Decision Making in Radiation Oncology: Volume 2

Medical Radiology Radiation Oncology Series Editors L.W. Brady, Philadelphia H.-P. Heilmann, Hamburg M. Molls, Munich C...

Author: Jiade J. Lu | Luther W. Brady

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Medical Radiology Radiation Oncology Series Editors L.W. Brady, Philadelphia H.-P. Heilmann, Hamburg M. Molls, Munich C. Nieder, Bodø

For further volumes: http://www.springer.com/series/4353

Jiade J. Lu · Luther W. Brady (Eds.)

Decision Making in Radiation Oncology Volume 2

Foreword by L.W. Brady, H.-P. Heilmann, M. Molls, and C. Nieder

Jiade J. Lu, MD, MBA Department of Radiation Oncology National University Cancer Institute National University Health Syetem National University of Singapore 1E Kent Ridge Road NUHS Tower Block, Level 7 Singapore 119228 Republic of Singapore Email: [email protected] Luther W. Brady, MD Department of Radiation Oncology Drexel University, College of Medicine Broad and Vine Streets Mail Stop 200 Philadelphia, PA 19102-1192, USA

Email: [email protected]

ISSN: 0942-5373 ISBN: 978-3-642-16332-6

e-ISBN: 978-3-642-16333-3

DOI: 10.1007/978-3-642-16333-3 Springer-Verlag Heidelberg Dordrecht London New York Library of Congress Control Number: 2010937231 © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, 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. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudio Calamar, Figueres, Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Foreword Foreword

With the development of the patterns of care study chaired by Dr. Simon Kramer, the decision tree concept was initiated for a number of tumor sites including the carcinomas of the larynx, base of the tongue, the anterior two-thirds of the tongue, prostate, bladder, etc. This led to the gathering of significant information in terms of clinical presentations, clinical work-up, and decisionmaking with regard to management during pretreatment, treatment, and post-treatment phases. This concept has been widely accepted in the community of oncologists and it has been the purpose of this book to strengthen that concept and to add the supporting data that make it a very useful clinical tool. The authors have done a superb job in presenting the information that allows for innovative approaches to management and outcome analysis not only in clinical practice but in properly designed clinical trials, and for careful assessment of current practice based on solid and credible clinical research using the concept of the patterns of care but also the concepts of evidence-based outcome studies in oncology. It is very important to have these kinds of information available in the clinical assessment of the patient in order to make the appropriate, proper decision relative to management. It is important for oncologists to have a clear understanding of how the clinical and work-up information can be used to make the appropriate, proper decision relative to management. The present volume is specifically aimed at identifying these resources and how they can be used along with evidence-based medicine not only in terms of outcome from radiation therapy treatment but also in terms of the appropriate, proper work-up that allows for appropriate decisions to be made. The book represents a significant and

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Foreword

important standard by which all oncologists can design their treatment management. Philadelphia - Luther W. Brady, M.D. Hamburg – Hans Peter Heilman, M.D. Munich – Michael Molls, M.D. Bodø – Carsten Neider, M.D.

Volume 1 Section I Section II Section III Section IV Section V

Palliative Treatment Head and Neck Cancers Breast Cancer Tumors of the Thorax Cancers of the Gastrointestinal Tract

Volume 2 Section VI Section VII Section VIII Section IX Section X Section XI

Tumors of the Genitalurinary System Gynecological Cancers Lymphomas Tumors of the Central Nervous System Skin Cancers and Soft Tissue Sarcoma Pediatric Tumors

Contents of Volume 1

Section I Palliative Treatment 1A Radiation Therapy for Brain Metastasis . . . . . . . . . . Ugur Selek, Simon S. Lo and Eric L. Chang 1B

3

Palliative Radiotherapy for Bone Metastases . . . . . . 25 Alysa Fairchild and Stephen Lutz

Section II Head and Neck Cancers 2 Nasopharyngeal Carcinoma . . . . . . . . . . . . . . . . . . . . . 45 Jiade J. Lu, Lin Kong and Nancy Lee 3

Cancer of the Oral Cavity and Oropharynx . . . . . . . . 75 Kenneth S. Hu and Louis B. Harrison

4 Cancer of the Major Salivary Glands . . . . . . . . . . . . . . 105 Hiram Gay and Surjeet Pohar 5

Cancer of Larynx and Hypopharynx . . . . . . . . . . . . . . 133 Jay S. Cooper

6 Squamous Cell Carcinoma of Unknown Head and Neck Primary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Ivan W.K. Tham 7 Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Roger Ove and Almond Drake III Section III Breast Cancer 8 Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Manjeet Chadha Section IV Tumors of the Thorax 9 Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Steven H. Lin and Joe Y. Chang

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Contents of Volume 1

10

Thymic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Jiade J. Lu, Ivan W.K. Tham and Feng-Ming (Spring) Kong

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Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Steven H. Lin and Zhongxing Liao

Section V Cancers of the Gastrointestinal Tract 12 Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 Jeremy Tey and Zhen Zhang 13 Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389 Jiade J. Lu and Vivek K. Mehta 14

Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . 419 Sarah E. Hoffe

15A Cholangiocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 Ravi Shridhar 15B Gallbladder Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . 469 Steven E. Finkelstein and Sarah E. Hoffe 16

Rectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487 Edward Kim and Luther W. Brady

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Anal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 Qing Zhang, Shen Fu and Luther W. Brady

Index of Volumes 1 and 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Contents of Volume 2

Section VI Tumors of the Genitalurinary System 18 Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 James S. Butler 19 Prostate Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 Bin S. Teh, Angel I. Blanco, Arnold C. Paulino and E. Brian Butler 20

Testicular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 Ugur Selek

Section VII Gynecological Cancers 21 Endometrial Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 Keyur J. Mehta, Nitika Thawani and Subhakar Mutyala 22

Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661 Nina A. Mayr, William Small Jr., and David K. Gaffney

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Vulva Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703 Kevin Albuquerque

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Vaginal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725 Nitika Thawani, Subhakar Mutyala and Aaron H. Wolfson

Section VIII Lymphomas 25 Non-Hodgkin’s Lymphoma . . . . . . . . . . . . . . . . . . . . . 747 Joanne W. Jang and Andrea K. Ng 26

Hodgkin’s Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . 771 Maryse Bernard and Richard W. Tsang

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Contents of Volume 2

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Multiple Myeloma and Plasmacytoma . . . . . . . . . . 811 Wee Joo Chng and Ivan W.K. Tham

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Cutaneous T-Cell Lymphoma . . . . . . . . . . . . . . . . . . 833 Ivan W.K. Tham

29 Primary Central Nervous System Lymphoma . . . . 853 Marnee M. Spierer and Evan M. Landau Section IX Tumors of the Central Nervous System 30 Meningioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873 Allison M. Quick, Eric L. Chang and Simon S. Lo 31

Adult Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895 Bernadine Donahue

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Pituitary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923 Keith H. C. Lim and Simon S. Lo

Section X Skin Cancers and Soft Tissue Sarcoma 33 Soft Tissue Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . 943 Heather McCarty, Colleen Dickie and Brian O’Sullivan 34

Cutaneous Malignant Melanoma . . . . . . . . . . . . . . . 977 José A. Peñagarícano and Vaneerat Ratanatharathorn

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Basal and Squamous Cell Carcinoma of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995 José A. Peñagarícano and Vaneerat Ratanatharathorn

Section XI Pediatric Tumors 36 Pediatric Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . .1011 Arnold C. Paulino 37

Retinoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037 David B. Mansur

Contents of Volume 2

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Neuroblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053 Natia Esiashvili

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Ewing Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073 Daniel Indelicato and Robert B. Marcus Jr.

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Wilms’ Tumor and Other Childhood Renal Tumors . . . . . . . . . . . . . . . . . . . . . . 1089 Arnold C. Paulino

Index of Volumes 1 and 2 . . . . . . . . . . . . . . . . . . . . . . . . . . 1105

Contributors

Kevin Albuquerque, MD, MS, FRCS Associate Professor, Radiation Oncology Department of Radiation and Oncology Loyola University Chicago Stritch School of Medicine McGuire Building, Room 2944 2160 South 1st Avenue Maywood, IL 60153, USA Email: [email protected] Maryse Bernard, MD Département de Radio-Oncologie Hôpital Maisonneuve-Rosemont, Centre affilié à l’Université de Montréal 5415, boulevard de l’Assomption Montréal (Québec) H1T2M4, Canada Email: [email protected] Angel I. Blanco, MD Assistant Professor Department of Radiation Oncology The Methodist Hospital Weill Cornell Medical College 6565 Fannin Street, DB1-077 Houston, TX 77030, USA Email: [email protected] E. Brian Butler, MD Professor and Chairman Department of Radiation Oncology The Methodist Hospital The Methodist Hospital Research Institute Weill Cornell Medical College 6565 Fannin Street, DB1-077 Houston, TX 77030, USA Email: [email protected]

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Contributors

James S. Butler, MD Department of Radiation Oncology Maimonides Cancer Center 6300 Eighth Avenue Brooklyn, NY 11220, USA Email: [email protected] Eric L. Chang, MD Professor of Radiation Oncology Department of Radiation Oncology UT MD Anderson Cancer Center, Unit 97 1515 Holcombe Blvd. Houston, TX 77030, USA Email: [email protected] Wee Joo Chng, MD Associate Professor and Senior Consultant Department of Hematology and Oncology National University Cancer Institute National University Health System National University of Singapore 1E Kent Ridge Road NUHS Tower Block, Level 7 Singapore 119228 Republic of Singapore Email: [email protected] Colleen Dickie, MSc, MRT(T)(MR) Sarcoma Research Radiation Therapist Radiation Medicine Department Princess Margaret Hospital 610 University Ave. Toronto, Ontario M5G2M9, Canada Email: [email protected] Bernadine R. Donahue, MD Clinical Director, Department of Radiation Oncology Maimonides Cancer Center 6300 Eighth Avenue Brooklyn, NY 11220, USA Email: [email protected]

Contributors

Natia Esiashvili, MD Assistant Professor Department of Radiation Oncology The Emory Clinic 1365 Clifton Road NE, Room A1301 Atlanta, GA 30322, USA Email: [email protected] David K. Gaffney, MD, PhD Professor and Vice Chair Department of Radiation Oncology Huntsman Cancer Hospital University of Utah 1950 Circle of Hope Dr., Ste 1570 Salt Lake City, UT 84112, USA Email: [email protected] Daniel J. Indelicato, MD Assistant Professor University of Florida Department of Radiation Oncology University of Florida Proton Therapy Institute 2015 N. Jefferson St. Jacksonville, FL 32206, USA Email: [email protected] Joanne W. Jang, MD, PhD Brigham and Women’s Hospital Department of Radiation Oncology 75 Francis Street, ASB1, L2 Boston, MA 02115, USA Email address : [email protected] Evan M. Landau, MD Montefiore Medical Center Radiation Oncology 111 East 210th Street Bronx, NY 10463, USA Email: [email protected]

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XVIII Contributors

Keith H. C. Lim, MD, MBBS, FRANZCR Consultant Department of Radiation Oncology National University Cancer Institute National University Health System National University of Singapore 1E Kent Ridge Road NUHS Tower Block, Level 7 Singapore 119228 Republic of Singapore Email: [email protected] Simon S. Lo, MD Visiting Associate Professor of Radiation Oncology Director of Neurologic Radiation Oncology and Radiosurgery Medical Director of Gamma Knife Center Department of Radiation Oncology Case Western Reserve University UH Case Medical Center Cleveland Cleveland, OH 44106, USA Email: [email protected] David B. Mansur, MD Associate Professor of Radiation Oncology Department of Radiation Oncology Siteman Cancer Center Center for Advanced Medicine Washington University 4921 Parkview Place, Lower Level St. Louis, MO 63110, USA Email: [email protected] Robert B. Marcus Jr., MD Professor, University of Florida Department of Radiation Oncology University of Florida Proton Therapy Institute 2015 North Jefferson Street Jacksonville, FL 32206, USA Email: [email protected]

Contributors

Nina A. Mayr, MD Professor of Radiation Oncology Department of Radiation Oncology Arthur G. James Cancer Hospital and Solove Research Institute The Ohio State University Medical Center 300 West 10th Avenue, Suite 080B Columbus, OH 43210, USA Email: [email protected] Heather McCarty, MD Consultant Clinical Oncologist Northern Ireland Cancer Centre Lisburn Road Belfast, BT9 7AB, UK Email: [email protected] Keyur J. Mehta, MD Assistant Professor Director of Brachytherapy Department of Radiation Oncology Montefiore Medical Center Albert Einstein College of Medicine 1625 Poplar St, Suite 101 Bronx, NY 10461, USA email: [email protected] Subhakar Mutyala, MD Chairman and Associate Professor Department of Radiation Oncology Scott and White Healthcare System Texas A&M Health Science Center College of Medicine 2401 South 31st Street Temple, TX 76508, USA Email: [email protected] Andrea K. Ng, MD, MPH Professor of Radiation Oncology Department of Radiation Oncology Brigham and Women’s Hospital and Dana-Farber Cancer Institute Boston, MA 02115, USA Email: [email protected]

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Contributors

Brian O’Sullivan MD, FRCPI, FRCPC, FFRRCSI (Hon) Bartley-Smith / Wharton Chair in Radiation Oncology Professor, Department of Radiation Oncology University of Toronto, Associate Director Radiation Medicine Program Leader, Head and Neck Oncology Site Program Radiation Oncology Sarcoma Site Program Leader Princess Margaret Hospital 610 University Avenue, Toronto, ON M5G2M9, Canada Email: [email protected] Arnold C. Paulino, MD Professor of Radiation Oncology Vice-Chair for Education Department of Radiation Oncology The Methodist Hospital Weill Cornell Medical College 6565 Fannin Street, DB1-077 Houston, TX 77030, USA Email: [email protected] José A. Peñagarícano, MD Associate Professor of Radiation Oncology Department of Radiation Oncology University of Arkansas for Medical Science 4301 W. Markham #771 Little Rock, AR 72205, USA Email: [email protected] Allison M. Quick, MD Clinical Instructor of Radiation Oncology Department of Radiation Oncology Arthur G. James Cancer Hospital Ohio State University Medical Center 300 West 10th Avenue Columbus, OH 43210, USA Email: [email protected] Vaneerat Ratanatharathorn, MD Professor and Chairman Department of Radiation Oncology University of Arkansas for Medical Science 4301 W. Markham #771 Little Rock, AR 72205, USA Email: [email protected]

Contributors

Ugur Selek, MD Department Chief of Radiation Oncology American Hospital Güzelbahçe Sokak, No. 20 Tesvikiye, 34365 Istanbul, Turkey and Adjunct Associate Professor of Radiation Oncology University of Texas M.D. Anderson Cancer Center 1515 Holcombe Boulevard Houston, TX 77030, USA Email: [email protected] William Small, Jr., MD, FACR, FACRO Professor and Vice Chairman Department of Radiation Oncology Associate Medical Director Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine NMH/Arkes Family Pavilion Suite 1820 676 N Saint Clair Chicago, IL 60611 USA Email: [email protected] Marnee M. Spierer, MD The Farber Center for Radiation Oncology 21 West Broadway New York, NY 10007, USA Email [email protected] Ivan W.K. Tham, MD Consultant Department of Radiation Oncology National University Cancer Institute National University Health System National University of Singapore 1E Kent Ridge Road NUHS Tower Block, Level 7 Singapore 119228 Republic of Singapore Email: [email protected]

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XXII Contributors

Nitika Thawani, MD Assistant Professor Department of Radiation Oncology Scott and White Healthcare System Texas A&M Health Science Center College of Medicine 2401 South 31st Street Temple, TX 76508, USA Email: [email protected] Bin S. Teh, MD Professor and Vice Chair Department of Radiation Oncology The Methodist Hospital The Methodist Hospital Research Institute Weill Cornell Medical College 6565 Fannin Street, DB1-077 Houston, TX 77030, USA Email: [email protected] Richard W. Tsang, MD Professor of Radiation Oncology Department of Radiation Oncology University of Toronto Princess Margaret Hospital 610 University Avenue Toronto, Ontario M5G 2M9, Canada Email: [email protected] Aaron H. Wolfson, MD Professor and Vice Chair Department of Radiation Oncology University of Miami Miller School of Medicine 1475 N.W. 12th Avenue Miami, FL 33136, USA Email: [email protected]

Section VI Tumors of the Genitalurinary System

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18 Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 James S. Butler 19

Prostate Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 Bin S. Teh, Angel I. Blanco, Arnold C. Paulino and E. Brian Butler

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Testicular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 Ugur Selek

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Bladder Cancer James S. Butler1

Key Points  Bladder cancer is the second most common cancer of the genitourinary tract, and is the second most common cause of deaths among genitourinary tract cancers.  Most patients present with hematuria (75%). A quarter of patients present with irritative and/or obstructive symptoms. Patients with advanced disease can present with decreased appetite, weight loss, bone pain, and/or pelvic pain.  Clinical diagnosis starts with history and physical examination, laboratory studies with urine cytology, then cystoscopy with pyelography (to rule upper tract tumors). If invasive disease is found, then imaging with chest X-ray and abdominal/pelvic computed tomography (CT), and a bone scan is performed.  Stage at diagnosis is the most important prognostic factor. Superficial disease is not immediately life threatening, as only invasive disease metastasizes. Invasive disease can be divided into four prognostic groups: organ confined, extravesicular extension, metastasis to the pelvic nodes, and metastasis to distant sites.  Prognostic factors that favor successful bladder preservation therapy include complete transurethral resection of bladder tumor (TURBT), complete regression of disease after chemoradiation therapy, solitary tumor, organ confined versus extravesicular extension, and no hydronephrosis.  Treatment is determined by the prognostic factors. If a patient has superficial disease then he/she is treated with TURBT, with or without intravesicular chemotherapy, and closely observed for development of other bladder cancers.  If invasive disease is localized, then a patient will be treated with cystectomy or chemoradiation therapy if he/she also has the correct prognostic factors conducive to bladder preservation.  If invasive disease is metastatic, then the patient is treated with chemotherapy: gemcitabine/cisplatin or methotrexate, vinblastine, doxorubicin and cisplatin (MVAC).

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James S. Butler, MD Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_1, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology The incidence of bladder cancer is 9.9/100,000 in men and 2.3/100,000 in women in the USA. There were 70,530 cases diagnosed in the U.S. in 2010, with 13,060 deaths. In 1999, there were 263,000 cases worldwide, representing 4% of all cancers. However, incidence varies throughout the world. In North Africa, it is estimated that more that 30% of cancers are bladder cancer. The incidence is twice as high in white Americans as in black or AsianAmericans, with the lowest incidence found in China. A number of risk factors have been identified for bladder cancer (Table 18.1). Table 18.1 Risk factors for bladder cancer Risk factor

Description Age and gender: most patients are diagnosed with bladder cancer when they are 60–70 years old. The male:female ratio is 4:1 Race: twice as common in white Americans than in nonCaucasians Lifestyle: cigarette smoking is felt to be responsible for approximately 50% of bladder cancers in the USA

Patient related

Past medical history: pelvic radiation, chemotherapy such as Cytoxan, bladder lithiasis, chronic catheterization, multiple urinary infections, exposure to schistosomiasis, transplant recipient Genetic predisposition: no genes have been identified as causing bladder cancer; however, multiple genes have been found to be associated with a poorer prognosis and higher chance of progression include human epidermal growth factor receptor (EGFR) 2, p53, ras oncogenes, RB, P21, P27, and P16, Ki-67, S100A2, S100A4, fragile histidine triad gene, and cyclin D1

Environmental

Industrial chemicals: exposure to industrial chemicals such as aniline dyes, naphthylamines, benzidines, biphenyls, coal soot, phenacetin, and arsenic

Chapter 18 Bladder Cancer

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Anatomy The bladder is a hollow, muscular organ located in the pelvis superiorly and posteriorly to the pubic bone (Figure 18.1). When full, the bladder holds about 500 ml of urine, extends superiorly into the abdomen to a level superior to the umbilicus, and has an ovoid shape. When empty, the bladder collapses into a tetrahedral shape.

Subperitoneal fatty-areolar tissue Obliterated umbilical art. Inf. epigastric vesseis Urachus Peritoneum Fascia iliaca Fascia nerve Psoas & Iliacus Ext. iliac art. & vein Ureter Rectus Vessels to urogenital organs

Sciatic nerve

Bladder Prostate (enlarged)

Ductus deferens Seminal vesicle Tendinous arch, Retropubic space Int. pudental art. & pudental nerve Ischiorectal fossa Artery to bulb, piercing perineal membrane

Bulbo-urethral glands in deep perineal pouch Perineal brs. of posterior Bulbo-spongiosus covering cutaneous nerve of tigh the bulb, and its nerve

Figure 18.1 Relation of bladder to urachus, peritoneum, ureters, and prostate (Reprint permission courtesy of Williams and Wilkins. Original figure appeared in Grants’ Atlas of Anatomy 7th edition.)

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The apex (anterior superior part of bladder) extends superiorly to taper at its attachment to the urachus, which attaches to the umbilicus. The superior surface is the only part of the bladder covered by peritoneum. The base is the posterior wall where the ureters enter. The base and inferior lateral walls then taper inferiorly to form the neck of the bladder, which then becomes the urethra (Figures 18.2 and 18.3). Bladder Rectovesical pouch Pubic symphysis Prostate Corpus cavernosum

Rectum

Urethera

Urogenital diaphragm

Corpus spongiosum

Corpus spongiosum

Glans penis

Figure 18.2 Relation of bladder to rectum, prostate, seminal vescicles, penis, urethra, and scrotal contents. (Source: OOZ © Fotolia)

Ovary Uterus Bladder Urethera Vagina

Rectum

Figure 18.3 Relation of the bladder, rectum, uterus, ovary, vagina, and urethra (Source: OOZ © Fotolia)

Chapter 18 Bladder Cancer

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Pathology See Table 18.2 regarding various pathologies. Table 18.2 Pathologic subtypes Type

Description

Transitional cell carcinoma

 Accounts for >90% of bladder cancer cases in the USA  ~70% are superficial carcinomas  Arise from normal urothelium and are associated with smoking and carcinogen exposure

Squamous cell carcinomas

 Caused by chronic irritation from urinary calculi, long-term indwelling catheters, chronic urinary infections, infections by schistosomiasis, or bladder diverticula. These irritants cause the transitional epithelium to develop squamous changes, from which these cancers can then arise  The incidence varies widely in different parts of the world. It accounts for only 1% of bladder cancers in England, 3–7% in the USA, about 50% in Egypt

Adenocarcinoma

 <2% of primary bladder cancers  Includes three groups: primary, urachal, and metastatic to bladder  Can occur in intestinal urinary conduits

Small-cell carcinoma

 <1% of all bladder cancers  Behaves similarly to small cell carcinoma found elsewhere in the body

Mixed histology

 Transitional cell with adenocarcinoma or squamous  >25% of cases  Treated in the same fashion as transitional cell carcinomas with the same results

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Routes of Spread/Recurrence Field effect leading to second primary, local extension, and regional (lymphatic) and distant (hematogenous) metastases are the three major routes of spread/recurrence in bladder cancer (Table 18.3). Table 18.3 Routes of spread/recurrence in bladder cancer Routes

Description

Field effect

 Superficial bladder cancer does not invade the bladder; therefore, it does not have access to blood or lymphatic vessels and cannot metastasize. However, it has a field effect wherein there can be multiple recurrences/formation of new urothelial cancers elsewhere in the bladder or in the urothelial lining of the ureters or kidney  Over time, superficial bladder cancers can dedifferentiate and gain the ability to become invasive  Invasive bladder cancers successfully treated with bladder conservation require surveillance as these tumors also have a field effect wherein there can be multiple recurrences/formation of new urothelial cancers elsewhere in the bladder or in the urothelial lining of the ureters or kidney  Invasive bladder cancers successfully treated with cystectomy can also have a field effect wherein there can be multiple recurrences/formation of new urothelial cancers in the urothelial lining of the ureters or kidney

Local extension

 Invasive bladder cancer grows directly into the wall of the bladder, then into extravesicular fat, and finally into adjacent organs  In cystectomy series, ~ 55% of patient have organ-confined disease, and ~ 20% have extravesicular extension  Bladder cancer can grow along the wall of the bladder as either a continuous sheet of tumor or it can be multifocal  Bladder cancer can grow along the wall of the bladder into the urethra or ureter(s)

Regional lymph node metastasis

 Lymph node metastases are seen in approximately 25% of patients who undergo cystectomy  Lymph nodes commonly involved include internal iliac, obturator, external iliac, and common iliac nodes

Chapter 18 Bladder Cancer

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Table 18.3 (continued) Routes

Description

Distant metastasis

Approximately a third of patients with invasive disease develop metastatic disease Sites of metastatic disease often initially include lymphatic spread into para-aortic lymph nodes, and hematogenous spread to bone and lung. Multiple other organs then can become involved Patients at the highest risk for development of metastatic disease include those with extravesicular extension, invasion into adjacent organs such as the prostate, and pelvic lymph node metastases

Lymph Node Metastasis Patterns of lymphatic spread is depicted in Figure 18.4. Figure 18.4 Lymph node groups commonly involved include internal iliac, obturator, external iliac, and common iliac Source: Roth B et al (2009) A new multimodality technique accurately maps the primary lymphatic landing sites of the bladder. Eur Urol. DOI:10.1016/j.eururo.2009.10.026

Figure 18.5 delineates the pattern of bladder lymphatic drainage by injection of technetium nanocolloid into bladder wall sites before extended pelvic lymph node dissection. This demonstrates that standard pelvic lymph node dissection limited to the anterior portions of the external iliac vessels, and the obturator fossa would remove only approximately 50% of all radioactive nodes, whereas extended pelvic lymph node dissection along and around all the major pelvic vessels distal to the crossing of the ureter and iliac vessels removes about 90%.

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Figure 18.5 Boundaries of pelvic lymph node dissection subdivided into different regions and distribution of corresponding TC99m-positive lymph nodes; external iliac (Ia), distal and (Ib) proximal, obturator fossa (IIa) distal and (IIb) proximal, internal iliac (IIIa) distal and (IIIb) proximal, common iliac (Iva) distal and (IVb) proximal, (V) para-aortic/caval Source: Roth B et al (2009) A new multimodality technique accurately maps the primary lymphatic landing sites of the bladder. Eur Urol. DOI:10.1016/j.eururo.2009.10.026

Diagnosis, Staging, and Prognosis Clinical Presentation Signs and symptoms of bladder cancer are outlined below in Table 18.4. Table 18.4 Commonly observed signs and symptoms in bladder cancer Signs/Symptoms  ematuria is the most common presenting symptom in patients H with bladder cancer (75%) Irritative/obstructive symptoms occur in a quarter of patients with bladder cancer elvic pain can occur in patients who have locally advanced disease invading P into adjacent organs Bone pain occurs in patients who have metastatic disease  ecreased appetite and weight loss occur in patients D who have large tumor burdens

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Diagnosis and Staging Figure 18.6 illustrates the diagnostic procedures for bladder cancer, including suggested examination and tests.

Hematuria or irritative urinary symptoms (Bladder cancer suspected)

Complete history and physical, Urine cytology, blood work, and CXR

Cystoscopy with pyelography

Invasive

Superficial (Muscularis must be present without tumor invasion)

Abdominal/Pelvic CT and Bone Scan

History includes noting symptoms as outlined in Table 18.4 Thorough physical includes bimanual exam to evaluate for pelvic mass and abdominal exam to asses for such signs as organomegaly and also boney palpation Urine cytology has sensitivity of 20 –50%, with 80–100% specificity. Cytology is a very useful noninvasive test that can establish presence or persistence of bladder cancer Blood work includes CBC, serum chemistry, and liver function tests Pyelography is necessary to rule out the coexistence of other primary urothelial cancers in the upper genitourinary tract. This can be accomplished at the time of cystoscopy with a retrograde pyelography or later with IV or CT pyelography Ultrasound, PET/CT, and MRI are optional tests

Figure 18.6 A proposed algorithm for diagnosis and staging of bladder cancer

Tumor, Node, and Metastasis Staging The tumor, node, and metastasis (TNM), and stage grouping systems as determined by the American Joint Committee on Cancer (AJCC) are outlined in Tables 18.5 and 18.6.

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Table 18.5 AJCC TNM classification of bladder cancer Stage

Description

Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Ta

Noninvasive papillary tumor

Tis

Carcinoma in situ, “flat tumor”

T1

Tumor invades subepithelial connective tissue

T2

Tumor invades muscularis propria

T2a

Tumor invades superficial muscularis propria (inner half)

T2b

Tumor invades deep muscularis propria (outer half)

T3

Tumor invades perivesical tissue

T3a

Microscopically

T3b

Macroscopically (extravesicle mass)

T4

Tumor invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall

T4a

Tumor invades prostatic stroma, uterus, vagina

T4b

Tumor invades pelvic wall, abdominal wall

Regional lymph nodes (N) include primary and secondary drainage regions. All nodes above the aortic bifurcation are considered distant metastases NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node)

N2

Multiple regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node)

N3

Lymph node metastases to the common iliac lymph nodes

Distant metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Berlin Heidelberg New York, Springer

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Table 18.6 Stage grouping of bladder cancer Stage Grouping T1

T2

T3

T4a

T4b

N0

I

II

III

III

IV

N1–3

IV

IV

IV

IV

IV

M1

IV

IV

IV

IV

IV

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Berlin Heidelberg New York, Springer

Prognosis Stage is the most important determinant of survival. The 5-year overall survival (OS) rates after cystectomy, according to stage, are detailed in Table 18.7. Some prognostic factors are listed in Tables 18.8 and 18.9. Table 18.7 5 year overall survival (OS) after cystectomy Type

Description

Stage

Superficial T0Pa; N0

Organ confined P2; N0

Extravesicle P3-4; N0

Node positive

5-Year survival

85%

T2a, 77% T2b, 64%

47%

31% 40% (1–4+) 25% (>4+)

P: Primary tumor category Source: Stein JP, Lieskovsky G, Cote R et al (2001) Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 19:666–675

Table 18.8 Prognostic factors for bladder preservation Factor

Favorable

Adverse

TURBT

Complete

Incomplete

Response to chemoradiation

Complete regression

Residual disease

Extent of tumor

Solitary

Diffuse or multiple

Disease invasion

Organ confined

Regional extension

Hydronephrosis

Absent

Present

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Table 18.9 Prognostic factors for recurrence-free survival in superficial bladder cancer Characteristic

Low risk

High risk

Total

Definitions

Low grade; papillary configuration

High grade; CIS; multifocal/rapid recurrence

Recurrences

50%

70%

70%

Progression to invasive disease

<5% (if solitary, 0%)

30%

15%

CIS: carcinoma in situ

Treatment Principle and Practice Treatment for bladder cancer is multimodal and determined by the patient’s prognostic factors:  Superficial bladder cancer is managed primarily by transurethral resection with or without intravesicular chemotherapy.  Localized invasive bladder cancer traditionally has been managed by cystectomy.  If the patient has prognostic factors predictive for bladder preservation, the patient can be treated with chemoradiation therapy.  Metastatic disease is primarily managed by chemotherapy, with palliative radiation therapy or surgery for symptomatic control.

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Treatment of Superficial Bladder Cancer See the proposed algorithm for treatment presented in Figure 18.7 and Table 18.10 for treatment of superficial bladder cancer.

Superficial Bladder Cancer

TURBT

Low Risk (low grade, papillary)

Superficial bladder cancer recurrence

High Risk (high grade, CIS, papillary)

Intravesicular chemotherapy

Cytoscopic surveillance (every 3 months ×2 years, then every 6 months × 2 years, then yearly

Invasive recurrence

Progressive high-risk disease not controlled

Bladder preservation therapy

Cystectomy

Figure 18.7 A proposed algorithm for treatment of superficial bladder cancer

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Table 18.10 Clinical evidence for the use of intravesicular chemotherapy after TURBT for superficial bladder cancer

a

Trial

Description

Pawlinski et al (Medical Research Council [MRC]/ EORTC metaanalysis)a

 Meta-analysis of MRC and EORTC prospective studies  2,535 patients entered in EORTC or MRC trials and randomized to no treatment or intravesicular chemotherapy with thiotepa, VM-26, doxorubicin, Epodyl, Epirubicin, or mitomycin C  Intravesicular chemotherapy reduced recurrence of bladder cancer by 20% at a median follow-up of 4.6 years  Unfortunately, intravesicular chemotherapy did not change chances of development of invasive disease, time to development of invasive disease, or survival

Sylvester et al (Meta-analysis)b

 Meta-analysis of randomized trials that compared intravesicle Bacillus Calmette-Guérin (BCG) vaccine to intravesicle chemotherapy  700 patients with CIS entered into 9 randomized trials, who received either BCG versus mitomycin C, epirubicin, adriamycin, or BCG versus sequential mitomycin C/adriamycin  70% of patients treated with BCG had complete regression of disease versus 50% on chemotherapy  34% of complete responders who were treated with BCG and 50% of those treated with chemotherapy recurred  At a median follow-up of 3.6 years, 47% of patients treated with BCG and 26% with chemotherapy were disease free  It is important to note that BCG cannot be given right after TURBT because it will be systemically absorbed

Source: Pawlinski A, Sylvester R, Kurth KH et al (1996) A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. J Urol 156:1934–1940 b Source: Sylvester RJ, van der Meijden AP, Witjes JA et al (2004) Bacillus CalmetteGuérin versus chemotherapy for the intravesicle treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol 174:86–91

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Treatment of Invasive Bladder Cancer See the proposed algorithm in Figure 18.8 for treatment of invasive bladder cancer.

Invasive Bladder Cancer

CT and bone scan No metastatic disease

Partial cystectomy if candidate

Unifocal, no hydronephrosis, no extravesicular disease

Yes

No

Locally advanced disease (T3/T4; N+)

Yes TURBT No Chemotherapy (preoperative RT controversial)

Chemoradiation

Complete regression of disease

No

Cystectomy

Yes Consolidative chemoradiation

Locally advanced disease (T3/T4; N+)

Chemotherapy

Figure 18.8 A proposed algorithm for treatment of invasive bladder cancer

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Definitive Surgical Intervention Radical Cystectomy Radical cystectomy involves removal of the bladder, prostate (cystoprostatectomy), and pelvic lymph node dissection in males. In a female, an anterior exenteration (removal of the bladder, urethra, anterior vaginal wall, and uterus) and pelvic lymph node dissection is performed. Standard pelvic lymphadenectomy begins medially to the genitofemoral nerve and involves dissecting the external iliac artery and vein up to the bifurcation of the common iliac artery. Inferiorly this dissection is carried to the endopelvic fascia. The lymphatic package is then dissected free of the iliac vessels and extends medially into the obturator fossa up to the bladder. Finally, the nodes are dissected from the hypogastric artery and vein. Extended lymphadenectomy yields more pathological information and may improve local control and survival. The superior limit of dissection extendeds up to the aortic bifurcation and takes the presacral nodes. After radical cystectomy (Table 18.11), urinary diversion is performed with a segment of bowel. The most common is the noncontinent ileal conduit. A continent diversion can be an orthotopic neobladder or an abdominal pouch. Continence in the abdominal pouch utilizes a catheterizable stoma. The orthotopic neobladder utilizes the patient’s urethral sphincter. Table 18.11 Efficacy of radical cystectomy for invasive urothelial bladder cancer Extent

Confined

Extravesicle

Node+

Total (no. of patients)

Hautmann et ala Local failure

4%

16%

20%

9% (788) 10 years

Distant metastases

9.5%

19%

45%

18%

T3a/b, 52%; T4, 35%

15%, 10 years

45%

Recurrence-free survival

T2a/b, 70%, 10 years

Madersbacher et alb Local failure

3%

11%

15%

8% (507)

Distant metastases

25%

37%

51%

Recurrence-free survival

73%, 5 years

56%, 5 years

33%, 5 years

62%

Survival

62%, 5 years

49%, 5 years

26%, 5 years

59%

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Table 18.11 (continued) Extent

Confined

Extravesicle

Node+

Total (no. of patients)

Local failure

6%

13%

13%

7% (1054), 5 years

Recurrence-free survival

85%, 5 years

58%

35%

68%

Survival

78%, 5 years

47%, 5 years

31%, 5 years

60%

81%,10 years

44%

33%

48% (248)

Stein et alc

Boström et al Survival

d

a

Source: Hautmann RE, Gschwend JE, de Petriconi RC et al (2006) Cystectomy for transitional cell carcinoma or the bladder: results of surgery only series in the neobladder era. J Urol 176:486–492 b Source: Madersbacher S, Hochreiter W, Burkhard F et al (2003) Radical cystectomy for bladder cancer today – a homogenous series without neoadjuvant therapy. J Clin Oncol 21:690–696 c Source: Stein JP, Lieskovsky G, Cote R et al (2001) Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 19:666–675 d Source: Boström PJ, Mirtti T, Kössi J et al (2009) Twenty-year experience of radical cystectomy for bladder cancer in a medium-volume centre. Scand J Urol Nephrol 43:357–364

Pre- or Postoperative Chemotherapy There is a modest improvement in survival for use of chemotherapy in patients who are known to have locally advanced bladder cancer prior to cystectomy (Table 18.12). There is also a possible improvement in survival for patients receiving chemotherapy after cystectomy, if they are found to have locally advanced bladder cancer (Table 18.13).

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Table 18.12 Evidence-documented efficacy of neoadjuvant chemotherapy Study

a

Chemotherapy regimen

Chemotherapy

No therapy

Benefit

MRC/ EORTCa

Methotrexate, vinblastine, cisplatin (MVC)

3-year survival: 55%

3-year survival: NS 50%

Nordic Ib

Cisplatin and doxorubicin

59% 5-year survival

51% 5-year survival

NS

Nordic IIc

Cisplatinmethotrexate

53% 5-year survival

46% 5-year survival

NS

SWOGd

MVAC

77-month median survival

46-month median survival

p = 0.06

ABC metaanalysise

Trials utilizing platinum-based chemotherapy

50% 5-year survival

45% 5-year survival

p = 0.02

Sources: [No authors listed.] (1999) Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet 354:533–540; Hall R et al (2002) On behalf of the International Collaboration of Trialists of the MRC Advanced Bladder Cancer Group, updated results of a randomized controlled trial of neoadjuvant cisplatinum, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer. Proc Am Soc Clin Oncol 21[Abstract]:178 b Source: Malmstrom PU, Rintala E, Wahlqvist R et al (1996) Five-year follow-up of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 155:1903– 190 c Source: Sherif A, Rintala E, Mestad O et al (2002) Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer – Nordic cystectomy trial 2. Scand J Urol Nephrol 36:419–425 d Source: Grossman HB, Natale RB, Tangen CM et al (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859–866 e Advanced Bladder Cancer Meta-analysis Collaboration (2008) Neoadjuvant chemotherapy for invasive bladder cancer. Cochrane Database Syst Rev. DOI: 10.1002/14651858.CD005246

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Table 18.13 Efficacy of adjuvant chemotherapy Study

Chemotherapy Chemoregimen therapy

No chemotherapy

USC–Skinner, 1991a

Cyclophosphamide, adriamycin, and platinum (CAP)

4.3-year median survival 47 patients

2.4-year median survival 44 patients

p = 0.006

German–Stockle, 1992b

Methotrexate, vinblastine, adriamycin/ epirubicin, and cisplatin (MV[A/E]C)

10-year OS: 26.9% 26 patients

10-year OS: 17.4% 23 patients

p = 0.069

Swiss–Studer, 1994c

Cisplatin

5-year OS: 57% 40 patients

5-year OS; 54% 37 patients

p = 0.65

Stanford–Freiha, 199d

5-year disease-free surCisplatin, vival (DFS): methotrexate, 50% and vinblastine 5-year OS: (CMV) 54% 25 patients

5-year DFS: 22% 5-year OS: 34% 25 patients

p = 0.01 p = 0.32

ABC metaanalysise

Adjuvant cisplatin based

50% 3-year survival: 245 patients

p = 0.19

59% 3-year survival 246 patients

Benefit

These studies are all small; therefore, adjuvant chemotherapy is not currently considered standard. The EORTC 30994 trial is currently investigating adjuvant chemotherapy a Source: Skinner DG, Daniels JR, Russell CA et al (1991) The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 145:459–464 b Source: Stockle M, Meyenburg W, Wellek S et al (1995) Adjuvant polychemotherapy of non–organ-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. J Urol 153:47–52 c Source: Studer UE, Bacchi M, Biedermann C et al (1994) Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol 152:81–84 d Source: Freiha F, Reese J, Torti FM (1996) A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 155:495–499 e Source: Advanced Bladder Cancer (ABC) Meta-analysis Collaboration (2006) Adjuvant chemotherapy for invasive bladder cancer (individual patient data). Cochrane Database Syst Rev. 9:CD006018

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Bladder Preservation Partial cystectomy (Table 18.14) can be performed in about 5% of patients. The cancer needs to be unifocal and in a place in the bladder that would allow resection with 2-cm margins. If these criteria are met, survival is equivalent to radical cystectomy. Patients need to be followed with serial cystoscopy as are patients treated with chemoradiation therapy. Table 18.14 Efficacy of partial cystectomy in the treatment of bladder cancer Trial

Description

SEER database

 7,243 patients treated with partial cystectomy (1,573) or cystectomy (5,670)  When patients were matched for age, race, pT stage, pN stage, number of lymph nodes, tumor grade, and year of surgery, the 5-year survival was 57% for partial cystectomy patients and 55% for cystectomy patients

Source: Capitanio U, Isbarn H, Shariat SF et al (2009) Partial cystectomy does not undermine cancer control in appropriately selected patients with urothelial carcinoma of the bladder: a population-based matched analysis. Urology 74:858–865

Radiation Therapy Radiation therapy alone (Table 18.15) was used extensively from the 1950s to the 1980s. Local control is inferior to cystectomy. Multiple studies have documented local control rates of 30–40% only. Table 18.15 Efficacy of radiation alone Trial

Description

Shelley et al (Meta-analysis)

 Meta-analysis compared surgery versus radiation therapy  Three randomized trials comparing preoperative radiotherapy, followed by radical cystectomy (surgery) versus radical radiotherapy  439 patients, 221 randomized to surgery and 218 to radical radiotherapy  36% 5-year survival for surgery versus 20% 5-year survival for radiation

Source: Shelley M, Barber J, Wilt T et al (2008) Surgery versus radiotherapy for muscle invasive bladder cancer. Cochrane Database Syst Rev. CD002079

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However, there is a subgroup of patients who are an exception: clinical T2 disease, no ureteric obstruction, complete transurethral resection of bladder tumor (TURBT), solitary tumor, and complete resolution of disease after radiation therapy (Table 18.16). Table 18.16 Evidence-documented efficacy of radiation therapy alone

a

Trial

Description

Shipley et al (Massachusetts General Hospital)a

55 patients with invasive bladder cancer treated with full-dose radiation therapy 45% survival of cT2 versus 9% for T4 Papillary tumor had 63% survival versus 20% for flat tumor 54% survival for complete TURBT versus 17% without 47% without ureteric obstruction versus 14% without

Prince of Wales Hospitalb

342 patients, radiation only, with a mean follow-up time of 7.9 years Multiple tumors and obstructed ureter, 91% local failure Single tumor and obstructed ureter, 69% local failure Multiple tumors and ureter non-obstructed, 68% local failure Single tumor T4, 50–55% local failure Single tumor T3, 40–45% local failure Single tumor T1/2, 34–37% local failure

Source: Shipley WU, Rose MA, Perrone TL et al (1985) Full-dose irradiation for patients with invasive bladder carcinoma: clinical and histological factors prognostic of improved survival. J Urol 134:679–683 b Source: Mameghan H, Fisher R, Mameghan J et al (1995) Analysis of failure following definitive radiotherapy for invasive transitional cell carcinoma of the bladder. Int J Radiat Oncol Biol Phys 31:247–254

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Brachytherapy Brachytherapy has been studied and practiced in Holland, but it is not commonly practiced in North America (Table 18.17). Table 18.17 Evidence-documented efficacy of brachytherapy

a

Trial

Description

University of Utrechta

 111 patients with 6.2-year median follow-up  T1G3–T2 bladder tumors <5 cm  External beam radiotherapy (28 Gy, 12 fractions), followed by iridium-192 (40 Gy)  67% disease-free survival  70% 5-year survival; 50% 15-year survival  82% disease-specific survival at 5 years and 73% at 15 years  Local recurrence in 27% patients  Bladder function preserved in 89%

University of Amsterdamb

 122 patients with solitary bladder tumor <5 cm and a median follow-up of 5 years  Patients received either 3× 3.5-Gy or 20× 2-Gy EBRT, followed by surgery 10 days later (37 patients received partial cystectomy), then 20–70 Gy via low dose rate or via pulsed dose rate (PDR) in 23 patients  76% 5-year local relapse-free survival  83% 5-year distant relapse-free survival  5- and 10 -year relapse-free survival rates were 69 and 66%  5- and 10-year survival rates were 73 and 49%

Source: van Onna IE, Oddens JR, Kok ET et al (2009) External beam radiation therapy followed by interstitial radiotherapy with iridium-192 for solitary bladder tumours: results of 111 treated patients. Eur Urol 56:113–121 b Source: Blank, LE, Koedooder K, van Os R et al (2007) Results of bladder-conserving treatment, consisting of brachytherapy combined with limited surgery and external beam radiotherapy, for patients with solitary T1–T3 bladder tumors less than 5 cm in diameter. Int J Radiat Oncol 69:454–458

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Chemoradiation Therapy Figure 18.9 presents an algorithm based on the results of a Canadian National Cancer Institute study of radiation therapy versus radiation/chemotherapy for the treatment of bladder cancer.

