radiotherapy for perineural invasion in cutaneous head and neck carcinomas: toward a risk-adapted treatment approach. Head Neck. 2009;31:604-610. doi:10.1002/hed.20991. National Comprehensive Cancer Network clinical practice guidelines: basal and squamous cell cancer. http://www.nccn.org/professionals/physician_gls/pdf/headand-neck.pdf. Version 2.2018.

81. What factors predict for LN involvement in cutaneous SCC of the H&N?

Higher-grade lesions, those with LVSI, those with invasion beyond the subcutaneous fat, larger lesions, and recurrent lesions are associated with significant risks of nodal metastases. In one study, 37% of lesions greater than 4 cm and 31% of lesions invading more than 8 mm were LN+. Consider superficial parotidectomy +/− LN dissection in patients with these high-risk features undergoing surgical management. Moore BA, Weber RS, Prieto V, et al. Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck. Laryngoscope. 2005;115:15611567. doi:10.1097/01.mlg.0000173202.56739.9f.

THYROID CANCER 82. What are the primary thyroid cancer histologies and their respective incidence?

The most common histology is papillary (60%), followed by follicular (25%), medullary (5%), and anaplastic (2%). Hurthle cell carcinoma (2%) is a rare form morphologically similar to follicular but with marked (>75%) hypercellularity. Swift PS, Larson S, Clark O, et al. Cancer of the thyroid. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:726-727.

83. What is the incidence of LN+ disease in the various histologies? What is their respective expected 10-year OS?

Papillary cancer has a 30% risk of LN+ and a 10-year OS of 90% to 95%. Follicular cancer has a 10% risk of LN+ disease and a slightly lower 10year OS of 85% to 90%. Medullary thyroid cancer has a worse survival of 80%, while anaplastic cancer is almost uniformly fatal. Swift PS, Larson S, Clark O, et al. Cancer of the thyroid. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:726-727. Pdf_Folio:35

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84. What are the important changes to the staging system for differentiated thyroid cancer in AJCC 8th edition?

These changes are summarized as follows: 1. The age at diagnosis cutoff used for staging is now 55 years (previously 45 years) 2. Minor extrathyroidal extension is no longer T3 3. T3a: tumor greater than 4 cm limited to the thyroid gland 4. T3b: tumor of any size with gross extrathyroidal extension invading only the strap muscles 5. N1a: now includes levels VI and VII (upper mediastinal nodes— previously N1b) 6. pN0: clarified as one or more cytologically or histologically confirmed benign node(s). Tuttle MR, Morris LF, Haugen BR, et al. Thyroid – differentiated and anaplastic carcinoma. In: AJCC Cancer Staging Manual. 8th ed. Chicago, IL: Springer Publishing; 2017:873890.

85. What are the indications for post-thyroidectomy I-131 ablation?

In addition to TSH suppression, I-131 ablation is indicated for the following: a tumor greater than 2 cm, +margin, multifocal disease, LN+ disease, aggressive histology (tall cell, columnar cell, poorly differentiated), or gross soft tissue involvement. National Comprehensive Cancer Network clinical practice guidelines: thyroid cancer. http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Version 2.2017.

86. What is the procedure for postop I-131 imaging and ablation?

The procedure is as follows:

• Only applicable for patients with papillary and follicular histology • Withhold Synthroid (T4; levothyroxine) for 4 to 6 weeks. Cytomel (T3; liothyronine) can be substituted for 3 to 4 weeks, but discontinued

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at least 2 weeks before radioiodine studies. Iodine restrict diet for 2 weeks prior to scan. Alternatively, rhTSH (Thyrogen) can be used to stimulate TSH without taking patients off of their Synthroid

• • • • • • • •

TSH should be 25 to 30 mU/L at the time of the radioiodine study Pregnancy test for females on day of test Administer 2 to 5 mCi I-131 tracer dose If high postop uptake (>10%), should have completion surgery All others with uptake can have treatment dose of I-131 Dose is 30 to 100 mCi for patients with residual normal thyroid tissue Dose is 150 to 200 mCi for residual malignant thyroid tissue Perform total body scan 4 to 7 days after treatment dose to confirm ablation. Dose can be repeated if indicated

• Administer levothyroxine suppressive therapy • Repeat total body scan in 6 months, and then at q2–3 year intervals. National Comprehensive Cancer Network clinical practice guidelines: head and neck cancer. http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Version 2.2017.

87. What are some acute and long-term side effects of I-131 ablation?

Acute side effects include sialadenitis, cystitis, and GI irritation. Patients are also instructed to use their own toilet, flush twice, wash hands well after urination, avoid close contacts for several days after ablation, especially with children, to avoid unnecessary exposure to others. Longterm toxicities may rarely include pulmonary fibrosis, oligospermia, and leukemias. Swift PS, Larson S, Clark O, et al. Cancer of the thyroid. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:732-733.

88. What are the indications for adjuvant EBRT for resected thyroid cancer?

For papillary and follicular histologies, indications for adjuvant EBRT include age >55 and pT4 tumor, gross disease in neck despite I-131 therapy, and gross residual disease with inadequate iodine uptake. EBRT is indicated in medullary cancers for patients with T4 disease and positive margins, bulky nodal disease, or with gross ECE. All patients with anaplastic cancer should be treated with adjuvant (chemo) radiotherapy. Swift PS, Larson S, Clark O, et al. Cancer of the thyroid. In: Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2010:733. Pdf_Folio:37

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89. What systemic therapy options exist for thyroid cancer by histology?

These include: Differentiated thyroid cancer 1. Lenvatinib 2. Sorafenib Medullary thyroid cancer 1. Vandetanib 2. Cabozantinib National comprehensive cancer network clinical practice guidelines: thyroid cancer. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Version 2.2017.

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Brain Metastases Glioblastoma

Central Nervous System

ARYAVARTA M. S. KUMAR AND MICHAEL A. WELLER

Questions 1–17 Questions 18–35

Low-Grade Gliomas

Questions 36–48

Craniopharyngioma

Questions 49–53

Anaplastic Gliomas

Questions 54–60

Prophylactic Cranial Irradiation Spine Metastases

Questions 62–68

Primary CNS Lymphoma Meningiomas

Question 61

Questions 69–74

Questions 75–79

Trigeminal Neuralgia

Questions 80–82

Vestibular Schwannomas

Questions 83–86

Arteriovenous Malformations Pituitary Tumors Optic Gliomas

Questions 87–91

Questions 92–98 Question 99

CNS Radiation Toxicities/Therapies for Toxicities Spinal Cord Tumors

Questions 107–114

Questions 100–106

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BRAIN METASTASES 1. What are the recommended doses for cranial radiosurgery for brain metastases as determined by the RTOG 90-05 dose escalation study?

In RTOG 90-05, single fraction dose escalation was performed to determine the MTD for each given size of tumor based on maximum diameter. For tumors 2 cm or less, the study did not meet MTD and the recommended dose was 24 Gy. For tumors 2.1 cm to 3.0 cm, the MTD was 18 Gy. For tumors 3.1 cm to 4 cm, the MTD was 15 Gy. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47:291–298. doi:10.1016/S03603016(99)00507-6.

2. What are the three prognostic groups for brain metastases based on the recursive partitioning analysis (RPA) from RTOG studies?

An analysis of three consecutive RTOG phase III brain metastases studies (1,200 patients) was performed to group prognostic factors and predict survival. The analysis compared different dosing schemes and radiation sensitizers for patients undergoing whole brain radiation therapy.

RPA Class

Characteristics

I

KPS≥ 70, age