T2–T4 Bladder Cancer

Locally advanced disease (T3/T4; N+)

40 Gy per 20 fractions (48 patients)

40 Gy per 20 fractions, CDDP 100 mg/m2 every 2 weeks ×3 (51 patients)

20 Gy per 10 fractions or cystectomy

20 Gy per 10 fractions or cystectomy

59% 5-year pelvic relapse

40 % 5-year pelvic relapse

36% bladder preservation

Figure 18.9 Canadian National Cancer Institute study

70% bladder preservation

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Concomitant cisplatin and radiation therapy is the standard therapy (Table 18.18). Table 18.18 Evidence-documented efficacy of concurrent cisplatin and radiation therapy Trial

Description

National Bladder Cancer Groupa

 62 patients with cT2–cT4 bladder cancer not fit for surgery  45 Gy per 25 fractions to pelvis, with bladder boost of 19.8 Gy per 11 fractions  Cisplatinum 70 mg/m2 every 3 weeks × 8  77% complete tumor regression; 73% of these patients maintained local control in bladder  64% 4-year survival for T2; 24% 4-year survival for T3/4  40% had diarrhea, with 16% needing to interrupt therapy; 23% had urinary frequency and dysuria, which caused 13% to interrupt treatment  3 patients had gastrointestinal (GI) complications requiring hospitalization, 1 had surgery, 1 had cystectomy for hematuria, 1 had hip replacement  1 patient developed renal failure, 3 developed sepsis, 80% developed nausea and vomiting – in 32%, the nausea and vomiting were severe enough for the patient to not be able to/refuse further cisplatinum

RTOG 8512b

 42 evaluable patients with cT2–cT4 bladder cancer  40 Gy per 20 fractions to pelvis; 2-week rest, then cystoscopy if negative, then bladder boost to 24 Gy per 12 fractions  Cisplatinum 100 mg/m2 every day 1 and 22, and with the bladder boost  66% complete tumor regression; 73% of these patients maintained their bladders  64% 3-year survival  1 patient developed grade 3 acute GI toxicity, 4 developed grades 3 or 4 nausea and vomiting, 4 experienced reversible grade 3 or 4 hematologic toxicity  1 late–grade 4 (bladder) and 1 grade 3 (small bowel) toxicity reported; 1 cystectomy for radiation injury

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Table 18.18 (continued)

a

Trial

Description

University Erlangenc

 415 patients with high-risk cT1 and cT2–cT4 bladder cancer  Median 45 Gy at 1.8–2 Gy per fraction to pelvis; median cumulative dose to bladder, 54 Gy  126 patients receiving radiation therapy (RT) alone; 145, cisplatinum 25 mg/m2/day × 5 days, 1st and 5th weeks; 95, carboplatin, 65 mg/m2/day × 5 days, 1st and 5th weeks; 49, cisplatin 20 mg/m2/day × 5 days, 1st and 5th week, with fluorouracil (5-FU), 600 mg/m2/day, 120-h continuous infusion  72% complete tumor regression. Of these patients, 65% have been free of disease in their bladders. 2% required cystectomy for RT damage although all these patients had multiple TURs  51% 5-year overall survival: 40% RT alone, 45% RT/ carboplatinum (CBBP), 62% RT/ cis-cisplatinum (II) (CDDP), 65% RT/CDDP and 5FU

RTOG 8903d

 123 patients with cT2–cT4 bladder CA  39.6 Gy per 22 fractions with cisplatinum 100 mg/m2 × 2 every 3 weeks. Then, 4 weeks later, cystoscopy. If negative, 25.2 Gy per 14 fractions with cisplatinum, 100 mg/m2  Patients were randomized to receive 2 cycles of MCV before RT/chemotherapy or not  49% overall 5-year survival, with no difference between arms  59% complete recovery at cystoscopy; 72% of these patients have maintained their bladders  20% of patients in the MCV arm experienced >grade 3 hematologic toxicity and nausea and vomiting; 3 of these patients died. Another patient subsequently died of a GI bleed after concomitant platinum/RT  6% of patients in the non-MCV arm experienced >grade 3 hematologic toxicity. 1 patient in the cisplatinum/RT alone arm died of a duodenal perforation

Source: Shipley WU, Prout GR, Einstein AB et al (1987) Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA 258:931–935 b Source: Tester W, Porter A, Asbell S et al (1993) Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 8512. Int J Radiat Oncol 25:783–790 c Source: Rodel C, Grabenbauer GG, Kuhn R et al (2002) Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 20:3061–3071 d Source: Shipley WU, Winter KA, Kaufman DS et al (1998) Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 16:3576–3583

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A proposed algorithm for bladder preservation with chemoradiation therapy is presented in Figure 18.10.

Bladder cancer eligible for organ preservation

Maximal TURBT

40–45 Gy to pelvis with CDDP (70–100 mg/m2 every 3 weeks). Can use lower, divided doses, as in Erlangen study

Cystoscopy 2–4 weeks after chemotherapy/ RT

Residual disease

Complete disease regression RT to bladder, cumulative mean dose of 64.8 Gy, with 1 more cycle of CDDP

Cytoscopic surveillance (every 3 months ×2 years, then every 6 months ×2 years, then yearly

Cystectomy

Recurrent invasive bladder cancer

Superficial tumor recurrence (see Fig. 18.6)

Figure 18.10 Proposed algorithm for bladder preservation with chemoradiation therapy

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Unfortunately, not all patients are able to tolerate cisplatin-based chemotherapy. Table 18.19 lists clinical trials utilized non-cisplatin-based chemotherapy used concurrently with radiation therapy. Table 18.19 Evidence-documented efficacy of concomitant non-cisplatin chemotherapy and radiation therapy

a

Trial

Description

SWOG 8733a

 81 patients with multiple comorbidities primary or recurrent muscle-invasive bladder cancer  20 Gy per 10 fractions with 5-FU, 1,000 mg/m2 × 4 days every 3 weeks  Operable patients who received 2 cycles underwent cystoscopy; if negative, they continued to a third cycle; 28% of evaluable patients had complete remission (CR). There was a 22% 5-year survival  Inoperable patients received 3 cycles; 49% of evaluable patients achieved CR. There was a 30% 5-year survival for this group  22 of 61 evaluable patients died of bladder cancers  This regimen was very tolerable, with 92% completing the regimen in the surgery group, and 100% in the inoperable group, with only 45% experiencing >grade 3 toxicity

University of Michiganb

 24 patients with cT2–3  Phase I study: 60 Gy per 30 fractions to bladder with gemcitabine biweekly; 10, 20, 30, and 33 mg/m2 during RT, then TURBT 4 weeks later  76% 5-year survival  62% of patients has bladder-intact survival  MTD of gemcitabine was calculated to be 27 mg/m2

University of Hallec

 42 patients with primary or recurrent bladder cancer  45–60 Gy with paclitaxel, 25–35 mg/m2 twice weekly  28 patients underwent restaging TURBT 6 weeks after therapy; 24 patients had CR  13 patients died; 7 of tumor  2-year follow-up  This regimen was very tolerable, with 16 patients experiencing >grade 3 toxicity

Source: Higano CS, Tangen CM, Sakr WA et al (2008) Treatment options for muscle-invasive urothelial cancer for patients who were not eligible for cystectomy or neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin report of Southwest Oncology Group Trial 8733. Cancer 112:2181–2187 b Source: Oh KS, Soto DE, Smith DC et al (2009) Combined-modality therapy with gemcitabine and radiation therapy as a bladder preservation strategy: long-term results of a phase I trial. Int J Radiat Oncol 74:511–517 c Source: Müller AC, Diestelhorst A, Kuhnt T et al (2007) Organ-sparing treatment of advanced bladder cancer: paclitaxel as a radiosensitizer. Strahlenther Onkol 183:177–83

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Current areas of investigation include hyperfractionated radiation with polychemotherapy. Patients in these studies have been reported to have higher rates of complete regression of their bladder tumor, as well as possibly higher rates of bladder preservation. However, there are no prospective randomized studies that compare these approaches to standard daily radiation therapy with cisplatin.

Treatment of Metastatic Bladder Cancer Bladder cancer is responsive to chemotherapy, and chemotherapy improves overall survival. The two most active regimens used for metastatic bladder include methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), and gemcitabine/cisplatin ([GC] the current standard) (Table 18.20). A number of regimens elicit responses are used as second- and even third-line therapy. Table 18.20 Efficacy of chemotherapy Trial

Description

MSKCCa

 133 patients with advanced bladder cancer treated with MVAC  CR and partial response (PR) rates were 36 and 36%, respectively  Median survival times were 38, 11, and 8 months for patients with CR, PR, or no response, respectively

International trialb

 405 patients with stage IV bladder cancer: GC versus MVAC  Response rates were 49 versus 46% response rate for GC versus MVAC; median survival times were 13.8 versus 14.8 months for GC versus MVAC (p = NS)  1 versus 3% toxic death rate. Patients receiving GC also had a better quality of life  GC regimen is considered the current standard

MSKCC: Memorial Sloan-Kettering Comprehensive Cancer Center a Source: Sternberg CN, Yagoda A, Scher H et al (1989) Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium efficacy and patterns of response and relapse. Cancer 64:2448–2458 b Source: von der Maase H, Hansen SW, Roberts JT et al (2000) Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 17:3068–3077

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Treatment of Non-urothelial Bladder Cancer Treatment of Small Cell Carcinoma Small cell carcinoma accounts for <1% of all bladder cancers in the USA. It is responsive to chemotherapy, and patients treated with chemotherapy have better survival that those who are not. Currently, there is no standard local therapy. Outcomes of two series of small cell bladder carcinoma studies are presented in Table 18.21. Table 18.21 Small cell bladder carcinoma studies Trial

Patients (n)

Chemotherapy

No chemotherapy

East Anglian Cancer Networka

20

33-month median survival

3-month median survival

46

77% 5-year cause-specific survival (chemotherapy before cystectomy)

36% 5-year cause-specific survival (chemotherapy after cystectomy)

MDACCb

MDACC: MD Anderson Comprehensive Cancer Center a Source: Mukesh M, Cook N, Hollingdale AE et al. Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the Anglian Cancer Network. BJU Int 2008; 103:747–752 b Source: Siefker-Radtke AO, Dinney CP, Abrahams N et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the MD Anderson cancer experience. J Urol 2004; 172:481–484)

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Treatment of Squamous Cell Carcinoma Squamous cell carcinoma is managed primarily by surgery. Preoperative radiation can be considered for locally advanced disease, as suggested by evidence presented in Table 18.22. Table 18.22 Treatment of squamous cell carcinoma studies RT  cystectomy

Cystectomy

U Mansouraa 92

10/30 P3-4, N +/-, 5-year survival

6/30 P3-4,N +/-, 5-year survival

MDACCb

10 patients downstaged had local control and survival

7/15 patients not downstaged had local failure and died

Trial

Patients

25

P: primary tumor category a Source: Ghoneim MA, Ashamallah AK, Awaad HK et al (1985) Randomized trial of cystectomy with or without preoperative radiotherapy for carcinoma of the bilharzial bladder. J Urol 134:266–268 b Source: Swanson DA, Liles A, Zagars G et al (1989) Preoperative irradiation and radical cystectomy for stages T2 and T3 squamous cell carcinoma of the bladder. J Urol 143:37–40

Treatment of Adenocarcinoma Adenocarcinoma is primarily managed by cystectomy, and adjuvant radiation therapy may be considered (Table 18.23). Table 18.23 Potential role for adjuvant RT Description

Results

NCI Egypt

192 patients with advanced bladder adenocarcinoma  69 patients who received postoperative RT for a 61% 5-year DFS and a local control of 92%  123 patients had cystectomy alone and had a 37% 5-year DFS and a 53% local control

Source: Zaghloul MS, Nouh A, Nazmy M et al (2006) Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients. Urol Oncol 24:13–20

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Radiation Therapy Techniques Simulation and Field Arrangements Radiation fields should encompass tumor bed plus regional lymph nodal areas for locoregional control. Patients are simulated and treated with an empty bladder. Field setup using a four-field technique (anterior/posterior[AP], PA, and opposed lateral fields) is illustrated in Figure 18.11a,b and detailed in Table 18.24.

Figure 18.11 a, b Four-field pelvis covering the internal/external iliacs (at least 2-cm rim of pelvis), the empty bladder, a prostate (if male), and b proximal urethra (if female)

Table 18.24 Pelvic fields for bladder cancer conservation therapy (Figure 18.11a,b) Field(s)

Borders

AP/PA

Superior: top of sacrum  Inferior: below the bladder to at least the bottom of the obturator foramen Lateral: include 2 cm of the pelvic rim

Lateral

Superior/inferior: as AP/PA fields Anterior: at least 2 cm anterior to the bladder Posterior: at least 2 cm posterior to the bladder Block small bowel superiorly/anteriorly

All fields should be irradiated on daily basis Some institutions’ protocols treat bladders with margin, only without pelvic nodes

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Dose and Treatment Delivery Conventional fractionation to a total dose of 40–45Gy is recommended to the pelvic fields. After cystoscopy confirmation of complete response, an additional 24 Gy (1.8–2 Gy per fraction) is delivered to the partial bladder to a total of 64–64.8 Gy, if the original tumor can be localized (Figure 18.12a,b). Otherwise, the entire bladder is treated (Figure 18.13a,b). It is important to respect the normal tissue tolerance of the neighboring bowel, which sometimes means that the cumulative dose must be lowered.

Figure 18.12 a, b Fields for partial bladder boost to the anterior bladder of a male patient. The patient had fiducial markers and dose verification system sewn onto the outside of the bladder overlying the tumor bed via laparoscopy. a His bladder was catheterized daily with 100 ml sterile water instilled, b then, he had localization with on-board imaging (OBI) and the dose verification system

Figure 18.13 a, b Cone-down field to irradiate the entire empty bladder (patient voiding daily just before going on the table)

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Follow-Up Follow-up after definitive therapy for bladder cancer is necessary, and the examinations recommended in each follow-up depend on the extent of disease and treatment modality utilized in definitive settings. Schedule of posttreatment surveillance as well as diagnostic interventions during follow-up are detailed in Figures 18.7 and 18.12, and Table 18.25. Table 18.25 Follow-up schedule and examinations Schedule

Frequency

First follow-up

 2 weeks after radiation therapy

Years 0–1

 Every 3 months

Years 2–5

 Every 6 months

Years 5+

 Annually

Examination History and physical

Laboratory tests

Imaging studies

 Complete history and physical examination  Cystoscopy for superficial bladder cancer or after bladder conservation for invasive disease during each followup session    

Urine cytology at each follow-up Complete blood counts (CBC) and serum chemistry Liver and renal function tests Lab tests are optional for superficial bladder cancer but recommended for invasive disease every 6 months

 Chest X-ray every 6 months for invasive disease  Imaging for collection system every 3–6 months for invasive disease

Adapted from: National Comprehensive Cancer Network [NCCN]. Clinical practice guidelines in oncology: bladder cancer v.1. 2010. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp. Cited 2009

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Sequelae of radical cystectomy include hyperchloremic metabolic acidosis and other electrolyte abnormalities, renal calculi, bacteriuria, sepsis, malabsorption of vitamin B12, fat-soluble vitamins and bile salts, short-bowel syndrome, urine incontinence, ureteral obstruction, renal deterioration, and bowel obstruction. Metabolic complications are more likely to occur in continent diversions than in noncontinent urinary diversions. A vitamin B12 shot annually is recommended if a patient had a continent orthotopic diversion. Acute side effects of chemoradiation therapy include frequency, urgency, dysuria, nausea, vomiting, and diarrhea. These side effects usually resolve. Late effects after chemoradiation therapy include hematuria, chronic frequency, contracted bladder that can sometimes necessitate cystectomy (<5%). Most of the patients who maintain their bladders have normal to nearnormal function, and they have reported higher quality of life than that can be achieved with cystectomy. Quality of life after bladder conversation seems to be better than after cystectomy (Table 18.26). Table 18.26 Quality of life after chemoradiation therapy Trial

Results

Karolinska

Questionnaires mailed to patients treated with RT, cystectomy, and some patients selected randomly from the population  58 irradiated patients, 251 cystectomy patients, and 310 population controls returned the forms 75% of irradiated patients reported little or no urinary symptoms 38% of irradiated patients had intercourse in the prior month, and 57% reported that they had ejaculated versus 13 and 0% of the cystectomy patients, respectively However, 32% of irradiated patients reported worse GI symptoms versus 24% of cystectomy patients versus 9% of controls

Source: Henningsohn L, Wijkstrom H, Dickman PW et al (2002) Distressful symptoms after radical radiotherapy for urinary bladder cancer. Radiother Oncol 62:215–225

19

Prostate Cancer Bin S. Teh1, Angel I. Blanco2, Arnold C. Paulino3 and E. Brian Butler 4

Key Points  Prostate cancer is the most commonly diagnosed malignancy in US men. The majority of diagnoses relate to the use of screening prostate-specific antigen (PSA), which remains controversial.  A combination of PSA level at diagnosis, clinical stage, and Gleason score is used to stratify patients into prognostic groups, with risk-adapted treatment assignment.  Expectant management is a valid alternative for patients with very low-risk (T1a, Gleason ≤6, PSA <10 ng/ml, less than three positive biopsy cores and <50% cancer per core, and PSA density <0.15 ng/ml) disease.  Because of screening PSA, most patients present with curative disease and, according to population studies, opt for treatment with curative intent. Validated first-line treatment options include radical prostatectomy and radiation therapy, via either interstitial seed implants or external-beam radiation (EBRT).  Radical prostatectomy is the surgical gold standard curative treatment and confers a reduction in mortality versus expectant management.  Surgical techniques have evolved considerably during the past several decades, and robotic-assisted laparoscopic prostatectomy (RALP) has been rapidly adopted in the USA.  Radiation therapy for localized prostate cancer leads to equivalent oncologic outcomes as compared with radical prostatectomy. Interstitial seed implants and EBRT appear clinically equivalent. Modality-specific toxicity profile and logistics should be incorporated into the decision-making process of the individual patient.  Owing to an increased probability of biochemical, clinical, and distant failure, treatment of locally advanced, nonmetastatic prostate cancer necessitates aggressive management.  Results from randomized studies have established the value of dose-escalated radiotherapy alone in the unimodality setting versus standard-dose irradiation in combination with neoadjuvant and concurrent hormones. The timing and optimal duration of hormone therapy in the era of dose escalation remain investigational.  Adjuvant radiation therapy improves clinical outcome (versus salvage radiation) for pT3 prostate cancer or positive surgical margins.

1

Bin S. Teh, MD 2 Angel I. Blanco, MD 3 Arnold C. Paulino, MD Email: Email: Email: [email protected] [email protected] [email protected]

4

E. Brian Butler, MD Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_2 © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Epidemiology data and risk factors of prostate cancer are presented in Table 19.1. Screening of prostate cancer in general population with serum prostatespecific antigen (PSA) is commonly practiced in the USA; however, such recommendation is controversial according to the conflict results of two largescale randomized clinical trials (Table 19.1). Table 19.1 Epidemiology data, risk factors, and screening for of prostate cancer Type

Description

Epidemiology

 Prostate cancer is the most commonly diagnosed cancer in US men  In 2010, an estimated 217,730 new cases will be diagnosed  Incidence rates exhibit wide geographical variation, with an 80-fold difference between China and North America

Risk factors

 Risk factors for prostate cancer are multiple   More established factors: increased life expectancy, rou tine adoption of PSA, ethnicity, and family history  Potential but less established factors: genetic and hor monal factors, obesity, dietary habits, exercise, prostatic inflammation, and infection

Screening for prostate cancer

 PSA screening has had a significant impact on prostate cancer incidence and mortality  Incidence of prostate cancer in USA rose substantially from the 1980s to 2001, with subsequent decline  The percentage of low-risk disease has increased, and the age-adjusted death rate from prostate cancer has declined  PSA screening in general population is controversial: The ERSPC trial demonstrated a 20% reduction in prostate cancer deaths with screening, while the North America PLCO study showed low overall mortality from prostate cancer, with or without screening

PSA: prostate-specific antigen; ERSPC: European Randomized Study of Screening for Prostate Cancer; PLCO: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Sources: Schroder FH, Hugosson J, Roobol MJ et al (2009) Screening and prostatecancer mortality in a randomized European study. N Engl J Med 360:1320 –1328; Andriole GL, Crawford ED, Grubb RL et al (2009) Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360:1310 –1319

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Anatomy The morphological and anatomical structures of prostate, as well as its relationship with surrounding structures are detailed in Table 19.2 and Figures 19.1 and 19.2. Table 19.2 Anatomy of the prostate Aspect

Description

Structure (Figure 19.1)

 Morphologically, the prostate comprises peripheral,  central, and transitional zones  ~75% of cancers originate in the peripheral zone   Prostate is divided into 5 lobes: 2 lateral, 1 posterior, 1  median, and 1 anterior lobe

Anatomic relationship (Figure 19.2)

 Shares important anatomic relationships with the   Rectum posteriorly  Seminal vesicles superoposteriorly  Neurovascular bundles laterally  Bladder anterosuperiorly  Surrounds the urethra between the bladder neck and the  genitourinary membrane  Traversed by the ejaculatory ducts 

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Figure 19.1 Anatomy of the prostate (~75% of all adenocarcinomas of the prostate occur in the peripheral zone). Diagram courtesy of Baylor College of Medicine. Used with permission

Figure 19.2 a–d a Coronal, b sagittal, c superior, and d inferior axial 3-Tesla MRI images obtained using torso coil, illustrating relevant prostate anatomic relationships. The yellow lines illustrate the levels of the selected coronal and axial slices. Note the 3D anatomic relationships of the prostate, bladder, rectum, seminal vesicles, and obturator internus muscles

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Pathology Adenocarcinoma is the most common histological subtype of prostate cancer. Histological evaluation provides important prognostic information in prostate cancer. The current scoring system for adenocarcinoma developed by Gleason et al was last revised in a 2005 International Society of Urological Pathology Consensus Statement. The Gleason score is based on the degree of loss of the normal glandular tissue architectures. The classic Gleason scoring diagram shows five basic tissue patterns that are technically referred to as tumor grades. The subjective microscopic determination of this loss of normal glandular structure caused by the cancer is abstractly represented by a grade, a number ranging from 1 to 5, with 5 being the worst grade possible (Figure 19.3, Table 19.3).

1

2

3

4

5

Figure 19.3 The Gleason score is derived by adding the sums of the two most common patterns of cancer observed, each assigned a grade from 1 to 5

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Table 19.3 Determination of Gleason Score Type

Description

Primary gleason grade

The Primary Gleason grade (ranges from 1–5) has to be greater than 50% of the total pattern seen (i.e. the pattern of the majority of the cancer observed)

Secondary Gleason grade

The Secondary Gleason grade (ranges from 1–5) has to be less than 50%, but at least 5%, of the pattern of the total cancer observed

Gleason score

The sum of the primary and secondary Gleason grades is the Gleason score (ranges from 2 to 10)

Other histologic subtypes of prostate cancer include urethral duct carcinoma, transitional cell carcinoma, ductal adenocarcinoma, neuroendocrine carcinoma, carcinosarcoma, sarcomatoid carcinoma, endometrial carcinoma, and sarcomas.

Routes of Spread Local extension, regional (lymphatic), and distant (hematogenous) metastases are the three major routes of spread in prostate cancer (Table 19.4). Table 19.4 Routes of spread in prostate cancer Route

Description

Local extension

 Local extension mainly involves direct extracapsular extension of prostate cancer or involvement of seminal vesicles  The probability of local extension can be estimated by serum PSA and Gleason score  A number of predictive models exist to estimate the probabilities of local extension, such as Partin’s Table and the Roach Formulas:  ECE (%) = 3/2 × PSA + 10× (Gleason-3)  Seminal vesicle involvement (%) = PSA + 10× (Gleason-6)  The presence of local extension affects treatment strategy, and in case of EBRT, the treatment portal

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Table 19.4 (continued) Route

Description

Regional lymph node metastasis

 Lymph node metastasis is a common mode of spread in prostate cancer  The probability of regional metastasis can be estimated by a number of predictive models  Using the Roach formula, such probability can be calculated as: LN metastasis (%) = 2/3 PSA + 10× (Gleason-6)  Lymph node metastasis, even regional, are staged as stage IV in prostate cancer

Distant metastasis

 The most common route of hematogenous metastasis is through Batson’s venous plexus to the vertebral body of the lumbar spine  Metastasis to other organs may occur but unlikely be the first incidence of distant metastasis

ECE: extracapsular extension; SV: seminal vesicles; LN: lymph node; EBRT: externalbeam radiation therapy Source: Roach M, Marquez C, Yuo HS et al (1994) Predicting the risk of lymph node involvement using the pre-treatment prostate specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 28:33 –37

Lymph Node Metastasis The primary lymphatic vessels from the prostate gland drain into the regional lymph nodes of the true pelvis (Figure 19.4). Regional and distant lymph node groups observed in prostate cancer metastases are listed in Table 19.5.

Figure 19.4 Lymph node anatomy in the pelvis. The diagram outlines the major nodal chains seen in the pelvis. Reprinted with permission from Magnetic Resonance Imaging Clinics of N America (2004)

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Table 19.5 Regional and distant lymph node groups in prostate cancer metastases Lymph nodes

Subclassification of lymph nodes

 Internal iliac (hypogastric) nodes Regional lymph  Obturator nodes  Presacral nodes (within true pelvis, +  Perivesical nodes N disease)  External iliac nodes Distant lymph nodes (beyond true pelvis, M1A disease)

 Deep and superficial inguinal nodes   Common iliac nodes   Retroperitoneal (aortocaval) nodes   Supraclavicular, cervical, and scalene nodes 

Diagnosis, Staging, and Prognosis Clinical Presentation Although most men diagnosed because of screening PSA are asymptomatic at the time of diagnosis, advanced tumors may invade adjacent organs, regional pelvic lymph nodes, or present with osseous metastases. Such cases may present with bladder outlet obstructive symptoms, hematuria, hematospermia, erectile dysfunction, hematochezia, changes in bowel function, and/ or bone pain. The presence of such symptoms, as well as baseline assessment of urinary (including the International Prostate Symptom Score [IPSS]), rectal, and erectile function, and medical comorbidities should be documented in a focused history.

Diagnosis and Staging Tables 19.6 and 19.7, and Figure 19.5 illustrate the diagnostic procedure of prostate cancer, including suggested examinations and tests.

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Table 19.6 Diagnostic procedures used in the diagnosis of prostate cancer Type

Description

Serum PSA

 PSA screening leads to the majority of prostate cancer diagnoses  Although sensitive, PSA is not specific, and false positives can result in cases of infection, benign prostatic hypertrophy, recent DRE, recent ejaculation, and other non-neoplastic conditions  PSA has been shown to increase as a function of age in healthy individuals, prompting age- and race-specific reference ranges, although the appropriateness of race-specific levels is controversial  The positive predictive value of PSA ≥4 ng/ml (a typical clinical threshold) ranges from 31 to 54%. Specificity increases when patient age and DRE status are considered  Additional laboratory values, including free PSA (percentage of protein-unbound PSA, associated with prostate cancer for ratios <0.2), PSA density (expressed as the ratio of serum PSA to prostate volume), and PSA velocity (or rise in PSA level as a function of time, with 0.75 mg/ml/year suggestive of prostate cancer), are often utilized  Persistent elevation in PSA and the presence of palpable prostatic nodules, alone or in combination, warrant consideration of transrectal ultrasound-guided (TRUS) needle biopsy

Physical examinations

 The physical exam should include a thorough digital rectal exam (DRE), noting baseline rectal tone, the presence of hemorrhoids or anorectal masses, and with specific focus on the prostate glands, including its size and consistency, presence of nodules, involvement of the lateral sulci and/or seminal vesicles  DRE forms the cornerstone for staging, although it is insensitive for assessment of extracapsular extension  DRE is insensitive for assessment of extracapsular extension

TRUS-guided needle biopsy

 This procedure represents the gold standard method for prostate cancer diagnosis, and typically consists of at least 6 cores  Since the procedure can miss 20 –30% of clinically significant cancer, a larger number of cores may be considered, particularly in patients with larger prostate volumes; the TRUS biopsy protocol recommended at present by the NCCN entails an extended biopsy with a ten cores  The length of each core specimen, and the length of tumor within each malignant sample, should be documented  Additional diagnostic techniques are under investigation;  among these, 3D prostate mapping biopsy appears promising and may improve the staging accuracy of standard core biopsy

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Table 19.7 Imaging studies used in the diagnosis and staging of prostate cancer Study type

Description

Imaging

 An assortment of imaging technologies, including 2D, 3D, and Doppler ultrasound, CT, and MRI, has been extensively evaluated in an attempt to improve staging accuracy, but are not considered replacements for DRE  Among these tools, TRUS and MRI permit optimal visualization of prostate anatomy relative to CT  Surface and endorectal MRI coils can yield complementary information, with the latter providing fine resolution of the prostatic structures and the former information on the adjacent organs and regional lymph nodes  T2-weighted sequences allow visualization of the zonal anatomy, vas deferens and seminal vesicles, neurovascular bundles, and penile bulb  MRI allows detection of seminal vesicle invasion and extraprostatic disease, although MRI staging is made difficult by postbiopsy hemorrhage  Anatomic T2-weighted MRI imaging is a sensitive diagnostic and technique whose specificity and diagnostic accuracy can be enhanced by magnetic resonance spectroscopy (MRS) and/or dynamic contrast-enhanced techniques (DCE-MRI)

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Prostate Cancer Suspected (e.g., elevated PSA on screening test)

Complete History and Physical Including DRE

Transrectal Ultrasound Guided Prostate Biopsy

If life expectancy is greater than 5 years or symptomatic: Recommend Treatment

If life expectancy is less than or equal to 5 years and asymptomatic: No Further Treatment

Risk Classification Based on PSA, DRE, and Gleason Score

Work-ups Dependent on Risk Classification

Bone Scan 1. T1-T2 and PSA greater than 20ng/ml 2. Gleason score greater than or equal to 8 3. T3/T4 disease 4. Symptomatic

Abdominal Pelvic CT/MRI 1. T3/T4 disease 2. T1-T2 and nomogram probability of lymph node Involvement greater than 20%

Multidisciplinary Treatment Based on Risk Classification Figure 19.5 Proposed algorithm for diagnosis and staging of prostate cancer. A bone scan is recommended if PSA >20, or in symptomatic patients with PSA of 10–20, and not recommended if PSA <10. A CT scan of the abdomen and pelvis is recommended for patients with high-risk disease

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Tumor, Node, and Metastasis Staging Diagnosis and clinical staging depends on findings from history and physical examination, imaging, and lab tests. Pathological staging depends on findings during surgical resection and pathological examination, in addition to those required in clinical staging. The 7th edn. of the tumor, node, and metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC) is presented in Tables 19.8 and 19.9. Table 19.8 AJCC TNM classification of adenocarcinoma of the prostate Stage

Description

Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1a

Tumor incidental histologic finding in 5% or less of tissue resected

T1b

Tumor incidental histologic finding in more than 5% of tissue resected

T1c

Tumor identified by needle biopsy (e.g., because of elevated PSA)

T2a/pT2a

Unilateral, one-half of one side or less

T2b/pT2b

Unilateral, involving more than one-half of side but not both sides

T2c/pT2c

Tumor involves both lobes (i.e., bilateral involvement)

T3a/pT3a

Extraprostatic extension or microscopic invasion of bladder neck

T3b/pT3b

Tumor invades seminal vesicle(s)

T4/pT4

Tumor is fixed or (pathologically) invades adjacent structures other than seminal vesicles (such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall)

Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

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Table 19.8 (continued) Stage

Description

Distant metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1a

Distant metastasis to non-regional lymph nodes

M1b

Distant metastasis to skeletal system

M1a

Distant metastasis to additional sites with or without skeletal metastasis

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer (AJCC), cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

Table 19.9 AJCC stage grouping of adenocarcinoma of the prostate Group

I

T

N

M

PSA

Gleason score

T1a–c

0

0

<10

≤6

T2a

0

0

<10

≤6

T1–2a

0

0

–

–

T1a–c

0

0

<20

7

T1a–c

0

0

10 –20

≤6

T2a

0

0

<20

<7

T2b

0

0

–

–

T2c

0

0

Any

Any

T1–2

0

0

≥20

Any

T1–2

0

0

Any

≥8

III

T3a–b

0

0

Any

Any

IV

T4

N1

M1

Any

Any

IIA

IIB

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer (AJCC), cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

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Prognoses Beyond Gleason score, pretreatment serum PSA, and stage at diagnosis, additional pathologic factors include percent positive biopsy cores, PSA density and velocity, length of core involvement by tumor, and presence of perineural invasion also portend prognostic significance. Since the clinical behavior of prostate cancer might range from indolent to highly aggressive, prognostic assessment is important for predicting outcome and treatment selection. A number of prognostic schemes have been developed. The multitiered clinical grouping system developed by the National Comprehensive Cancer Network (NCCN) is summarized, along with suggested treatment recommendations, in Table 19.10.

Table 19.10 NCCN Prostate Cancer Risk Classification and suggested treatment strategies Risk group

Criteria

Treatment options

Very low

T1a, Gleason ≤6, PSA <10 <3 Positive biopsy cores and <50% cancer per core, and PSA density <0.15 ng/ml

Active surveillance using PSA and DRE, if expected survival <20 years

Low

T1-T2a, Gleason ≤6, and PSA <10

Active surveillance using PSA and DRE if expected survival <10 years; using PSA, DRE, and repeat biopsy if expected survival ≥10 years, or Definitive therapy using IG-IMRT, brachytherapy, or radical prostatectomy (RP)

Intermediate

T2b-T2c, Gleason 7, or PSA 10 –20

IG-IMRT with or without shortterm ADT with or without brachytherapy boost or RP

High

T3a, Gleason 8–10, or PSA >20

IG-IMRT and long-term ADT or radical prostatectomy plus PLND with or without adjuvant RT

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Table 19.10 (continued) Risk group

Criteria

Treatment options

Locally advanced: very high

T3b–T4

IG-IMRT plus long-term ADT or radical prostatectomy plus PLND with our without adjuvant RT or ADT

Locally advanced: LN

N1

ADT or IG-IMRT and longterm ADT

Locally advanced: DM

M1

ADT

PSA: prostate-specific antigen (nanograms per milliliter); DRE: digital rectal examination; IG-IMRT: image-guided intensity-modulated radiation therapy; PLND: pelvic lymph node dissection; ADT: androgen depravation therapy; LN: lymph node involvement; DM: distant metastasis Source: NCCN clinical practice guidelines in oncology: prostate cancer v.1.2010. Available at: http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf. Cited 21 June 2010

Treatment Principles and Practice Localized prostate cancer can be treated with surgery, radiation therapy, or the combination of both. In addition, hormonal therapy plays a major role in the treatment of locally advanced disease. For selected patients with very low- or low-risk diseases, active surveillance may be a valid option.

Treatment of Localized Prostate Cancer A risk-adapted schematic defining standard treatment algorithms for localized prostate cancer is listed in Table 19.10. In summary, accepted treatment options include surveillance versus active treatment with radiotherapeutic, surgical, and systemic modalities selected as a function of disease stage, side effect profile, and patient comorbidities (Table 19.11).

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Table 19.11 Treatment modalities used in prostate cancer Type

Description

Active surveillance

Indications

 Indicated but controversial in patients with very low-risk disease (if life expectancy <20 years) or low-risk disease (if life expectancy <10 years)  Populations studies suggested that only a small proportion of prostate cancer patients choose active surveillance

Facts/issues

 Guidelines for active surveillance include regular PSA, DRE, and/or repeat needle biopsy  Definitive treatment recommended if clinical (PSA, exam) or pathologic (higher Gleason score, increased number of positive biopsy cores) disease progression is documented  Advantages of active surveillance include avoidance of unnecessary treatment and potential side effects  Potential disadvantages of tumor progression and potential need for more aggressive and potentially toxic treatment, increased anxiety, and the requirement of multiple evaluations and periodic biopsies

Radical prostatectomy (RP)a

Indications

 Indicated and a common treatment for patients with  clinically localized prostate cancer, with life expectancy exceeds 10 years  RP is considered as the standard surgical treatment 

Facts/issues

 The only local treatment that reduces mortality (RR =  0.56), local progression (RR = 0.33), and metastasis (RR = 0.6) over observation  The procedure has evolved from perineal to retropubic,  retropubic nerve sparing, laparoscopic, and robot assisted approaches  Potential side effects include intra-operative bleeding,  urinary incontinence, and erectile dysfunction  Overall prostate-cancer-specific mortality of 12% (range  of 5–38%) at 15 years after surgery

External-beam radiation therapy (EBRT)

Indications

 As monotherapy for low-risk and selected intermediaterisk patients  In concurrent with ADT for intermediate-, high-, and very high-risk patients  Adjuvant postprostatectomy treatment for high-risk patients  Palliative treatment to primary or metastatic foci

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Table 19.11 (continued) Type

Description

External-beam radiation therapy (EBRT)

Facts/issues

 Intensity-modulated radiation therapy (IMRT) represents the current standard of care for prostate EBRT  Similar results in disease control relative to prostatectomy and seed implant if dose of EBRT >72 Gy

Interstitial brachytherapy Indications and contraindications

 Generally well applicable modality for curative treatment of localized prostate cancer  Selection criteria from the ABS and contraindications are detailed in Table 19.10

Facts/issues

 Highly conformal dosimetry  Moderate invasiveness, outpatient nature  Minimal number of treatment visits (i.e., typically volume study and implant dates)  ABS guidelines for monotherapy or as boost following EBRT are summarized in Table 19.12

Androgen ablation

Indications

 Short-term ADT in intermediate-risk prostate cancer  Long-term and adjuvant ADT in high to very high-risk prostate cancer  Mainstay treatment for palliative therapy in metastatic disease  Unproven role as a component of salvage therapy, al though it is utilized empirically in selected high-risk patients

Medications/ procedures

 Orchiectomy or LHRH agonists (e.g., leuprolide, goserelin) block 90 –95% of testosterone  Anti-androgen (e.g., flutamide, bicalutamide, cyproterone acetate)  TAB utilizes orchiectomy or LHRH agonist plus anti-androgen for complete testosterone blockade  Estrogen as a second-line hormonal therapy

RR: relative risk; ADT: androgen-deprivation therapy; TAB: total androgen blockade; LHRH: luteinizing hormone-releasing hormone a Sources: Bill-Axelson A, Holmberg L, Ruutu M et al (2005) Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 352:1977–1984; Stephenson AJ, Kattan MW, Eastham JA et al (2009) Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol 27:4300430 –5

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The treatment algorithm of prostate cancer based on the NCCN risk classification is illustrated in Figure 19.6. Diagnosis of Prostate Cancer

Risk Classification of Prostate Cancer

Low Risk T1-2a, G≤6, or PSA<10

Interm. Risk T2b-c, G=7, or PSA 10-20

High Risk T3a, G=8-10, or PSA>20

IG-MRT +/Brachytherapy Boost

IG-MRT +/Brachytherapy Boost

Very High Risk T3b-T4, N0, M0

Opt to Active Surveillance?

No

IG-IMRT

+/-

+/-

Yes

Definitive Treatment?

No

OR Brachytherapy

Short-term ADT (4-6 months)

Long-term ADT (2-3 years)

Radiation Therapy

Radiation Therapy

Radiation Therapy

OR

Radical Prostatectomy

OR

OR

Radical Prostatectomy

Palliative ADT

Radical Prostatectomy +PLND +/Adjuvant Radiation Therapy Surgical Therapy

Active Follow-Up Figure 19.6 Proposed treatment algorithm for adenocarcinoma of the prostate

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It should be noted that no randomized trial exists comparing modern radiation with prostatectomy techniques, and that oncologic outcomes for localized prostate cancer appear similar when appropriate (≥72 Gy) radiation doses are employed (Table 19.12) (Source: Kupelian PA, Potters L, Khuntia D et al (2004) Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1–T2 prostate cancer. Int J Radiat Oncol Biol Phys 58:25 –33). Table 19.12 American Brachytherapy Society selection criteria for permanent prostate brachytherapy Treatment type/ contraindication

Criteria

Monotherapy

 Clinical stage T1–T2a,  Gleason sum 2–6, and  PSA <10 ng/ml

EBRT boost

 Clinical stage T2b–T2c,  Gleason sum 8–10, or  PSA >20 ng/ml

EBRT boost (other)

 Perineural Invasion  Multiple positive biopsies  Bilateral positive biopsies, or  MRI evidence of capsular penetration

Monotherapy or boost plus neoadjuvant androgen suppression

 Initial prostate volume >60 ml, with response

Disease related

 Prior pelvic radiation therapy  Prominent median lobe  Gland volume >60 ml  Seminal vesicle invasion

Non-disease related

 Medical inoperability  History of multiple pelvic surgeries  IPSS score >15  Pubic arch interference  Large TURP defect

Source: Nag S, Beyer D, Friedland J et al (1999) American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 44:789 –799

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Dose Escalation and Treatment Outcome of External-Beam Radiation Therapy External-beam radiation therapy (EBRT) is one of the most important definitive treatment modality for localized prostate cancer of all stages. Intensitymodulated radiation therapy (IMRT) represents the current standard of care for prostate EBRT. Details of target volume delineation and selection, as well as dose and delivery are detailed in the “Radiation Therapy Technology Section.” Following initial single-institution reports of improved efficacy and therapeutic ratio by Hanks et al, dose-escalation strategies have become an important focus of prostate cancer research endeavors. Importantly, the maturing three-dimensional (3D)-conformal and emerging IMRT studies collectively suggest improvements in biochemical control and reduced toxicity rates as compared with 2D approaches. Clinical evidence for dose escalation in EBRT is presented in Table 19.13 (for nonrandomized studies) and Table 19.14 (for randomized clinical trials). With respect to biochemical control, dose escalation has shown improved outcomes on several phase III studies listed above; however, likely owing to patient heterogeneity, inadequate power, or different definitions of PSA relapse, the results have been inconsistent when analyzed according to risk groups. Table 19.13 Clinical evidences support dose escalation in EBRT for prostate cancer: non-randomized studies Studies

Description

Hanks et al (1998)a

 Retrospective of 232 patients with prostate cancer treated using 3D-CRT for outcome of radiation dose escalation  A dose response was observed for patients with pretreatment PSA >10 ng/ml, based on 5-year bNED results  5-year bNED rates of 35% at 70 Gy, and 75% at 76 Gy (p = 0.0049) if PSA ranged from 10 to 19.9 ng/ml  No dose response was observed for patients with pretreatment PSA <10 ng/ml  Dose response was observed for FC-LENT grade 2 and grades 3,4 GI sequelae, and for LENT grade 2 GU sequelae  The improvement in 5-year bNED rates for patients with PSA levels >10 ng/ml suggested a benefit of radiation dose escalation

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Table 19.13 (continued) Studies

Description

RTOG 9406 dose level Vb

 Phase I/II study for radiation dose escalation in the treatment of stage T1 and T2 prostate adenocarcinoma  225 patients were treated to 78 Gy to the prostate alone (if probability of seminal vesicles [SV] involvement <15%) or 78 Gy to prostate and 54 Gy to SV (if SV involvement probability ≥15%)  The frequency of grade 3 or worse late effects was compared with a similar group of patients treated in 2 other RTOG studies  Acute toxicity at dose of 78 Gy was low: grade 3 acute effects in 4% of patients treated to prostate only, and 2% of patients treated to both prostate and SV. No Grade 4 or 5 acute toxicity was reported

bNED: biochemical no evidence of disease a Source: Hanks GE, Hanlon AL, Schultheiss TE et al (1998) Dose escalation with 3D conformal treatment: 5-year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 41:501–510 b Source: Michalski JM, Winter K, Purdy JA et al (2005) Toxicity after three-dimensional radiotherapy for prostate cancer on RTOG 9406 dose Level V. Int J Radiat Oncol Biol Phys 62:706 –713 Table 19.14 Clinical evidences support dose escalation in EBRT for prostate cancer: randomized trials Randomized trial

Description

Dearnaley et ala

 Randomized clinical trial compared 3D-CRT versus conventional RT to 64 Gy  225 patients were randomized  The primary endpoint was the development of late radiation complications (>3 months after treatment)  Reduced grade 1–2 late radiation proctitis in patients received 3D-CRT as compared with conventional techniques  No difference in disease control was observed

Koper et al (Dutch Randomized Trial)b

 Randomized clinical trial reported anorectal morbidity with the use of 3D-CRT versus conventional RT to 66 Gy  266 patients with T1–4N0M0 prostate carcinoma treated with same planning, treatment, and portal imaging procedure  However, patients in the conventional treatment arm were treated with rectangular, open fields, whereas conformal radiotherapy was performed with conformally shaped fields  A reduction in GI toxicity was observed after 3D-CRT (32 and 19%, p = 0.02), mostly due to the reduced grade 2 rectum/sigmoid and anal toxicity from 3D-CRT  No difference in urological toxicity was observed 7

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Table 19.14 (continued) Randomized trial

Description

MD Andersonc

 Randomized clinical trial compared 78 versus 70 Gy of EBRT using 3D-CRT  301 patients with stage T1b to T3 prostate cancer were randomized  A significant 8-year biochemical DFS improvement in patients randomized to receive 78 Gy of radiation (78 versus 59%, p = 0.004)  The largest benefit among patients with pretreatment PSA >10 ng/ml  No significant difference in GI or GU toxicity was observed

Dutch multicenter randomized triald

 Randomized trial compared 78 versus 68 Gy using 3DCRT for prostate cancer  669 patients with T1b–T4 diseases were enrolled  Primary end point was freedom from failure (FFF), defined by the ASTRO definition. Other end points were freedom from clinical failure (FFCF), overall survival (OS), and toxicity  With a follow-up of 51 months, 5-year FFF was significantly better after 78 Gy 3D-CRT (64 versus 54%)  No significant differences in FFCF or OS were observed  No difference in late GU or GI toxicity

PROG/ACR 95-09e

 Randomized trial compared 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high) proton radiation in earlystage prostate cancer  393 patients with T1b–T2b and PSA ≤ 5 ng/ml were randomly assigned to either arm, without androgen suppression therapy  End points included local failure (LF), biochemical failure (BF), and OS  High-dose radiation therapy reduced LF, with a HR of 0.57  The 10-year ASTRO BF rates were 32.4 versus 16.7%, favored high-dose RT (p < 0.0001)  This difference was due largely to differences in low- and probably intermediate-risk disease  There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1 versus 30.4%, p = 0.06)  11 versus 6% of patients subsequently required ADT for recurrence after conventional- versus high-dose RT (p = 0.047)  There remains no difference in OS (78.4 versus 83.4%; p = 0.41) and toxicity rates (1–3% of grades 3–4) between the 2 arms

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Table 19.14 (continued) RT: radiation therapy; DFS: disease-free survival; ADT: androgen deprivation therapy; HR: hazard ratio; PROG: Proton Radiation Oncology Group; ACR: American College of Radiology; ASTRO: American Society of Therapeutic Radiology Oncology a Source: Dearnaley DP, Khoo VS, Norman AR et al (1999) Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomized trial. Lancet 353:267–272 b Source: Koper PC, Stroom JC, van Putten WL et al (1999) Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study. Int J Radiat Oncol Biol Phys 43:727–734 c Source: Kuban DA, Tucker SL, Dong L et al (2008) Long-term results of the MD Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 70:67–74 d Source: Peeters ST, Heemsbergen WD, Koper PC et al (2006) Dose response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 24:1990 –1996 e Source: Zietman AL, Bae K, Slater JD et al (2010) Randomized trial comparing conventional-dose with high-dose conformal RT in early-stage adenocarcinoma of the prostate: long-term results from PROG/ACR 95 –09. J Clin Oncol 28:1106 –1111

Hormonal Therapy for Locally Advanced Disease Androgen-deprivation therapy (ADT), consisting of a combination of luteinizing-hormone-releasing hormone (LHRH) suppression and an antiandrogen, has been evaluated as an adjunct to standard-dose EBRT as an alternative strategy to improve outcomes in patients with intermediate- and high-risk prostate cancer. The supportive trials, although heterogeneous in their patient selection criteria and radiation treatment volumes, generally demonstrate statistically and clinically significant improvements in local control and disease-free survival (DFS), with inconsistent improvements in overall survival (Tables 19.15 and 19.16). Evidence in support of androgen suppression is most mature in patients with high-risk disease. Beginning in the 1980s, research organizations in the USA (including the Radiation Therapy Oncology Group [RTOG]) and Europe launched a series of trials for which mature follow-up data are now available, and which have systematically evaluated the efficacy, timing, and duration of androgen suppression therapy (Table 19.16). Proposed algorithms for the treatment of intermediate- and high-risk prostate cancers based on the above-listed level I evidence are presented in Figures 19.7 and 19.8. Given the long natural history of prostate cancer, recent studies have examined the incidence of long-term toxicities after combined androgen suppression and EBRT (Table 19.17).

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Table 19.15 Clinical evidence on combined EBRT with hormonal therapy for intermediate-risk prostate cancer Randomized trial

Description

D’Amico et al (intermediate risk)a

 Phase III clinical trial to compare RT with or without 6 months of ADT  80% of 206 randomized patients had intermediate-risk prostate cancer  Conformal radiation comprised 70.35 Gy in 36 fractions prescribed to the prostate and seminal vesicles with a cone-down boost to the prostate  Initial results at a median follow-up of 4.5 years revealed statistical improvements in prostate cancer-specific survival, survival free of salvage androgen deprivation, and OS rates  Updated results after a median follow-up of 7.6 years showed that all-cause mortality was significantly greater in the RT alone arm (HR 1.8, p = 0.01)  Subgroup analyses suggest that the significant difference was primarily in patients with no or minimal comorbid illness

TROG 96.01 of (Australia)b

 Randomized clinical trial studies the optimal duration of  short-course hormonal therapy  A 3-arm study compared prostate-only radiation to 66 Gy,  versus 3 or 6 months of androgen deprivation before and during radiation for intermediate-risk patients  Results revealed a significant improvement in prostate cancer-specific mortality with 6 (HR = 0.56) but not 3 (HR: 0.95) months of STAD

DFS: disease-free survival; OS: overall survival; TROG: Trans-Tasman Radiation Oncology Group (Australia); STAD: short-term androgen deprivation a Sources: D’Amico AV et al (2008) Androgen suppression and radiation versus radiation alone for prostate cancer: a randomized trial. JAMA 299:289 –295; D’Amico AV et al (2004) Six-month androgen suppression plus radiation therapy versus radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 292:82182–82187 b Source: Denham JW et al (2008) Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality: evidence from the TROG 96.01 randomized controlled trial. Lancet Oncol 9:1058 –1068

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Table 19.16 Clinical evidence on combined EBRT with hormonal therapy for high-risk prostate cancer Randomized trial

Description

RTOG 85-31a

 Randomized trial of 977 patients to adjuvant goserelin  versus observation  Eligible patients had advanced tumor characteristics (cT3,  N+, or pathologic penetration through the capsule to the resection margin or SV involvement)  Goserelin was administered indefinitely or until disease  progression  RT portals included treatment of the regional lymphatics  to an initial 44 –46 Gy (except in node-negative postoperative cases) followed by a prostate boost to 65–70 Gy  10-year updated results demonstrated significant im provements in: local failure (23 versus 38%), disease-specific mortality (16 versus 22%), DM (24 versus 39%)  NED survival (37 versus 23%), and OS (49 versus 29%), fa voring the use of adjuvant goserelin

RTOG 86-10b

 Randomized clinical trial evaluated the cytoreductive and  potentiating effect of androgen suppression  Randomizing patients to neoadjuvant and concurrent  goserelin and flutamide for 2 months prior and 2 months during RT versus observation  Enrolled patients had “bulky” primary tumors (≥5 × 5 cm),  with or without pelvic lymph node involvement  RT target volumes and doses were similar to RTOG 85–31,  also including the regional lymphatics to an initial 44 –46 Gy, followed by a prostate boost to 65–70 Gy  Updated results at 10 years demonstrated significant im provements DM (35 versus 47%), disease-specific mortality (23 versus 36%), DFS (11 versus 3%), and biochemical failure (65 versus 80%)  A nonsignificant trend toward improved OS with also  observed  No significant impact on the risk of fatal cardiac events  was seen

EORTCc

 Phase III study (103) compared EBRT with long-term (con current and adjuvant) androgen suppression  EBRT initially targeted the prostate and pelvic nodes to  50 Gy, with a subsequent prostate-only boost to an additional 20 Gy  Hormonal therapy consisted of monthly goserelin admin istration for 3 years, beginning on the first day of EBRT and 1 month of cyproterone acetate  With a median follow-up of 66 months, clinically and statisti cally relevant improvements in DFS (40 versus 74%), DSS (79 versus 94%), and OS (62 versus 78%) rates were observed 7

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Table 19.16 (continued) Randomized trial

Description

RTOG 92-02d

 Randomized trial studied the optimal duration of androgen suppression therapy  EBRT was directed to the prostate and pelvic nodes (44 –50 Gy), followed by a prostate boost to 65–70 Gy  All patients received 4 months of goserelin and flutamide, 2 months before and after RT (the experimental arm of 86 –10)  Patients were randomization to no further treatment versus 24 months of goserelin  10-year updated results demonstrated significant improvements for long- versus short-term androgen suppression for multiple endpoints  DFS (13 versus 23%), DSS (84 versus 89%), local progression (22 versus 12%), DM (23versus 15%), and biochemical failure (68 versus 52%) favored long-term androgen suppression  OS was not improved, except for the subgroup of patients with Gleason 8–10 tumors

SV: seminal vesicle; DM: distant metastases; DFS: disease-free survival; DSS: diseasespecific survival; OS: overall survival a Sources: Pilepich MV et al (1997) Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol 15:1013 –1021; Pilepich MV et al (2005) Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma – long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 61:1285 –1290 b Sources: Pilepich MV et al (2001) Phase III radiation therapy oncology group (RTOG) trial 8610 of androgen deprivation adjuvant to definitive RT in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243 –12252; Roach M 3rd et al (2008) Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol 26:585 –591 c Source: Bolla M et al (2002) Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 360:103 –106 d Sources: Hanks GE et al (2003) Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the RTOG protocol 92-02. J Clin Oncol 21:3972–3978; Horwitz EM et al (2008) Ten-year follow-up of radiation therapy oncology group protocol 92–02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 26:24972–504.

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Ongoing studies will help define the role of androgen suppression in intermediate-risk disease in the setting of dose escalation.

Definitive Treatment Radiation Therapy Intermediate Risk Prostate Cancer T-Classification T2b,N0,M0 T2c,N0,M0 Gleason Score 7 PSA 10-20ng/mL

Image-guided IMRT (≥ 78 Gy / 43 Fractions) Or EBRT+Brachytherapy (EBRT:40-50 Gy)

Chemotherapy

Follow-Up Recommended: History/Physical Exam Annual DRE Serum PSA (Every 6-12 months for 5 years, then annually)

Neoadj. and Concurrent ADT (Total 4-6 months)

If radical prostatectomy and lymph node dissection were performed with adverse features (positive margin, extracapsular or seminal vesicle extension, detectable PSA), adjuvant radiation therapy should be considered For patients with <10-year expected survival time, active surveillance with PSA (every 6 months) and DRE (annually) can also be considered Clinical target volume may encompass pelvic lymph node regions in intermediate-risk cases (if risk >15%) If EBRT plus brachytherapy is used, boost dose of brachytherapy boost is 100–110 Gy

Figure 19.7 Proposed treatment algorithm of definitive treatment of intermediate-risk prostate cancer with external-beam radiation therapy (EBRT) and hormonal therapy

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Definitive Treatment Radiation Therapy High Risk Prostate Cancer T-Classification T3,N0,M0 T4,N0,M0 Gleason Score 8-10 PSA >20 ng/mL

Image-guided IMRT (≥ 78 Gy / 43 Fractions) Or EBRT+Brachytherapy (EBRT: 40-50 Gy)

Chemotherapy Neoadj. ADT (2 months) Concurrent ADT (2 months) Adjuvant ADT (2-3 years)

Follow-Up Recommended: History/Physical Exam Annual DRE Serum PSA (Every 6-12 months for 5 years, then annually)

A number of medications and combinations can be considered for androgen deprivation treatment (ADT) or total androgen blockade For locally advanced (T3b–4) prostate cancer, ADT alone is a valid option of treatment If radical prostatectomy and lymph node dissection were performed with adverse features (positive margin, extracapsular or seminal vesicle extension, detectable PSA), adjuvant radiation therapy should be considered Clinical target volume can encompass pelvic lymph node regions in high-risk cases EBRT plus brachytherapy can be used in selected patients but high-risk patients are usually poor candidates for permanent implant

Figure 19.8 Proposed treatment algorithm of definitive treatment of high-risk prostate cancer with external-beam radiation therapy (EBRT) and hormonal therapy

Treatment Outcome After Low-Dose Rate Brachytherapy Modern series continue to demonstrate excellent outcomes for radioactive seed implantation, either as monotherapy for low-risk cases or selected highrisk patients, or as boost treatment in conjunction with external beam therapy

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Table 19.17 Studies examined long-term toxicities of androgen suppression treatment used with EBRT Study

Results

RTOG dataset analysisa

 Long-term pelvic toxicity does not appreciably worsen with the addition of androgen suppression  On the contrary, patients treated with EBRT and shortterm suppression had a statistically significant lower probability of ≥ grade 3 GI, GU, and other toxicities as compared with RT  Patients treated with long-term suppression and EBRT had a statistically significant lower probability of ≥ grade 3 GU toxicity as compared with RT alone

RTOG 92-02b

 Analysis for the potential for cardiovascular toxicity after hormonal treatment for prostate cancer  Demonstrated no increased cardiovascular mortality from 24 versus 4 months of adjuvant goserelin

Harvard phase III trialc

 Postrandomization analysis of the Harvard phase III trial  Indicated that the benefit of androgen deprivation was restricted to those men with none/mild versus moderate/ severe comorbidities

a

Source: Lawton CA et al (2008) Long-term treatment sequelae after external beam irradiation with or without hormonal manipulation for adenocarcinoma of the prostate: analysis of radiation therapy oncology group studies 85-31, 86 -10, and 92-02. Int J Radiat Oncol Biol Phys 70:437–441 b Source: Efstathiou JA et al (2008) Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02. Eur Urol 54: 816 –823 c Source: Nguyen PL et al (2009) Radiation with or without 6 months of androgen suppression therapy in intermediate- and high-risk clinically localized prostate cancer: a postrandomization analysis by risk group. Int J Radiat Oncol Biol Phys 77:1046–1052

for high-risk disease (Table 19.18). Outcomes are related to implant quality and biological effective dose (BED).

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Table 19.18 Representative series describing modern outcomes following radioactive seed implantation for prostate cancer Author

Patients (n)

Risk group

Stonea

1078

Isotope(s)

Endpoint (years)

Biochemical control (%)

Intermediate Yes and high

125 103

5

All: 80%

Sylvester 223

All

Yes

125 103

I/

Pd

15

Low risk: 88% Int risk: 80% High risk: 68%

Taira

Low and Interme- No diate

125 103

Pd

12

Low risk: 97% Intermediate risk - 96%

5

V100 ≥ 90%: 100 V100 < 90%: 94%

8

Low risk: 82% Intermediate risk: 70% High risk: 48%

Zelefsky

462

562

Zelefskyb 2693

All

All

EBRT?

No

No

I/

I/

125

Pd

I

125 103

I/

Pd

EBRT: external-beam radiation therapy a Excellent outcomes seen in intermediate and high-risk patients treated with a combination of androgen deprivation, EBRT, and seed implantation, particularly if BED >220 Gy b As demonstrated in a recent multi-institutional study of 2,693 men with T1–2 prostate cancer, D 90 ≥ 130 Gy emerged as a highly significant predictor of 8-year PSA relapsefree survival (93 versus 76%, p < 0.001)

Adjuvant Radiation Therapy While prostatectomy provides good control rates for patients with organconfined disease, failure rates for patients with cancer extension beyond the capsule are substantial, particularly in cases of high Gleason grade and positive margins. Published level I evidence indicates a strong benefit for upfront postoperative EBRT of patients with pathologic high-risk disease (pT3N0 and/or positive margins) (Table 19.19).

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Table 19.19 Clinical evidence for adjuvant radiation therapy for postoperative EBRT with pathologic high-risk disease

a

Trial

Description

SWOG 8794a

 Randomized 425 patients with T3N0M0 prostate cancer to 60 –64 Gy in 30 –32 fractions versus observation  The primary study endpoint was metastasis-free survival (MFS)  Updated results with median follow-up exceeding 12 years demonstrated a significant improvement in MFS (10-year estimate 71 versus 61%, HR: 0.71)  OS was improved with adjuvant RT (59 versus 48%, HR: 0.72), particularly noteworthy given that a third of the patients in the observation group received salvage RT  Subset analysis was unable to identify a subset of patients that should not receive RT

EORTC 22911b

 Randomized 1,005 patients with pT3 disease or positive surgical margins to observation versus 60 Gy  Initial results presented with median follow-up of 5 years demonstrated a significant improvement in biochemical PFS and locoregional failure, with immediate versus deferred postoperative RT  Updated analysis incorporating central pathology review described surgical margin positivity as the strongest predictor of prolonged biochemical DFS

ARO 96–02 (Germany)c

 Phase III trial randomizing patients with pT3N0 disease and (in contrast to the prior 2 studies) an undetectable PSA level after RP to adjuvant RT (60 Gy) versus observation  5-year results demonstrated a highly significant reduction in biochemical PFS (72 versus 54%, HR: 0.53) with acceptable toxicity (0.3% incidence of ≥grade 3 toxicity)

Source: Thompson IM, Tangen CM, Paradelo J et al (2009) Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term follow-up of a randomized clinical trial. J Urol 181:956 –962 b Sources: Bolla M et al (2005) Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 366:572–578; Van der Kwast TH et al (2007) Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 25:4178 –4186 c Source: Wiegel T et al (2009) Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96 -02/AUO AP 09/95. J Clin Oncol 27:2924 –2930

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The potential utility of hormonal treatment in the adjuvant setting has been addressed in RTOG 9601, a phase III randomized trial comparing prostate bed to 68.4 Gy in 36 fractions with 2 years of bicalutamide versus placebo. Results of this study are pending.

Metastatic Prostate Cancer (T1–4, N0–1, M1) Advanced prostate cancers include those with distant metastases or nonregional lymph node metastases. Treatment of stages IVb and IVc patients usually requires ADT and palliative radiation therapy for symptomatic foci.

Treatment of Recurrent Prostate Cancer An estimated 20 –40% of prostate cancer patients will experience an increasing PSA level within 10 years of definitive local treatment. Diagnostic evaluation seeks to distinguish local recurrence versus systemic metastases, and may include physical examination, laboratory evaluation, computed tomography (CT) and/or magnetic resonance imaging (MRI) scans, MRI spectroscopy, and/or ProstaScint scanning. No phase III trials have addressed the efficacy and toxicity of salvage radiation therapy and, therefore, treatment decisions are typically made based on:  Patient’s performance status and comorbidities  Postoperative PSA level  Pathologic Gleason grade, extent of disease  Margin status Salvage RT appears less efficacious than adjuvant treatment is (Figure 19.8). A retrospective multicenter analysis of a cohort of 501 patients who underwent postprostatectomy salvage radiotherapy demonstrated a 4-year progression-free probability of 45%, which was significantly predicted by Gleason score 8–10, preradiotherapy PSA level ≥2.0 ng/ml, negative surgical margins, PSA doubling time ≤10 months, and seminal vesicle invasion.

Radiation Therapy Techniques External Beam Radiation Therapy for Definitive Therapy IMRT represents the current standard of care for prostate EBRT.

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Simulation for IMRT Modern prostate EBRT requires accurate patient setup at the time of simulation (Table 19.20). Table 19.20 Patient set up and planning for prostate cancer IMRT Aspect

Details

Patient preparation

 Patients should be instructed to present with an empty rectum and comfortably full bladder  Patients are positioned either supine or prone (with or without a rectal balloon depending on institutional practice) on a custom immobilization device

Planning imaging

 A volumetric CT scan employing a slice thickness ≤3 mm is obtained through the volume of interest and imported into a computer for organ segmentation and treatment planning  A urethrogram or, alternatively, MRI fusion, is employed to delineate the prostatic apex. MRI fusion enhances definition of the prostate-rectum interface, the prostatic apex, and neurovascular bundles. The use of a T2-weighted volumetric sequence is suggested.  When MRI fusion is not available, contouring fidelity can be improved by inspection of the prostate contours on a sagittal CT image and recognition of anatomic structures (e.g., GU diaphragm)

Intra-/ interfraction changes

 Given susceptibilities for organ deformation, intra- and interfraction organ motion, IMRT is typically combined with daily image guidance.  A variety of methods, including ultrasound, fiducial implantation and KV imaging, KV cone-beam CT, MVCT, and intrafraction tracking using transponders are in clinical use  Pelvic radiation using IG-IMRT and incorporating intraprostatic fiducial markers can reduce the volumes of rectum and bladder receiving high doses thus reduce toxicities

kV: kilovoltage; MVCT: megavoltage CT

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Target Delineation The optimal strategy for target delineation, especially whole-pelvic lymph nodes versus prostate-only radiation therapy, has not been determined. Two clinical trials have addressed this issue with inconclusive results (Table 19.21). Table 19.21 Clinical evidence on the optimal selection of radiation portal: whole-pelvis versus prostate-only radiation therapy Randomized trial

Description

RTOG 94-13a

 A 4-arm randomized trial attempted to discern the relative merits of pelvic nodal irradiation versus prostate-only EBRT in patients with an estimated risk of lymph node involvement of 15%, and timing (adjuvant versus neoadjuvant and concurrent) of hormonal therapy  The total duration of hormonal treatment was 4 months  An OS difference was seen among all study groups, yet there were no significant differences in PFS or OS between neoadjuvant versus adjuvant hormones, or pelvis versus prostate-only radiation  When neoadjuvant hormone therapy is used in conjunction with EBRT, pelvic nodal irradiation yields an improved PFS versus prostate-only RT  Neoadjuvant hormones plus pelvic nodal RT improved OS versus adjuvant hormones plus pelvic nodal RT  Late severe GU toxicities were similar in the 4 arms, though severe GI toxicities were more frequent in the neoadjuvant hormone and whole-pelvis arm

GETUG-01b

 Randomized phase III trial also studied the role of pelvic  and prostate versus prostate-only RT  The trial stratified patients according to risk of lymph  node involvement  Initial results with limited follow-up of 42 months demon strated indicated no significant differences in 5-year PFS between the study groups, either in the high or low-risk strata

PFS: progression-free survival; OS: overall survival; DFS: disease-free survival; RT: radiation therapy a Sources: Roach M 3rd et al (2003) Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: RTOG 9413. J Clin Oncol 21:1904 –1911; Lawton CA et al (2007) An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys 69:646 –555 b Source: Pommier P et al (2007) Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01. J Clin Oncol 25:5366 –5373

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Definitions of gross target volume (GTV), clinical target volume (CTV), and planning target volume (PTV) in IMRT in prostate-only radiation include prostate on imaging studies as GTV, with 0.5- to 1-cm margins in 3D to achieve PTV (per RTOG protocols). The CTV of seminal vesicles and pelvic lymph node regions (if select to treat) are defined in Table 19.22. The probability of involvement can be determined by stage, pretreatment PSA, PSA doubling time and/or velocity, highpercent biopsy core involvement, the presence of perineural invasion, and the Roach formulas and/or Partin tables. The commonly used Roach formulas are detailed in Table 19.4. Table 19.22 CTV of seminal vesicle and/or pelvic lymph nodes Organ

Coverage for >15%a chance of involvement

Seminal vesicle

 Include the proximal 1 cm, as this volume is thought at  highest risk for microscopic involvement  Volume reduction to include the prostate only after  45–55.8 Gy is typically employed in such cases

Pelvic nodes

 Include distal common, internal, and external iliac re gions, presacral, and obturator regions  Contouring can be accomplished by outlining the corre sponding vasculatures with margin

a

Typical thresholds for inclusion of SV/pelvic nodes are set by probability of involvement exceeding 15%

Salvage Treatment

Local recurrence and slow PSA doubling times

Distant recurrences, or with short PSA doubling times

Prostatectomy, pelvic irradiation, or brachytherapy*

Chemotherapy, ADT, and/or local treatment**

* Depending on initial treatment ** Recommend clinical trial setting

Figure 19.9 Suggested salvage treatment for prostate cancer recurrence

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The RTOG has recently published consensus guidelines for postprostatectomy prostate bed CTV definition (Figure 19.9). Structures of interest and lymph nodal regions (CTV) contouring recommendations are listed in Table 19.23. Table 19.23 Structures of interest and lymph nodal regions (CTV) contouring recommendations in IMRT for prostate cancer CTV

Recommendation

Structures of interest

 Vesicourethral anastomosis (VUA)   Anterior rectal wall   Levator ani and obturator internus muscles   Mesorectal fasia   Posterior bladder wall   Vas deferens   Sacrorectogenitopubic fascia 

Lymph node contouring

 Add 7 mm around iliac vessels, carving out bowel, blad der, and bone  Commence contouring at distal common iliac vessels at  L5–S1 interspace  Stop external iliac contours at top of femoral heads  (boney landmark for inguinal ligament)  Stop contours of obturator nodes at top of pubic symphysis   Subaortic presacral lymph nodes are included in CTV 

Dose and Treatment Delivery Conventional fractionation to a total dose of >72 Gy is recommended. As detailed above, dose escalation does not increase acute or late adverse effects if conformal therapy is used, but may improve biochemical failure rates.

Interstitial LDR Brachytherapy Preparation of LDR Brachytherapy Suitable candidates for LDR brachytherapy are dispositioned for treatment by using either a preplanned or intraoperative technique (Table 19.24). Radiation precautions should be carefully explained to the patient and written guidelines provided. Important discussion topics should include handling of any seeds passed in the urine, minimizing radiation exposure to small children and pregnant women, and condom use during the initial postimplant period.

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Table 19.24 Comparison of the preplanned and intraoperative LDR implant procedures Techniques

Procedure of implant

Preplanned (Seattle) technique

 Utilizes a volume study prior to the date of the procedure  A transrectal ultrasound is used to capture sequential axial images of the prostate in 0.5-cm increments  A planning target volume is constructed to provide dosimetric margin around the prostate volume and including the proximal 1 cm of the seminal vesicles  Offline planning is performed to determine an optimal seed implantation pattern using the principle of modified uniform peripheral loading to limit the urethral dose to less than 150% of the prescription dose  The required seeds (typically in combination of loose and stranded patterns) are ordered and the patient scheduled for the implant procedure

Intraoperative method

 Performs the planning and implant steps in a single procedure  The operative procedure involves patient positioning in the lithotomy position, with careful matching of preimplant positioning if applicable  Has the advantages of improved patient convenience, decreased use of resources, potentially improved dosimetric conformality, and minimal change in patient positioning

The use of a high-resolution biplanar ultrasound is recommended Needle insertion is performed under direct TRUS guidance using a template and “stepping unit,” which allows the probe to be moved in and out using 0.5-cm increments A post-implant cystoscopy may be performed to remove potential blood clots and misplaced seed in the urethra or bladder. Fluoroscopy may also be used to assess the adequacy of seed placement

Dose and Treatment Delivery 125

I or 103Pd are the two most commonly used radioactive isotopes for prostate cancer LDR brachytherapy. The current American Brachytherapy Society (ABS) prescription recommendations considered both the revised dosimetry and longstanding clinical experience and outcomes. Isotope choice remains arbitrary (Table 19.25).

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Table 19.25 American Brachytherapy Society prescription guidelines for LDR prostate brachytherapy Isotopea

Energy (keV)

Half-life (days)

Monotherapy dose (Gy)

Boost dose (Gy)

125

28

59.4

145

100 –110

21

17

125

90 –100

I

103

Pd

a

The ABS does not recommend the routine use of one radionuclide over the other due to lack of conclusive clinical evidence. Source: Rivard MJ, Butler WM, Devlin PM et al (2007) American Brachytherapy Society recommends no change for prostate permanent implant dose prescriptions using iodine-125 or palladium-103. Brachytherapy 6:34 –37

Routine assessment of post-implant CT dosimetry (typically performed within 30 days post-implant in a consistent fashion in consideration of postimplant edema) is advocated by the ABS. Post-implant dosimetry provides prognostic information and may identify systematic technical errors. The ABS recommendations include urethral delineation and reporting of the urethral dose to 5% of the volume (UrD5), UrD30, and UrV150 (urethral volume receiving 150% of the prescription dose). The rectal wall should be delineated and RV100 and RV150–the corresponding volumes of the rectal wall receiving the threshold doses–calculated. To evaluate target coverage, the dose relative to the prescribed dose (D90) criterion is typically used, and is associated with improved outcomes in a multi-institutional multivariate analysis.

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EBRT for Adjuvant Therapy Simulation and Target Volume Delineation The recently published RTOG consensus document represents a valuable guideline for postoperative target delineation, either in the adjuvant or salvage setting (Table 19.26). Examples of CTV delineation for positive apical margins, after biochemical failure, and extracapsular extension at the base and involvement of seminal vesicle are presented in Figures 19.10 and 19.11).

Table 19.26 Anatomical borders of postoperative CTV for prostate cancer Location

Comments

Below the superior edge of the symphysis pubis Anterior

Posterior edge of pubic

Posterior

Anterior rectal wall

Inferior

8–12 mm below vesicourethral anastomosis

Lateral

Levator ani muscles, obturator internus

May need to be concave around lateral aspects May include more if concern for apical margin. Can extend to slice above penile bulb if vesicourethral anastomosis not well visualized

Above the superior edge of the symphysis pubis Anterior

Posterior 1–2 cm of the bladder wall

Posterior

Mesorectal fascia

Superior

Level of cut end of vas deferens or 3–4 cm above top of symphysis

Lateral

Sacrorectogenitopubic fascia

Vas might retract postoperative; include seminal vesicle remnants if pathologically involved If concerned about extraprostatic disease at base, may extent to obturator internus

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a

b

c

d

e

Figure 19.10 a–e Representative pelvic lymph node clinical target volume (CTV) contours from consensus CT. a Common iliac and presacral CTV lymph node volumes (L5/ S1). b External, internal, and presacral CTV lymph node volumes (S1–S3). c External and internal Iliac CTV lymph node volumes (below S3). d End of external iliac CTV lymph node volumes (at top of femoral head, boney landmark for the inguinal ligament). e Obturator CTV lymph node volumes (above the top of the pubic symphysis). Source: Lawton CA, Michalski J, El-Naqa I et al (2009) RTOG GU radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 74:383–387. Used with permission

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Figure 19.11 Examples of consensus contours for patients with apical positive margins and biochemical recurrence

Figure 19.12 Examples of consensus contours for patient with extracapsular extension at base and involvement of seminal vesicle. Source: Michalski JM, Lawton C, El Naqa I et al (2010) Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 76:361–368. Used with permission

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Dose and Treatment Delivery Whereas the phase III randomized trials for adjuvant RT utilized 60 –64 Gy, image-guided IMRT may allow safe dose escalation and improvement in therapeutic ratio, with acceptable toxicity levels. A total dose of 65–68 Gy and 66 –70 Gy for adjuvant and salvage treatment, respectively, in conventional fractionation is recommended.

Normal Tissue Tolerance Organs at risk (OARs) in EBRT of prostate cancer, in both adjuvant and definitive settings, include rectum and bladder. Suggested DVH constraints for dose-escalated IMRT (prescribed to deliver 79.2 Gy in 44 fractions) are listed in Table 19.27, below. Table 19.27 RTOG DVH constraints for prostate cancer Organ

Dose limit to specified percentage of organ volume (Gy) 15%

25%

35%

50%

Bladder

80

75

70

65

Rectum

75

70

65

60

Source: RTOG active protocols. http://rtog.org/members/active.html. Cited 15 May 2010

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Follow-Up Posttreatment surveillance aims to identify suitable candidates for salvage therapy, potentially preventing disease dissemination (Table 19.28). Salvage therapy is advocated for (1) postprostatectomy patient(s) with failure of PSA to fall to undetectable levels, or with detectable PSA that increases on two subsequent measurements or (2) post-RT patients with rising PSA ≥2 ng/ml above the nadir or with positive DRE. Table 19.28 Follow-up schedule and examinations Schedule

Frequency

First follow-up

 4 –6 weeks after radiation therapy

Years 0–1

 Every 3–4 months

Years 2–5

 Every 6 months

Years 5+

 Annually

Examination History and physical

 Complete history and physical examination  Annual DRE

Laboratory tests

 PSA every 6 –12 months for 5 years then annually  Other lab tests based on clinical indication only

Imaging studies

 Based on clinical indication only

20

Testicular Cancer Ugur Selek1

Key Points  Testicular cancer is a well-treatable and often curable cancer of mainly young and middle-aged men.  Testicular cancer is roughly divided into seminoma and nonseminoma types for treatment planning due to highly radiosensitive seminomas.  The cure rate of seminoma (all stages combined) exceeds 90%, and approaches 100% for early-stage diseases.  The tumor, node, metastasis (TNM) staging system is used for staging for seminoma.  The serum markers are important for the diagnosis and follow-up including alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (-hCG), and lactate dehydrogenase (LDH).  A computed tomography (CT) scan to evaluate the retroperitoneal lymph nodes is important for staging. However, 25–30% of patients with negative scans have microscopic disease. Nonseminoma frequently requires surgical staging.  Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the standard procedure for diagnosis and treatment. Biopsy prior to orchiectomy is usually not recommended.  Radiation or chemotherapy is the option for adjuvant therapy in stage I low-risk seminoma.  High-risk stage I seminoma (tumor ≥4 cm or Rete testis invasion) and stage IIB cases (nodal disease <5 cm) are recommended radiotherapy.  For more extensive diseases, i.e., stage IIC or higher, chemotherapy is the treatment choice for adjuvant therapy.  Follow-up is recommended to detect second primary tumors, local or distant recurrences, and to monitor for potential long-term side effects.

1

Ugur Selek, MD () Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_3, © Springer-Verlag Berlin Heidelberg 2011

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Incidence and Genetics An estimated 8,480 new cases of testicular cancer will be diagnosed in the USA in 2010, and ~350 patients died from the disease. Testicular cancer is more commonly diagnosed in Caucasians. The age-adjusted testicular cancer incidence rate is ~6 per 100,000 Caucasian men annually, as compared with 1.5 and 3.8 per 100,000 in African-American and Hispanic males, respectively. A number of risk factors have been identified for testicular cancer and are listed in Table 20.1. Table 20.1 Risk factors for testicular cancer Factor

Description Age: the median age at testicular diagnosis is ~35 years Approximately 75% of cases are diagnosed between ages 20 and 44 years History of cryptorchidism: 10- to 40-times increased risk of testis cancer, and 10% of patients with germ cell tumors have a history of cryptorchidism. Abdominal testis is more likely to be seminoma, testis brought to scrotum by orchiopexy is more likely to be non-germ cell tumors (NSGCT)

Patient related

Bilateral disease: ~1–3% of testicular cancer cases are bilateral Family medical history: significant familial history increases fourfold in a male with a father who had a germ cell tumors (GCT), and ninefold with an affected brother Genetic predisposition: amplifications and deletions are observed mainly in the 12p11.2–p12.1 chromosomal regions. 12p Sequence gain is seen with invasive growth of both seminomas and NSGCTs. Chromosome 9 gain points out spermatocytic seminoma. The incidence of contralateral CIS (carcinoma in situ) in a patient with testicular carcinoma is 5% (50% of them develop carcinoma in 5 years)

Environmental

Industrial chemicals: workers in manufacturing 2-naphthylamine, benzidine, gasoline derivatives have ~fivefold increased risk

Sources: Hemminki K, Li X (2004) Familial risk in testicular cancer as a clue to a heritable and environmental aetiology. Br J Cancer 90(9): 1765-70. Miller FH, Whitney WS et al (1999). “Seminomas complicating undescended intraabdominal testes in patients with prior negative findings from surgical exploration.” AJR Am J Roentgenol 172(2): 425-8

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Anatomy and Routes of Spread As the embryonic origin of testis is pertinent to the pattern of lymphatic spread, they are addressed together in Table 20.2. Table 20.2 Origin and pattern of spread of testicular cancer Origin/spread

Route(s)

Embryonic origin

 The testis starts descending through the inguinal canal to the scrotal sac from the genital ridge, located near the second lumbar vertebra  Testicular lymphatics accompany the vessels of the spermatic cord through the inguinal canal and into the retroperitoneum

Local spread

Local extension involves the rete testis, epididymis, or spermatic cord but rarely areas outside the tunica albuginea

Distant metastasis

Lymphatic route is the predominant way of spread of seminoma, while nonseminoma favors hematogenous spread.  Retroperitoneal nodes  posterior mediastinal nodes  left supraclavicular nodes  Iliac nodes  Inguinal nodes (very rare)  The right testis: drainage is along the inferior vena cava first into the inter-aortocaval region, then to the pre-aortic and para-aortic lymph nodes, with possible cross-over within the retroperitoneum  The left testis: drainage is first into the nodes of preaortic and para-aortic lymph nodes around the left renal hilum and then to the inter-aortocaval nodes mostly without cross-over

Lymphatic route

 The retroperitoneal lymph nodes are located anterior to the T11 to L4 vertebral bodies concentrated at the L1–L3 level  Nodal spread to iliac chain is ipsilaterally but infrequent (~3%)  Inguinal node spread is less than 5% without lymphatic disruption by prior surgery  Scrotal skin: lymphatics drain into the inguinal and external iliac nodes regardless of the testicular lymphatics. The organization of lymphatics reasons the orchiectomies through inguinal route, which avoids possible violence of the inguinal drainage basin

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Pathology Table 20.3 summarizes the distribution of testicular tumors. Table 20.4 details the characteristics of different histological subtypes commonly diagnosed. Table 20.3 Pathology subtypes of testicular tumors Tumor type

Incidence(%)

Germ cell tumor (GCT)

95%

Non-GCT (NGCT)

5%

Subtypes

Indicence (%)

Semimona

40%

Non-seminoma

60%

Lymphoma, rhabdomyosarcoma, melanoma or stromal tumors (Sertoli or Leydig cell tumors)

Intratubular germ cell neoplasia (IGCN) may be a precursor of all types of GCT except for spermatocytic seminoma and infantile testicular cancer. Invasive component of GCT usually accompanies adjacent IGCN, and approximately 5% of patients with unilateral GCT have IGCN in the contralateral testicle. Sources: Jacobsen GK, Henriksen OB, Vonder Maase H et al (1981) Carcinoma in situ of testicular tissue adjacent to malignant germ-cell tumors: a study of 105 cases. Cancer 47:2660–2002; Coffin CM, Ewing S, Dehner LP et al (1985) Frequency of intratubular germ cell neoplasia with invasive testicular germ cell tumors. Histologic and immunocytochemical features. Arch Pathol Lab Med 109:555–559; Dieckmann KP, Skakkebaek NE et al (1999) Carcinoma in situ of the testis: review of biological and clinical features. Int J Cancer 83:815–822

Table 20.4 Characteristics of commonly diagnosed histological subtypes of testicular cancers Pathologic subtypes

Characteristics of disease

Seminoma

Classic

 85% of seminomas are of the classic variety  The new Armed Forces Institute of Pathology (AFIP) classification allows for a variant containing syncytiotrophoblastic cells

Anaplastic

 10–12% of cases have increase nuclear pleomorphism  Tends to be more aggressive but equally radiosensitive  No longer included as a separate entity by the elderly AFIP

Spermatocytic

 4–6% and mostly diagnosed in advanced–age patients  Very well differentiated, with excellent prognosis  Low probability for distant metastasis

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Table 20.4 (continued) Pathologic subtypes

Characteristics of disease

Non-seminoma Embryonal cell carcinoma

 Accounts for 20% of germ cell tumors  Known as yolk sac tumor or endodermal sinus tumor in infants

Choriocarcinoma

 Less than 1% of germ cell tumors  Very high β-hCG at presentation  Highly malignant

Teratoma

 5% of germ cell tumors  Contains elements of ectoderm, endoderm, and mesoderm. Benign in infants but may metastasize in adults

Mixed

 Nearly 40% contain elements of more than one type of tumor, i.e., showing more than one histologic pattern  Teratocarcinoma is the most common form

Clinical Presentation Table 20.5 summarizes the key points of clinical presentation and diagnosis. Table 20.5 Clinical presentation of testicular cancer Characteristics

Presentation

Age at presentation

Between 15 and 35 years old

Pain

Rare, usually painless testicular lump: testicular swelling possibly accompanied by swelling in cases of orchitis or epididymitis

Frequent differential misdiagnoses

Epididymo-orchitis or hydrocele

Fertility

Might have abnormal semen analysis at presentation (subfertile)

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Diagnosis, Staging, and Prognosis Figure 20.1 reviews the algorithm steps to be taken in case of a suspicious testicular mass. There is no role for trans-scrotal biopsy in the diagnosis of testicular tumors.

Seminoma Suspected

Complete History and Physical Examination

Serum Chemistry & Serum Tumor Markers (Table 20-6) α-FP β-hCG LDH

Recommended Chest X-ray Abdomen and Pelvis CT Optional Testicular Ultrasound Thorax CT (if + chest X-ray or abdominopelvic CT) FDG PET Imaging Studies

Lab Studies

Discuss Sperm Banking

Radical Inguinal Orchiectomy with high ligation of the spermatic cord

Figure 20.1 The algorithm steps to be taken in a case of a suspicious testicular mass

Fluorodeoxyglucose-positron emission tomography (FDG–PET) has no benefit over computed tomography (CT) alone except restaging for residual masses (ability to differentiate fibrotic residual mass from residual tumor) (Source: Spermon JR, De Geus-Oei LF, Kiemeney LA et al (2002) The role of 18fluoro-2-deoxyglucose positron emission tomography in initial staging and re-staging after chemotherapy for testicular germ cell tumours. BJU Int

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89:549–556; Tsatalpas P, Beuthien-Baumann B, Kropp J et al (2002) Diagnostic value of 18F-FDG positron emission tomography for detection and treatment control of malignant germ cell tumors. Urol Int 68:157–163; Hinz S, Schrader M, Kempkensteffen C et al (2008) The role of positron emission tomography in the evaluation of residual masses after chemotherapy for advanced stage seminoma. J Urol 179: 936–940; discussion 940). Table 20.6 details the characteristics of serum markers commonly used in the diagnosis and staging of testicular cancer. Table 20.6 Serum markers of testicular cancer Serum markersa

AFP

β-hCG

LDH

Half-lifeb

Characteristics

5–7 days

 A glycoprotein produced in the yolk sac, liver, and gastrointestinal tract  Nonseminoma, presence without underlying cause for elevation shifts patient into treatment of NSGCT  False positivity seen in: smoking (≈10% elevation), pregnancy, alcohol abuse, cirrhosis, hepatitis, inflammatory bowel disease, ataxia telangiectasia, Wilson’s disease, hereditary tyrosinosis, WiskottAldrich syndrome

24–48 h

 Produced in the syncytiotrophoblastic cells, both seminoma and nonseminoma  Measurement of the beta subunit reduces luteinizing hormone (LH) cross-reactivity  Marker after resection for seminoma used for surveillance

N/A

 Elevated in both seminoma and nonseminoma  Mainly used in response evaluation if increased initially

AFP: -fetoprotein; -hCG: -human chorionic gonadotropin; LDH: lactate dehydrogenase a Serum markers need to be evaluated at initial diagnosis, and during and after the treatment for response. Level for diagnosis must be drawn preoperatively due to rapid fall after orchiectomy b Prolonged half-life times implies the presence of residual disease after orchiectomy

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Staging The first-echelon lymph nodes for seminoma is retroperitoneal (stage II). The next level lies proximally to mediastinal and supraclavicular lymph nodes (stage IIIA). Advanced disease is rare with lung (stage IIIA) and non-pulmonary (bone, liver and brain) (stage IIIC) involvement. Staging of testicular tumor aim to determine the tumor (T), node (N), metastasis (M), and serum tumor marker (S) classifications. Clinical examination (i.e., assessments indicated in the diagnostic and staging algorithm) and histologic evaluation are required for clinical staging, and histologic evaluation of the radical orchiectomy specimen is used for primary tumor (pT) classification. The modified Royal Marsden Hospital staging system was the previous staging system (Table 20.7). The American Joint Committee on Cancer (AJCC) TNM staging system (2009) is the currently recommended staging system (Tables 20.8 and 20.9). Approximately 85% of pure seminoma is localized (i.e., stage I). Table 20.7 Modified Royal Marsden Staging System for seminoma Stage

Description

I

Tumor confined to the testis

II

Infradiaphragmatic nodal involvement

IIA

Greatest dimension of involved nodes < 2 cm

IIB

Greatest dimension of involved nodes ≥2 cm but < 5 cm

IIC

Greatest dimension of involved nodes 5 cm or more but < 10 cm

IID

Greatest dimension of involved nodes ≥10 cm

III

Supraclavicular or mediastinal involvement

IV

Extranodal metastases

Source: Thomas G, Jones W, VanOosterom A et al (1990) Consensus statement on the investigation and management of testicular seminoma 1989. Prog Clin Biol Res 357:285–294

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Table 20.8 AJCC TNM staging for seminoma Stage

Description

Primary tumor (T)a pTX

Primary tumor cannot be assessed

pT0

No evidence of primary tumor (e.g., histologic scar in testis)

pTis

Intratubular germ cell neoplasia carcinoma in situ

pT1

Tumor limited to the testis and epididymis without lymphatic/vascular invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis

pT2

Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis

pT3

Tumor invades the spermatic cord with or without vascular/lymphatic invasion

pT4

Tumor invades the scrotum with or without vascular/lymphatic invasion

Regional lymph nodes (N) clinical NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis with a lymph node mass ≤2 cm in greatest dimension; or multiple lymph nodes ≤2 cm in greatest dimension

N2

Metastasis with a lymph node mass > 2 cm but ≤5 cm in greatest dimension; or multiple lymph nodes, any one mass > 2 cm but ≤5 cm in greatest dimension

N3

Metastasis with a lymph node mass > 5 cm in greatest dimension

Pathologic (pN) pNX

Regional lymph nodes cannot be assessed

pN0

No regional lymph node metastasis

pN1

Metastasis with a lymph node mass ≤2 cm in greatest dimension and less than or equal to five nodes positive, none > 2 cm in greatest dimension

pN2

Metastasis with a lymph node mass > 2 cm but ≤ 5 cm in greatest dimension; or more than five nodes positive, none 5 cm; or evidence of extranodal extension of tumor

pN3

Metastasis with a lymph node mass > 5 cm in greatest dimension

▶

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Table 20.8 (continued) Stage

Description

Distant metastasis (M) M0

No distant metastasis Distant metastasis

M1

M1a: nonregional nodal or pulmonary metastasis M1b: distant metastasis other than to nonregional lymph nodes and lungs

Serum tumor markers (S)

a

SX

Marker studies not available or not performed

S0

Marker study levels within normal limits

S1

LDH less than 1.5 × Nb hCG less than 5,000 (mIU/ml) AFP less than 1,000 (ng/ml)

S2

LDH 1.5–10 × Nb or hCG 5,000–50,000 (mIU/ml) or AFP 1,000–10,000 (ng/ml)

S3

LDH more than 10 × N or hCG more than 50,000 (mIU/ml) or AFP more than 10,000 (ng/ml)

Except for pTis and pT4, the extent of primary tumor is classified by radical orchiectomy. TX may be used for other categories in the absence of radical orchiectomy b N indicates the upper limit of normal for the LDH assay Source: Seventh Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Handbook, Testis, Chapter 42, page 539-546, Springer-Verlag, New York, NY (2010)

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Table 20.9 Stage grouping of testicular cancer Stage

Group

0

pTis, N0, M0, S0

IA

pT1, N0, M0, S0

IB

pT2–4, N0, M0, S0

IS

Any pT/Tx, N0, M0, S1–3

IIA

Any pT/Tx, N1, M0, S0–1

IIB

Any pT/Tx, N2, M0, S0–1

IIC

Any pT/Tx, N3, M0, S0–1

IIIA

Any pT/Tx, any N, M1a, S0–1

IIIA

Any pT/Tx, N1–3, M0, S2 Any pT/Tx, any N, M1a, S2

IIIC

Any pT/Tx, N1–3, M0, S3 Any pT/Tx, any N, M1a, S3 Any pT/Tx, any N, M1b, any S

Source: Seventh Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Handbook, Testis, Chapter 42, page 539-546, Springer-Verlag, New York, NY (2010)

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Prognostic Factors The commonly reported prognostic factors for stage I seminoma and effects on disease-free survival (DFS) are listed in Table 20.10. The only prognostic factor described for stage II seminoma is the bulk of the lymphadenopathy: Local recurrence related with size could be approximately summarized as 6% for tumor (T) < 3 cm, 18% for T = 3–6 cm, 36% for T > 6 cm. Factors independently predict worse prognosis for non-seminomatous cancer include presence of liver, bone, or brain metastases: very high serum markers, primary mediastinal nonseminoma, and large number of lung metastases. Table 20.10 Prognostic factors for stage I seminoma Factor

Effects on long-term DFS (%) (+)

(−)

Post-orchiectomy elevated -hCG

87%

97%

Spermatic cord involvement

86%

98%

Lymphovascular invasion

51%

78%

Size of tumor (≥4 cm versus <4 cm)

76%

87%

Age (<34 versus >34 years old)

70%

91%

Source: Dosmann MA, Zagars GK et al (1993) Post-orchiectomy radiotherapy for stages I and II testicular seminoma. Int J Radiat Oncol Biol Phys 26:381–390

Treatment Principles and Practice Treatment for testicular cancer including surgery, followed by active surveillance, radiation therapy, or chemotherapy (Table 20.11). Current standard approach for initial diagnosis is radical inguinal orchiectomy with high ligation without scrotal violation. Scrotal violation (secondary to trans-scrotal biopsy) is associated with increased local/regional recurrence and should be avoided. Seminoma is extremely radiosensitive. Radiation therapy is often used for adjuvant therapy for early-stage seminoma, and its use in non-seminoma germ cell tumors (GCT) is limited. Hence, the following discussion is focused on the treatment of seminoma.

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Table 20.11 Adjuvant treatment modalities Treatment

Description

Radiation therapy Indications

 Adjuvant therapy after orchiectomy for stages I–IIb diseases  Salvage of locoregional failure after surgery or chemotherapy  Palliative treatment to locoregional or distant metastatic sites

Techniques

 External-beam radiation therapy to regional lymph nodes using high-energy radiation  Doses range 20–30 Gy (2 Gy per fraction) depends on extent of disease

Chemotherapy Indications

 As an alternative to adjuvant radiation therapy for stages I–II seminoma  Adjuvant therapy for stages II–IV seminoma

Regimens

 Single-agent carboplatin become an alternative to radiation therapy for adjuvant treatment for stage I seminoma  A number of regimens including BEP, EP, PVB, and VIP have been used and reported for stages II–IV diseases (Table 20.13)

Surveillance Indications

 An option, as potentially 80–85% of patients will not develop recurrence, and salvage by radiotherapy or chemotherapy is effective if recurs  Contraindicated in tumor >6 cm (>4 cm, HR 2), elevated post-orchiectomy β-HCG, spermatic cord invasion, and noncompliance

Facts/issues

 Costly and inconvenient

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An adjuvant treatment algorithm for seminoma after radical orchiectomy is summarized in Figure 20.2a,b. Chemotherapy is standard approach for stages III and IV.

Seminoma Stage I

High Risk Factors ≥ 4 cm Rete testis invasion

High Risk

Low Risk

- Paraaortic Radiotherapy

- Surveillance - Paraaortic Radiotherapy - Single dose Carboplatin

a

Seminoma Stage II

Nonbulky Node

Bulky Node (≥ 5 cm)

Paraaortic & Ipsilateral Iliac Nodal Radiotherapy

Chemotherapy

b

Figure 20.2 a, b a Adjuvant treatment algorithm for stage I seminoma after radical orchiectomy. b Adjuvant treatment algorithm for stage II seminoma after radical orchiectomy

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Treatment for Stages I–II Seminoma After definitive surgery, adjuvant radiation therapy, chemotherapy, or active surveillance are options for management of patients with stage I seminoma. Regional lymph node irradiation has been the most commonly used adjuvant therapy, and relapse-free survival is >95% for stage I and 80% for stage II diseases after orchiectomy and radiation. Single-agent chemotherapy and active surveillance are valid options after orchiectomy in stage I seminoma. Evidence supporting their use is listed in Table 20.12. Table 20.12 Evidence supporting the use of adjuvant chemotherapy or surveillance after surgery for early-stage seminoma Trial

Description

MRC/EORTC b

 Compared 1 course of carboplatin (C) at AUC × 7a with adjuvant radiotherapy (RT) for stage I seminoma  Found equivalent relapse rates after a median followup period of 4 years  The results indicate that a single cycle of outpatient carboplatin is not inferior to radiotherapy  Updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214) with 6.5 years of follow-up with documented minimum 5 years on 1,148 patients revealed relapse-free rates at 5 years as 95% (C) and 96% (RT)  There was a significant difference in the rate of new GCTs (2 on C versus 15 on RT)  Analysis of the available data on pathological risk factors demonstrated that larger tumors (>4 cm) had poorer RFR (HR: 3.68)

Von der Masse et alc

 Retrospective review of 261 patients observed without any selection criteria  The failures were mostly within 3 years, and the relapse rate was 19% (15% paraaortic, 2% pelvic, 1% inguinal, and 1% lung)  Only prognostic factor for relapse free survival at 4 years was tumor size >6 cm (94 versus 64%)  11% of the patients who recurred and were salvaged had second relapse

Warde and Gaspodarowicz d

 Retrospective review of 172 surveillance patients demonstrating 18% failure (age younger than 34 years was the only predictor) ▶

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Table 20.12 (continued) Randomized trial

Description

Duchesne et ale

 Retrospective study of 133 surveillance patients  Relapse rate of 16% at 3 years

Warde et alf

 A pooled analysis of 638 patients from the four largest surveillance studies (Princess Margaret Hospital, Danish Testicular Cancer Study Group, Royal Marsden Hospital, and Royal London Hospital)  With a median follow-up of 7 years, multivariate analysis revealed tumor size (≤4 cm versus >4 cm, HR 2, DFS (87 versus 76%), and invasion of the rete testis (HR 1.7, DFS of 86 versus 77%) remained as important predictors for relapse  Lymphovascular invasion was not a significant prognosticator

AUC: target area under the concentration versus time curve in mg/ml·min a Carboplatin dosing: total dose (mg) = (target AUC) × (GFR + 25) b Sources: Oliver RT, Mason MD, Von der Maase H et al (2005) Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 366:293–300; Oliver RT, Mead GM, Fogarty PJ et al (2008) Radiotherapy versus carboplatin for stage I seminoma: Updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214). J Clin Oncol 26:Abstract 1 c Source:Von der Maase H, Specht L, Jacobsen GK et al (1993) Surveillance following orchidectomy for stage I seminoma of the testis. Eur J Cancer 29A:1931–1934 d Source: Warde P, Gospodarowicz MK, Panzarella T et al (1995) Stage I testicular seminoma: results of adjuvant irradiation and surveillance. J Clin Oncol 13:2255–2262 e Source: Duchesne GM, Stenning SP, Aass N et al (1997) Radiotherapy after chemotherapy for metastatic seminoma – a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 33:829–835 f Source: Warde P, Specht L, Horwich A et al (2002) Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 20:4448– 4452

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Treatment for Stages II–IV Seminoma Four cycles of chemotherapy (Table 20.13) after definitive surgery is recommended for stage II (if nodal mass >5 cm) and stages III–IV seminoma. Empiric radiation of residual persistent abnormalities that is ≥3 cm is controversial (Source: Duchesne GM, Stenning SP, Aass N et al (1997) Radiotherapy after chemotherapy for metastatic seminoma – a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 33:829–835). Table 20.13 Treatment for stages II–IV seminoma

Regimens

Chemotherapeutic agents

BEP

Bleomycin plus etoposide plus cisplatin

EP

Etoposide plus cisplatin (in patients with good prognosis)

PVB

Cisplatin plus vinblastine plus bleomycin

VIP

Etoposide (VP-16) plus ifosphamide plus cisplatin (worse hematologic toxic effects)

In rare cases where chemotherapy is initiated before orchiectomy, the disappearance of testicular mass does not avoid orchiectomy (Source: Herr HW, Sheinfeld J, Puc HS et al (1997) Surgery for a post-chemotherapy residual mass in seminoma. J Urol 157:860–862).

Treatment for Non-seminomatous Testicular Cancer The non-seminomatous testicular cancers are less sensitive to radiation and chemotherapy, and spread rapidly. As radiation therapy plays a limited role, detailed discussion on the treatment of nonseminomatous testicular cancer is beyond the scope of this chapter. In general, radical orchiectomy and staging work-up is followed by observation, retroperitoneal lymph node dissection, or systemic chemotherapy.

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Radiation Therapy Techniques Preparation and Simulation Discussion on consequences of radiation therapy, including infertility is crucial, and sperm banking should be offered if appropriate. Table 20.14 summarizes the preparation and simulation for external-beam radiation therapy for seminoma. Table 20.14 Simulation for radiation therapy for seminoma Setup

Detail

Position and immobilization

Supine with a pillow or headrest placed behind the head, arms placed by the patient’s side and legs straight, with feet stabilized with a foam wedge underneath the knees

Slice thickness of CT

5 mm

Marks

Placed on the patient’s skin laterally as well as anteriorly for alignment

Intravenous contrast

Usually not necessary but may be administered to improve soft tissue and vascular definition

Shielding

Contralateral testis is shielded with a lead clamshell device. The mean dose values to the contralateral testicle in case of para-aortic (PA) or para-aortic and IL iliac (PAI) fields (PA: 1.86 versus 0.65 cGy; PAI: 3.89 versus 1.48 cGy, without or with gonadal shielding respectively)

Source: Bieri S, Rouzaud M, Miralbell R et al (1999) Seminoma of the testis: is scrotal shielding necessary when radiotherapy is limited to the para-aortic nodes? Radiother Oncol 50:349–353

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Target Volumes and Doses The recommended clinical target volumes (CTVs) and doses for adjuvant radiation therapy (RT) are described in Tables 20.15 and 20.16 for stage I and II seminoma, respectively. RT field for stage II disease are hockeystick field, including the para-aortic, paracaval, common iliac, and external iliac nodal regions (Figures 20.3, 20.4, 20.5, 20.6, and 20.7) (Source: Fossa SD, Horwich A, Russell JM et al (1999) Optimal planning target volume for stage I testicular seminoma: a Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 17:1146). Table 20.15 Radiation therapy field for stage I seminoma Aim

Description

Conventional block margins

   

Elective paraaortic nodal contouring

 Begin at T12–L1 interspace, finish at aortic bifurcation  Contour aorta and vena cava together as vessel contour (VC)

Elective CTV

 Paraaortic nodal CTV: VC plus 7 mm, excluding bones  For left testis: include renal hilum in CTV

Planning target volume (PTV)

 Depending on anticipated set-up accuracy, usually CTV plus 3–5 mm

Superior: T11–T12 interspace Inferior: L5–S1 interspace Lateral: transverse process For left testis: cover renal hilum

CTV: clinical target volume; PTV: planning target volume

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Table 20.16 Radiation therapy field for stage II seminoma Aim

Conventional block margins

Para-aortic nodal contouring

CTV nCTV (Positive Nodal CTV) PTV

Description  Superior: T11–T12 interspace  Inferior: mid-obturator foramen  Lateral: transverse process down to L5–S1 interspace, then diagonally to the lateral edge of the acetabulum, then vertically downward to the median border of the obturator foramen  For left testis: cover renal hilum  Begin at T12–L1 interspace, finish at obturator foramen  Contour aorta, vena cava and ipsilateral iliac nodes as VC  Stop iliac contours at top of femoral heads as a boney landmark for Inguinal ligament  Paraaortic nodal CTV: VC plus 7 mm, excluding bones  For left testis: include renal hilum in CTV  Gross tumor volume plus 1 cm, excluding bones  Usually 2-cm margin around the node to the block margin  Depending on anticipated set-up accuracy, usually CTV (CTV plus nCTV) plus 3–5 mm

Sources: Classen J, Schmidberger H, Meisner C et al (2003) Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol 21:1101–1106; Dosmann MA, Zagars GK (1993) Post-orchiectomy radiotherapy for stages I and II testicular seminoma. Int J Radiat Oncol Biol Phys 26:381– 390; Zagars G K, Pollack A (2001) Radiotherapy for stage II testicular seminoma. Int J Radiat Oncol Biol Phys 51:643–649

Figure 20.3 Clinic target volume (CTV) is generated by adding 7 mm to the contour of aorta and vena cava together as vessel contour (VC), with exclusion of bones

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Figure 20.4 Elective paraaortic field for stage I seminoma (from T11–T12 interspace to L5–S1 interspace)

Figure 20.5 Paraaortic and ipsilateral inguinal field for stage II left testicular seminoma, with inclusion of the renal hilus

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Figure 20.6 Paraaortic boost field for a 3-cm left lymphadenopathy for stage IIB left testicular seminoma to a total dose of 30 Gy covering nodal CTV

Figure 20.7 The 20-Gy dose line needs to cover T12 in sagittal view for stage I seminoma cases

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Clinical evidence favors the omission of prophylactic radiation therapy to both the mediastinum and neck. However, supraclavicular failure in stage IIa was 0% with mediastinal radiotherapy and 20% without mediastinal radiotherapy was reported (Source: Dosmann MA, Zagars GK (1993) Post-orchiectomy radiotherapy for stages I and II testicular seminoma. Int J Radiat Oncol Biol Phys 26:381–390). Prescription of RT and dose recommendations are summarized in Tables 20.17 and 20.18. Table 20.17 Prescription of radiation therapy in the treatment of seminoma Aspect

Amount

Reason

Normalization

As low as 95%

 To achieve optimal coverage in order to reduce the hourglass effect of the AP/PA beams

Ideal dose distribution

98% Isodose line

 Encompassing the entire treatment area and a hot spot no greater than 10% above the prescription dose

>10 MV

 Equal weighting on the AP/PA beams is optimal  PA beam may be weighted slightly more than the AP beam to reduce the dose to the small bowel

Energy

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Table 20.18 Recommended doses for radiation therapy for adjuvant treatment of seminoma with supporting clinical evidences Dose

Total (Gy)

Dose per daily fraction (Gy)

Elective (stage I)

20

2

Nodes <3 cm

26

2

Nodes 3–5 cm

30

2

MRC (EORTC 30942, MRC TE 18)a

 Randomized multi-institutional clinical trial compared 30 Gy (2 Gy/day) versus 20 Gy (2 Gy/day) adjuvant radiotherapy for stage I seminoma  20-Gy arm had equivalent relapse rates and reduced morbidity (mainly fatigue)

Fossa et al (MRC)b

 Randomized 478 men to receive PA versus PAI fields irradiation (30 Gy per 15 fractions)  No difference in relapse-free survival was detected  Slightly more pelvic recurrences in PA alone group: the risk of hemipelvic failure is ~3%; and the risk of mediastinal failure is ~2%

MRC: Medical Research Council; EORTC: European Organization for the Research and Treatment of Cancer a Source: Jones WG, Fossa SD, Mead GM et al (2005) Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: a report on MRC Trial TE18, EORTC Trial 30942 (ISRCTN18525328). J Clin Oncol 23:1200–1208 b Source: Fossa SD, Horwich A, Russell JM et al (1999) Optimal planning target volume for stage I testicular seminoma: a Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 17:1146 Non-bulky stage II disease has a cure rate of more than 90% with radiation alone at doses of 30 to 36 Gy (Source: Mason BR, Kearsley JH (1988) Radiotherapy for stage 2 testicular seminoma: the prognostic influence of tumor bulk. J Clin Oncol 6:1856–1862; Classen J, Souchon R, Hehr T et al (2002) Radiotherapy for early stages testicular seminoma: patterns of care study in Germany. Radiother Oncol 63:179–186)

Normal Tissue Tolerance RT doses used in the treatment of seminoma are generally low, thus usually within the tolerance of normal surrounding organs. However, the effect of fractionated radiation on fertility is substantial, as detailed in Table 20.19.

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Table 20.19 Spermatogenesis and effects of fractionated radiation therapy to male fertility Aspect

Fact/result

Normal sperm count

 Estimated to be 120 million/ml

Spermatogenesis over 67 days

 21 days from stem cells to primary spermatocytes, plus 46 days to become mature spermatozoa

Radiation sensitivity to single fraction diminishes rapidly with progression along maturation pathway

 Spermatogonia (~0.1–0.2 Gy)  Spermatocytes (~2–3 Gy)  Spermatids (~4–6 Gy)  Azospermia takes approximately 60–70 days after a single dose below 2 Gy, due to damage to spermatogonia, but develops faster in case above 4 Gy, with concurrent damage to spermatids

Recovery of spermatogenesis

 Dose dependent and requires a long time for recovery of spermatogonia (sperm recovery: 1–1.5 years for <1 Gy, 2–5 years for 4–6 Gy, most probably permanent azospermia for 6–8 Gy)  Spermatogenesis is more sensitive to fractionated radiotherapy damage, due to long (~16 day) cell cycle of sperm stem cells  Oligospermia/azospermia occurs with 0.7–0.9 Gy (frequent recovery at 1–1.5 years)  Permanent azospermia likely appears with fractionated doses as low as 1.2 Gy (most likely after 2 Gy)

FSH

 Stimulates Sertoli cells to make androgen-binding protein as well as inhibin, which inhibits follicle-stimulating hormone (FSH) (negative feedback) and dose of 0.75–6 Gy might cause an increase in FSH

LH

 Stimulates Leydig cells to make testosterone, inducing spermatogenesis, and 0.75 Gy might increase LH levels through loss of negative feedback. Therefore testosterone levels are lower shortly after radiotherapy and will take time to return to normal (up to a year)

Endocrine dysfunction with subtle Leydig cell damage is rare after cumulative 2 Gy in fractionated therapy, but testosterone production is impaired after 14 Gy in 2 Gy per fraction Sources: Shapiro E, Kinsella TJ, Makuch RW et al (1985) Effects of fractionated irradiation of endocrine aspects of testicular function. J Clin Oncol 3:1232–1239; Petersen PM, Giwercman A, Daugaard G et al (2002) Effect of graded testicular doses of radiotherapy in patients treated for carcinoma in situ in the testis. J Clin Oncol 20:1537– 1543; Howell SJ, Shalet SM et al (2005) Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr 34:12–17

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Follow-Up After completion of definitive treatment, long-term follow-up to detect second primary tumors, recurrences, or late side effects is recommended (Table 20.20). Table 20.20 Follow-up schedule and examinations with treatment of seminoma Schedule

Frequency

Years 1–3

 Every 3–4 months 

Years 4–7

 Every 6 months 

Years 7+

 Every 12 months 

Examination History and physical

 Complete history and physical examination 

Imaging studies

  Abdominal/pelvic CT at every visit for surveillance  cases  Pelvic CT alone annually for 3 years for patients sta tus post only paraaortic radiotherapy  Chest X-ray at alternate visits 

Laboratory tests

 AFP, -hCG, LDH 

Adapted from: National Comprehensive Cancer Network (NCCN). Clinical practice uidelines in oncology: Testicular Cancer v.2.2010 (http://www.nccn.org/professionals/ physician_gls/PDF/testicular.pdf) Cited on September 14, 2010.

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Acute adverse effects during radiation therapy for seminoma are usually mild, and may include nausea/vomiting, diarrhea, fatigue, and transient decline in blood count. Late adverse effects are detailed in Table 20.21. Long-term side effects would probably diminish with decreased doses and radiation fields in comparison with previous series, with an increased risk after 15 years for cardiovascular and secondary cancer mortalities (Zagars GK, Ballo MT, Lee AK et al (2004) Mortality after cure of testicular seminoma. J Clin Oncol 22:640–647). Table 20.21 Late toxicities of radiation therapy in treatment of seminoma Adverse event

Sterilization

Occurrence  Generally, seminoma treatment might cause 30–180 cGy to the contralateral testis and oligospermia (CTCAE v3, infertility/sterility, grade 2) or azospermia (CTCAE v3, infertility/sterility, grade 3) followed by recovery in 18–24 months (30 cGy for PA and hemipelvic fields, and 60 cGy for hemiscrotal treatment using a testicular clamshell)  In the randomized trial (PA versus PA/dog leg), the risk of azospermia at 12 months post-RT was 10% (PA nodes) versus 30% (PA/dog leg)a

a

Peptic ulcer

 Rare

Small bowel obstruction

 Very rare

Chronic diarrhea

 Very rare

Second malignancy

 ~5%, approximately 2× risk of subsequent malignancy at 10–15 yearsb

Source: Jacobsen KD, Olsen DR, Fossa K et al (1997) External beam abdominal radiotherapy in patients with seminoma stage I: field type, testicular dose, and spermatogenesis. Int J Radiat Oncol Biol Phys 38:95–102 b Source: Travis LB, Fossa SD, Schonfeld SJ et al (2005) Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 97:1354– 1365

Section VII Gynecological Cancers

VII

21 Endometrial Cancer. . . . . . . . . . . . . . . . . . . . . . . . . 641 Keyur J. Mehta, Nitika Thawani and Subhakar Mutyala 22

Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661 Nina A. Mayr, William Small Jr. and David K. Gaffney

23

Vulva Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703 Kevin Albuquerque

24

Vaginal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725 Nitika Thawani, Subhakar Mutyala and Aaron H. Wolfson

21

Endometrial Cancer Keyur J. Mehta1, Nitika Thawani 2 and Subhakar Mutyala3

Key Points  Endometrial cancer is the most common gynecologic malignancy and the 4th most common cancer in women in the United States.  Risk factors of the disease include length of exposure of unopposed estrogen, and the most common presenting symptom is postmenopausal bleeding.  Most (>90%) cases of endometrial cancer are adenocarcinoma.  Route of spread is through local extension, lymphatic or hematogenous. Stage, depth of invasion, lymphovascular space involvement, and lymph node involvement are the most important prognostic factors.  The majority of patients (>70%) are diagnosed early at stage I, leading to overall good prognosis: >80% local control and >70% overall survival.  Surgery (total extrafascial hysterectomy with bilateral salpingo-oophorectomy, peritoneal cytology, and pelvic/para-aortic lymph node dissection) is the mainstay of diagnosis, pathologic staging, as well as treatment  Early-stage endometrial cancer can usually be treated with surgery with or without radiation therapy.  Adjuvant radiation therapy (external-beam pelvic radiation and/or vaginal cuff brachytherapy) has been shown to decrease local recurrence.  Locoregionally advanced endometrial cancer is treated with a combination of surgery, radiation therapy, and chemotherapy.  Chemotherapy with or without hormonal therapy has been shown to benefit locally advanced or metastatic endometrial cancer.

2 Nitika Thawani, MD Keyur J. Mehta, MD () Email: [email protected] Email: [email protected] 1

3

Subhakar Mutyala, MD Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_4, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology There are 42,160 new diagnoses of endometrial cancer expected in the USA in 2010. It is the 4th most common cancer in women, and ranks 8th among causes of cancer death. It is the most common gynecologic malignancy. Endometrial carcinoma arises from hyperplasia of the endometrial lining, resulting from exposure to unopposed estrogens. Table 21.1 outlines the other risk factors associated with this malignancy. Table 21.1 Risk factors of endometrial cancer Risk factor

Description Age: typical patients are postmenopausal between 55 and 85 years of age; incidence rate is higher than 95 per 100,000 women 65–80 years of age Endogenous estrogen exposure: early menarche, nulliparity, infertility, late menopause, estrogen-producing ovarian tumors

Patient related

Exogenous estrogen exposure: hormonal replacement therapy, hormonal replacement therapy, tamoxifen Past medical history: hypertension, diabetes mellitus Family history: although observed, < 1% of all endometrial cancers are due to familial factors Genetic predisposition: mutations in the MLH1 or MSH2 genes that mark the defect in HNPCC (Lynch syndrome II); patients with this syndrome have a 20% risk of developing endometrial cancer before age 50, and 60% before age 60

HNPCC: hereditary non-polyposis colon cancer

Anatomy The uterus is a pelvic organ bordered by the bladder anteriorly and the rectum posteriorly, and is covered by peritoneal reflections (Figure 21.1 and Table 21.2).

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Figure 21.1 Anatomy of the uterus

Table 21.2 Anatomic description of the uterus Anatomy

Description

Gross

 The uterus is divided into the fundus, isthmus, and the cervix  The uterine wall has an outer smooth muscle layer (myometrium) and an inner layer composed of glandular epithelium (endometrium); the uterus is covered by a serosal lining  Supported by 5 ligaments: broad, round, cardinal, uterosacral, and vesico-uterine

Blood supply

 The uterine artery, a branch of the hypogastric artery, enters the uterus at the isthmus

Lymphatics

 The myometrium drains into a rich subserosal lymphatic network and joins larger lymphatic channels before exiting the uterus  The fundus drains toward the adnexa and infundibulopelvic ligaments; the middle and lower uterus drains in the base of the broad ligament toward the pelvic sidewall  Nodal regions at risk: obturator, external iliac, internal iliac, common iliac, and para-aortic

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Pathology The majority of uterine epithelial tumors are adenocarcinomas of endometrioid subtype. The World Health Organization (WHO) recommends a classification system for other subtypes and histologic variants (Table 21.3). Table 21.3 WHO histologic classification of tumors of the uterus Tumor type

Subdivision

Epithelial

 Adenocarcinoma  Endometrioid adenocarcinoma (75%)  Serous adenocarcinoma (5–10%)  Mucinous adenocarcinoma (1–3%)  Clear cell adenocarcinoma (1–5%)  Mixed cell adenocarcinoma  Non-adenocarcinoma  Squamous cell carcinoma  Transitional cell carcinoma  Small cell carcinoma  Undifferentiated carcinomas  Smooth muscle tumors  Leiomyoma  Leiomyosarcoma

Mesenchymal

Mixed epithelial and mesenchymal

 Smooth muscle tumor of uncertain malignant potential  Endometrial stromal tumors  Endometrial stromal sarcoma  Endometrial stromal nodule  Undifferentiated endometrial sarcoma  Miscellaneous Mesenchymal tumors  Mixed endometrial stromal and smooth muscle tumor  Adenomatoid tumor  Perivascular epithelial cell tumor     

Adenofibroma Adenomyoma Adenosarcoma Carcinofibroma Carcinosarcoma (malignant mixed Müllerian tumor)

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Routes of Spread The pattern of spread as read on pathologic specimens lends to many of the prognosticators used to risk-stratify patients (Table 21.4). Table 21.4 Routes of spread in endometrial cancer Routes

Description

Local extension

 Longitudinal growth: local extension along the endometrial surface, which may spread to the Fallopian tubes, lower uterine segment, and the cervix  Radial growth: results in myometrial invasion, subsequently leading to lymphovascular space invasion and lymphatic spread  More aggressive local extension leads to serosal penetration, involvement of the parametrial tissues, and direct invasion of the bladder and rectum

Regional lymph node metastasis

 Nodal regions at risk: obturator, external iliac, internal iliac, common iliac, and para-aortic  The fundus can drain directly to the para-aortic lymph nodes

Distant metastasis

 Peritoneal seeding may occur from direct serosal penetration or from spillage through the Fallopian tubes  Hematogenous spread is uncommon, but occurs usually with high-grade tumors and unfavorable histologies  The most common metastatic sites include the lungs, liver, and bones

Diagnosis, Staging, and Prognosis Clinical Presentation The most common presenting symptom is vaginal bleeding. In postmenopausal patients, vaginal bleeding is unexpected and may range from spotting to heavy blood loss. Pre- or perimenopausal patients may present with menorrhagia and/or metrorrhagia. Another presenting symptom is profuse, watery discharge. Although uncommon, a routine Pap smear for cervical cancer screening may detect abnormal endometrial cells.

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Diagnosis The diagnosis of endometrial cancer depends on the clinical presentation, history and physical examination, including a thorough gynecologic examination, imaging studies, and laboratory tests (Figure 21.2).

Endometrial Cancer Suspected by clinical presentation

Complete History and Physical Examination

Endometrial biopsy

-

+/-

Trans-vaginal ultrasound

Non-diagnostic

+

Dilatation and curettage +/- hysteroscopy

Observe

-

Pre-operative assessment +

Figure 21.2 Diagnosis of endometrial cancer

Tumor, Node, and Metastasis/Federation of Gynecology and Obstetrics Staging Endometrial cancer staging is determined by pathologic criteria. Recent changes in the Federation of Gynecology and Obstetrics (FIGO) and the American Joint Committee on Cancer (AJCC) staging recommendations were made to coincide with prognosis and are reflected in Table 21.5.

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Table 21.5 FIGO and American Joint Committee on Cancer (AJCC 7th edition) TNM staging for endometrial cancer FIGO staging (2008)

AJCC 7th edn (2009) TNM staginga

Group

T

N

M

IA

T1a

0

0

Limited to the endometrium or invades less than half of the myometrium

IB

T1b

0

0

Invades half or more of the myometrium

II

T2

0

0

Invades cervical stromal tissue but does not extend beyond the uterus

IIIA

T3a

0

0

Involves serosa and/or adnexa

IIIB

T3b

0

0

Vaginal involvement or parametrial involvement

IIIC1

T1–3

1

0

Metastasis to pelvic lymph nodes

IIIC2

T1–3

2

0

Metastasis to para-aortic lymph nodes

IVA

T4

any

0

Invades bladder mucosa and/or bowel mucosa

IVB

Any

Any

1

Distant metastasis

Description

a

Changes from the AJCC 6th edition and the previous FIGO staging recommendations (1988):

 No longer includes uterine sarcoma (now staged with a new staging system)  Positive peritoneal cytology is no longer considered (previously was T3a/ IIIA)  Involvement of the endocervical glands is not longer considered (previously was stage IIA)  Stages IA and IB combined (now: IA). IC moved to IB  Stage IIIC subdivided into IIIC1 and IIIC2 Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

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Prognostic Factors Survival is strongly influenced by the stage at diagnosis (Table 21.6). Adverse prognostic factors include:  More advanced age: associated with higher chance of recurrence (age > 70 have more recurrence versus 50–70)  Higher grade: associated with higher chance of recurrence (grades 2–3)  Aggressive histology: clear cell adenocarcinoma, undifferentiated papillary serous carcinoma are associated with worse prognosis due to more distant failure pattern  Depth of myometrial invasion (>66%)  Lymphovascular space invasion Gynecologic Oncology Group Trial 99 (GOG 99; Figure 21.4) outlines the prognostic factors in directing treatment. Table 21.6 Survival rate at 5 years, based on stage classification Extent of disease at diagnosis

5-year survival rate (%)

Localized Regional Distant

96% 68% 24%

All stages

83%

Principles and Practice A total extrafascial hysterectomy with bilateral salpingo-oophorectomy, peritoneal cytology, and pelvic/para-aortic lymph node dissection remains the standard initial treatment for endometrial cancer. Traditionally done through a vertical midline incision, a laparoscopic technique has recently been used. Pathologic data has shown that certain high-risk pathologic features predict higher rates of local recurrence. Therefore, adjuvant radiation therapy is recommended for these patients. Systemic therapy is typically used in locoregionally advanced, recurrent, or metastatic disease (Table 21.7).

Treatment of Early-Stage Endometrial Cancer Surgical resection is the initial management of choice. The pathologic specimen is then examined for the risk factors listed in “Prognostic Factors” along with patient-related factors to determine a patient’s risk of locoregional recurrence. The patient may be offered adjuvant therapy based on a significant risk of recurrence (Table 21.8 and Figure 21.3).

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Table 21.7 Treatment modalities used in endometrial cancer Treatment

Description

Total extrafascial or laparoscopic-assisted vaginal hysterectomy with bilateral salpingo-oophorectomy (including peritoneal cytology and pelvic/para-aortic lymph node staging) Indications

 Curative treatment modality, leads to surgical staging

system  A vaginal hysterectomy may be used in morbidly complicated patients Facts

 A minimally invasive (laparoscopic) approach has been

gaining popularity  Surgical lymph node staging is controversial  Only 30–40% of patients undergo nodal assessment Radiation therapy Indications

 Adjuvant treatment for patients with high-risk patho-

logic features  May be given as definitive therapy in inoperable cases Techniques

 EBRT using conventional four fields, 3D-CRT, or IMRT  Intravaginal LDR or HDR brachytherapy  Rotte-Y or Heyman capsule applicators in inoperable

cases Chemo-/hormonal therapy Indications

 Chemotherapeutic agents are used in locoregionally

advanced, recurrent or metastatic disease  Hormonal agents used in inoperable or recurrent cases Medications

 Chemotherapeutic agents: alkylating agents, cisplatin,

anthracyclinces, antimetabolites, vincas, epipodophyllotoxins, topoisomerase I inhibitor, taxanes  Hormonal agents: progestins, anti-estrogens, aromatase inhibitors  Targeted agents are under investigation EBRT: external-beam radiation therapy; 3D-CRT: 3-dimensional conformal radiation therapy; IMRT: intensity-modulated radiation therapy; LDR: low-dose rate; HDR: high-dose rate

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Table 21.8 Treatment of early-stage endometrial cancer FIGO stage

Grade I

II

III

IA

Observation

Observation or VB

VB or EBRT with or without VB

IB

VB or EBRT with or without VB

VB or EBRT with or without VB

EBRT with VB

II

EBRT with VB

EBRT with VB

EBRT with VB

 In the previous FIGO staging system (1988), stage IA tumors (limited to the endometrium) could generally be observed; however, VB was considered for grade 3  EBRT may be omitted in a patient with an adequate negative lymph node dissection; alternatively, EBRT is generally recommended in patients in whom the lymph nodes were not addressed and poor prognosticators were present on pathology

VB: vaginal brachytherapy; EBRT: external-beam radiation therapy Light blue cells low-intermediate risk, olive cells intermediate-high risk, red cells high risk

Surgical resection provides invaluable pathologic data that guides treatment decisions

Pathologic factors and patient-related factors determine: Treatment recommendations must be tailored to each individual patient:

Total extrafascial hysterectomy + bilateral salpingo-oophorectomy (open or minimally invasive technique)

Low-risk

Intermediate-risk

High-risk

Observation

Vaginal brachytherapy or EBRT +/vaginal brachytherapy

EBRT + vaginal brachytherapy

Figure 21.3 Proposed algorithm for treatment of early-stage endometrial cancer

Adjuvant External Radiation Therapy Table 21.9 lists four randomized trials that evaluated adjuvant external-beam radiotherapy versus observation after a surgical resection for early-stage endometrial carcinoma. The general trend shows a local control benefit, but this does not translate into a survival difference. Of note, there are inherent differences between the studies with respect to lymph node surgical staging and treatment with vaginal brachytherapy that make concrete conclusions difficult to make.

1980

2000

2004

2009

Norwegian

PORTEC

GOG-99

MRC ASTEC and NCIC CTG EN.5

906

392

715

540

No. of patients

No

No

Yes

IB–ICb IB, G2–3; IC, G1–2 IB–IC; occult II IA–IB, G3; IC, G1–3; 30% serous papillary; clear cell; IIA

Treatment LN dissection

Eligibilitya

52%

No

No

Yes

VB

Observation

50.4 Gy per 28 fractions Observation 40–46 Gy per 20–25 fractions 6

85 (NS)

85 (NS)

86 (NS)

12 3

92 (NS)

85 (NS)

3

14

81 (NS)

4

Observation

87 (NS) 90 (NS)

2 7

40 Gy Observation 46 Gy per 23 fractions

OS (%)

Vaginal/pelvic recurrence (%)

Randomized to EBRT

G: grade; TAH/BSO: total abdominal hysterectomy/bilateral salpingo-oophorectomy; NS: not statistically significant; LN: lymph node; VB: vaginal brachytherapy a FIGO stages refer to 1988 staging system b Subset analysis of Norwegian study showed locoregional control benefited patients in the IC, grade 3 subgroup the most (5 versus 20%) Sources : Aalders J, Abeler V, Kolstad P et al (1980) Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 56:419–427; Creutzberg CL, van Putten WL, Koper PC et al (2000) Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomized trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 22:1404–1411; Keys HM, Roberts JA, Brunetto VL et al (2004) A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 92:744–75; ASTEC/EN.5 Writing Committee. (2009) Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet 373):137–146

Year

Study

Table 21.9 Randomized trials evaluating the role of adjuvant radiotherapy in early-stage endometrial cancer after TAH/BSO

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As seen in the preceding tables and algorithm, there is a mixed recommendation of treatment options for the intermediate risk group of patients. This occurs due to the various disease- and patient-related factors that help make a risk assessment. GOG 99 identifies this high-intermediate subgroup of patients, and shows that adjuvant therapy may be more beneficial in this subgroup (Figure 21.4).

Grade 2/3 histology Lymphovascular invasion Outer 1/3 myometrial invasion

Age <50

Age 50-70 Age >70

3 risk factors needed

2 risk factors needed

Only 1 risk factor needed

Figure 21.4 GOG-99 high-intermediate risk subgroup

Brachytherapy Intravaginal brachytherapy may be given alone or in combination with external-beam radiotherapy (EBRT), depending on the risk of pelvic lymph node involvement. Alternatively, it may be omitted when external pelvic irradiation is used as in the Post-Operative Radiation Therapy for Endometrial Carcinoma (PORTEC) and GOG-99 studies, while maintaining good locoregional control rates as shown in Table 21.9 (although the majority of failures in these studies occurred at the vaginal cuff). The details of vaginal brachytherapy technique and dose fractionation are discussed below.

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Locoregionally Advanced Endometrial Cancer Adjuvant Radiation Therapy Patients with locoregionally advanced endometrial cancer as determined by surgical pathology are recommended to undergo adjuvant pelvic irradiation. Para-aortic irradiation may be added in cases where pelvic or para-aortic lymph nodes are positive. Vaginal brachytherapy is often given in addition to EBRT, due to the high risk of vaginal cuff recurrence. Adjuvant Systemic Therapy The GOG conducted a randomized trial to evaluate the role of adjuvant systemic therapy, as seen in Table 21.10. Table 21.10 Evaluation of the role of adjuvant chemotherapy for locoregionally advanced endometrial carcinoma Trial

Description

GOG 122

 Randomized 388 patients with stages III–IV endometrial carcinoma after TAH/BSO, surgical staging and <2 cm residual tumor to whole-abdominal irradiation (WAI) versus doxorubicin-cisplatin (AP) chemotherapy  WAI equals 30 Gy in 20 fractions AP/PA plus boost to pelvic/para-aortic LNs to 15 Gy in 8 fractions  AP equals doxorubicin and cisplatin every 3 weeks for 8 cycles  5-year stage-adjusted PFS was 38% for WAI versus 50% for AP (SS)  5-year stage-adjusted OS was 42% for WAI versus 52% for AP (SS)  Recurrence after WAI was 54% (13% pelvis, 16% abdomen, 22% distant); recurrence after AP was 50% (18% pelvis, 14% abdomen, 18% distant  AP had more grade 3–4 hematologic and gastrointestinal (GI) toxicity  Chemotherapy improves PFS and OS as compared to WAI for stage III/IV patients after surgical resection  Statistical rationale of this study is questioned as all statistically significant data is given for stage-adjusted patients

Source: Randall ME, Filiaci VL, Muss H et al (2006) Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 24:36-44

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Treatment of Less Common Histologic Subtypes Certain histologic subtypes, such as carcinosarcoma and serous adenocarcinoma, have a different natural history and course of disease than the more common endometrioid adenocarcinoma subtype. The treatment course for these less common subtypes is less well defined, although some studies are available to guide our treatment decisions (Tables 21.11 and 21.12) while others are ongoing. Table 21.11 Evaluation of the role of adjuvant chemotherapy for carcinosarcoma of the uterus Trial

Description

GOG 150

 Randomized 206 patients with stages I–IV carcinosarcoma of  the uterus after TAH/BSO, surgical staging and <1 cm residual tumor to whole WAI versus cisplatin-ifosphamide with mesna (CIM) chemotherapy  WAI equals 30 Gy in 30 fractions (BID) or 20 fractions (QD) AP/  PA plus boost to pelvic LNs to 20 Gy in 20 fractions (BID) or 19.8 Gy in 11 fractions (QD)  CIM equals cisplatin and ifosphamide with mesna every  3 weeks for 3 cycles  Estimated crude probability of relapse within 5 years (stage and age-adjusted) was 29% lower for the CIM group (NS)  Estimated crude probability of surviving at least 5 years  (stage- and age-adjusted) was 29% lower for the CIM group (p = 0.085)  Recurrence after WAI was 57% (3.8% vagina, 13.3% pelvis,  27.6% abdomen, 25.7% distant); recurrence after CIM was 51% (9.9% vagina, 13.8% pelvis, 18.8% abdomen, 23.8% distant) (NS)  Estimated probability of recurring within 5 years for stage I, II,  III, or IV disease is 37, 46, 63, and 80%, respectively (p < 0.001)  Estimated probability of surviving at least 4 years for stage I,  II, III, or IV disease is 65, 45, 26, and 26%, respectively  CIM had more grades 3–4 anemia and neuropathy; WAI pa tients experienced more grade 2–4 GI events  Chemotherapy appears to delay the onset of recurrence as  compared to WAI for patients, although it does not significantly alter the outcomes of those who recur

Source: Wolfson AH, Brady MF, Rocereto T et al (2007) A Gynecologic Oncology Group Randomized phase III Trial of whole abdominal irradiation (WAI) versus cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I–IV carcinosarcoma (CS) of the uterus. Gynecol Oncol 107:166–168

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Table 21.12 A phase II trial of adjuvant radiation therapy and chemotherapy for uterine papillary serous carcinoma (UPSC) Trial

Description

Fields et al

 30 patients with stages I–IV UPSC were treated with pelvic  radiation therapy (RT) “sandwiched” between 6 cycles of paclitaxel/platinum (TP) chemotherapy after TAH/BSO  Pelvic RT equals 45 Gy in 25 daily fractions with a four-field  pelvic technique; a para-aortic field was added when 2 or more lymph nodes were positive; patients also received vaginal brachytherapy  TP equals 3 cycles of paclitaxel and platinum (cisplatin or carboplatin) were given every 3 weeks; the final 3 cycles were also given every 3 weeks after radiation therapy  Median survival for all patients was 34 months  Stages I–II patients had a 3-year DFS and OS of 69 and 75%,  respectively  Stages III–IV patients had a 3-year DFS and OS of 54 and 52%,  respectively  Grades 3–4 neutropenia, thrombocytopenia, or anemia  occurred in 42, 1, and 3%, respectively

Source: Fields AL, Einstein MH, Novetsky AP et al (2008) Pilot phase II trial of radiation “sandwiched” between combination paclitaxel/platinum chemotherapy in patients with uterine papillary serous carcinoma. Gynecol Oncol 108:201–206

Radiation Therapy Techniques Simulation and Field Arrangements A computed tomography (CT) scan (2.50- to 5-mm cut) should be performed from the top of L4 to the bottom of the lesser trochanters of the femurs. Aides that may be used during the simulation included a Foley catheter, intravaginal cuff marker, oral, and/or intravenous contrast. Organs at risk (see Table 21.17) should be delineated. External radiation fields should encompass the vaginal cuff (or the entire uterus in inoperable cases) and regional pelvic lymph nodes. Field setup is illustrated in Figure 21.5 and Table 21.13.

Dose and Treatment Delivery The pelvis is treated with external-beam radiation therapy to 45–50 Gy in 25–28 daily fractions using 6- to 18-MV photon beams.

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Figure 21.5 External beam radiation field setup

Table 21.13 Treatment fields/borders used in the treatment of endometrial cancer Fields

Borders

AP/PA

Superior: top of L5 Inferior: bottom of the obturator foramina Laterally: 2 cm beyond the bony margins of the pelvic inlet

Lateral

Superior/inferior: as AP/PA fields Anterior: in front of the pubis symphysis Posterior: S2–S3

Three-Dimensional Conformal Radiation Therapy and Intensity-Modulated Radiation Therapy, and Target Volume Delineation The benefits of three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) radiation techniques are to spare normal tissue while treating the target volumes (Figure 21.6 and Table 21.14). Definitions of gross tumor volume (GTV), clinical target volume (CTV), planning target volume (PTV), and internal target volume (ITV) in 3D-CRT and IMRT are as follows:  GTV: the entire uterus (in inoperable cases)  CTV: vaginal cuff, obturator lymph nodes, and external/internal/common iliac lymph nodes  PTV: CTV plus 0.5–1.0 cm or ITV plus 0.5 cm Organs at risk to be contoured are bladder, small bowel, rectum, bone marrow, and the femoral heads.

Chapter 21 Endometrial Cancer

DHV Structure Aproval line Status Bladder Bowel Femoral Head, LT PTV 45 CTV Femoral Head, RT Rectum

Plan

Course

Volu- Dose Samp- Min me Cover ling Dose Cover (cm3) (%) (Gy) (%)

Max Dose (Gy)

657

Mean Dose (Gy)

Approved A-PTV imrt # Study-kjm 366.3 100.0 100.0 8.747 49.379 35.800 Approved A-PTV imrt # Study-kjm 968.5 100.0 100.0 0.544 48.679 11.543 Approved A-PTV imrt # Study-kjm 90.1 100.0 100.0 2.972 40.921 18.473 Approved A-PTV imrt # Study-kjm 705.8 100.0 100.1 35.530 49.446 46.423 Approved A-PTV imrt # Study-kjm 499.1 100.0 100.1 35.530 49.446 46.466 Approved A-PTV imrt # Study-kjm 93.9 100.0 99.9 2.374 45.858 15.699 Approved A-PTV imrt # Study-kjm 129.5 100.0 100.0 9.648 49.446 36.305

Figure 21.6 IMRT plan for adjuvant radiotherapy for endometrial cancer. PTV (red) was prescribed to 45-Gy EBRT

Table 21.14 Intensity-modulated whole-pelvic radiation therapy in patients with gynecologic malignancies Trial

Description

Roeske et al

 Compared a standard “four-field box” plan with an IMRT plan on the same patient  45 Gy in 25 fractions four-field box plan versus IMRT plan  IMRT reduced the volume of bowel undergoing more than 30 Gy RT  IMRT reduced the average volume of rectum and bladder irradiated at the prescription dose  PTV coverage did not differ significantly

Source: Roeske JC, Lujan A, Rotmensch J et al (2000) Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies. Int J Radiation Oncology Biol Phys 48:1613–1621

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Brachytherapy Intravaginal brachytherapy allows the delivery of a high dose to the vagina while minimizing dose to organs at risk. A vaginal cylinder is the most common applicator used, and the largest diameter feasible is preferable. The radiation is delivered with low-dose-rate (LDR) or high-dose-rate (HDR) radiotherapy. The LDR prescription to the surface is 50–60 Gy over 60–70 h when used alone. The prescription dose is reduced to 25–30 Gy when combined with EBRT. The HDR dose prescriptions as recommended by the American Brachytherapy Society (ABS) are shown in Tables 21.15 and 21.16. Table 21.15 Suggested doses of HDR alone for adjuvant endometrial cancer Number of HDR fractions

HDR dose/fraction (Gy)

Dose-specific point

3

7.0

0.5-cm depth

4

5.5

0.5-cm depth

5

4.7

0.5-cm depth

3

10.5

Vaginal surface

4

8.8

Vaginal surface

5

7.5

Vaginal surface

Source: Nag S, Erickson B, Parikh S et al (2000) The American Brachytherapy Society Recommendations for high-dose-rate brachytherapy for carcinoma of the endometrium. Int J Radiation Oncology Biol Phys 48:779–790

Table 21.16 Suggested doses of HDR to be used with 45-Gy EBRT for adjuvant endometrial cancer Number of HDR fractions

HDR dose/fraction (Gy)

Dose-specific point

2

5.5

0.5-cm depth

3

4.0

0.5-cm depth

2

8.0

Vaginal surface

3

6.0

Vaginal surface

Source: Nag S, Erickson B, Parikh S et al (2000) The American Brachytherapy Society Recommendations for high-dose-rate brachytherapy for carcinoma of the endometrium. Int J Radiation Oncology Biol Phys 48:779–790

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Normal Tissue Tolerance Organs at risk (OAR) in radiation therapy of endometrial cancer include the bladder, rectum, small intestine, and the femoral heads (Table 21.17). Table 21.17 Dose limitations of OARs in radiation therapy for pelvic malignancies OAR

Dose limitations

Bladder

V80 < 15%, V75 < 25%, V70, V65 < 50%

Rectum

V50 < 50%, V60 < 35%, V65 < 25%, V70 < 200%, V75 < 15%

Small intestine

TD5/5: 45 Gy, V45 < 10% 150 ml < 40 Gy

Femoral heads

Max < 40 Gy

Vn%: volume of tissue receiving n% of Gy Sources: Viswanathan AN, Yorke ED, Marks LB et al (2000) Radiation dose–volume effects of the urinary bladder. Int J Radiation Oncology Biol Phys 76:S116–S122 ; Michalski JM, Gay H, Jackson A (2000) Radiation dose–volume effects in radiation-induced rectal injury. Int J Radiation Oncology Biol Phys 76:S123–S129

Common acute radiation-induced adverse effects include fatigue, cystitis, loose bowel movements, and diarrhea. Late adverse effects include chronic cystitis, chronic proctitis, intractable diarrhea, small bowel obstruction, and vaginal stenosis and dryness.

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Follow-Up Patients should follow-up with their surgeon and radiation oncologist at regular intervals (Table 21.18). The patient may be given a vaginal dilator at the first follow-up visit to help prevent vaginal stenosis. Table 21.18 Follow-up schedule and examinations Schedule

Frequency

First follow-up

 4 –6 weeks after radiation therapy

Years 0–2

 Every 3–4 months

Years 3–5

 Every 6 months

Years 5+

 Annually

Examinations History and physical

 Complete history and physical examination

Laboratory tests

 Vaginal cuff cytology

Imaging studies

 Chest X-ray (if clinically indicated)  CT of the abdomen and pelvis (if clinically indicated)

22

Cervical Cancer Nina A. Mayr1, William Small Jr. 2 and David K. Gaffney3

Key Points  Cervical cancer is the fifth most common cancer in women and the third leading cause of cancer death in women worldwide.  Risk factors include exposure to human papilloma virus (HPV), which HPV is sexually transmitted, and smoking.  Screening has reduced the incidence of invasive disease and mortality in many Western countries.  Most carcinomas (80–90%) are squamous cell, 10–20% are adenocarcinoma; less common histologies include neuroendocrine carcinoma, mixed mesodermal, lymphomas, and clear cell carcinoma.  Common signs and symptoms include vaginal bleeding and/or discharge, and pelvic or back pain.  International Federation of Gynecology and Obstetrics (FIGO) staging is based on clinical examination findings, plain radiographs, cystoscopy, and proctoscopy. However, cross-sectional imaging and positron-emission tomography (PET) further refine disease delineation and therapy planning.  Stage, lymph node involvement, and tumor size are the most important prognostic factors.  Overall survival is approximately 80–90% for stage IB, 70–80% for stage II, 60% for stage III, and 15% for stage IVA disease.  Lung, liver, and bones are the most common metastatic sites.  Primary treatment selection is guided by FIGO stage. Stage IA1 tumors are primarily treated surgically, stages IA2-IIA with surgery or radiation therapy, and stages IIB-IVA are treated with definitive radiation and concurrent chemotherapy.  Brachytherapy is integrated with external-beam radiation therapy (RT) and is an indispensable component of definitive RT.  Chemotherapy concurrent with RT increases local control, reduces distant metastasis, and increases disease-free and overall survival. The role of adjuvant chemotherapy following concurrent radiation/chemotherapy remains to be determined.  Concurrent chemotherapy includes weekly cisplatin during RT; 5-fluorouracil (5-FU); taxanes, also have activity.

1

Nina A. Mayr, MD () Email: [email protected]

2

William Small Jr., MD Email: [email protected]

3

David K. Gaffney, MD Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_5, © Springer-Verlag Berlin Heidelberg 2011

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Key Points (continued)  Total treatment course duration of more than 8 weeks is associated with decreased survival.  Post-hysterectomy RT is indicated for deep stromal invasion, bulky tumor size, and/or lymphovascular space invasion; post-hysterectomy radiation with concurrent chemotherapy is indicated for involved lymph nodes, parametria, and/ or margins.  Radiation and chemotherapy are used for post-hysterectomy pelvic recurrence and to palliate metastatic disease.  Outcome of recurrent cervical cancer after hysterectomy or definitive RT is extremely poor.  Palliative chemotherapy regimens for recurrent of metastatic cervical cancer include cisplatin, taxenes, 5-FU, topotecan, and gemcitabine.

Epidemiology and Etiology Cervical cancer is the fifth most common cancer in women worldwide. In 2010, it is estimated that approximately 11,270 new cases will be diagnosed and 4,070 deaths occur in the USA. The incidence in the USA has declined over the past four decades, largely because of successful screening. However, the incidence remains high worldwide, with an estimated 471,000 new cases and 300,000 deaths annually. In many medically underserved countries, cervical cancer remains the most common cancer and the leading cause of death for women. Human papilloma virus (HPV) vaccines and screening have the potential to decrease the incidence of this disease on a global level. Risk factors for cervical cancer are shown in Table 22.1.

Anatomy Figure 22.1 details the anatomy of the uterus and pelvis.

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Table 22.1 Risk factors for cervical cancer Risk factor

Description

Patient related

Life style: Early age of first sexual intercourse, high number of lifetime sexual partners, exposure to sexually transmitted diseases, and high parity reflect the correlation of HPV infection with the risk of cervical cancer in epidemiologic studies Smoking is associated with increased risk due to accumulation of carcinogens in the cervical mucus. Oral contraceptive use is controversial

Environmental

Infectious exposure: HPV infection: HPV DNA is present in >90% of cervical cancers. HPV-16 and HPV-18 are most commonly associated with squamous cell carcinoma, HPV-31, HPV-33, and HPV-35 less commonly. Very few HPV infections result in invasive cervical cancer, suggesting that other factors, e.g., host immune response, also play a role HIV-related immunosuppression: cervical cancer is an AIDSdefining neoplasm Environmental exposure: Smoking (active and passive exposure) DES exposure in utero is associated with for clear cell adenocarcinoma

HPV: human papilloma virus

Fallopian tube Ovary Fundus Parametria Bony pelvis

Lower uterine segment

Cervix Vagina

Figure 22.1 Anatomy of the cervix and uterus. Tumors of the cervix grow exophytically on the portio or expand into the endocervical region. Spread occurs superiorly along the lower uterine segment, laterally to the parametria and uterosacral ligaments toward the pelvic walls and pelvic lymphatics, posteriorly to the perirectal region, and anteriorly to the bladder. Despite the proximity of bladder and rectum, mucosal involvement of these organs is uncommon. Adapted from: Kepp R, Stemmler HJ (eds) Lehrbuch der Gynäkologie, 10th edn. Thieme, Stuttgart, 1971, p 305

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Pathology Squamous cell carcinomas (SCCs) occur in approximately 80% and tend to originate at the squamocolumnar junction and are frequently associated with in situ precursors, progressing from mild, moderate, and severe dysplasia, to carcinoma in situ, to invasive carcinoma. Adenocarcinoma occurs in 10–20% of cases and can arise in the high endocervical region, where diagnosis is more difficult. Most adenocarcinomas are of endocervical gland origin. While SCCs have decreased in the USA, the incidence of adenocarcinoma appears to be increasing. Clear cell carcinoma, an adenocarcinoma variant, is associated with in utero diethylstilbestrol (DES) exposure. Rare histologies include neuroendocrine carcinoma, mixed mesodermal tumors, and lymphomas.

Routes of Spread Cervical cancer spreads by way of local extension along adjacent structures, lymphatics, and distant hematogenous metastasis routes, as detailed in Table 22.2. Table 22.2 Routes of spread in cervical cancer Routes

Description

Local extension

 Direct extension along the parametria, uterosacral ligaments, vesicovaginal space, and perirectal space; distally by direct extension to vagina  Ovarian spread may occur in adenocarcinomas but is rare

Regional lymph node spread

 Generally, stepwise progression along lymphatic echelons from pelvic to para-aortic (PA) lymph nodes to thoracic duct to left supraclavicular lymph nodes  Proximal, e.g., PA node, metastases in the absence of pelvic node involvement is uncommon

Distant metastasis

 Distant metastases are uncommon in the absence of extensive local or lymph node involvement  Most common distant metastatic sites are lung, liver, and bone

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Lymphatic Spread The draining lymph node (LN) regions for cervical cancer are summarized in Table 22.3 and Figure 22.2. Table 22.3 Involvement of lymph node groups (in %) by stage Lymph node group

Stage I

II

III

Pelvic LN

15%

30%

50%

Para-aortic LN

5%

20%

30%

Extra-abdominal lymphatic spread occurs from the PA LN through the cysterna chyli and thoracic duct to the left supraclavicular LN.

Figure 22.2 Lymphatic drainage pattern. Adapted from: Plentl AA, Friedman EA (1971) Lymphatic system of the female genitalia. Saunders, Philadelphia, p 83

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Diagnosis, Staging, and Prognosis Clinical Presentation Common symptoms of cervical cancer are presented in Table 22.4. Table 22.4 Commonly observed signs and symptoms in cervical cancer Symptoms

Description

General

 Abnormal vaginal bleeding (>80%)  Vaginal discharge  Symptoms of pelvic organ compression or extension/ invasion

Early-disease symptoms

 Abnormal vaginal bleeding  Dyspareunia, pelvic pain

Late-disease symptoms

 Triad:  Sciatic pain (from lumbosacral plexus involvement/ compression by tumor)  Lower extremity edema (from extensive pelvic lymph node involvement/lymphatic obstruction)  Hydronephrosis (from ureteral obstruction)  Pelvic pain, urinary, rectal symptoms (e.g., bowel and/or urinary obstruction, vesicovaginal/rectovaginal fistula)

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Diagnosis and Pretherapy Evaluation Figure 22.3 presents a proposed algorithm for diagnosis and staging of cervical cancer. The diagnostic procedures and techniques used for cervical cancer are listed in Table 22.5.

Cervical Cancer Suspected

Complete History and Physical Examination

Physical Exam Focus: Pelvic and rectovaginal examination: - Cervical portio, os - Tumor extension to vagina, parametria - Abdominal exam - Palpation of supra - Clavicular lymph nodes

Procedures: - Colposcopy (15 x magnification) - Pap smear if no bleeding - 4 quadrant punch biopsies - Cold-knife conization if no gross lesion visible, and/or microinvasive carcinoma suspected

Radical hysterectomy vs. definite radiation/ chemotherapy

FIGO staging

Lab: - CBC/differentiel - Blood chemistries - Urinalysis

Radiology: - Chest x-ray - CT or MRI of abdomen and pelvis - and/or PET, PET/CT

Exam under anesthesia Cystoscopy, proctoscopy, ureteral stent placement as indicated

Multidisciplinary Treatment Figure 22.3 Proposed diagnosis and staging of cancer of uterine cervix

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Table 22.5 Diagnostic procedures in cervical cancer Studier

Description

Tissue diagnosis

 Diagnosis is made by Pap smear and/or biopsy  Normal Pap smear in the presence of visible abnormality does not exclude tumor  Biopsy, endocervical curettage, and if negative, cold-knife conization must be performed

Lab work-up

 CBC to assess hemoglobin levels in view of the commonly present significant vaginal bleeding and need for intervention  CBC and differential count for screening blood counts in anticipation of chemotherapy  Serum chemistries to assess renal function in view of ureteral obstruction and chemotherapy

Imaging studies

 FIGO staging only admits information from physical exam, procedures, and plain radiographs for staging  Chest X-ray or thoracic CT is recommended for assessment for pulmonary metastasis  Cross-sectional imaging generally improves delineation of disease extent  Abdominopelvic CT and MRI are equally efficacious in assessment of lymph node involvement, liver, lung, and bone metastasis  MRI is better than CT is in delineation of the tumor extent within the uterus and pelvic tumor extension (parametrial, uterosacral), bladder and rectal invasion  PET or PET/CT has shown higher sensitivity in staging for lymphatic or distant metastasis

CBC: complete blood count

International Federation of Gynecology and Obstetrics, and Tumor, Node, and Metastasis Staging Diagnosis and staging are based on history and physical examination, and radiologic and laboratory workup. The most commonly used International Federation of Gynecology and Obstetrics (FIGO) staging is largely based on clinical examination (tumor palpation) findings and investigative procedures, including colposcopy, examination under anesthesia, cystoscopy, and proctoscopy. FIGO staging permits only minimal radiologic information from plain radiographs, and does not incorporate information on LN involvement, which is

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an important prognostic factor. Despite not altering stage categories, cross-sectional imaging, including computed tomography (CT) and magnetic resonance imaging (MRI) and recently positron-emission tomography (PET) or PET/CT, and invasive surgical staging provide important additional information on the extent of the locoregional nodal involvement and distant-disease status. FIGO remains the gold standard for cervical cancer staging. However, radiographic and surgical staging add prognostic information in approximately one fourth of clinical FIGO stage IB, half of IIA-IIB, two thirds of IIIA, and over 90% of IIIB patients. Upstaging to more extensive disease status or higher stage occurs in 26% of stage IB, 40% of IIA, 50% of IIB, 66% of IIIA, and 75% of IIIB tumors (Sources: Averette HE, Ford JHJ, Dudan RC et al (1994) Staging of cervical cancer. Clin Obstet Gynecol 18:215–232; Eifel PJ (1994) Problems with the clinical staging of carcinoma of the cervix. Sem in Radiat Oncol 4:1–8). FIGO staging and the corresponding TNM stages are presented in Table 22.6. Table 22.6 FIGO and TNM staging of cervical cancer FIGO

TNM

Description

–

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

–

Tis

Carcinoma in situ (pre-invasive carcinoma)

I

T1

Cervical carcinoma confined to uterus (extension to corpus should be disregarded)a

IA

T1a

Invasive carcinoma diagnosed only by microscopy (all macroscopically visible lesions are stage IB/T1b tumors). Stromal invasion with a maximum depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification

IA1

T1a1

Measured stromal invasion 3.0 mm or less in depth and 7.0 mm or less in horizontal spread

IA2

T1a2

Measured stromal invasion more than 3.0 mm and not more than 5.0 mm, with a horizontal spread 7.0 mm or less

IB

T1b

Clinically visible lesion confined to the cervix or microscopic lesion greater than IA1/IA2

IB1

T1b1

Clinically visible lesion 4.0 cm or less in greatest dimension

IB2

T1b2

Clinically visible lesion more than 4.0 cm in greatest dimension

II

T2

Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina ▶

– a

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Table 22.6 (continued)

a

FIGO

TNM

Description

IIA

T2a

Tumor without parametrial invasion

IIA1

T2a1

Lesion 4.0 cm or less in greatest dimension

IIA2

T2a2

Lesion more than 4.0 cm in greatest dimension

IIB

T2b

Tumor with parametrial invasion

III

T3

Tumor extends to pelvic wall and/or involves lower third of vagina, and/or causes hydronephrosis or nonfunctioning kidney

IIIA

T3a

Tumor involves lower third of vagina, no extension to pelvic wall

IIIB

T3b

Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney

IV

T4

Bladder and/or rectal invasion or distant spread

IVA

T4a

Tumor invades mucosa of bladder or rectum, and/or extends beyond true pelvis (bullous edema is not sufficient to classify a tumor as IVA)

IVB

T4b

Distant metastasis (including peritoneal spread, involvement of supraclavicular or mediastinal lymph nodes, lung, liver, or bone)

¾

Nx

Regional lymph nodes cannot be assessed regional lymph node metastasis

¾

N0

No regional lymph node metastasis

¾

N1

Regional lymph node metastasis

¾

M0

No distant metastasis (no pathologic M0; use clinical M to complete stage group)

¾

M1

Distant metastasis (including peritoneal spread, involvement of supraclavicular or mediastinal lymph nodes, lung, liver, or bone)

FIGO staging no longer includes stage 0 (Tis) Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

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Prognosis Cervical cancer is curable when diagnosed early, accounting for improved outcome and lesser prevalence of invasive and high-stage disease in countries with ample access to health care and cytologic screening. In more advanced disease, tumor recurs in approximately one third of patients. Outcome has significantly improved with the introduction of concurrent chemotherapy in stage IB2–IVA disease (Tables 22.10 and 22.11). Neuroendocrine carcinoma of the cervix has high propensity for distant metastasis, poor prognosis, and a spread pattern similar to that of small cell lung cancer.

Table 22.7 Prognostic factors for cervical cancer based on treatment modality Treatment type

Description

Resected tumors

   

Intact tumor treated with RT

 Clinical stage and tumor size (diameter), LVSI  Pelvic and PA lymph node involvement  Hemoglobin before and during RT

Histological tumor size, depth of stromal invasion, LVSI Pelvic and PA lymph node involvement Parametrial involvement Status of surgical margins

LVSI: lymph–vascular space invasion

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Low hemoglobin levels – a possible surrogate of tumor oxygenation – have been associated with decreased local control and survival rates, particularly when persisting during radiation therapy (RT). Imaging and molecular markers of hypoxia have also been associated with poor outcome, suggesting that hypoxia-imparted radioresistance plays a role in cervical cancer. Tumor control and disease-free survival (DFS) by FIGO stage from representative series are presented in Table 22.8.

Table 22.8 Local tumor control and survival by stage in cervical cancer

Local Control (%)

Disease-free Survival (%)

Treatment

IA - IB1

93-95% 98%

92% 96-100%

Surgery Radiation therapy

IB2

all: 94% 4-5 cm: 90% >5 cm: 82%

all: 81–85% 4–5 cm: 86% >5 cm: 67%

Radiation therapy

IIA

94-96%

70-85%

Radiation therapy

IB2-II

87%

74%

Radiation/chemotherapy

III-IV

71%

40–50%

Radiation/chemotherapy

IVB

–

0%

Palliative therapy (chemotherapy with/without radiation)

Stage

Sources: Based on the findings of randomized clinical trials detailed in Tables 22-10 and 22-11, as well as the following reports: Gadducci A, Sartori E, Maggino T et al. The clinical outcome of patients with stage Ia1 and Ia2 squamous cell carcinoma of the uterine cervix: a Cooperation Task Force (CTF) study. Eur J Gynaecol Oncol. 2003;24:513516. Eifel PJ, Morris M, Wharton JT, et al. The influence of tumor size and morphology on the outcome of patients with FIGO stage IB squamous cell carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1994;29:9-16. Lowrey GC, Mendenhall MW, RR M. Stage IB or IIA-B carcinoma of the intact uterine cervix treated with irradiation: a multivariate analysis. Int J Radiat Oncol Biol Phys 1992;24:205-210. Perez CA, Grigsby P, Nene S, et al. Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 1992;69:2796-2806. Komaki R, Brickner T, Hanlon A, et al. Long-term results of treatment of cervical carcinoma in the United States in 1973, 1978, and 1983: patterns of care study (PCS). Int J Radiation Oncology Biol Phys 1995;31:978-982. Barillot I HJ, Pigneux J, et al. Carcinoma of the intact uterine cervix treated with radiotherapy alone: a French cooperative study: update and multivariate analysis of prognostic factors. Int J Radiation Oncology Biol Phys 1997;38:969-978.

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Treatment Principles and Practice Primary surgical management with hysterectomy is indicated in stage IA, non-bulky IB, and early-stage IIA tumors. Primary RT results in similar outcome in these stages. For more advanced disease, RT alone (for stage IB1 tumors) and with concurrent cisplatin-based chemotherapy (for disease stages ≥ IB2) is the treatment of choice. Radical hysterectomy that has been performed in stage IIB tumors results in a greater incidence of urinary complications than does primary RT, and commonly in a need to add radiation with or without chemotherapy postoperatively because of adverse histologic findings (Tables 22.7 and 22.8). An overview of treatment modalities is given in Table 22.9. Figure 22.4 presents an overview of general treatment approach for all stages. Table 22.9 Overview of treatment modalities, techniques, and indications Modality

Description

Modified radical hysterectomy (type II)a Indication Technique

Facts

 Stage IA2 without LVSI  Resection of uterus, cardinal ligament at the level of the ureter, partial resection of uterosacral ligaments, 1–2 cm of vaginal cuff  Pelvic LN dissection; PA LN sampling can be considered  Risk of nodal involvement is 5% for stage IA2 disease  Survival >95% after surgical therapy  Has the advantage of preserving ovarian function in selected younger patients (with low risk of ovarian metastasis)  Avoidance of rare late radiation therapy morbidities

Radical hysterectomy (Meigs III)a Indications

Technique

Facts

 Stage IA2 with LVSI, IB1  Non-bulky IB2-IIA  Resection of uterus, cardinal ligaments at the pelvic wall, uterosacral ligaments at the posterior pelvic insertion, upper third to upper half of vagina  Pelvic LN dissection and PA LN sampling  Survival 80–90% after radical hysterectomy  54% of patients with stage IB1 and 84% of stage IB2 disease require post-hysterectomy RT ▶

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Table 22.9 (continued) Modality Radiation therapy

Indications

RT technique

Description a

 Definitive treatment for stage I-IIA (resectable) disease with same efficacy as surgery  Definitive treatment (with concurrent chemotherapy) for stage IIB–IVA  Recommended with concurrent chemotherapy in bulky >5 cm- to 6-cm stage IB2-IIA, because of common need of post-hysterectomy RT and increased complication risk with combined surgery/RT  Postoperative pelvic radiation is well-established for involved LN, involved parametria or involved surgical margins  EBRT to pelvis ± PA LN irradiation  Integrated with brachytherapy (BT)  Radiation therapy should be completed within 7 weeks

Chemotherapyb

Chemotherapy

Chemotherapy drugs

a

 As part of definitive treatment (concurrent with external beam RT [EBRT]) for locally advanced cervical cancer  Stage IB1: concurrent chemotherapy not validated  Adjuvant chemotherapy (following concurrent radiation/ chemotherapy) may reduce the overall recurrence rate and is currently under investigation  Commonly used for palliation for local, regional or systemic disease  Weekly cisplatin at 40 mg/m2 during 5 weeks of pelvic EBRT with or without chemotherapy during BT is the current standard of care  3-weekly cisplatin/5-FU is also validated by level I evidence (Tables 22.10 and 22.11)  Meta-analysis results indicate no particular benefit to cisplatin as compared with other types of chemotherapy  5-FU alone is not recommended as a concurrent regimen with radiation

Source: Landoni F, Maneo A, Colombo A et al (1997) Randomised study of radical surgery versus radiotherapy for stage Ib–IIa cervical cancer. Lancet 350:535–540 b Sources: Dueñas-González A, Zarba J, Alcedo J et al (2009) A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 27:18; Gaffney DK, Du Bois A, Narayan K et al (2007) Practice patterns of radiotherapy in cervical cancer among member groups of the Gynecologic Cancer Intergroup (GCIG). Int J Radiat Oncol Biol Phys 68:485–490; Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (2008) Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and metaanalysis of individual patient data from 18 randomized trials. J Clin Oncol 26:5802–5812; Lanciano R, Calkins A, Bundy BN et al (2005) Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a gynecologic oncology group study. J Clin Oncol 23:8289–8295

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Diagnosis of Cervical Cancer

Clinical/Radiological Staging of Cervical Cancer

Stage IA-B1

Stage IB2-IIA

LN + (by imaging)

RH pelv LN dissection ± PA LN samplinga)

or

ERBT + BT

Stage IIB-IVA

consider: Retroperitoneal LN dissection/debulking

RH pelv LN dissection ± PA LN sampling*

ERBT + BT concurrent chemotherapy

or ERBT + BT concurrent chemothrapy

High-risk features LVSI, depth, invasion, size b)

High-risk features Margins, LN, parametria c)

Post-op RT

Post-op RT concurrent CT

Active Follow-Up Figure 22.4 A proposed algorithm for the treatment of cervical cancer (all stages) RH: radical hysterectomy: a) see Table 22.9; b) see. 22.5; c) see. 22.6

Treatment of Stage I–IIA (Resectable) Cervical Cancer Radical hysterectomy and primary RT result in equivalent tumor control and survival in stage IA–IIA disease. One trial randomizing stage IB patients to radical hysterectomy versus RT yielded no difference in disease-free (74%), overall-survival (83%), and local-recurrence (26 versus 25%) rates, but demonstrated a higher toxicity rate with surgery (28 versus 12%, p = 0.0004) (Table 22.9).

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Adjuvant Therapy Two randomized trials have defined the utility of adjuvant radiation, and adjuvant radiation with concurrent chemotherapy after hysterectomy. Figures 22.5 and 22.6 summarize level I evidence and rationale for postoperative RT and postoperative combined RT/chemotherapy, based on highrisk histologic features. Eligibility criteria LVSI Positive Positive Positive Negative

Stromal Invasion Deep 1⁄3 Middle 1⁄3 Superficial 1⁄3 Deep or Middle 1⁄3

Tumor Size Any ≥ 2 cm ≥ 5 cm ≥ 4 cm

RANDOMIZATION

ARM 1

ARM 2

Pelvic RT 46 Gy 23 Fractions 50.4 Gy 28 Fractions

Observation n=140

n=137 RESULTS 1. 46% reduction in risk of recurrence favoring RT arm: hazard ratio (HR) was 0.54 (90% confidence interval [CI] was 0.35–0.81, p = 0.007) 2. Difference in overall survival was not significant (p = 0.074) 3. RT particularly beneficial in adenosquamous or adenocarcinoma: 9% recurrence with RT versus 44% recurrence without RT

Figure 22.5 Schema of GOG protocol 92: Clinical stage IB patients with lymphovascular space involvement (LVSI), large clinical tumor diameter, and more than a third of stromal invasion were randomized to post-hysterectomy pelvic RT versus no further treatment. Recurrence rate was improved, but overall survival was not significantly different. Sources: Sedlis A, Bundy BN, Rotman MZ et al (1999) A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a Gynecologic Oncology Group Study. Gynecol Oncol 73:177–183; Rotman M, Sedlis A, Piedmonte MR et al (2006) A phase III randomized trial of postoperative pelvic irradiation in Stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 65:169–176

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Postoperative pelvic radiation has been well established for involved LNs, parametria, or positive margins. The intergroup Gynecologic Oncology Group (GOG) Trial 109 evaluated whether the addition of concurrent chemotherapy is of benefit (Figure 22.6). Stage IA2, IB, or IIA patients treated with a radical hysterectomy and pelvic RT, were randomized to 4 cycles of cisplatin/5-FU versus RT without chemotherapy. Overall survival was significantly improved. Post hoc analysis showed particular benefit for larger tumor sizes and/or multiple involved LNs (Source: Peters WA III, Liu PY, Barrett RJ II et al (2000) Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18:1606–1613). Clinical Stage IA2, IB, IIA with any of the following: 1. postive lymphnodes 2. positive parametria 3. positive margins

RANDOMIZATION

ARM 1 Pelvic RT 49.3 Gy 29 Fractions n=116

ARM 2 Same RT Cisplatin/5 FU 96 hr infusion every 3 weeks x 4 n=127

RESULTS 1. HR for overall survival was 1.96 (p = 0.007), favoring RT/concurrent chemotherapy 2. Overall survival at 4 years was 71% with RT and 81% with RT and chemotherapy. Only 60% of patients received all 4 chemotherapy cycles

Figure 22.6 Schema of GOG protocol 109

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The decision pathway for adjuvant therapy after hysterectomy for cancer of the cervix is shown in Figure 22.7.

Diagnosis of Cervical Cancer

GOG 92 Eligibility requirements: 2 of 3: - LVSI - Tumor > 4 cm - >1/3 stromal invasion

Clinical Stage IA2-IIA

Radical Hysterectomy

Meets GOG 92 eligibility

No

Positive margins?

Yes

Pelvic RT 45-50.4 Gy

Yes

Chemo RT (cisplatin based, 45-50.4 Gy ± 2 cycles out back chemo) plus vaginal apex brachytherapy

Positive LNs or parametria?

Yes

Chemo RT (cisplatin based, 45-50.4 Gy ± 2 cycles out back chemo)

Active Follow-Up

Figure 22.7 Decision pathway for adjuvant therapy after hysterectomy for cancer of the cervix

Treatment of Stage IIB–IVA Cervical Cancer Radiation therapy with concurrent chemotherapy is the standard of care for stage IB2–IVA cervical cancer. Table 22.10 summarizes the level I evidence for the benefit from 5 randomized trials evaluating radiation with concurrent

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cisplatin-based chemotherapy versus radiation alone. The trial of the National Cancer Institute of Canada (NCIC) was the only negative study (Tables 22.10 and 22.11).

Table 22.10 Level I evidence for radiation and concurrent chemotherapy in advanced cervical cancer Trial

GOG 85

FIGO stage

IIB–IVA

Number Comparison Followof up patients

368

HR

Increase in survival (%) 10%

PF versus HU

8.7 years

0.7

RTOG 9001

IB 388 (>5 cm)–IVA

PF versus none

43 months

0.59 15%

GOG 120

IIB–IVA IIB–IVA

526 526

P versus HU PFHU versus HU

35 months 35 months

0.61 18% 0.58 18%

GOG 123

IB2 (>4 cm)

369

P versus none

36 months

0.54

9%

NCI/Canada

IB 253 (>5 cm)–IVA

P versus none

64 months

0.91

3%

Meta-analysis

IB–IVA

Chemotherapy versus none

62 months

0.78 ¾%

3,452

HR: hazard ratio, P: cisplatin, F: 5-fluorouracil, HU: hydroxyurea Source: Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (2008) Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26:5802–5812

Table 22.11 details the radiation techniques, the dose, type, and schedule of chemotherapy, and the outcome data in the 5 randomized trials. After the publication of the NCI clinical alert, radiation therapy with concurrent chemotherapy promptly became the standard of care for stage IIB– IVA cervical cancer.

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Table 22.11 Radiation and concurrent chemotherapy: details of treatment regimens and results of five randomized trials Trial

Description Randomized PF versus HU (1986–1990) Eligibility: IIB–IVA, negative LN based on surgical staging

GOG 85, SWOG 8695a

RT: stage IIB: 40.8/1.7 Gy/day EBRT; stage II–IVA: 51 Gy/1.7 Gy/ day. 40 Gy (Point A) LDR BT, total Point A: 80–81 Gy; parametrial boost to 55–60 Gy CT: HU 80 mg/kg 2 x per week versus P 50 mg/m2, days 1 , 21; F 100 mg/m2/day × 4 days Outcome: significant changes in 5-year PSF 57% with PF versus 47%; OS 62% with PF versus 50%; less hematologic toxicity with PF no change in 3-year late complication rate Conclusion: P-based regimen superior to HU Randomized PF/pelvic RT versus pelvic plus PA RT (1990–1997) Eligibility: IB–IIA (>5 cm), IIB–IVA, negative LN by surgical staging or lymphangiogram RT: 45 Gy/1.8 Gy/day, ≥40 Gy LDR BT, total Point A: ≥85 Gy; parametrial boost to 55–60 Gy

RTOG 9001b

CT: P 75 mg/m2, 5FU 1,000 mg/m2 × 4 days × 3 cycles (#3 during BT) every 3 weeks Outcome: significant change in 8-year DFS, 61% with PF versus 46%; OS 67 versus 41%; reduction of locoregional failure 85 versus 35%; distant failure, 20 versus 35%; no change in PA failure without PA RT; no change in complication rates Conclusion: concurrent chemotherapy superior to pelvic/PA RT Randomized weekly P versus P F HU versus HU (1992–1997) Eligibility: IIB–IVA, negative LN by surgical staging RT: stage IIB: 40.8/1.7 Gy/day EBRT; stage II–IVA: 51 Gy/1.7 Gy/ day. 40 Gy (Point A) LDR BT, total Point A: 80–81 Gy; parametrial boost to 55–60 Gy

GOG 120c

CT: weekly P 40 mg/m2 versus P 50 mg/m2, F 1,000 mg/m2 × 4 days × 2 cycles during EBRT, HU 2 mg/kg 2 × per week versus HU 3 g 2 × per week Outcome: significant change in 3-year OS, 65% in P-based arms versus 47%; significant change in pelvic recurrence (20 versus 30%); less acute toxicity for weekly P Conclusion: P-based arms superior to HU, weekly P less toxic

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Table 22.11 (continued) Trial

Description Randomized concurrent weekly P versus RT alone followed by extrafascial hysterectomy (1992–1997) Eligibility: IB2 (>4 cm), negative LN by CT, lymphangiogram, or surgical staging RT: EBRT: 45 Gy/1.8 Gy/day; LDR BT, total Point A: 75 Gy

GOG 123d

CT: weekly P 40 mg/m2 × up to 6 cycles during EBRT or last dose during BT Outcome: significant change in 3-year PFS, 79% with P versus 67%; OS 83 versus 74%; pelvic control 91 versus 79%, complete pathologic response 52 versus 41% Conclusion: weekly P superior to RT alone in bulky stage IB2 Randomized (1991–1996) Eligibility: IB,IIA (>5 cm or histologically + LN), IIB–IVA

NCI/Canadae

RT: EBRT: 45 Gy/1.8 Gy/day, BT (LDR or HDR) equivalent Point A dose of 35 Gy(LDR), total Point A: 80 Gy; RT to be completed within 7 weeks CT: weekly P 50 mg/m2 × 5 cycles during EBRT Outcome: no change in 5-year PSF and OS, 62 versus 58% Conclusion: no benefit of concurrent weekly P. Possible reasons: shorter treatment duration, only imaging-based staging, more anemia in the chemotherapy arm, smaller sample size

P: cisplatin, F: 5-fluorouracil, HU: hydroxyurea, PFS: progression-free survival, DFS: disease-free survival, OS: overall survival a Source: Whitney CW, Sause W, Bundy BN et al (1999) Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB– IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17:1339–1348 b Sources: Morris M, Eifel PJ, Lu J et al (1999) Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137–1143; Eifel PJ, Winter K, Morris M et al (2004) Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer an update of Radiation Therapy Oncology Group trial (RTOG) 90-01. J Clint Once 22:972–880 c Source: Rose PG, Ali S, Watkins E et al (2007) Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25:2804–2810 d Source: Keys HM, Bundy BN, Stehman FB et al (1999) Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154–1161 e Source: Pearcey R, Brundage M, Drouin P et al (2002) Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20:966–972

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The management of patients with cancer of the cervix treated definitely with radiation and chemotherapy is shown in Figure 22.8.

Diagnosis of cervical cancer

Figure 22.8 Treatment for stage IIB–IVA cervical cancer

Clinical staging and imaging

Consider retroperitoneal LN dissection or surgical staging

45 Gy with cisplatin-based chemo LDR or HDR BT Point A/ tumor should receive 80-85 Gy LDR equivalent

Active Follow-Up PET/CT preferred at 3 months then clinical follow-up

Para-aortic Radiation Prophylactic radiation of the para-aortic nodes remains controversial. It decreases para-aortic recurrences, without proven survival benefit. Para-aortic radiation can be considered in patients with a risk of subclinical para-aortic node involvement. This may include patients with common iliac and/or extensive pelvic-node metastases in the absence of surgical para-aortic LN staging.

Treatment of Recurrent or Metastatic Cervical Cancer Locoregional Recurrence Post-hysterectomy recurrence is treated with individualized EBRT and brachytherapy with largely interstitial and concurrent cisplatin-based chemotherapy should be considered. In favorable patients with central small recurrences, survival rates of more than 60% are achievable with salvage radiation therapy. For patients with recurrent cancer after radiation therapy, repeat radiation has been employed in rare instances. However, pelvic exenteration is the

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mainstay of salvage therapy in selected patients with central failures. Favorable prognostic factors for survival after salvage RT include no previous chemotherapy or radiation therapy; a long, disease-free interval; and no preceding use of cisplatin-based therapy. Improvements in surgical technique used in pelvic exenteration have reduced the morbidity and mortality. Patients with central recurrence alone have the most favorable survival rates; those with pelvic sidewall disease experience poor outcomes. Metastatic Disease Survival of patients with metastatic disease remains poor, with a median of 3–9 months. Poor prognostic factors for response of metastatic cervical cancer are black race (odds ratio [OR] = 0.49), poor performance status (OR = 0.60), pelvic site of recurrence (OR = 0.58), previous radiosensitizer use (OR = 0.52), and first recurrence within 1 year (OR = 0.61). Cisplatin has an overall response rate of 38%: 50% for untreated and 17% for previously treated patients. A combination of cisplatin and topotecan improved response rate, and improved median overall survival to 9.4 months from 6.5 months with cisplatin alone, but did not improve overall survival rate. Combination of cisplatin and bevacizumab resulted in progression-free intervals of 6 months or longer in 25% of patients with metastatic cervical cancer.

RT Techniques Definitive RT Definitive RT for cervical cancer requires the integration of two elements, EBRT (with pelvic and parametrial and nodal boosts if appropriate) and BT. Treatment must be individualized, based on the patient’s initial tumor extent, normal tissue anatomy, and tumor-response characteristics during therapy. EBRT EBRT fields encompass the primary tumor in the cervix/uterus, local tumor extension (parametria/uterosacral ligaments, vagina), draining regional lymphatics, and known areas of LN involvement. Simulation, Target Volume Delineation and Field Arrangement Three-dimensional image-guided planning is highly recommended to improve the delineation of target structures and exclusion of normal tissues, including

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bowel, bladder, and bone marrow. Intravenous contrast for CT can be helpful in the differentiation of regional LNs from vessels, and delineation of the bladder. Oral contrast given 1–1.5 h before simulation improves differentiation of bowel from LNs, vascular structures, and tumor. CT allows delineation of the uterus, but it does not differentiate tumor from normal uterus. With MRI, the gross tumor extent within the uterus, parametria, and the parametrial tumor extent can be delineated. MRI is otherwise equivalent to CT in the delineation of LNs and normal structures. Placement of a gold seed marker into the cervix or into the most distal visible or palpable vaginal tumor extent is recommended. Rigid vaginal markers, rectal markers, or rectally administered bowel contrast are not recommended, and may cause upward displacement of the cervix, or rectal distension and cervical displacement. If such displaced anatomy is used for target delineation, geographical miss of tumor can occur during actual treatment. Guidelines for target delineation, clinical target volume (CTV), and planning target volume (PTV) design currently used in Radiation Therapy Oncology Group (RTOG) and GOG protocols are summarized in Table 22.12. The sum of the primary tumor PTV and nodal PTV results in a confluent final PTV (Figure 22.9). Because of viabilities in the aortic bifurcation, 40% Table 22.12 Target volume for definitive radiation therapy using CT-based planning Target

Primary cervical tumor

Description GTV: entire uterus and tumor extensions to parametria, uterosacral ligaments and vagina based on imaging and implanted markers (from palpation/inspection) CTV: additional 0.7-cm- to 1-cm margin. 3-cm margin distal to the cervix or lowest vaginal tumor extent PTV: + 0.5-cm to 1-cm margin (to account for setup variability) GTV: grossly involved LN

Regional lymphatics

CTV: grossly involved LN plus 1-cm margin. Normal-appearing obturator, external, and common iliac LNs; in stage IIIA and distal-half vaginal extension, also inguinal LN; postsurgical clips and postoperative seromas. Add 0.7-cm margin, 1–2 cm anterior to S1–S3 PTV: + 0.5-cm to 1-cm margin (to account for setup variability)

Sources: Small W Jr, Mundt AJ. RTOG Gynecologic Pelvic Atlas (http://www.rtog.org/ atlases/contour.html); Small W Jr, Mell LK, Anderson P et al (2008) Consensus guidelines for the delineation of the clinical target volume for intensity modulated pelvic radiotherapy in the postoperative treatment of endometrial and cervical cancer. Int J Radiat Oncol Biol Phys 71:428–434; Lim K, Small W, Portelance L et al (2010) Consensus guidelines for delineating of clinical target volume for intensity-modulated pelvic radiotherapy for definitive treatment of cervical cancer. Int J Radiat Oncol Biol Phys 2010 May 14 [Epub ahead of print]

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of common iliac LNs are reported to be located above the L4–L5 interspace. Therefore, the upper border of the EBRT field should be individualized. If higher-level common iliac LNs are involved, an increase of the upper margin for one to three vertebral bodies should be considered to include lowerlevel para-aortic LNs.

Figure 22.9 a–c MRI-based target delineation of tumor (outlined in red), uterus (outlined in dark blue), parametria (outlined in green and orange), bladder, and rectum according to consensus guidelines of the Gyn IMRT Consortium. a Axial view. b sagittal view; the dotted line indicates the plane of the axial image. c CT-based delineation of external and common iliac vessels and LN CTV. Figure 22.9a and 22.9b reprinted with permission from Lim K, Small W, Portelance L et al Consensus guidelines for delineating of clinical target volume for intensity-modulated pelvic radiotherapy for definitive treatment of cervical cancer Int J Radiat Oncol Biol Phys 2010 May 14 [Epub ahead of print]

To design parametrial boost fields, the isodose distribution from the BT (Figure 22.10) must be taken into account to prevent overlap of dose from the BT and external-beam contributions. Such overlap, caused by a standard, 4-cm midline block, has been shown to result in higher risk of late ureteral complications.

Figure 22.10 a, b CT-fusion for parametrial boost planning. a Coronal: Projection of BT ring applicator (green) and contours of uterus (blue), (bladder (yellow), involved pelvic lymph node GTV (solid red) and PTV (red line). b AP DRR: Projection of the BT prescription dose distribution is used to design right parametrial boost PTV

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Contouring of normal structures includes the rectum (up to the rectosigmoid junction), bowel (including large bowel above the rectum) and intraperitoneal contents (small bowel and mesentery) within 5 cm above the upper border of the target volume, the bladder, and femoral heads. If three-dimensional (3D) imaging is not available, field design should be guided by bony landmarks only (Table 22.13). Table 22.13 Fluoroscopy-based fields for radiation therapy in EBRT of cervical cancer Field

Borders

AP/PA

 Superior: L4/L5 interspace  Inferior: 3 cm below the lowest tumor extent (determined by gold seed or contrast tampon) or bottom of obturator foramen  Lateral: 2 cm lateral to the pelvic brim and including any surgical clips with 1- to 1.5-cm margin

Lateral

   

Superior: same as in AP/PA Inferior: same as in AP/PA Anterior: 1 cm anterior to the pubic symphysis Posterior: at least anterior half of the sacrum

Dose and Treatment Delivery EBRT prescription dose to the PTV ranges from 45 to 50.4 Gy in 1.8-Gy factions. After BT, parametrial boosts are delivered, ranging from 5.4 to 14.4 Gy, to result in a total parametrial dose (including initial pelvic fields and parametrial fields) of 50 Gy for small stage IB tumors, 55 Gy for tumors with moderate parametrial involvement, and 60 Gy for bulky parametrial involvement. For grossly involved pelvic or para-aortic LNs, doses up to 60 Gy (including whole-pelvic EBRT) should be delivered via 3D conformal or intensity-modulated RT (IMRT) techniques (Figure 22.11). The inclusion of BT dose contributions into the parametrial boost dose prescription has been variable, and has ranged from total parametrial doses of 50.4–54 Gy (not including BT contribution to Point B) to 55–60 Gy (including the BT contribution).

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Figure 22.11 Comparison between four-field 3D conformal RT and seven-field IMRT, showing dose reduction in region of small bowel (arrows)

IMRT IMRT (Figure 22.11) is being studied in the treatment of cervical cancer and has been shown to decrease bowel and bladder doses in pelvic RT, to reduce acute grade 3 or higher gastrointestinal toxicity, bone marrow dose, and hematologic toxicity. However, IMRT is more vulnerable to inter- and intrafractional organ motion, and meticulous attention has to be paid to allow sufficient PTV margins and/or to control organ motion to prevent geographic tumor miss. The RTOG has studied IMRT in postoperative pelvic radiation and demonstrated successful inter-institutional implementation. Standardization of target volume definitions for IMRT in intact cervical cancer are in development. (Source: Lim K, Small W, Portelance L et al (2010) Consensus guidelines for delineating of clinical target volume for intensity-modulated pelvic radiotherapy for definitive treatment of cervical cancer. Int J Radiat Oncol Biol Phys 2010 May 14 [Epub ahead of print]

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BT BT is a critical component of definitive RT for cervical cancer, and its use is critical to achieve tumor control and improve survival. BT provides the ultimate conformal therapy for cervical cancer, and it enables the delivery of high doses of 85 Gy or more to the paracervical regions, which are needed for tumor control and cannot be delivered with EBRT alone. BT can be delivered in an intracavitary or interstitial fashion. The two main forms of BT are a high-dose rate (HDR) and a low-dose rate (LDR) BT (Table 22.14; Figure 22.12). Intracavitary BT generally utilizes an intra-uterTable 22.14 Patterns of care in BT for cervical cancer Evaluation

Type of BT HDR

Advantage

 Outpatient delivery  No need for bed  Radiobiologic rest advantages of  Less radiation low dose rate: personnel exposublethal damsure age repair  Better individual-  Longer track reization of source cord position and do Only 1–2 procesimetry dures needed  Improved displacement of normal tissues

Disadvantage

 Large dose fractions, narrower therapeutic ratio (- sublethal damage repair)  Labor intensive dosimetry planning process  High impact of errors

Practice pattern 14 in USA (%)a a

LDR

Interstitial

 Advantage in tumors that cannot be encompassed in intracavitary dose distribution

 Need for inpatient facility  Prolonged best  May result in rest, risk for vehigher complicanous thrombosis tion rates  Regulatory issues,  Highly operator maintenance of dependent sealed sources  Personnel exposure 78

8

Source: Erickson B, Eifel P, Moughan J et al (2005) Patterns of brachytherapy practice for patients with carcinoma of the cervix (1996–1999): a patterns of care study. Int J Radiat Oncol Biol Phys 63:1083–1092

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ine tandem and ovoid applicators in LDR, and tandem and ovoid or ring applicators in HDR. HDR BT utilizes a source that delivers a dose rate of >12 Gy/h and generally is performed on an outpatient basis over several treatment fractions. LDR delivers <2 Gy/h and is delivered on an inpatient basis. Pulsed-dose rate (PDR) generates pulses of radiation therapy, with the aim to mimic the radiobiologic properties of LDR therapy and is generally performed on an inpatient basis (hourly). Interstitial BT uses interstitial needles inserted through the perineum into the tumor target tissue, frequently with the use of a perineal template. This can be combined with intracaviatry radiation. Interstitial BT should be utilized when intracavitary radiation therapy cannot deliver adequate doses to

Figure 22.12 a–e AP a and lateral b simulation films of LDR Fletcher-Delclos tandem and ovoid BT applicators and of HDR ring and tandem applicators (c and d, respectively). Imaging-compatible HDR ring and tandem applicators (e) allow CT–MRI fusion for more accurate delineation of the uterus and pelvic organs. The intra-uterine portion of the tandem shows dark signal on MRI, while the more distal portion of the and the rectal retractor are visible as bright contrast on the CT

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the target tissue; it provides a more favorable dose distribution regarding the relative dose to tumor and organs at risk. Typical indications for interstitial brachytherapy include obliteration of the cervical os, narrow fornices, tumor extension into the lower vagina, or lateral parametrial infiltrations. Local control rates of 100, >90, and 75% have been reported for stages I, II–III, and IV cervical cancer, respectively (Source: Demanes JD, Rodriguez RR, Bendre DD et al (1999) High dose rate transperineal interstitial brachytherapy for cervical cancer: high pelvic control and low complication rates. Int J Radiat Oncol Biol Phys 45:105–112). BT Dose Specification and Prescription Traditional cervical BT has been prescribed to Point A or equivalent paracervical points, with calculation of doses to Point B and organs at risk, including point doses representing bladder, rectum, and vaginal mucosa. For LDR BT, a Point A dose of 40 Gy in one or two BT applications, resulting in a total Point A dose of at least 85 Gy (from EBRT and BT contributions), has been well accepted as the minimum dose, resulting in improved tumor control. Close integration with the external-beam course is critical. For HDR BT, dose schedules are highly variable. When delivered in an HDR schedule, nominal doses result in significantly greater normal tissue effects. Dose schedules that are consistent with the biological effect of established LDR schedules are derived with the linear-quadratic (LQ) model defining the biologically effective dose (BED) as a function of the total dose (D) and dose per fraction (d) and ratio (/) according to: BED = D × [1+d/(/)], using an / ratio of 10 for the tumor BED (Gy10) and 3 for the normal tissue BED (Gy3). Prescription points and calculation points for target and normal tissue are listed in Table 22.15. The doses in Table 22.13 refer to the total of EBRT and BT doses converted to the low-dose rate equivalent dose for 2-Gy fractions. BT dose schedules are influenced by variabilities in fraction size, total doses, and external-beam dose. No one “correct” or “best” dose/fractionation schedule has been established. Most commonly used fractionation schedules and general guidelines are presented in Table 22.16.

Significance  Paracervical point, where ureters cross uterine vessels  Problems: Point A is applicator dependent and may not represent tumor involvement  Similar to Point A, (commonly used instead of Point A in HDR)

 Represents the location of the obturator LN (used by some for parametrial boost prescription)

 Represents the location of the pelvic wall (not commonly used)

Description

 AP film: 2 cm superior, 2 cm lateral to external cervical os or cervical end of the tandem (following the long axis long axis of the tandem)  Lateral film: along tandem

 AP film: 2 cm superior, 2 cm lateral to external cervical os  Lateral film: 2 cm superior to ovoids on lateral film

 AP film: 2 cm superior to the cervical os, 5 cm lateral of the long axis of the pelvis (independent from the direction of the endocervical canal)  Lateral film: along tandem

 AP film: 2 cm superior to the cervical os, 6 cm lateral of the long axis of the pelvis (independent from the direction of the endocervical canal)  Lateral film: along tandem

 AP film: at the mid-level of the ovoid sources or most distal tandem source; at center  ICRU bladder point for organ at risk  Lateral film: 0.5 cm posterior to the vaginal wall (packing or rectal retractor)

Dose point

A

M

B

C

Rectal

Table 22.15 Dose prescription points for BT in cervical cancer

 <70 Gy

▼

 Usually receives 15–20% of the Point A or M dose

 Usually receives 15–20% of the Point A or M dose

 85–90 Gy (early stage I: 80 Gy)

 85–90 Gy (early stage I: 80 Gy)

Dose goal (EBRT plus BT)

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Bladder

 <75 Gy

Dose goal (EBRT plus BT)

ICRU: International Commission on Radiological Units and Measurements Sources: Petereit DG, Pearcey R (1999) Literature analysis of high-dose-rate brachytherapy fractionation schedules in the treatment of cervical cancer: is there an optimal fractionation schedule? Int J Radiat Oncol Biol Phys 43:359–366; Mai J, Erickson B, Rownd J et al (2001) Comparison of four different dose specification methods for high-dose-rate intracavitary radiation for treatment of cervical cancer. Int J Radiat Oncol Biol Phys 51:1131–1141

 <100–120 Gy (LDR)  Vaginal mucosal dose limiting point  140–160% of Point A dose (HDR)

 ICRU rectal point for organ at risk

 AP film: at center of the Foley balloon (filled with 7 ml contrast), level of the vaginal sources  Lateral film: at posterior surface of balloon

 AP film: at the lateral edge of the ovoids at the 9:00 o’clock position on the right Vaginal surface and 3:00 o’clock on the left on the AP  Lateral film: center of ovoids

Significance

Description

Dose point

Table 22.15 (continued)

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Table 22.16 HDR BT dose recommendations Stage

Early

Advanced

External-beam dose (Gy)

HDR fractions (n)

HDR dose per fraction (Gy)

20

6

7.5

20

7

6.5

20

8

6

45

5

6

45

6

5.3–5.5

45

5

6.5

45

6

5.8

50.4

4

7

50.4

5

6

50.4

6

5.3

Adapted from: Petereit DG et al (1999) High-dose-rate versus low-dose-rate brachytherapy in the treatment of cervical cancer: analysis of tumor recurrence – the University of Wisconsin experience. Int J Radiat Oncol Biol Phys 45:1267–1274; Nag S, Chao C, Erickson BA et al (2002) The American Brachytherapy Society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 52: 33–48

Normal Tissue Tolerance The addition of BT to EBRT for cervical cancer increases the risk of normal tissue toxicity. It is critical that the dose to organs at risk including rectum, bladder, and vagina are respected. It is recommended that normal tissue doses be calculated. Currently, the most widely accepted system includes the normal tissue dose points, based on International Commission on Radiation Units (ICRU) Report 38. Guidelines for normal tissue point dose limits are presented in Table 22.17. Doses include contributions from both EBRT and BT. Doses for HDR are presented in LDR equivalent doses (for 2-Gy fractions) and in BED. If the rectal dose exceeds 100 Gy3 and/or the bladder dose 120 Gy3, adjustments in applicator placement may have to be made and/or the dose/fractionation schedules adjusted to a higher number of fractions, with a lesser dose for each fraction to reduce normal tissue dose effects.

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Table 22.17 Recommendations for normal tissue dose limits Organ

BT LDR (Gy)

HDR LQED2 Gy (Gy)a

HDR BED (Gy3)

Rectum

<75

<75

<100

Bladder

<80

<80

<120

Vaginal mucosal surface

135

140–160% of Point A

<140

a

The nominal HDR dose has been converted to the low-dose rate equivalent dose at 2-Gy faction using the LQ formula). The BED is given as Gy3 in column “HDR BED” Sources: Petereit DG, Pearcey R (1999) Literature analysis of high-dose-rate brachytherapy fractionation schedules in the treatment of cervical cancer: is there an optimal fractionation schedule? Int J Radiat Oncol Biol Phys 43:359–366; Nag S, Chao C, Erickson BA et al (2002) The American Brachytherapy Society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 52: 33–48; Mai J, Erickson B, Rownd J et al (2001) Comparison of four different dose specification methods for high-dose-rate intracavitary radiation for treatment of cervical cancer. Int J Radiat Oncol Biol Phys 51:1131–1141

Timing of BT and Overall Treatment Time The overall treatment course should be completed within 8 weeks, because protraction of therapy decreases survival. A decrease in survival rate by 0.5– 1% for each additional day has been estimated. The timing of BT is critical. There is no rationale to wait 1–2 weeks after EBRT completion to begin BT. The timing of BT should be individualized, as illustrated in Figure 22.13. Optimal timing depends on regression speed of the tumor and the development of adverse anatomical normal tissue changes.

Tumor Volume (%) Degree of adverse anatomical change (%)

100

Optimal timing to begin brachytherapy

50

fast

slow inte rme diat e

0 EBRT Week # 1 2 3 4 5 Dose level (Gy) 9-10 18-20 27-30 36-40 45-50

6

7

External Beam Radiation Therapy Course

Volume Volume within BT dose larger than BT distribution dose distribution

Integration of EBRT and Brachytherapy

Figure 22.13 Optimized timing for BT. Balance between tumor regression (red curves) and onset of adverse anatomic tissue changes (black curves) influence BT start in fast (••••••), intermediately (), and slowly (- - -) regressing tumors

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Tumor shrinkage during EBRT incrementally improves the geometry of the tumor for BT and allows the tumor to be encompassed by the BT isodose distribution (light-gray shaded area in Figure 22.13). Simultaneously, as the tumor volume gradually reduces, the normal cervical/vaginal anatomy also deteriorates from the development of fibrosis and stenosis of the vagina and cervix, which can impair optimal applicator placement and BT dose distribution. The point of optimal tumor shrinkage and least adverse anatomical change is the best time to begin BT. Timing and approach have to be in tailored to the dynamics of tumor response (fast, intermediate, and slow; Figure 22.13) and normal tissue characteristics of individual patients. Interval assessment of the tumor during RT by clinical examination and/or imaging is critical in making this determination. Once BT has started, all fractions should be completed within a 10- to 14day interval for LDR, or with once-weekly HDR fractions during pelvic EBRT, and twice weekly (>72 h apart) fractions once the pelvic EBRT has been completed. Parametrial boosts should start in the interval between BT procedures as soon as pelvic EBRT and the first BT procedure are completed. Image-Guided BT Image-guided BT may further improve precision and quality of treatment, as compared with conventional plain film based BT planning. Commonly used imaging techniques include ultrasound, CT, and MRI (Table 22.18). A recent American Brachytherapy Society (ABS) survey showed that ultrasound, CT, and MRI are used routinely for applicator placement in 56, 70, and 2% of cases, respectively, and that contouring of bladder and rectum is commonly performed (Source: Viswanathan AN, Erickson BA (2010) Three-dimensional imaging in gynecologic brachytherapy: a survey of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 76:104–109). Adjuvant (Postoperative) RT The same general principles as for definitive pelvic EBRT apply for postoperative pelvic-RT planning. Because of the removal of uterus and adnexae, more small bowel is excepted to be located within the pelvis. Prone positioning and the use of IMRT to more effectively exclude bowel from the treatment field should be considered. The LN target is identical to that of definitive EBRT. The postoperative CTV in the central pelvis includes the vaginal and paravaginal tissues, with the obturator muscle as the lateral margin, and at least 3 cm of vagina, as defined by the RTOG protocol 0418 and the RTOG Gynecologic Pelvic Atlas (http://www.rtog.org/atlases/contour.html).

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Table 22.18 Imaging techniques used in imaging-guided BT for cervical cancer Technique

Description

Ultrasounda

 Interactive use of intraoperative ultrasound during the applicator placement allows real-time adjustment of the applicators  Enables successful applicator placement in difficult cases, including retroverted uterus, cervical stenosis, or large uterine fibroids  Reduces malplacements and uterine perforations to essentially none  Likely reduces bowel and bladder complications

CT scana

 CT after applicator placement detects essentially all uterine perforations, thus further improving the therapeutic ratio  With traditional metallic (non-imaging compatible) applicators the tandem, ovoids, or ring, boundaries of the uterus, rectum, and bladder can usually be visualized

MRIb

 MRI (using imaging-compatible BT applicators) allows significantly improved soft tissue delineation (Figure 22.13)  MRI can delineate the actual tumor extent within the uterus and parametria and enables the transition from point dose prescription to image-guided, volume-based BT prescription  Utilizing the GEC ESTRO guidelines for BT dose prescription based on GTV, high-risk-CTV and intermediate risk–CTV may improve tumor control and reduce complications

a

Source: Shin KH, Kim TH, Cho JK et al (2006) CT-guided intracavitary radiotherapy for cervical cancer: Comparison of conventional point A plan with clinical target volume-based three-dimensional plan using dose-volume parameters Int J Radiat Oncol Biol Phys 64:197–204 b Sources: Pötter R, Haie-Meder, Van Limbergen C et al (2006) Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 78:67–77; Pötter R, Dimopoulos J, George P et al (2007) Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer. Radiother Oncol 83:148–155

Postoperative pelvic doses range from 45 to 50.4 Gy. Postoperative vaginal-cuff BT is controversial, but can be considered in patients with bulky central disease, or those with close or involved surgical margins.

Follow-Up Active follow-up after treatment of cervical cancer is recommended (Table 22.19). Most recurrences present within 2 years, and failures after 5 years are exceedingly uncommon.

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Table 22.19 Follow-up schedule and examinations Schedule

Frequency

First follow-up after RT

 4–6 weeks; if residual tumor, continue monthly monitoring

Years 0–2

 Every 3 months

Years 3–5

 Every 6 months

Years 5+

 Annually

Examinations History and physical

 Complete history and physical examination including pelvic examination  Pap smear

Laboratory tests

 If clinically indicated

Imaging

 Chest X-ray yearly  MRI at 1 month or PET/CT at 3 months after treatment may be predictive for outcome  Other imaging studies based on clinical indication

Sources: Kidd EA Siegel BA, Dehdashti F et al (2007) The standardized uptake value for F-18 fluorodeoxyglucose is a sensitive predictive biomarker for cervical cancer treatment response and survival. Cancer 110:1738–1744; Mayr NA, Wang JZ, Lo SS et al (2010) Translating response during therapy into ultimate treatment outcome: a personalized 4-dimensional MRI tumor volumetric regression approach in cervical cancer. Int J Radiat Oncol Biol Phys 76:719–727

Treatment Toxicity Short-term (acute) and late side effects, their causes, risk factors, and management are listed in Tables 22.20 and 22.21. Most acute side effects are controllable with supportive care. The frequency of late complications requiring hospitalization or surgical interventions ranges from 5 to 14%. Bowel complications are seen in less than 5%. Most complications occur within the first 5 years; however, a low risk of urinary complications persists over a 25year period (Source: Eifel PJ, Levenback C, Wharton TJ et al (1995) Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 32:1289–1300; Lanciano RM, Martz D, Montana GS et al (1992) Influence of age, prior abdominal surgery, fraction size, and dose on complications after radiation therapy for squamous cell cancer of the uterine cervix. A patterns of care study. Cancer 69:2124–2130).

 Urinary frequency, burning  Pelvic EBRT, BT  Hematuria  Pelvic EBRT, BT

Gastrointestinal

Genitourinary

Hematologic

 Chemotherapy, PA EBRT  RT and chemotherapy (especially 5-FU)  RT and chemotherapy  Pelvic EBRT, BT

 Nausea, vomiting, gastric irritation  Diarrhea, cramping  Dehydration  Rectal/peri-rectal irritation and bleeding

 Chemotherapy and RT (dose to bone marrow)  Chemotherapy, RT, bleeding from tumor  Chemotherapy and RT

 Chemotherapy, RT

 Fatigue  Anorexia

Constitutional

 Neutropenia, thrombopenia  Anemia  Infectious complications

Cause

Side effect

System

Table 22.20 Short-term (acute) side effects of therapy for cervical cancer

 Treatment break for abs. neutrophil count <500,000, platelet count <50,000; colony stimulating factors neutropenic precautions  Transfusions, oral iron supplement  Treatment break, hospitalization, antibiotic coverage, colony stimulating factors

 Antispasmodics, urinary tract analgesics; urine culture to exclude urinary tract infection  Monitor hemoglobin, bladder irrigation; in severe cases, laser fulguration, electrocoagulation

 Antiemetics: for 3–4 days after each cisplatin, before each PA RT fraction; proton pump inhibitors  Low-fiber/-residue diet, antidiarrheals; in severe cases, stop RT, monitor electrolytes, paregoric, tincture of opium; stool culture/ treatment for Clostridium difficile  IV fluid/electrolyte replacement, IV/oral anti-emetics  Topical and/or rectal steroids; steroid suppositories, pain control

 Mild exercise, rest as needed  Nutritional supplements

Management

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Cause  BT insertion  BT delivery, prolonged bed rest (LDR)  Chemotherapy

Side effect

 Bleeding, perforation, infection, anesthesia complications  Venous thrombosis, pulmonary embolism

 Cisplatin, 5-FU allergy (extremely rare)

System

Procedural

Allergic

Table 22.20 (continued)

 Acute management of anaphylaxis

 Intra-operative ultrasound, perioperative antibiotics for intra-uterine procedures  Thrombosis prophylaxis (anticoagulants, SCDs)

Management

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 EBRT, BT  Risk factors: postmenopausal, elderly age  ERBT  Risk factors: osteoporosis, elderly age

 Hematuria  Vesicovaginal fistula  Ureteral stricture

 Vaginal atrophy, dryness, stenosis  Dyspareunia

 Femoral fractures  Sacral fractures mostly asymptomatic

Genitourinary

Vaginal stenosis

Bone

 Intramedullary rod, hip replacement  Conservative therapy, pain control, treatment of osteoporosis

 Topical vaginal estrogen, vaginal dilators  Vaginal lubricants, estrogen

 Intravesial therapy, laser, cauterization of bleeding vessels  Urinary diversion  Ureteral stent, urinary diversion, percutaneous nephrostomy

 RT, BT  Risk factors: high bladder BT dose, large fraction, bladder invasion  ERRT, BT, radical hysterectomy  Risk factors: straight midline block for parametrial boost

   

Gastrointestinal

Management  Low-fiber diet, long-term oral antidiarrheals  Conservative management (bowel rest, nasogastric suction)  For acute abdomen, bowel resection with anastomosis or bowel diversion colostomy  Steroid enemas, cauterization or laser of bleeding vessel(s), supportive care pain control, transfusions  Bowel diversion, colostomy

Cause, risk factor  EBRT, BT, hysterectomy  Risk factors: trans-peritoneal LN dissection, prior pelvic surgeries, adhesions, pelvic inflammatory disease; weight <54 kg, smoking, large EBRT volumes, low-energy beams, large fractions  EBRT, BT  Risk factors: high rectal-point BT dose, large BT fractions

Side effect

Small bowel Persistent diarrhea Bowel obstruction, Bowel perforation, fistula  Rectum  Chronic rectal bleeding, ulceration  Rectal stricture, rectovaginal fistula

System/situation

Table 22.21 Long-term (chronic) side effects of therapy for cervical cancer

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 Compression stockings, sequential compression device

 ERBT  Risk factors: LN involvement, LN dissection  EBRT  RT, chemotherapy

 Lower extremity edema

 Ovarian failure (menopause)

 Sarcomas, leukemias , others

Lymphatic

Endocrine

Second cancers

 Disease=specific tumor therapy

 Hormonal replacement therapy

Management

Cause, risk factor

Side effect

System/situation

Table 22.21 (continued)

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23

Vulva Cancer Kevin Albuquerque1

Key Points  Carcinoma of the vulva is a relatively uncommon malignancy. Eighty to 90% of primary vulvar tumors are squamous carcinomas. Tumors of the vestibular glands (Bartholin’s glands) often are adenocarcinomas or adenocystic carcinomas, but 30–50% of tumors have squamous histology.  Symptoms can be subtle in very early lesions, but generally with advanced disease, vulvar cancer–specific symptoms, such as pruritus, pain, spotting or bleeding, and discharge, may be evident.  Progression of disease occurs in a stepwise locoregional fashion (locally to adjacent organs), while lymphatic spread is to inguinofemoral nodes (superficial and deep).  Lymph node involvement increases with tumor size and depth of stromal invasion. Distant metastases are uncommon but may occur to bone and lung.  Clinical diagnosis is based on history, physical examination, and biopsy confirmation, with laboratory and imaging studies playing an ancillary role.  Lymph node involvement at diagnosis is the most important prognostic factor for overall survival. Tumor and treatment related factors determine local failure.  Preservation of function, as well as anatomy, is paramount in the decision-making process for the treatment of vulvar cancer. Except for diseases with very limited volume and extent that can be treated with surgical excision only, the majority of cases require multidisciplinary management with limited surgery and radiation therapy (RT).  Surgery has become less extensive, with (radical being >1 cm) wide local excision (WLE) preferred over total vulvectomy and the exploration of sentinel lymph node biopsy (SLNB) as a replacement for groin node dissection (GND) with its attending morbidities.  Adjuvant RT is added selectively to reduce morbidities of combined treatments. Indications for RT to primary tumor and nodal beds should be determined separately, based on pathological prognostic features of each.  RT (with concurrent chemotherapy) plays a major role in locoregionally advanced disease or lesions with extension to the midline structures. This is combined with inguinal dissection and function-preserving completion surgery. 1

Kevin Albuquerque, MD, MS, FRCS () Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_6, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Vulva cancer accounts for about 4% of cancers of the female reproductive organs and 0.6% of all cancers in women in the USA. The Surveillance, Epidemiology and End Results (SEER) Program estimated that in 2009, about 3,580 cases of vulva cancer would be diagnosed in the USA, and about 900 of those women would die of this cancer. Predisposing factors are shown in Table 23.1. Table 23.1 Risk factors of vulva cancer Factor

Description Age: generally advanced age (median age at diagnosis is 70). Diagnosis at younger age is associated with HPV and VIN Lifestyle: cigarette smoking

Patient related

Past medical history: previous or vaginal cancer; previous HPV infection 16, 18, 31; HIV infection; previous cervical or vaginal cancer; hypertension; chronic granulomatous and dystrophic vulvar lesion; women exposed to immunosuppression therapy Preinvasive lesions: VIN, 2–5% progress; Bowen’s disease; Paget’s disease, erythroplasia

HPV: human papilloma virus, VIN: vulvar intraepithelial neoplasia

Anatomy The parts of the vulva are as shown in Figure 23.1, viz., the mons pubis, clitoris, labia majora and minora, and vaginal vestibule. Anteriorly, the vulva blends with the urinary meatus and posteriorly with the perineum (body) and anus. Bartholin’s glands – two small, mucous-secreting glands – are situated within the subcutaneous tissue of the posterior labia majora. The ducts of Bartholin’s glands open onto the posterolateral portion of the vestibule. The perineal body is a 3- to 4-cm band of skin that separates the vaginal vestibule from the anus and forms the posterior margin of the vulva.

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Figure 23.1 Pattern of lymphatic spread showing parts of vulva anatomy (curved arrows show lymphatic drainage of different components of vulva, which generally occurs in stepwise fashion from inguinal to pelvic nodes)

Pathology Approximately 80–90% of primary vulvar tumors are squamous cell carcinomas (SCC). Tumors of the vestibular glands (Bartholin’s glands) often are adenocarcinomas or adenocystic carcinomas, but 30–50% of SCC have squamous histology. The remaining, less common histologies include melanoma, basaloid, neuroendocrine carcinoma (Merkel cell carcinoma), and sarcoma. Diagnosis of vulva cancer requires biopsy of the primary tumor, usually under local anesthesia.

Routes of Spread Local extension and regional (lymphatic) metastases are the two major routes of spread in vulva cancer. Distant metastasis (hematogenous) is less common (Table 23.2).

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Table 23.2 Routes of spread in vulva cancer Routes

Description

Local extension

 Occurs in a stepwise progressive fashion from a distal-toproximal direction  Direct involvement of a third of the lower urethra, a third of lower vagina and/or extension to the anus is first (FIGO stage II)  More extensive cases: further progression proximally involves upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixation to bony pelvic structures (FIGO stage IVA)

Regional lymph node metastasis

 The overall risk of groin node metastasis ranges between 10 and 50%, and depends on the presence of one or more of the following factors: size of the primary tumor, depth of invasion, and the presence of lymphovascular space invasion  Stromal invasion of <1 mm leads to nearly 0% of nodal involvement (hence, separately staged as 1A); stromal invasion of 2–5 mm of stromal invasion leads to 8–10% chance of nodal involvement  Clitoris can theoretically drain directly to pelvic nodes (Figure 23.1), but this is rare without inguinofemoral involvement  Overall incidence of pelvic lymph node metastasis is 5%  Deep femoral node involvement without superficial inguinal node metastasis has been reported – from clitoris and Bartholin’s gland tumors  ~25% clinical negative or nonsuspicious inguinal nodes are pathologically positive  65–75% clinically palpable/suspicious nodes are pathologically positive (FNA of enlarged groin lymph nodes should be performed to determine nodal involvement)  Contralateral spread without ipsilateral nodal involvement occurs in <15% of cases  A GOG study also found an unexpectedly high incidence of ipsilateral groin recurrences presumed due to involvement of lymph nodes deep to the cribriform fascia despite negative superficial nodes. Hence, both superficial and deep inguinal nodes need to be dissected

Distant metastasis

 Hematogenous metastasis is rare  However, the risk is 66% if ≥3 lymph nodes are involved

GOG: Gynecologic Oncology Group, FNA: fine-needle aspiration Source: Stehman FB, Bundy BN, Dvoretsky PM, Creasman WT (1992) Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol 79:490–497

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Diagnosis, Staging, and Prognosis Clinical Presentation Vulvar cancer-specific symptoms such as pain, spotting or bleeding, discharge, and pruritus, may be evident with visible lesions. With advanced disease, symptoms are due to invasion of adjacent organs, viz., difficulty urinating or defecating or with intercourse. Presentation with edema of the lower extremities secondary to disease in the groins is rare.

Diagnosis and Staging Figure 23.2 illustrates a diagnostic algorithm of vulva cancer, including suggested examinations and tests.

Tumor, Node, and Metastasis, and International Federation of Gynecology and Obstetrics Staging Diagnosis and clinical staging depends on findings from detailed history and physical examination, and imaging. Pathological staging depends on findings during surgical resection and pathological examination, in addition to those required in clinical staging. The 7th edition of the tumor, node, and metastasis (TNM) staging systems and groupings of the American Joint Committee on Cancer (AJCC), and the International Federation of Gynecology and Obstetrics (FIGO) and are presented in Tables 23.3 and 23.4. Two prognostic principles applied based on new knowledge: (1) size is not a significant factor for survival if the lymph nodes are negative and (2) number and size of nodal metastasis seem to be prognostic, and these have been separated in the new version of staging.

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Early stage vulva lesion

Early stage midline lesion

Well lateralized lesion

Yes

It tumor T1A(≤ 1mm thin and CLS negative

WL E alone

No

Radical WL E & bilateral groin node dissection

Unfavorable primary

Unfavorable primary

Depth > 5mm and CLS+

No

No

Margins < 8mm

>1 positive, or1 through capsule?, or macroscopic?

No Yes

Residual vulvar didease?

No

Observation Yes

Consider adjuvant radiotherapy to vulva

BGND & Simple excision (if possible) + adjuvant chemoradiation to vulva OR pre-op chemoradiation

Unfavorable primary

Observation Yes

Possible to perverse sphincters & clitoris with radical surgery?

Yes

Further excision (if anatomy preservation possible) or Adjuvant radiotherapy to vulva

Observation

Adjuvant RT to pelvic & inguinal nodes

Yes

Local excision (if possible) or radical surgery if not

Histological confirmation of vulvar cancer is essential and requires biopsy of the primary tumor, which can be performed under local anesthesia by punch or incision. Fine-needle spirate of enlarged groin lymph nodes should be done to determine nodal involvement A thorough gynecologic examination with Pap smear of the cervix is indicated to evaluate the extent of the disease and to screen for cervical cancer. Examination under anesthesia (EUA), cystoscopy, and sigmoidoscopy should be used as needed depending on the extent of the tumor (in advanced tumors) CT of the pelvis and abdomen may be indicated * consider RT if node positive and less than 5 nodes dissected; chemoRT for three or more positive nodes

Figure 23.2 A proposed algorithm for diagnosis, staging and management of early stage vulva cancer WLE: wide local extension, CLS: capillary lymphatic space, BGND: bilateral groin node dissection

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Table 23.3 AJCC TNM and FIGO staging of vulvar cancer TNM

FIGO

Description

Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor a

Tis

Carcinoma in situ

T1a

IA

Lesions 2 cm or less in size, confined to the vulva or perineum and with stromal invasion 1.0 mm or lessb

T1b

IB

Lesions more than 2 cm in size or any size with stromal invasion more than 1.0 mm, confined to the vulva or perineum

T2c

II

Tumor of any size with extension to adjacent perineal structures (lower/distal third of urethra, lower/distal third vagina, anal involvement)

T3d

IVA

Tumor of any size with extension to any of the following: upper/ proximal two thirds of urethra, upper/proximal two thirds of vagina, bladder mucosa, rectal mucosa, or fixed to pelvic bone

Regional lymph nodes (N)e NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1a

IIIA

One lymph node metastasis each 5 mm or less

N1

b

IIIB

One lymph node metastasis 5 mm or greater

N2

a

IIIB

Three or more lymph node metastases each less than 5 mm

N2b

IIIB

Two or more lymph node metastases 5 mm or greater

N2c

IIIC

Lymph node metastasis with extracapsular spread

N3

IVA

Fixed or ulcerated regional lymph node metastasis

Distant metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1 a

IVB

Distant metastasis (including pelvic lymph node metastasis)

FIGO no longer includes stage 0 (Tis) The depth of invasion is defined as the measurement of the tumor from the epithelial–stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion c FIGO used the classification T2/T3. This is defined as T2 in TNM d FIGO used the classification T4. This is defined as T3 in TNM e An effort should be made to describe the site and laterality of lymph node metastasis Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York b

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Table 23.4 Stage grouping of vulvar cancer Stage Grouping T1

T2

T3

T4

N0

IA

IB

II

IVA

N1a,b

IIIA

IIIA

IIIA

IVA

N2a,b

IIIB

IIIB

IIIB

IVA

N2c

IIIV

IIIC

IIIC

IVA

N3

IVA

IVA

IVA

IVA

M1

IVB

IVB

IVB

IVB

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

Prognosis Important prognostic factors for overall survival and local control in vulva cancer are detailed in Table 23.5. Most deaths are because of uncontrolled locoregional disease. Table 23.5 Prognostic factors for overall survival and local control in vulva cancer Prognostic factor

Description

For overall survival

 Most important factor is presenting stage, particularly lymph node status  Patients with 1 groin node involvement have lower risk of recurrence than have those with 2 or nodes involved  Patients with unilateral groin nodal involvement have better survival than do those with bilateral disease  Positive nodal status reduces survival by 40% (Table 23.6)  Most deaths are because of uncontrolled locoregional disease, not distant metastasis

For local control

 Positive or close surgical margins (most powerful predictor) of local vulvar recurrence: margin <8 mm 50% recurrence  Lymphovascular space invasion  Deep stromal invasion of >5 mm  Large primary tumor size

Source: Heaps JM, Fu YS, Montz FJ et al (1990) Surgical–pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 38:309–314

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Table 23.6 presents post-2005 trials results of overall survival. Table 23.6 Overall survival (OS) according to extend of disease (results of trials published after 2005) Extent of disease

Percent at diagnosis (%)

5-year OS (%)

Localized

65%

80–90%

Regional

30%

45–50a %

Metastatic

5%

15%

Sources: Surveillance, Epidemiology and End Results (SEER) Program stat fact sheet on vulva cancer (http://seer.cancer.gov/statfacts/html/vulva.html); Kunos C, Simpkins F, Gibbons H et al (2009) Radiation therapy compared with pelvic node resection for node-positive vulvar cancer. Obstet Gynecol 114:537–546; and other trials detailed in the next section)

Treatment Principles and Practice Modalities used for vulva cancer are descussed in Table 23.7. A proposed treatment algorithm based on the best available clinical evidence is presented in Figure 23.2. Table 23.7 Treatment modalities used in vulva cancer Treatment

Description

Vulvectomy/wide local excision plus inguinofemoral lymphadenectomy

Indications

 The only curative treatment modality   Radical in concept but function preserving   It is used for T1 and possibly T2 disease   Consider induction therapy (chemoradiation) for unresectable tumors or potentially mutilating surgery

Facts

  Minimum pathological margin of 8 mm around primary tumor is essential to minimize risk of local recurrence   The incision should be carried down to the inferior fascia of the urogenital diaphragm   Inguinal lymph node dissection (LND), including superficial and deep nodes, is usually recommended for all cases with invasive disease of more than 1-mm depth with clinically negative groins (GOG 88 study)   Contralateral LND is performed if ipsilateral positive lymph nodes are present   Bilateral groins dissection (BGND) needed if central vulvar disease present or for stage 2 and above ▶

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Table 23.7 (continued) Treatment

Description

Radiation therapy

Indications

  An adjuvant treatment after complete resection to primary tumor and nodal beds   Preoperative or definitive treatment (with chemotherapy)   Palliative treatment to primary or metastatic foci

Techniques

  EBRT using 3D-CRT or IMRT   Interstitial brachytherapy may have a role in extensive lesions where function preserving surgery not possible

Chemotherapy

Indications

Medications

  Adjuvant treatment after surgery (with EBRT) being studied   Induction or definitive treatment with concurrent EBRT for unresectable disease   Mainstay treatment for palliative therapy   Anal cancer protocols often used with 5-FU plus MMC

or cisplatin plus 5-FU

EBRT: external-beam radiation therapy, 5-FU: 5-flourouracil, MMC: mitomycin C

Treatment of Early-Stage (T1N0–2) Disease Treatment of early-stage vulva cancer (T1N1–2) and possibly T2 is mainly surgical with wide local excision (WLE) or radical vulvectomy and inguinofemoral lymphadenectomy, and then by adjuvant radiation if indicated. Clinical evidence for inguinofemoral lymphadenectomy over radiation is presented in Table 23.8. Complications of bilateral groin dissection (BGND) are significant and morbidity is high, with wound infection and breakdown in 20–30% and lower extremity lymphedema in 30–60% of cases. Hence, BGND should not be routinely performed. In selected cases (unifocal FIGO IB lateralized tumor without pathological nodes), unilateral lymph node dissection (LND) is associated with a <1% risk of contralateral groin node metastases in multiple observational studies, and it can avoid morbidity with careful selection. Sentinel node biopsy (SLNB) is under investigation as an alternative to inguinofemoral LND as a means of reducing morbidity of groin LND.

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Table 23.8 Clinical trials for managing nodes in vulva cancer Randomized trial

Description

GOG 88a

  Randomized trial of 121 patients with IB–III disease and nonsuspicious nodes (N0–1) treated with radical vulvectomy   Patients randomized to bilateral inguinal femoral lymph node dissection or external radiation (50 Gy to 3 cm below skin surface) to the groin   If pelvic lymph nodes were involved, patients received radiation to bilateral inguinal and pelvic nodes   Study was closed after interim analysis of only 58 patients. Five of 27 patients (18.5%) in radiation group suffered groin failure   2-year overall survival rate favored the surgery group (90 versus 70%). Thus, radiation to groins not recommended for sub-clinical nodes   Criticisms: poor radiation techniques of radiation dose prescription to a depth of 3 cm, resulting in all inguinal nodes that recurred receiving less than prescribed dose

Koh et al, Katz et al

  Spiral CT–based 3-D studies demonstrated that the average depth of the femoral vessels was 6 cm but can range from 2 to 18 cmb   Using proper radiation planning of techniques, a dose of 50 Gy should sterilize subclinical microscopic disease, as shown by several series and spare morbidity of BGNDb

a

Source: Stehman FB, Bundy BN, Thomas G et al (1992) Groin dissection versus groin radiation in carcinoma of the vulva: a GOG study. Int J Radiat Oncol Biol Phys 24:389–396 b Source: Koh WJ, Chiu M, Stelzer KJ et al (1993) Femoral vessel depth and the implications for groin node radiation. Int J Radiat Oncol Biol Phys 27:969–974 c Source: Katz A, Eifel PJ, Jhingran A, Levenback CF (2003) The role of radiation therapy in preventing regional recurrences of invasive squamous cell carcinoma of the vulva. Int J Radiat Oncol Biol Phys 57:409–418

There is little margin for error in detecting occult-positive nodes, because groin recurrence in vulvar cancer is usually fatal; hence, this is not yet accepted as standard of care. Except for a few case series, not enough data are available – a Gynecologic Oncology Group (GOG) 173 validation study is awaiting publication, although initial results are promising. The results of a large prospective study from Europe are available (Table 23.9).

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Table 23.9 The Netherlands sentinel node biopsy (SLNB) observational study Type

Description

GROningen INternational Study on Sentinel Nodes in Vulvar Cancer (GROINSS-V)

  403 women with squamous cell vulvar cancer (tumor size <4 cm) had sentinel node detection with a combination of radioactive tracer and blue dye   If SLN was detected and negative (n = 276), no further treatment was given; If SLN was detected and positive or if no SLN was detected, inguinofemoral LND was performed   Median follow-up was 35 months, median time to recurrence was12 months; 3-year survival rate was 97%   259 patients with unifocal vulvar disease and a negative sentinel node resulted in 6 groin recurrences (i.e., 2.3% recurrence with negative SLNB)   SLNB only patients had less short- and long-term morbidity, as compared to groin node dissection (GND) patients.

Source: Van der Zee AG, Oonk MH, De Hullu JA et al (2008) Sentinel node dissection is safe in the treatment of early-stage vulvar cancer. J Clin Oncol 26:884–889

Radiation Therapy in Resectable Vulva Cancer The uses of radiation therapy (RT) in resectable vulva cancer are indicated as follows:  Preoperative RT (with concurrent chemotherapy) plays a major role in locoregionally advanced disease or in lesions with extension to the midline structures. This is combined with inguinal dissection and function-preserving completion surgery.  Postoperative RT to primary tumor and nodal beds is determined separately based on pathological prognostic features of each.  Adjuvant RT for primary tumor is used when limited surgery has been performed for organ preservation or when high-risk pathologic features, such as large tumor (>4 cm), positive or close (<8 mm) surgical margin, lymphovascular space invasion, and depth of stromal invasion >5 mm, are present.  Adjuvant RT for nodal regions is indicated in patients with two or more involved inguinal nodes, gross extracapsular extension (ECE), or gross residual nodal disease as per the GOG trial 37 (Table 23.10). Long-term results of GOG 37 results confirm benefit and demonstrate importance of a lymph node–positive ratio (Table 23.10). Number of nodes dissected will influence indication for radiation of groin and pelvis even if only one node is positive. Generally, > 5 nodes considered adequate, but there is no consensus. If contralateral groin negative on dissection in a well-lateralized lesion with a positive ipsilateral groin, the standard approach is to radiate the opposite pelvis, but some feel this can be omitted.

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Table 23.10 Clinical trials for adjuvant lymph node irradiation Randomized trial

Description

GOG 37a

  This was a randomized trial with 114 patients with positive inguinal nodes after radical vulvectomy and bilateral inguinal node dissection   Patients were randomized to pelvic node dissection versus postoperative radiotherapy   Radiation (45–50 Gy prescribed to mid-plane, using AP/PA fields) was delivered bilaterally to the pelvic and inguinal nodes while shielding the central vulva area   Interim analysis revealed a significant survival advantage for patients receiving radiotherapy (2-year survival of 68 versus 54%) because of a lower rate of groin relapse in the radiotherapy arm (5 versus 24%)   Subset analysis suggested that this survival advantage was particularly noted if clinically suspicious or if fixed, ulcerated groin nodes or 2 or more positive groin nodes were present

GOG 37b (longterm results)

  GOG 37 trial with a median follow-up of 74 months   6 -year overall survival for radiation arm, 51% compared with 41%; hazard ratio of 0.61   Cancer-related death rate significantly higher for pelvic node resection, as compared with radiation (51% compared with 29%) at 6 years   A ratio of more than 20% positive ipsilateral groin nodes (number positive/number resected) significantly associated with contralateral lymph node metastasis, relapse, and cancer-related death   Benefits of radiation preserved in long-term follow-up

a

Source: Homesley HD, Bundy BN, Sedlis A et al (1986) Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 68:733–740 b Source: Kunos C, Simpkins F, Gibbons H et al (2009) Radiation therapy compared with pelvic node resection for node-positive vulvar cancer. Obstet Gynecol 114:537–546

Radical vulvectomy has been considered sufficient for treatment for vulvar carcinoma, and postoperative radiation can be directed only to the lymph nodes. However, results from a retrospective study suggested that the application of a midline block to protect the radiosensitive vulva resulted in a 48% central recurrence rate (versus the less than 10% reported historically). Long-term results from GOG-37 do not show this, however. The primary tumor bed should be radiated only if high-risk features present. The additional benefit of concurrent chemotherapy with postoperative radiation in patients with high-risk features for relapse is unclear and is being studied in cooperative group studies.

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Decision making regarding which treatment modalities to be used depends on location of primary in relation to midline (Figure 23.2).

Treatment of Locally Advanced Diseases (Most T2–3, N2c-3) Primary surgery is either not possible or will result in tremendous morbidity; hence, the use chemoradiation should be explored. Extended radical vulvectomy and BGND or pelvic exenteration may be required for tumors involving the rectum, vagina, or urethra. Preoperative radiation or combined chemoradiation therapy, or definitive chemoradiation, should be considered for organ preservation, to be succeeded by function-preserving limited surgery. Results of an important GOG study are summarized in Table 23.11. Table 23.11 Preoperative chemoradiation therapy for locally advanced diseases Trial

Description

GOG 101

  Phase II GOG study of patients with stages III–IV (unresectable) squamous cell vulvar carcinoma   All patients enrolled judged capable of tolerating chemoradiation succeeded by surgical resection and bilateral inguinofemoral LND (high performance status)   Preoperative chemoradiation of 47.6 Gy (twice daily for the 1st week of 2-week cycle with a split course with an elective 2-week break, and then next 2-week cycle of chemoradiation); concurrent chemotherapy used cisplatin plus 5-FU   48.5% of patients with clinical complete response (CR), no visible vulvar cancer at the time of planned surgery, only 2.8% had residual unresectable disease   95% of N2c–N3 groin nodes rendered resectable; in only 3 patients was it not possible to preserve urinary and/or gastrointestinal continence   Next GOG trial to increase radiation dose and eliminate “elective break”

Source: Moore DH, Thomas GM, Montana GS et al (1998) Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group. Int J Radiat Oncol Biol Phys 42:79–85

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Unresectable or Inoperable Diseases Definitive chemoradiation therapy is indicated for unresectable or medically inoperable vulvar cancers. Chemotherapy regimens similar to those used in anal canal cancer, infusional 5-FU plus cisplatin or mitomycin, have been described. High response rates have been reported, and the majority of patients achieving complete response have durable local control (Table 23.12; Figure 23.3 for an algorithm for management of advanced vulva cancer). Most of the definitive chemoradiation studies in vulvar cancer are single institutional and limited by small sample size. There is considerable toxicity associated with chemoradiation, including severe skin desquamation and hematologic toxicity, infection, lymphedema, etc. The preferred approach for patients with inoperable primary tumors or lymph nodes is preoperative chemoradiation, if a salvage operation can be performed. Chemoradiation is offered as an alternative to radical surgery in an effort to avoid colostomy and urostomy in stage IVA disease. If residual disease remains after chemoradiation, then local resection is indicated. The most recent GOG 205 trial is exploring weekly cisplatin with doses of 57.6 Gy for locally advanced vulvar cancer and results from this are awaited. Table 23.12 Comparison of surgery and primary chemoradiation (PCRT) in advanced SCC of vulva

Randomized trial

Description

University of Oklahoma

  A retrospective study of 63 patients with stages III (n = 47) and IV (n = 16) SCC of vulva   30 patients received extended primary surgery (PS), and 33 unresectable tumors by vulvectomy and underwent PCRT   Patients treated with PCRT were younger (61 versus 72 years; p= 0.09), had less nodal metastasis (54 versus 83%, p = 0.01), and larger tumors (6 versus 3.5 cm, p = 0.0001), as compared with patients who received PS   Clinical CR rate was high at >85%, but the majority had undergone node dissection prior to PCRT   Despite these differences, OS rates at 31 months were 69 and 76%, respectively, for PS and PCRT groups (p = NS); no differences were seen in PFS or recurrence rates either between the 2 groups   Multivariate analysis showed age was the only significant predictor of OS or PFS

Source: Landrum LM, Skaggs V, Gould N et al (2008) Comparison of outcome measures in patients with advanced SCC of the vulva treated with surgery or PCRT. Gynecol Oncol 108:584–590

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-

+

Groin nodes

Negative on clinical examination and by diagnostic imaging

Positive by needle aspiration or excisional biopsy

Preoperative chemoradiation to vulvar primary and elective chemoradiation to bilateral groin nodes. No groin dissection.

Fixed or ulcerated nodes? No

Yes

Billateral groin node dissection Residual primary disease? No Yes

Unfavorable node features? Yes

Biopsy, if negative observe

Resect by functionally conservative excision if feasible. If not, boost to radical dose with chemoradiation - may use brachytherapy.

Chemoradiation to vulva, groins, and pelvic nodes

Chemoradiation to Ipsilateral or bilateral groin and pelvic nodes along with primary

No

Observe groins ChemoRT to primary

Resectable? Yes

If residual primary disease

No

Resect Boost residual residual nodes gross nodes after a preto a radical operative chemodose of radiation chemodose level radiation

Figure 23.3 A proposed treatment algorithm for advanced carcinoma of the vulva

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Radiation Therapy Techniques Simulation Patients must be treated with equipment with photon energy of 6 MV for pelvic irradiation. Computed tomography (CT)-based planning is essential to obtain the depth of inguinal nodes. Delineation of the femoral lymph nodes is critical for adequate coverage of the inguinal nodes. Location of the inguinofemoral nodes is depicted in Figure 23.4. Figure 23.4 Topographic distribution of inguinal lymph node metastases in patients with carcinoma of the anus and low rectum (circles, n = 50), vulva vagina–cervix (triangles, n = 17), and urethra (squares, n = 17). The field arrangement described provided adequate coverage of 86% of all inguinal lymph nodes. Adapted from Wang, CJ, Chin, YY, Leung SW et al (1996) Topographic distribution of inguinal lymph nodes metastasis: significance in determination of treatment margin for elective inguinal lymph nodes irradiation of low pelvic tumors. Int J Radiat Oncol Biol Phys 35:133–136. (Used with permission from Elselvier)

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Patients are simulated in supine, frog-leg positions (to minimize the bolus effect from skin folds) with full bladders (to minimize the volume of small bowel in the radiation field), with custom immobilizations. Palpable lymph nodes, vulva tumor, scars, and anal verge should be outlined with sticky wire for identification on planning CT. Markers to be used to indicate extent of vaginal involvement if present. Four-field three-dimensional (3D) conformal technique may spare rectum and posterior skin as well as femurs (Figure 23.5), and avoids problems of matching fields.

Figure 23.5 Sagittal view of advanced vulvar cancer CTV (blue outline) treated by four-field conformal technique. Part of the rectum and posterior skin can be spared

Field Arrangements Field arrangement of conventional RT available for vulvar cancer treatment is detailed in Table 23.13. A wide anterior-posterior (AP) field includes the pelvic and inguinal regions, and a narrow posterior–anterior (PA) field covers only the pelvis and spares the femoral heads. The dose to inguinal regions is supplemented by separate anterior electron fields matched to the PA field to bring the dose to the inguinal nodal region to 45 Gy (Figure 23.6). A wide AP field and narrow PA field with a partial transmission block are placed in the central portion of the AP field. The desired dose at a specific depth is delivered to the inguinal nodes through the AP field.

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Table 23.13 Field arrangement in RT for vulva cancer Field

Borders

Wide AP (Figure 23.6)

  Superior: mid–sacroiliac joint to include external and internal iliac node involvement; L4–L5 to include the common iliac nodes if internal/external iliac nodes suspicious or positive   Inferior: flash entire vulva or inferior margin of the tumor (whichever is lower)   Lateral: 2 cm beyond the widest point of the pelvic inlet on the PA field, and greater trochanter to include inguinal lymph nodes in the AP field

Narrow PA

  Superior: same as AP field  Inferior: same as AP field  Lateral: off femur and match supplemental electron fields

Supple electron

 Anterior electron fields to the lateral inguinal region  Matched with the exit PA field  Energy based on CT depth of femoral vessels

Cone down

  Primary tumor and involved inguinal lymph nodes plus

2- to 3-cm margin after 45 Gy to the pelvis

 All fields should be irradiated on daily basis  Bolus material should be used to ensure adequate dose to the superficial portions of the groin or tumor

Figure 23.6 Treatment borders demonstrating the wide anterior field (outer border) and the narrow posterior field (shaded region). The pelvis, vulva, perineum, and inguinal lymph nodes will be treated with the AP–PA technique to include lateral inguinal nodes within AP fields but not PA fields. The patient lies supine with a full bladder

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Intensity-Modulated Radiation Therapy Intensity-modulated radiation therapy (IMRT) has been demonstrated to offer an advantage over 3D-conformal radiation for vulvar cancer by improving conformality and eliminating matching problems (Figure 23.7). In addition, IMRT reduces the dose to normal structures, such as the bladder, rectum, small bowel, and femoral heads, and eliminates problems with matching between electrons and photons. Definitions of clinical target volume (CTV) and planning target volume (PTV) in 3D-CRT and IMRT are as follows:  CTV: 1-cm margin around the entire vulvar region and around the bilateral external iliac, internal iliac, and inguinofemoral nodes  PTV: CTV plus 1 cm The Radiation Therapy Oncology Group (RTOG) has formulated a (consensus) contouring atlas for IMRT for anal canal tumors, which includes guidelines for groin nodes. Simultaneous integrated boost (SIB) can also be delivered with IMRT. An example is shown in Figure 23.7, where clinically negative groin nodes received 45 Gy with chemotherapy (with sparing of femurs) and vulvar CTV received 53 Gy. However, long-term results for IMRT for vulva cancer are lacking.

Figure 23.7 Slice through vulvar IMRT plan showing how 45-Gy isodose line spares femoral neck, and 52.9 Gy (98% of prescribed dose) covers advanced vulvar tumor in a tight, conformal manner

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Dose and Treatment Delivery Dose and fractionation of pre- and postoperative RT is detailed in Table 23.14. EBRT should be delivered as a continuous course at 1.8–2.0 Gy per daily fraction. Table 23.14 Radiation dose in vulva cancer treatment Setting

Scenario

Dose of RT (Gy)

Preoperative

–

45–50a

Microscopic residual Postoperative

Definitive a

50 +

Extracapsular external or N

55–60

Gross residual

65–70

Concurrent chemoradiation

60–65

Response in ~90% of cases after radiation alone can be expected

Normal Tissue Tolerance Organs at risk (OARs) in RT of vulva cancer, in both adjuvant and definitive settings, include small bowel, bladder, femoral heads, and vagina. Dose limitation is detailed in Chap. 22, Table 22.17.

Follow-Up Life-long follow-up (Table 23.15) is required for all patients with vulvar cancer treated with curative intent for early detection of tumor recurrence and second primary gynecological malignancies. In addition to recurrent vulvar cancer, there is a higher risk of cervical and anal cancer. Common radiation-induced adverse effects (acute and late) are presented in Table 23.16.

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Table 23.15 Follow-up schedule and examinations Schedule

Frequency

First follow-up

 4 –6 weeks after RT

Years 0–2

 Every 3–4 months

Years 3–5

 Every 6 months

Years 5+

 Annually

Examinations History and physical

 Complete history and physical examination 

Imaging studies

 Chest X-ray (if clinically indicated)  CT of the abdomen and pelvis (if clinically indicated) 

Table 23.16 Commonly observed acute and late adverse effects after treatment Stage

Description

Acute

 The most significant is the skin reaction in the vulva–perineal region and inguinal folds  Moist desquamation by the 3rd–5th weeks of treatment is common; a treatment break is usually necessary  Diarrhea and cystitis are other common acute side effects  Acute hematologic toxicity is common and depends on the type and intensity of the chemotherapy used

Late

 Common late toxicities include telangiectasia, atrophy of skin, fibrosis, dryness, and shortening/narrowing of the vagina  Avascular necrosis of the femoral head has been reported   Femoral neck fracture is associated with osteoporosis and  smoking  Groin radiation can cause lymphocyst formation, lymph edema, and infection

Other

 Significant psychosexual consequences relating to sexual function and body image may occur

24

Vaginal Cancer Nitika Thawani1, Subhakar Mutyala 2 and Aaron H. Wolfson3

Key Points  The vagina can be a common site of secondary involvement, either through direct extension from the cervix and vulva or by lymphatic and vascular spread.  Invasive cancers most commonly present with irregular vaginal bleeding or discharge (often postcoital), followed by vaginal discharge or dysuria. Vaginal intraepithelial neoplasia (VaIN) is diagnosed on routine screening.  Diagnostic workup should include a thorough examination under anesthesia, as secondary involvement from the cervix or vulva is more common than primary cancer is. Biopsy is the mainstay for diagnosis, and staging is clinical. Whole-body fluorodeoxyglucose-positron-emission tomography/computed tomography (FDG-PET/CT) scans can provide information on the nodal status, and magnetic resonance imaging (MRI) of the pelvis helps to determine the depth of invasion and assessment of extent of disease.  There is a lack of prospective randomized studies of patients with vaginal cancer because of the rarity of the disease. Treatment decisions are thus based on retrospective data and individual assessment.  Carcinoma in situ of the vagina and highly selected early-stage patients with tumors in the upper vagina can be treated with surgery alone (there are reported local control rates of 75–100%).  In more advanced stages, radiation therapy is chosen as the standard treatment to avoid exenterative surgery, preserve anatomy and function, and to treat known or presumed lymph node metastasis.  Because the etiology and epidemiology of vaginal carcinoma appears identical to those of patients with invasive cervical carcinoma, patients with advanced vaginal carcinoma are treated with radiation and cisplatin-based chemotherapy.

1

Nitika Thawani MD Email: [email protected]

2

Subhakar Mutyala, MD () Email: [email protected]

3

Aaron H. Wolfson, MD Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_7, © Springer-Verlag Berlin Heidelberg 2011

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Anatomy The vagina is a dilatable, tubular, structure averaging 8.5 cm in length, lined by nonkeratinizing, stratified, squamous epithelium, extending from the vestibule to the cervix of the uterus. It lies dorsal to the base of the bladder and the urethra, and ventral to the rectum. The vagina is a fibromuscular sheath of three layers: mucosa, muscle, and adventitia (Figure 24.1).

Figure 24.1 Vaginal anatomy

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Table 24.1 Risk factors for vaginal cancer Risk factor

Description Age: incidence peaks in the 6th and 7th decades. Incidence increasing in younger women secondary to the increased prevalence of human papilloma virus (HPV) infection or other sexually transmitted diseases

Patient related

Lifestyle: increased risks with 5 or more sexual partners, onset of sexual intercourse before 17 years, smoking, low socioeconomic status Past medical history: prior history of HPV infection, cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), immunosuppression, history of hysterectomy, and possibly previous pelvic irradiation Infections: HPV is recovered from 80% of the VaIN lesions and 60% of squamous cell lesions. High-risk HPV strains (HPV-16, -18, -31, and -33) frequently responsible

Environmental

Clear cell adenocarcinoma: in utero exposure to diethylstilbestrol (DES) during the first 16 weeks of pregnancy doubles the risk of development of vaginal intraepithelial neoplasia (VaIN) by enlarging the transformation zone – at increased risk for infection with HPV

Pathology Squamous cell carcinoma (SCC) represents about 80–90% of primary vaginal cancers. Vaginal intraepithelial neoplasia (VaIN) is a precursor of SCC and is graded I–III, depending on the degree of nuclear atypia and crowding, and the proportion of the epithelium involved. These tumors are most common on the upper posterior wall of the vagina. Clear cell adenocarcinoma (CCA) is associated with diethylstilbestrol (DES) exposure and has a predilection for involving the submucosa of the upper third of the vagina and the exocervix. Malignant melanomas account for 4% of all vaginal neoplasms and involve the lower third and the anterior vaginal wall most commonly. Sarcomas represent 3% of all the vaginal tumors, with different types including leiomyosarcomas, carcinosarcoma, endometrial stromal sarcoma, and angiosarcoma. Embryonal rhabdomyosarcoma/sarcoma botryoides is a rare pediatric tumor.

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Natural History Table 24.2 details the natural history (without treatment) of vaginal cancer. Table 24.2 Routes of spread for vaginal cancer Routes

Description

Local

 The tumor may spread along the vaginal walls to involve the cervix and the vulva  Anterior wall lesion may infiltrate the vesicovaginal septum and/or the urethra  Posterior wall lesions may involve the rectovaginal septum and extend to the rectal mucosa  Tumors in the vagina can extend the parametrium and the tissues of the paracolpos to invade the obturator fossa, cardinal ligaments, lateral pelvic walls, and the uterosacral ligaments

Regional lymph node involvement

 Fine lymphatics course through the submucosa and the muscularis to coalesce into small trunks, running laterally along the walls of the vagina  Upper anterior vagina drains along the cervical channels to the interiliac chain. Upper posterior wall drains into the inferior gluteal, presacral, and the anorectal nodes  Distal vagina lymphatics drain into the inguinal and femoral, and from there into the external iliac nodes  Mid-vagina may drain either way

Distant metastases

 Incidence rates: stage I, 16%; stage IIA, 31%; stage IIB, 46%; and stage III, 62%  Metastases are seen with advanced disease at presentation or with tumor recurrence after failure of primary therapy  The most common sites of distant spread include the lungs, liver, and bony skeleton

Diagnosis, Staging, and Prognosis Clinical Presentation VaIN is most often asymptomatic and is usually detected by means of cytology and routine screening. Invasive cancers most commonly present with irregular vaginal bleeding (often postcoital), followed by vaginal discharge and dysuria. Pelvic pain can occur if the tumor extends beyond the vagina.

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Diagnostic Workup Figure 24.2 presents a proposed algorithm in the workup of the diagnosis of vaginal cancer.

Suspected Vaginal Malignancy

Complete History and Physical Examination (including detailed speculum inspection, digital speculum inspection, digital palpation, and colposcopic and cytological evaluation with biopsy)

Complete blood count

CT/MRI of the abdomen and pelvis

Liver and renal function tests

Intravenous urography

Vaginoscopy with aetic acid and Schiller‘s iodine Cystoscopy

Chest X-ray HIV (clinical suspicion)

FDG-PET

Laboratory Tests

Imaging Studies

Proctoscopy Exam under anesthesia

Secondary cancers of the vagina are more common thus complete metastatic workup is necessary Figure 24.2 A proposed algorithm for the diagnosis of cancer of the vagina

Staging Primary carcinoma of the vagina is staged clinically. The results of the biopsy/fine-needle aspiration (FNA) of the inguinal nodes may be included in the clinical staging. As per the 2010 American Joint Committee on Cancer (AJCC) system, the tumor, node, and metastasis (TNM) system corresponds to the Federation Internationale de Gynecologie et d’Obstetrique (FIGO) staging system (Tables 24.3 and 24.4).

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Table 24.3 TNM and FIGO classifications of malignant tumors of the vagina TNM

FIGO

Description

Primary tumor (T) Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor a

Tis

Carcinoma in situ (pre-invasive cancer)

T1

I

Tumor confined to the vagina

T2

II

Tumor invades the paravaginal tissues either microscopically (T2a) or grossly (T2b) but does not extend up to the pelvic side wall

T3

III

Tumor extends to the pelvic side wall

T4

IVA

Tumor invades mucosa of the bladder or rectum and/or extends beyond the true pelvis

Regional lymph nodes (N)

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

III

Pelvic or inguinal lymph node metastasis

Distant metastasis (M)

M0 M1

No distant metastasis IVB

Distant metastasis present

a

FIGO: staging no longer includes stage 0 (Tis) Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

Table 24.4 Stage grouping of malignant tumors of the vagina Stage Grouping T1

T2

T3

T4

N0

I

II

III

IVA

N1

III

III

III

IVA

M1

IVB

IVB

IVB

IVB

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

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Prognosis Prognostic factors (Tables 24.5 and 24.6):  Stage at the time of diagnosis is the most important prognostic factor. Advanced stages have the worst disease-specific survival and cause-specific survival rates.  Location of the lesion (upper versus lower), size of the tumor (>4 cm versus <4 cm), age (older than versus younger than 60 years), and histologic type and grade (squamous versus adenocarcinomas) are all considered to be significant prognostic factors.  CCA have an increased propensity for distant metastasis to the lung and supraclavicular lymph nodes, as compared with SCC.  Patients with vaginal melanomas do more poorly, as compared with SCC, carrying a higher chance of distant metastases. Table 24.5 Outcome of vaginal cancer correlated with stage Trial

Stage 0 (%)

I (%)

II (%)

III (%)

IV (%)

Creasman et al (5-year relative survival)a

96%

73%

58%

36%

36%

Perez et al (10-year DFS)b

94%

75%

IIa: 55% IIb: 43%

32%

0%

Frank et al (5-year DSS)c

–

85%

78%

58%

58%

DFS: disease-free survival, DSS: disease-specific survival a Source: Creasman WT, Phillips JL, Menck HR (1998) The National Cancer Data Base report on cancer of the vagina. Cancer 83:1033–1040 b Source: Perez CA, Camel HM, Galakatos AE et al (1988) Definitive irradiation in carcinoma of the vagina: long-term evaluation of results. Int J Radiat Oncol Biol Phys 15:1283–1290 c Source: Frank SJ, Jhingran A, Levenback C et al (2005) Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 62:138–147

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Table 24.6 Outcome of vaginal cancer correlated with treatment modality 5-years

Radiation alone: stages I–IVA (%)a

RT and chemotherapy: stages II–IVA (%)b

OS

58%

66%

DSS

75%

75%

Local control

81%

92%

Complication rate 10%

17%

OS: overall survival, DSS: disease-specific survival a Source: Frank SJ, Jhingran A, Levenback C et al (2005) Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 62:138–147 b Source: Samant R, Lau B, E C et al (2007) Primary vaginal cancer treated with concurrent chemoradiation using Cis-platinum. Int J Radiat Oncol Biol Phys 69:746–750

Treatment Treatment of VaIN General Principles Table 24.7 details various modalities for the treatment of VaIN.  The natural history of VaIN has not been fully characterized, but the recommendation is to treat VaIN because it has the potential to progress to invasive carcinoma. The rate of conversion is reported to be from 9 to 28% in various series.  Involvement is commonly multifocal and associated with concomitant cervical intraepithelial neoplasia (CIN) or vulvar intraepithelial neoplasia (VIN).  Treatment is guided by multifocal disease, medical comorbidities, the desire to preserve sexual function, to previous treatment failures, and to rule out invasive disease.

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Table 24.7 Different modalities available for treatment of non-invasive carcinoma of the vagina Modality

Description

Non-radiotherapy treatment options Techniquesa

Excision, carbon dioxide ablation, and topical 5-FU chemotherapy have been used, with control rates ranging from 50 to 100%

Low-dose-rate brachytherapy (<200 cGy/h)

Techniqueb

Intracavitary vaginal cylinder with the intent of vaginal surface dose between 60 and 80 Gy. Largest possible diameter that can be comfortably accommodated by the patient should be used to improve the ratio of the mucosa to the tumor and eliminate vaginal rotation

High-dose-rate brachytherapy (>1,200 cGy/h) Techniquec

Applicators similar to low-dose rate can be used with a 10-Ci single iridium (Ir-192) source. Generally, 1–6 insertions with the dose per fraction ranging from 30 to 80 Gy can be used

a

Sources: Hoffman MS, Roberts WS, LaPolla JP et al (1991) Laser vaporization of grade 3 vaginal intraepithelial neoplasia. Am J Obstet Gynecol 165:1342–1344; Fanning J, Manahan KJ, McLean SA (1999) Loop electrosurgical excision procedure for partial upper vaginectomy. Am J Obstet Gynecol 181:1382–1385; Krebs HB (1989) Treatment of vaginal intraepithelial neoplasia with laser and topical 5-fluorouracil. Obstet Gynecol 73:657–660 b Source: Chyle V, Zagars GK, Wheeler JA et al (1996) Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 35:891–905 c Sources: MacLeod C, Fowler A, Dalrymple C et al (1997) High-dose-rate brachytherapy in the management of high-grade intraepithelial neoplasia of the vagina. Gynecol Oncol 65:74–77; Ogino I, Kitamura T, Okajima H et al (1998) High-dose-rate intracavitary brachytherapy in the management of cervical and vaginal intraepithelial neoplasia. Int J Radiat Oncol Biol Phys 40:881–887

Treatment of Invasive SCC General Principles  Several surgical series have reported excellent outcomes in well-selected patients; however, surgery has a limited role, in part because of the close proximity of the bladder and rectum to the surgical site.  Radiation therapy (RT) is the primary treatment modality, as noted by the Society of Gynecologic Oncologists in their practice guidelines published in 2006. RT can provide excellent tumor control rates and satisfactory functional results.

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Table 24.8 outlines some modalities for vaginal cancer; Table 24.9 outlines treatment strategy studies and results; Figure 24.3 presents an algorithm for treatment. Table 24.8 Different modalities available for treatment of invasive carcinoma of the vagina Type

Description

Surgery

Indications

 In patients with stage I disease involving the upper posterior vagina: if the uterus is still in situ, radical hysterectomy, upper vaginectomy to achieve clearance of at least 1 cm, and pelvic lymphadenectomy may be performed, whereas if hysterectomy has been previously performed, radical upper vaginectomy and pelvic lymphadenectomy may be appropriate  In young patients who require radiation therapy: pretreatment laparotomy may allow ovarian transposition, surgical staging, and resection of any bulky positive lymph nodes  In patients with stage IVA disease, particularly if a rectovaginal or vesicovaginal fistula is present: Primary pelvic exenteration is a suitable treatment option for such patients, combined either with pelvic lymphadenectomy or with preoperative radiation. Bilateral groin dissection should be considered in such patients if the lower third of the vagina is involved  In patients with a central recurrence after RT: Surgery will usually necessitate some type of pelvic exenteration in such patients

Radiation therapy Indication

 RT is the treatment of choice for most patients with vaginal cancer, and comprises an integration of teletherapy and intracavitary/interstitial therapy

Techniques

 External-beam RT (EBRT): to treat the pelvic and inguinal lymph nodes and the primary tumor  Intracavitary brachytherapy (ICBT): with a vaginal cylinder applicator with low- or high-dose-rate brachytherapy. To treat superficial lesions <0.5 cm in depth from the vaginal surface  Interstitial brachytherapy (ITB): to treat tumors involving >0.5 cm of depth from the vaginal surface, with a template or interstitial freehand implant

Chemotherapy Indication Drugs used

 There is limited reported experience with concurrent

chemoradiation for vaginal cancer  Cisplatin and 5-FU may be used as radiosensitizing

agents

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Table 24.9 Treatment strategy for vaginal cancer and supporting evidence

a

Trial

Description

Frank et ala

 Retrospective review of 193 patients treated at a single institution between 1970 and 2000  Disease-specific survival (DSS) and pelvic disease control rates correlated with International Federation of Gynecology and Obstetrics (FIGO) stage and tumor size  At 5 years, DSS rates were 85% for stage I, 78% for stage II, and 58% for stage III–IVA disease (p = 0.0013)  Five-year DSS rates were 82 and 60% for patients with tumors <4 cm or >4 cm, respectively (p = 0.0001)  At 5 years, pelvic disease control rates were 86% for stage I, 84% for stage II, and 71% for stage III–IVA (p = 0.027)  The predominant mode of relapse after definitive radiation therapy was locoregional (68 and 83%, respectively, for patients with stages I–II or III–IVA disease)  The incidence of major complications was correlated with FIGO stage; at 5 years, the rates of major complications were 4% for stage I, 9% for stage II, and 21% for stage III– IVA (p < 0.01)

Samant et alb

 Retrospective review of all primary vaginal cancer patients treated with curative intent at the Ottawa Hospital Regional Cancer Centre between 1999 and 2004, using concurrent cisplatin (Cis)-platinum CRT  12 patients treated with concurrent weekly CRT  Median age at diagnosis 56 years (range, 34–69 years), and the median follow-up was 50 months (range, 11–75 months)  Stage distribution: 6 (50%) stage II, 4 (33%) stage III, and 2 (17%) stage IVA  All patients received pelvic external-beam radiotherapy (EBRT), 45 Gy per 25 fractions concurrently with weekly intravenous Cis-platinum chemotherapy (40 mg/m2), followed by brachytherapy (BT) with a median dose of 30 Gy  The 5-year overall survival, progression-free survival, and locoregional progression-free survival rates were 66, 75, and 92%, respectively  Late toxicity requiring surgery occurred in 2 patients (17%)

Source: Frank SJ, Jhingran A, Levenback C et al (2005) Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 62:138–147 b Source: Samant R, Lau B, E C et al (2007) Primary vaginal cancer treated with concurrent chemoradiation using Cis-platinum. Int J Radiat Oncol Biol Phys 69:746–750

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Diagnosis of Primary Vaginal Cancer

Staging and Workup

Stage I

Stage II

Stage III/IVa

Large-volume EBRT with concurrent chemotherapy

Pelvic RT

Parametria involved Yes Parametrial boost

Boost to the primary tumor

Intracavitary brachytherapy for lesions <0.5 cm

EBRT boost with 3D or IMRT

Active Follow-Up Figure 24.3 Proposed algorithm for treatment of vaginal cancer

Interstitial brachytherapy for lesions >0.5 cm

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RT Technique Early-Stage Disease (Stage I) Brachytherapy alone is usually adequate for superficial stage I patients, with 95–100% local control with intracavitary and interstitial techniques. External-beam RT (EBRT) can be combined for larger, more infiltrating, or poorly differentiated tumors with high risk of lymph node metastasis. Intermediate-Stage Disease (Stage II) Treatment should include EBRT to the pelvic lymph nodes, with a brachytherapy boost. A parametrial boost should be prescribed if the parametria are involved. Locally Advanced Disease (Stage III–IVa) These patients should receive EBRT to the pelvic lymph nodes, with an additional parametrial dose and a brachytherapy boost (Table 24.10). If brachytherapy is not feasible, they can be treated with a shrinking-field technique. Chemotherapy can improve outcomes in these patients, as indicated by data from some early studies. Table 24.10 Dose prescription for stages I–IVa vaginal cancer Target

Modality

Dose (Gy)

Pelvis

 EBRT

40–50

Primary boost

 Intracavitary (<5 mm deep)  Interstitial (>5 mm deep)  3DCRT/IMRT (post-lesions)

Up to 50 (for apical) 25–30 20

Additional boost (total with pelvis dose)

 Parametrial involvement  Pelvic sidewall involvement

65 60

Source: Gay H (2008) Vaginal cancer. In: Lu JJ, LW Brady (eds) Radiation oncology: an evidence-based approach. Springer, Berlin Heidelberg New York

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Simulation and Target Volumes  Computed tomography (CT) simulation with vessel contouring for lymph node localization provides precise and individualized field delineation (Source: Finlay MH, Ackerman I, Tirona RG et al (2006) Use of CT simulation for treatment of cervical cancer to assess the adequacy of lymph node coverage of conventional pelvic fields based on bony landmarks. Int J Radiat Oncol Biol Phys 64:205–209).  Patient should lay supine. The frog-leg position can be utilized if treating the inguinal areas.  A small radio-opaque marker or seed can be inserted at the tumor site.  Bladder and rectal filling – leading to target motion – should be accounted for at the time of simulation. Full- and empty-bladder scans are options, and the vaginal contour drawn on both scans be fused to obtain internal target volume (ITV) (Source: Thawani N, Mutyala S, Lukaj A et al (2008) Bladder filling status strongly influences target volume changes in posthysterectomy patients treated with intensity-modulated radiation therapy (IMRT) for gynecologic cancers. Int J Radiat Oncol Biol Phys 72:S357).  Vacuum-bag immobilization should be used for the legs. Treatment Techniques for EBRT Treatment Volumes Dose constraints are listed in Table 24.11, techniques of dose delivery in Table 24.12, and techniques for brachytherapy in Table 24.13. Table 24.11 Dose constraints for normal tissues Site Small bowel Bladder Rectum

Dose Individual bowel loops: V15 < 120 ml Entire potential space: V45 < 195 ml V45 < 35% (should be assessed in conjunction with the brachytherapy dose) V30 < 60% (should be assessed in conjunction with the brachytherapy dose)

Femoral heads

V30 < 15%

Bone marrow

Total marrow: V10 < 95%, V20 < 80%, V30 < 64%, and D75 < 24.5 Gy

Vn: volume of tissue receiving at least n Gy, D75: 75% dose Sources: RTOG protocol 0418, Marks LB, Yorke ED, Jackson A et al (2010) Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 76:S10–S19; Mutyala S, Thawani N, Vainshtein JM et al (2008) Dose constraint recommendations and a predictive nomogram of incidence of hematological toxicity for cervix cancer patients treated with concurrent cisplatin and intensity modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys 72:S359–S360

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 Gross tumor volume (GTV): tumor volume as defined by clinical exam, MRI (T2-weighted image) with contrast, and RT-planning CT  ITV: tumor volume obtained after fusion of the filled- and empty-bladder scans  Clinical target volume (CTV): lymph nodes including medial inguinofemoral, external and internal iliac, obturator, and presacral. For upper vaginal lesions, proximal perirectal lymph nodes at the level of the lesion should be included, as well as bilateral parametria  Planning target volume (PTV): CTV plus Internal target Volume(ITV), with margin expansions for setup error per institutional protocol (usually 0.7–2 cm) Table 24.12 Techniques of dose delivery Type

Description

Conventional anteroposterior (AP) fields

Field borders

 AP field  Superior: L5–S1  Inferior: 3–4 cm below the vaginal marker  Lateral: 1.5–2 cm of the true pelvic rim and medial half of the femoral heads  PA field  Lateral: block for the femoral head  Inguinal lymph nodes (different techniques to avoid overdose to the femoral heads)  Wide AP fields to cover inguinal regions with nar-

row post-fields with 2:1 weighting  Combination of low- and high-energy photons

(4–6 MV AP, 15–18 MV PA)  Equally weighted beams with a central transmis-

sion block on AP field  Small AP photon or electron field ( depth measured

on CT to select energy for electrons) with matching for daily boost to inguinal nodes 3D conformal

Field borders

 AP and PA fields as above  Lateral fields  Anterior: pubic symphysis  Posterior: 1 cm into the sacrum, up to S2–S3

IMRT  Inverse treatment planning to cover 95% of the Borders

PTV with at least 95% of the dose, with no hot spots above 107%, and the normal tissue dose constraints with a 7- to 9-beam field arrangements and beam energy of 12–18 MV

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Table 24.13 Treatment techniques for brachytherapy Type

Description

Low-dose-rate brachytherapy (<200 cGy/h) a

Techniques

 Intracavitary single or multichannel cylinder of superficial lesions and interstitial implant freehand or with templatebased needles. Dose recommended is 65–80 Gy if used alone, or 30–40 Gy if used in conjunction with EBRT

Medium-dose-rate brachytherapy (200–1,200 cGy/h) Techniqueb

 Applicators similar to low-dose rate, using Cs-137 source

High-dose-rate brachytherapy (>1,200 cGy/h)

Techniquec

 Applicators similar to low-dose rate can be used with a 10-Ci single iridium (Ir-192) source. CT-based treatment planning with or without MRI fusion can be used  Generally, 3–6 insertions with the dose per fraction ranging from 5 to 8 Gy can be used if used alone or 3–4 insertions for 5–8 Gy in conjunction with EBRT

a

Source: Chyle V, Zagars GK, Wheeler JA et al (1996) Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 35:891–905 b Source: Rutkowski T, Białas B, Rembielak A et al (2002) Efficacy and toxicity of MDR versus HDR brachytherapy for primary vaginal cancer. Neoplasma 49:197–200 c Source: Beriwal S, Heron DE, Mogus R et al (2008) High-dose-rate brachytherapy (HDRB) for primary or recurrent cancer in the vagina. Radiat Oncol 13:3–7

Side Effects of Treatment Early side effects include proctitis, cystitis, and vaginal mucositis during treatment. Late complications include vaginal ulceration, vaginal stenosis (incidence can be decreased by use of vaginal dilators, from 50 to 11%), cystitis, urethral strictures, development of fistula, and femoral-head necrosis. The incidence of late side effects is 10% with the conventional radiation techniques at 5 years, and increases to about 17% with chemotherapy.

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Follow-Up Suggested follow-up schedules and examinations are detailed in Table 24.14. Table 24.14 Follow-up schedule and examinations

Schedule

Frequency

First follow-up

 2 weeks; vaginal dilator should be given 

Years 0–2

 Every 3 months 

Years 3–5

 Every 6 months 

Years 6+

 Annually 

Examinations History and physical

 Including a bimanual pelvic examination 

Imaging

 Chest x-ray 

Pap smear

 Annually 

Treatment of Adenocarcinoma, CCA, and Melanoma The outcomes of these are poorer than SCC. The principles of treatment are similar however and may be combined with targeted therapies when available for other sites.

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Figure 24.4 a–e Treatment fields for a patient being treated for vaginal cancer with pelvic and inguinofemoral nodal radiation. a AP field to treat the pelvis and inguinals. b PA field to treat pelvis only and (c and d) small AP boost fields for daily boost to the inguinal areas. e Axial dose distribution in color wash with sparing of the femoral heads

Section VIII Lymphomas

VIII 25

Non-Hodgkin’s Lymphoma . . . . . . . . . . . . . . . . . 747 Joanne W. Jang and Andrea K. Ng

26 Hodgkin’s Lymphoma . . . . . . . . . . . . . . . . . . . . . . 771 Maryse Bernard and Richard W. Tsang 27

Multiple Myeloma and Plasmacytoma . . . . . . 811 Wee Joo Chng and Ivan W.K. Tham

28

Cutaneous T-Cell Lymphoma . . . . . . . . . . . . . . . 833 Ivan W.K. Tham

29 Primary Central Nervous System Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . 853 Marnee M. Spierer and Evan M. Landau

25

Non-Hodgkin’s Lymphoma Joanne W. Jang1 and Andrea K. Ng2

Key Points  Non-Hodgkin’s lymphoma (NHL) is a group of malignancies comprising many different types of lymphoma, and has historically been classified a variety of ways.  Current classification schemes take into account the cells of origin for NHL. The clinically relevant classification schemes divide the diseases into indolent and aggressive NHL.  Although systemic symptoms (fever, night sweats, weight loss, a.k.a. B symptoms) can occur, most symptoms vary, depending on the site involved.  Important prognostic factors include age, stage, number of extranodal sites, performance status, and lactate dehydrogenase (LDH) level, which have all been incorporated into the widely used International Prognostic Index.  Other important prognostic factors include tumor size, pathologic subtype, β2-microglobulin concentration, the presence of B symptoms, bone marrow involvement, response to treatment, and duration of remission.  Treatment of NHL depends on the clinical classification of the tumor (indolent versus aggressive) and the stage, but can include observation, chemotherapy, radiation, or a combination of chemotherapy and radiation.  Radiation plays an important role in the treatment of limited-stage indolent and aggressive lymphomas, and may be of benefit for certain patients with advanced-stage aggressive NHL.

1

Joanne W. Jang, MD, PhD Email: [email protected]

2

Andrea K. Ng, MD, MPH () Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_8, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology The incidence of non-Hodgkin’s lymphoma (NHL) is 19.5 per 100,000 in the United States. It was estimated that in 2010, 65,540 patients were diagnosed with NHL, and 20,210 patients died. Multiple risk factors have been determined for NHL and are delineated in Table 25.1. Table 25.1 Risk factors for NHL Factor

Description Part medical history: previous NHL, Hodgkin’s lymphoma, other lymphoproliferative or hematopoietic malignancies, basal cell or squamous cell skin cancers Family history: twofold increase in risk for those who have at least one 1st-degree relative with NHL Genetic predisposition: polymorphisms in TNF, interleukin-10 genes, various translocations associated with different NHL

Patient related

Immunosuppression: congenital autoimmune disorders (e.g. Sjögren’s syndrome, lupus, celiac disease, rheumatoid arthritis), organ transplantation Infections: HIV associated with NHL, HTLV-1 associated with adult T-cell leukemia/lymphoma, HHV-8 associated with NHL, EBV associated with Burkitt’s lymphoma, Helicobacter pylori associated with gastric B-cell lymphomas (particularly MALT lymphoma)

Environmental

Occupational: farmers, livestock workers, printers, teachers, woodworkers, dry cleaners, barbers, hairdressers

HTLV: T-cell lymphotropic virus type 1, HHV-8: human herpes virus type 8, MALT: mucosa-associated lymphoid tissue

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Classification The 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid neoplasms takes into account morphology, immunophenotype, and genetic and clinical factors (Table 25.2). NHL is often subdivided into categories that are indicative of their clinical behaviors (Table 25.3). The most common histologic subtype is diffuse large B-cell lymphoma (DLBCL), and the second most common subtype is follicular lymphoma; these subtypes account for 25 and 20% of all NHL, respectively. Table 25.2 WHO classification of lymphoid neoplasms Category

Description

Precursor lymphoid neoplasms

 Precursor B-cell lymphoblastic leukemia/lymphoma  Precursor T-cell lymphoblastic leukemia/lymphoma

Mature B-cell neoplasms

 Mantle cell lymphoma  B-cell prolymphocytic leukemia  Chronic lymphocytic leukemia/small lymphocytic lymphoma  Follicular lymphoma  Diffuse large B-cell lymphoma  Burkitt’s lymphoma  Marginal zone lymphoma, extranodal and nodal  Primary cutaneous follicle center lymphoma  Lymphomatoid granulomatosis  Plasmablastic lymphoma  Hairy cell leukemia  Lymphoplasmacytic lymphoma  Waldenström’s macroglobulinemia  Heavy chain diseases  Plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmactyoma  Large B-cell lymphoma

Hodgkin’s lymphoma

 Nodular lymphocyte predominant  Classical

Mature T-cell or NK-cell neoplasms

      

T-cell prolymphocytic leukemia Anaplastic large cell lymphoma Cutaneous peripheral T-cell lymphoma Adult T-cell lymphoma/leukemia T-cell large granular lymphocyte leukemia NK-cell large granular lymphocyte leukemia Aggressive NK-cell leukemia

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Table 25.3 NHL classified by clinical behavior Category

Description

Indolent

 Chronic lymphocytic leukemia/small lymphocytic lymphoma  Lymphoplasmacytic lymphoma  Plasma cell myeloma, plasmacytoma  Hairy cell leukemia  Follicular lymphoma, grades I and II  Marginal zone B-cell lymphoma  Mantle cell lymphoma  T-cell large granular lymphocyte leukemia  Cutaneous peripheral T-cell lymphoma  T-cell prolymphocytic leukemia  NK-cell large granular lymphocyte leukemia

Aggressive

    

Follicular lymphoma, grade III Diffuse large B-cell lymphoma Mantle cell lymphoma Peripheral T-cell lymphoma Anaplastic large cell lymphoma

Highly aggressive

   

Burkitt’s lymphoma Precursor B lymphoblastic leukemia/lymphoma Adult T-cell lymphoma/leukemia Precursor T lymphoblastic leukemia/lymphoma

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Diagnosis, Staging, and Prognosis Clinical Presentation A thorough history and physical, including the presence of B symptoms and a complete lymph node and skin evaluation, should be the first objective, and is essential in guiding further testing. Approximately two thirds of patients present with painless lymphadenopathy. Other symptoms vary widely, depending on the histologic subtype and areas of involvement. Those symptoms are detailed in Table 25.4. Table 25.4 Common signs and symptoms of NHL Signs/Symptoms

Description

Patient history

 Painless lymphadenopathy is present  B symptoms include fever >38°C, weight loss >10% of body weight over 6 months, and night sweats  Obstructing symptoms present in the thorax or abdomen from a nodal mass  Mediastinal lymphadenopathy can cause cough, chest discomfort, and/or SVC syndrome  Gastrointestinal lymphomas can cause anorexia, weight loss, nausea, vomiting, pain, early satiety, abdominal fullness, gastrointestinal bleeding, or perforation  CNS involvement can result in headache, nausea, vomiting, seizures, or focal neurologic deficits

Abnormalities in common laboratory studies

 Thrombocytopenia, neutropenia, and anemia are unreliable indicators of bone marrow involvement  Blood urea nitrogen (BUN) and creatinine can indicate ureteral obstruction or, rarely, kidney involvement by NHL  Liver chemistries (serum glutamic-oxaloacetic transaminase [SGOT], total bilirubin, alkaline phosphatase) can indicate hepatic involvement and assess liver function  Elevated alkaline phosphatase in isolation can indicate skeletal involvement  Hypercalcemia can occur in aggressive lymphomas

SVC syndrome: superior vena cava syndrome

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Diagnostic and Staging Procedures Table 25.5 outlines the various methods of obtaining tissue for diagnosis. Once tissue is obtained, Figure 25.1 can be used as a demonstration of one diagnostic process for NHL. Table 25.5 Types of biopsy Type

Description

Excisional biopsy

 The gold standard

Fine-needle aspiration (FNA)

 Pros: quicker, less painful, easier, less expensive, does not require general anesthesia or hospital admission  Cons: may lead to false negatives, does not provide histologic architecture, may provide inadequate amounts of tissue for ancillary testing, such as flow cytometry, immunohistochemistry (IHC), and molecular genetic studies

Core needle biopsy

 Pros: can be either CT- or ultrasound-guided, can provide more tissue and architectural features, as compared with FNA  Cons: still provides less tissue and architectural information, as compared with excisional biopsy

Tissue biopsy

Formalin fixation

Fresh material

H&E staining with thorough microscopic exmination

Flow cytometry or cytogenetics

IHC

If needed, PCR or FISH to confirm clonality, detect specific translocations or gene rearrangements

Figure 25.1 A proposed diagnostic algorithm for NHL

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Recommended studies for the initial evaluation of a patient suspected of having NHL are delineated in Table 25.6. Table 25.6 Recommended studies Type

Description  Recommended

Laboratory studies

 Complete blood count (CBC) with differential, peripheral blood smear  lactate dehydrogenase (LDH), β2-microglobulin  BUN, creatinine, albumin, SGOT, total bilirubin, alkaline phosphatase, calcium, uric acid  Serum protein electrophoresis  If indicated: viral serologies, hepatitis B, hepatitis C, HIV, HTLV-1  Recommended  Bone marrow aspirate and biopsy  Chest radiograph (posterior–anterior [PA] and lateral)  CT of the chest, abdomen, and pelvis  Optional: PET scan  If clinically indicated

Radiologic studies or special procedures

 MRI (bone marrow involvement)  Ear, nose, and throat examination  Slit-lamp examination (central nervous system, ocular lymphoma)  Testicular ultrasound of contralateral testis in testicular lymphoma  Gastrointestinal evaluation  Skeletal evaluation  Head CT or MRI  Lumbar puncture and CSF analysis  Mammogram  Echocardiogram or multiple-gated cardiac exam

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Clinical Staging of NHL The Ann Arbor Staging Classification is used for NHL, as detailed in Table 25.7. Table 25.7 Ann Arbor staging system Stage

Tumor location

I

Involvement of a single lymph node* or of a single extranodal organ or site (IE)

II

Involvement of 2 or more lymph node regions on the same side of the diaphragm, or localized involvement of an extranodal site or organ (IIE) and 1 or more lymph node regions on the same side of the diaphragm

III

Involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by localized involvement of an extranodal organ or site (IIIE) or spleen (IIIS) or both (IIISE)

IV

Diffuse or disseminated involvement of 1 or more distant extranodal organs with or without associated lymph node involvement

*

The spleen is considered nodal Cases are subclassified to indicate the absence (A) or presence (B) of B symptoms

Prognosis The International Prognostic Index (IPI) is a commonly used model that incorporates five different adverse factors (Table 25.8) to predict relapse-free survival (RFS) and overall survival (OS). Each adverse factor accounts for 1 point. The IPI is shown in Table 25.9. Table 25.8 Factors of the International Prognostic Index Risk factor

At risk when:

Age

>60 years

LDH

Abnormal

Performance status (ECOG)

≥2

Stage

III–IV

Number of extranodal sites

>1

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Table 25.9 International Prognostic Index Risk group

Risk factor

5-Year OS (%)

Low

0–1

73%

Low intermediate

2

51%

High intermediate

3

43%

High

4–5

26%

Source: The International Non-Hodgkin’s Lymphoma Prognostic Factors Project (1993) A predictive model for aggressive non-Hodgkin’s lymphoma: N Engl J Med 329:987– 984

There are multiple variants of the IPI, including age adjusted, stage adjusted, the revised IPI in the rituximab era, a follicular lymphoma IPI, and a second-line IPI. Other prognostic factors not accounted for in the IPI are listed in Table 25.10. Table 25.10 Additional prognostic factors Factor

Description

Clinical

     

Treatment related

 Time to complete response  Mid-treatment 18F-FDG-PET imaging

Relapsed or refractory disease

 Response to second-line chemotherapy  Duration of remission  Primary refractory disease, as compared with relapsed disease

Histopathologic subtype Tumor size B symptoms β2-microglobulin concentration Number of nodal sites Bone marrow involvement

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Treatment Principles and Practice In general, treatment for NHL depends on the behavior of the tumor (indolent versus aggressive) and the stage (stages I–II versus III–IV). A proposed treatment algorithm is presented in Figure 25.2.

Diagnosis an staging of NHL

Aggressive NHL

Indolent NHL

Limited stage (I-II)

Advanced stage (III-IV)

Limited stage (I-II)

Advanced stage (III-IV)

Involved field radiation (IFRT) to 30 GY-36 GY

Observation. Chemotherapy or radiation for symptomatic disease

Chemotherapy for3-8 cycles followedby IFRT to 30 Gy-40 Gy

Chemotherapy for 6-8 cycles followed by IFRT to bulky or partial response sites to 30 Gy-40 Gy

Figure 25.2 Treatment algorithm for NHL

Treatment of Limited-Stage Indolent NHL Only 15–30% of patients with indolent lymphomas present with limitedstage disease. Although data are limited, radiation is the primary treatment for these patients. Selected retrospective studies with at least 100 patients treated with radiation are presented in Table 25.11. Recommended treatment is involved-field or regional radiation therapy (involved nodal region plus one additional uninvolved region on each side of the involved nodes) to 30–36 Gy. This is associated with a local control rate of >90%, and a long-term freedom-from-treatment-failure rate of approximately 50%.

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Table 25.11 Clinical evidence of treatment of limited-stage indolent NHL Study

Description

Vaughan Hudson et al (BNLI)a

 Retrospective review of 208 patients with stage I low-grade NHL treated with radiation alone  35 Gy suggested, but actual radiation doses and fields unknown  98% achieved complete remission (CR) for at least 3 months  10-year freedom from treatment failure (FFTF) was 47%; 10-year OS was 64%  Age ≥50 years significantly associated with worse FFTF and OS

Petersen et al (Princess Margaret Hosp.)b

 Retrospective review of 460 patients with stage I (74%) and II (26%) follicular lymphoma treated with radiation alone  Involved-field radiation to a median dose of 35 Gy  Median follow-up was12.5 years  10-year FFTF, 51%; 10-year OS, 62%

Mac Manus et al (Stanford Univ.)c

 Retrospective review of 177 patients with stage I (41%) and II (59%) follicular lymphoma treated with radiation  Involved-field (IF), extended-field or total lymphoid irradiation to 35–40 Gy. Most patients had chemotherapy afterward  Median follow-up, 7.7 years  10-year FFTF was 44%; 10-year OS was 64%  Age ≥60 years, extranodal involvement, stage II disease, and radiation on only 1 side of the diaphragm associated with worse FFTF and OS

Soubeyearan et al (Foundation Bergonié)d

 Retrospective review of 103 patients with stage I (44%) and II (56%) follicular lymphoma treated with radiation with or without chemotherapy  Involved-field (54%) or regional-field (46%) radiation from 35 to 40 Gy  70% of patients received chemotherapy  Median follow-up, 8.3 years  10-year FFTF was 49%; 10-year OS was 56%  Age ≥60 years and B symptoms were significantly associated with worse FFTF and OS ▶

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Table 25.11 (continued) Study

Description

Guadagnolo et al (Harvard Univ.)e

 Retrospective review of 106 patients with stage I (74%) and II (26%) grades 1–2 follicular lymphoma treated with radiation with (24%) or without chemotherapy (76%)  Median follow-up, 12 years  Involved-field (60%), regional-field (34%), or extended field (6%) radiation to a median dose of 36.7 Gy  10-year FFTF, 46%; 10-year OS, 75%  Tumor size associated with worse FFTF; age ≥60 years associated with worse OS

BNLI: British National Lymphoma Investigation a Source: Vaughan Hudson B, Vaughan Hudson G, MacLennan KA et al (1994) Clinical stage 1 non-Hodgkin’s lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69:1088–1093 b Source: Petersen PM, Gospodarowicz M, Tsang R et al (2004) Long-term outcome in stage I and II follicular lymphoma following treatment with involved field radiation therapy alone. In: Abstract of the 2004 ASCO annual meeting proceedings (post-meeting edition). J Clin Oncol 22:S6521 c Source: Mac Manus MP, Hoppe RT (1996) Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14:1282–1290 d Source: Soubeyearan P, Eghbali H, Bonichon F et al (1988) Localized follicular lymphomas: prognosis and survival of stages I and II in a retrospective series of 103 patients. Radiother Oncol 13: 91–98 e Source: Guadagnolo BA, Li S, Neuberg D et al (2006) Long-term outcome and mortality trends in early-stage, grade 1–2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 64:928–934

Treatment of Advanced-Stage Indolent NHL The majority of patients with indolent NHL present with advanced-stage disease. Observation is recommended for select patients with asymptomatic, low-volume disease. Clinical evidence for this approach is presented in Table 25.12. In specific situations such as outlined in Table 25.13, palliative localized radiotherapy can be very effective. Lower doses to 20–30 Gy can be used in this setting. There is a growing body of literature that also supports the use of very low doses of involved-field palliative radiation to 4 Gy, with very good response rates, as delineated in Table 25.14.

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Table 25.12 Clinical evidences on treatment of advanced-stage indolent NHL Study

Description

Ardeshna et al (BNLI)a

 309 patients with asymptomatic advanced-stage lowgrade NHL randomized to immediate chlorambucil versus delayed chlorambucil for progressive disease  Localized RT to 15–20 Gy allowed  Median follow-up, 16 years  10-year OS, 35% for the chlorambucil group and 34% for the observation group. Median OS, 5.9 years for the chlorambucil group and 6.7 years for the observation group (p = 0.84)  In the observation group, 73% eventually received chemotherapy, with a median time to treatment of 2.6 years. At the time of publication, 13 patients were still alive without systemic treatment ; 5 had local radiation; 7 had spontaneous remissions

Portlock et al (Stanford Univ.)b

 Retrospective review of 44 patients with stages III–IV lowgrade NHL that were observed until treatment became indicated, and 112 patients who participated in randomized controlled trials involving chemotherapy  For the observation cohort, median time to treatment was 31 months, with 19 patients still on observation at the time of publication. Median OS, 121 months  4-year OS was 77.3% for the observation cohort and 83.2% for the treatment cohort (p = 0.6)

a

Source: Ardeshna KM, Smith P, Norton A et al (2003) Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362:516–522 b Source: Portlock CS, Rosenberg SA (1979) No initial therapy for stage III and IV nonHodgkin’s lymphomas of favorable histologic subtypes. Ann Intern Med 90:10–13

Table 25.13 Indications for palliative radiation in advanced-stage indolent NHL Indications Localized chemotherapy-resistant disease Prevention or treatment of symptomatic spinal cord or nerve root involvement Superior vena cava syndrome or obstructive pneumonia To reduce the risk of fracture of an involved bone Venous obstruction from a large pelvic mass Local symptomatic relief (e.g., orbit, stomach) Cosmetic

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Table 25.14 Clinical evidence on low-dose radiation for advanced-stage indolent NHL

a

Study

Description

Haas et al (The Netherlands)a

 Phase II study was of 109 patients (304 total sites) with recurrent indolent B-cell NHL. 90% of patients had follicular NHL  94% had prior systemic therapy, 28% had prior radiotherapy  27% had 4 Gy in 1 fraction; 73% had 4 Gy in 2 fractions  Overall response rate of 92%: 61% achieved complete response (CR) and 31% had partial response (PR)  Median time to local progression was 25 months; median time to local or distant progression was 14 months

Girinsky et al (France)b

 Retrospective study of 48 patients (135 sites) with relapsed or refractory low-grade NHL treated with 4 Gy in 2 fractions  94% had prior systemic therapy  Median follow-up was 4.5 years  Median overall survival was 10.7 years  At the 1- to 2-month follow-up, 43% achieved CR and 35% had PR; at the 3- to 4-month follow-up, 57% achieved CR and 24% had PR  2-year freedom from local progression was 56%  On univariate analysis, tumor size ≥5 cm, >1 prior chemotherapy regimens, and age ≥65 years associated with worse 2-year freedom from local progression

Luthy et al (Harvard University)c

 Retrospective review of 33 patients (43 sites) with advanced or recurrent indolent NHL were treated with 4 Gy in 2 fractions  Median follow-up was 14 months  Overall response rate of 95%: 84% achieved CR and 12% had PR  Median time to local progression was 9 months and median time to any progression was 4 months  Site of disease (head and neck) and size ≤4 cm associated with CR

Source: Haas RL, Poortmans P, de Jong D et al (2003) High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21:2474–2480 b Source: Girinsky T, Guillot-Vals D, Koscielny S et al (2001) A high and sustained response rate in refractory or relapsing low-grade lymphoma masses after low-dose radiation: analysis of predictive parameters of response to treatment. Int J Radiat Oncol Biol Phys 51:148–155 c Source: Luthy SK, Ng AK, Silver B et al (2008) Response to low-dose involved-field radiotherapy in patients with non-Hodgkin’s lymphoma. Ann Oncol 19:2043–2047

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If systemic therapy is indicated, alkylating agents or purine analogs are often used. Common historical chemotherapy regimens are listed in Table 25.15. More recently, the use of rituximab, an anti-CD20 monoclonal antibody, in combination with some of these regimens has been shown in randomized clinical trials to significantly improve outcome. As a result, it is now often given as a single agent or in combination with other chemotherapeutic agents. For patients with relapsed or refractory disease who require treatment, there is no standard therapy. Options for, and descriptions of, treatment are listed in Table 25.16. Table 25.15 Common chemotherapeutic regimens for indolent NHL Regimen

Combination of (drug)s

–

Fludarabine (single agent)

–

Chlorambucil (single agent)

CVP

Cyclophosphamide, vincristine, and prednisone

CHOP

Cyclophosphamide, adriamycin, vincristine, and prednisone

MCP

Mitoxantrone, chlorambucil, and prednisone

FCM

Fludarabine, cyclophosphamide, and mitoxantrone

Table 25.16 Treatment of relapsed/refractory advanced-stage indolent NHL Treatment Chemotherapy Immunotherapy

Radioimmunotherapy

Hematopoietic stem cell transplant (HCT)

Description  Clinical trials of new chemotherapy agents, or different combinations of existing agents  Rituximab, with or without additional chemotherapeutic agents  Monoclonal antibodies are linked to radioisotopes  Ibritumomab tiuxetan (Zevalin) is murine anti-CD20 conjugated to Yttrium-90  Tositumomab (Bexxar) is murine anti-CD20 conjugated to Iodine-131  Controversial, but may have a role in select patients  Autologous HCT may be beneficial for some patients in complete or near-complete remission after their first chemotherapy regimen  Autologous HCT may be of benefit for patients who have a CR or PR to second-line chemotherapy for relapsed disease  Although treatment-related mortality is approximately 30%, myeloablative allogeneic HCT may be curative in some patients. Non-myeloablative (reduced intensity) allogeneic HCT decreases treatment-related mortality and can provide long-term progression-free survival (PFS)

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Treatment of Limited-Stage Aggressive NHL Historically, radiation alone was the standard of care for limited-stage aggressive NHL, with 5-year recurrence free survival approaching 50%. The addition of chemotherapy improved recurrence free and overall survival, and the standard of care is now monoclonal antibody rituximab combined with cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone/prednisolone (R-CHOP) with or without radiation. Table 25.17 outlines some of the randomized trials assessing the role of radiation therapy for patients with early-stage aggressive NHL. Of note, none of the trials used R-CHOP, which is the current standard systemic therapy for B-cell marker CD-20–positive aggressive NHL.

Table 25.17 Radiation for limited-stage aggressive NHL Study

Description

Horning et al (ECOG 1484)a

 352 patients with bulky stage I, IE, or II aggressive NHL randomized to CHOP for 8 cycles, succeeded by observation if achieved a CR versus CHOP for 8 cycles, followed by IFRT to 30 Gy if they achieved a CR. If PR, received IFRT to 40 Gy  Powered to detect a difference in disease-free survival (DFS) but not OS  61% of patients achieved CR  Median follow-up 12 years  6-year DFS was 53% for the observation arm, and 69% for the radiation arm (p = 0.04)  6-year OS was 67% for the observation arm, and 79% for the radiation arm (p = 0.23)  16% of patients in the observation arm, and 4% of patients in the radiation arm relapsed in a previously involved site (p = 0.06)

Miller et al (SWOG 8736)b

 401 patients with stage I and non-bulky stage II disease to CHOP for 3 cycles, followed by IFRT to 40–55 Gy versus CHOP for 8 cycles, followed by observation  5-year PFS was 77% in the radiation arm, and 64% in the observation arm (p = 0.03)  5-year OS was 82% in the radiation arm, and 72% in the observation arm (p = 0.02)  Updated results: at 7 years, there was no longer a difference in PFS and at 9 years, there was no longer a difference in OS  Subanalysis revealed that patients in the radiation arm without any stage-adjusted IPI risk factors had a 5-year OS of 94%

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Table 25.17 (continued) Study

Description

Reyes et al (GELA LNH 93-1)c

 631 patients 60 years or younger with stage I–II low-risk aggressive NHL randomized to chemotherapy with ACVBP versus CHOP for 3 cycles, followed by IFRT to 40 Gy  Median follow-up was 7.7 years  5-year event-free survival (EFS) was 74% in the radiation arm, and 82% in the chemotherapy-alone arm (p < 0.001)  5-year OS was 81% in the radiation arm, and 90% in the chemotherapy-alone arm (p = 0.001)  14% of patients in the chemotherapy-alone arm relapsed (41% in an initial site, 38% in a distant site, and 21% in both), and 24% of patients in the radiation arm relapsed (23% in the radiation field, 72% outside of the radiation field, and 5% in both)  ACVBP with a theoretical dose intensity of at least 150% greater than CHOP for 3 cycles

Bonnet et al (GELA 93-4)d

 518 patients older than 60 years with stage I–II low-risk aggressive NHL randomized to CHOP for 4 cycles, followed by observation versus CHOP for 4 cycles, followed by IFRT to 40 Gy  Median follow-up was 7 years  5-year EFS was 64% in the radiation arm, and 61% in the chemotherapy-alone arm (p = 0.6)  5-year OS was 68% in the radiation arm, and 72% in the chemotherapy-alone arm (p = 0.5)  29% of patients in the chemotherapy-alone arm relapsed (47% in an initial site, 37% at a distant site, and 16% in both) and 22% of patients in the radiation arm relapsed (21% in the radiation field, 66% outside of the radiation field, and 13% in both)

ECOG: Eastern Cooperative Oncology Group, SWOG: Southwest Oncology Group, GELA: Groupe d’Etude des Lymphomes de l’Adulte, ACVBP: Adriamycin (doxorubicin), cyclophosphamide, vindesine, bleomycin, prednisone a Source: Horning SJ, Weller E, Kim K et al (2004) Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 22:3032–3038 b Source: Miller TP, Dahlberg S, Cassady JR et al (1998) Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 339:21–26. Updated results shown at the 2001 American Society of Hematology annual meeting c Source: Reyes F, Lepage E, Ganem G et al (2005) ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 352:1197–1205 d Source: Bonnet C, Fillet G, Mounier N et al (2007) CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the GELA. J Clin Oncol 25:787–792

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In summary, involved-field radiation therapy (IFRT) reduced the risk of relapse at initial sites of disease, but this benefit in local control can only manifest as a benefit in disease-free or overall survival, with improved control of distant metastases obtained by using optimal chemotherapy. Radiation is not able to compensate for inferior or inadequate chemotherapy, except in a select group of highly favorable patients. Although current treatment regimens vary widely among institutions, they commonly include three to eight cycles of R-CHOP, succeeded by IFRT. Radiation is usually given to 30–36 Gy for initial sites of disease, especially if a complete response (CR) to chemotherapy is achieved. For patients with partial response (PR) to chemotherapy with residual fluorodeoxyglucose (FDG) avidity, doses of at least 40 Gy should be considered.

Treatment of Advanced-Stage Aggressive NHL Chemotherapy is the mainstay of treatment for patients with disseminated aggressive NHL. CHOP or CHOP-like chemotherapy regimens have resulted in 4-year disease-free state (DFS) rates of 35–45%. The addition of rituximab has increased the rates of survival by 10–15%, and a regimen of six to eight cycles of R-CHOP is now standard of care. The use of radiation is more controversial. However, some studies have shown a benefit to radiation to bulky sites of disease (Table 25.18). Many institutions will also give IFRT to sites with residual FDG avidity after completion of chemotherapy. As a result, although it is controversial, radiotherapy will be often given after chemotherapy for sites of bulky disease, or for presumed residual disease seen on positron-emission tomography (PET) scan.

Table 25.18 Radiation for advanced-stage aggressive NHL Study

Description

Avilés et al (Mexico)a

 341 patients with nodal bulky (>10 cm) stage IV DLBCL who had a CR to 6 months of chemotherapy (cyclophosphamide, vincristine, epirubicin, prednisone, bleomycin) randomized to observation versus radiation to site of bulky disease  Median follow-up was 10.1 years  5-year EFS was 55% for the observation arm, and 82% for the radiation arm (p < 0.001)  5-year OS was 66% for the observation arm, and 87% for the radiation arm (p < 0.01)  45% of patients in the observation arm (63% at site of bulky disease) and 18% of patients in the radiation arm (7% at site of bulky disease) relapsed (p < 0.001)

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Table 25.18 (continued) Study

Description

Schlembach et al (MDACC)b

 Retrospective review of 59 patients with stage III–IV intermediate-grade or large-cell lymphoma, with at least PR to 6 cycles or more of CHOP-based chemotherapy, followed by IFRT to 30–50 Gy  Median follow-up was 53 months  5-year local control (LC) was 89% for the radiation arm, and 52% for the observation arm (p = 0.001)  5-year freedom from progression (FFP) was 85% for the radiation arm, and 51% for the observation arm (p = 0.003)  5-year OS was 87% for the radiation arm, and 81% for the observation arm (p = 0.6)  Improved LC and FFP mostly for patients with bulky (≥4 cm)

Ferreri et al (Italy)c

 Retrospective review of 94 patients with stage III–IV DLBCL, 38 with bulky disease (≥10 cm), and 56 with semibulky disease (6–9 cm), in CR after chemotherapy, then treated with or without radiation  40 patients given radiation (50% with bulky disease), 54 patients observed (33% with bulky disease)  Of patients that received radiation, 70% had IFRT to 30– 45 Gy, and 30% had EFRT to 30–46 Gy  5-year OS was 66% for radiation group, compared with 44% for observation group (p = 0.01). This benefit was mostly seen in patients with bulky disease  Patients in the radiation arm had a statistically longer time to relapse (TTR)  Patients with bulky DLBCL treated with radiation had fewer relapses at the site of bulky disease, and patients with semi-bulky DLBCL treated with radiation had fewer relapses overall, compared with patients in the observation arm

MDACC: MD Anderson Comprehensive Cancer Center a Source: Avilés A, Fernándezb R, Pérez F et al (2004) Adjuvant radiotherapy in stage IV diffuse large cell lymphoma improves outcome. Leuk Lymphoma 45:1385–1389 b Source: Schlembach PJ, Wilder RB, Tucker SL et al (2000) Impact of involved field radiotherapy after CHOP-based chemotherapy on stage III–IV, intermediate grade and large-cell immunoblastic lymphomas. Int J Radiat Oncol Biol Phys 48:1107–1110 c Source: Ferreri AJ, Dell’Oro S, Reni M et al (2000) Consolidation radiotherapy to bulky or semibulky lesions in the management of stage III-IV diffuse large B cell lymphomas. Oncology 58:219–226

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Radiation Therapy Techniques Traditionally, extended fields have been used to treat sites of active disease as well as treat adjacent nodal volumes that were presumed to be at high risk for spread. Table 25.19 lists and describes these fields. More recently, IFRT has been found to be adequate in many cases. An involved field includes the involved lymph nodes as well as other lymph nodes within the same lymph node region (Figure 25.3). Commonly used fields are described in Table 25.20 and Figure 25.4. Table 25.19 Extended radiation treatment fields for NHL Field

Mantle (Figure 25.4)

Modified mantle

Para-aortic

Description  Used to treat the bilateral cervical, supraclavicular, submental, mediastinal, hilar, and axillary lymph nodes  Simulate with arms up to pull axillary lymph nodes away from the chest wall, and with neck hyperextended to limit dose to oral cavity  Extend fields to allow at least a 2-cm margin from disease  Borders  Lateral: beyond humeral heads, flash the axilla  Inferior: 5 cm below the carina (~T10)  Superior: 1 cm above mastoid tip or from the bottom of the lower lip to the external auditory meatus  Blocks  Larynx: usually after 18 Gy if giving radiation alone. Approximately 2 × 2 cm, with the inferior border at the bottom of C5  Lungs: start from the top of the 4th rib (or 2 cm below the clavicle), extending downward laterally to reach the chest wall by the 6th rib. Hilar margin is 1.5 cm if positive or 1.0 cm if negative for disease  Wing block: tip of scapula  Mouth: posterior mouth block on PA only  Can block humeral heads, but need to make sure entire axilla is being irradiated  Modifications to decrease the size of the mantle field can often be made, depending on the extent of disease  Similar to a mantle field but may exclude the upper neck and/or the axillae  Used to treat the paraaortic lymph nodes. Extend fields to allow at least a 2-cm margin from disease  Borders:  Superior: top of T11  Inferior: bottom of L4  Lateral: transverse processes  Blocks: kidneys if possible

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Table 25.19 (continued) Field

Description

Inverted Y

 Used to treat the bilateral iliac, inguinofemoral, and paraaortic lymph nodes, with or without splenic irradiation  Shield testes in men, consider oophoropexy in women  Extend fields to allow at least a 2-cm margin from disease  Borders:  Superior: top of T11  Inferior: 5 cm below the lesser trochanter  Lateral: greater trochanter  Medial: split obturator foramen  Blocks: kidneys if possible

Total lymphoid irradiation (TLI)

 Mantle field radiation followed by inverted-Y field radiation

Subtotal TLI (STLI)

 TLI without the pelvic irradiation (mantle plus paraaortic fields)

Figure 25.3 Lymph node regions based on the Rye Classification for staging. (Adapted from the Surveillance, Epidemiology, and End Results (SEER) Web site at http://seer. cancer.gov)

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Table 25.20 Involved-field radiation therapy (IFRT) for NHL Field

Description

Neck

 Includes the ipsilateral cervical and supraclavicular lymph nodes  Borders:  Medial: contralateral pedicles  Lateral: extends out laterally to include two thirds of the clavicle, often where coracoid process is seen  Inferior: 1 cm below clavicular head  Superior: 1 cm below mastoid tip

Mediastinum

 Includes the mediastinum with bilateral hilar, subcarinal, and medial supraclavicular lymph nodes  Extend fields to allow at least a 2-cm margin from disease  Borders:  Superior: C5/C6  Inferior: 5 cm below the carina  Lateral: 1.5 cm margin from the hilum

Axilla

 Includes the ipsilateral axillary, supraclavicular, and infraclavicular lymph nodes  Extend fields to allow at least a 2-cm margin from disease  Borders:  Superior: C5/C6  Inferior: lower tip of the scapula, approximately the 6th rib  Lateral: flash the axilla  Medial: ipsilateral cervical transverse process or pedicle  Blocks: lung

Abdomen

 Includes the paraaortic lymph nodes  Extend fields to allow at least a 2-cm margin from disease  Borders:  Superior: top of T11  Inferior: bottom of L4  Lateral: transverse processes  Blocks: kidneys if possible

Inguinal

 Includes the ipsilateral lower pelvic, inguinal, and femoral lymph nodes  Extend fields to allow at least a 2-cm margin from disease  Borders:  Superior: middle or bottom of sacroiliac joint  Inferior: 5 cm below the lesser trochanter  Lateral: greater trochanter of the femur  Medial: medial border or middle of the obturator foramen

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Figure 25.4 Mantle field for NHL radiation therapy. (Adapted from Koh ES, Tran TH, Heydarian M et al (2007) A comparison of mantle versus involved-field radiotherapy for Hodgkin’s lymphoma: reduction in normal tissue dose and second cancer risk. Radiat Oncol 2:13)

Follow-Up The National Comprehensive Cancer Network (NCCN) has established guidelines for follow-up of patients with NHL (Table 25.21). Table 25.21 Follow-up schedule and recommendations Category

Description

Indolent NHL

 Every 3 months for the first year, then every 3–6 months afterward

Aggressive NHL

 Every 3 months for years 0–2, then every 6 months for years 2–5

Monitoring techniques

 Careful history and physical  Complete blood counts and serum chemistries (including LDH)  Imaging study as clinically indicated

Source: NCCN clinical practice guidelines in oncology for NHL. Available at: http:// www.nccn.org/professionals/physician_gls/PDF/nhl.pdf)

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PET scan has emerged as a useful modality for pretreatment staging, and mid- or posttreatment restaging, and to assess the response of NHL to therapy, such as for patients with DLBCL. However, some NHL are not reliably FDG avid, and the utility of PET imaging is limited, such as for many indolent NHL. For routine surveillance, the use of computed tomography (CT) or PET scan has not been validated, but is used in many institutions. Patients with NHL respond variably to treatment, and current response definitions are shown in Table 25.22. Table 25.22 Response definitions for NHL Response

Description

Complete remission (CR)

Disappearance of all evidence of disease  If previously PET avid nodal disease or with palpable spleen or liver, disease is now PET negative and not palpable  Regression of lymph nodes to normal size  If involved prior to treatment, bone marrow biopsy shows no disease

Partial remission (PR)

   

Stable disease (SD)

 Failure to attain CR, PR, or PD  One or more previously involved sites remain FDG avid  No change in size of previous lesions

Relapsed or progressive disease (PD)

 New lesions or an increase of disease  New lesions ≥1.5 cm or ≥50% increase in any diameter of a previously involved site  ≥50% increase in size of liver or spleen at their nadir size during treatment  New or recurrent bone marrow involvement

Regression of disease and no new sites ≥50% decrease in size of up to 6 largest masses One or more previously involved sites remain FDG avid No increase in the size of the liver or spleen

Source: Cheson BD, Pfistner B, Juweid ME et al (2007) The International Harmonization Project on Lymphoma: revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586

26

Hodgkin’s Lymphoma Maryse Bernard 1 and Richard W. Tsang2

Key Points  An estimated 8,490 new cases of Hodgkin’s lymphoma were diagnosed in the USA in 2010.  Reed–Sternberg cells are the malignant cells in classical Hodgkin’s lymphoma (CD15+, CD30+, and CD45−). In nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL), these cells express B-cell markers (CD20+, CD79a+, and CD45+) and are CD15− and CD30−.  Common presentation is an asymptomatic lymph node enlargement in supradiaphragmatic areas (neck, mediastinum). Approximately 70% will have stage I or II disease.  For early-stage disease, the standard approach is a combined modality with short-course chemotherapy (ABVD: Adriamycin, bleomycin, vinblastine, dacarbazine), followed by moderate-dose radiation targeting involved lymph node region(s). When subdivided into favorable and unfavorable groups, 5-year disease-free survival rates of approximately 90–95% (favorable) and 85–90% (unfavorable) are expected, respectively.  The majority of patients with NLPHL present at an early stage and have excellent prognoses with radiation alone.  For advanced-stage disease, chemotherapy is the main modality, and the focus recently has been on intensifying chemotherapy to improve efficacy. When a complete response has been obtained with ABVD chemotherapy or its equivalent, there is no role for consolidation radiation therapy. Overall 5-year diseasefree survival is 60–85%.  High-dose therapy with autologous stem cell transplant is the salvage therapy of choice for refractory patients or for those who relapse after a short initial remission from chemotherapy.  Different types of radiation fields have been used in Hodgkin’s lymphoma and involved-field radiation therapy (IFRT) is the current standard. It covers involved lymph nodes before chemotherapy and the nodal region (wholly or partially) in which the involved lymph node(s) is/are located.  The radiation doses used in combined-modality protocols are well within the tolerance of normal tissues in virtually all supradiaphragmatic areas.

1

Maryse Bernard, MD Email: [email protected]

2

Richard W. Tsang, MD () Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_9, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Hodgkin’s disease was initially described as an inflammatory disease (hence the term “disease”), but is clearly recognized and treated as a malignant lymphoma (hence the more accurate term Hodgkin’s lymphoma (HL) is used synonymously with Hodgkin’s disease). An estimated 8,490 new cases of HL were diagnosed (4,670 males and 3,820 females), and 1,320 deaths (740 males and 580 females) occurred in the USA in 2010. The incidence of HL has remained stable over the last two to three decades and is bimodal, with the first peak in the third decade in life, and a second, smaller peak after 50 years of age. The etiology of HL is unknown, but a limited number of factors documented to be associated with a higher risk include a positive family history, higher socioeconomic status, prior Epstein-Barr virus (EBV) infection, and human immunodeficiency virus (HIV) infection.

Pathology The three main morphologic features of HL include an effacement of the involved lymph node, with destruction of its normal architecture, an inflammatory cellular infiltrate, and the presence of malignant cells, the Reed– Sternberg (RS) cells. The various subtypes of HL (Table 26.1) have distinct morphologic, immunophenotypic, and clinical characteristics. Classical HL is considered separately from nodular lymphocyte-predominant HL (NLPHL) in the 4th edn. of the World Health Organization (WHO) classification.

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Table 26.1 WHO classification (4th edn.) for HL (2008) and characteristics HL type

Characteristics

NLPHL  Has unique pathology and biologic behavior, and in the early stage, a different treatment approach is warranted  Accounts for <5% of HL NLPHL

 Usually presents in middle-aged males, with localized peripheral lymph node involvement (cervical, axillary, and inguinal regions).  It is characterized by the presence of an RS cell variant known as L & H cell or popcorn cell. These cells express Bcell markers (CD20+, CD79a+, CD45+, and J chain+), and are negative for CD15 and CD30

Classical HLa  Characterized by a nodular growth pattern, presence of collagen bands, and the RS cell variant known as the lacunar cell Nodular sclerosis subtype

 The most common subtype of HL, accounting for 65–70% of cases, and is the only subtype without a male predominance (male:female ratio approximately 1:1)  Typically, the cervical and mediastinal areas are involved

Lymphocyte-rich subtype

 Represents ~5% of HL  Similar to NLPHL clinically, with localized disease at presentation involving a peripheral lymph node region  Represents 10–15% of cases

Mixed-cellularity subtype

Lymphocytedepleted subtype

 Commonly presenting in advanced stages, with a tendency to involve spleen, bone marrow, and a lesser tendency for mediastinal involvement  Very rarely seen in primary presentation, as many of the previous cases were probably misdiagnosed, and have now been recognized as being non-Hodgkin’s lymphomas  Has the worse prognosis among the HL subtypes

a

In classical HL the RS cells are positive for CD30 and CD15, while CD45 and the J chain are negative. EBV-related proteins are detected in approximately 40% of cases Source: Swerdlow SH, Campo E, Harris NL et al (eds) (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC Press, Lyon, France

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Diagnosis, Staging, and Prognosis Clinical Presentation Clinical presentations of HL are presented in Table 26.2. Table 26.2 Signs and symptoms of HL Signs/symptoms

Description

Most common presentation

 Asymptomatic lymph node enlargement in supradiaphragmatic areas, typically in the neck

Stage at presentation

 ~70% present with stage I or II disease

Primary disease location

Systemic symptoms

 Mediastinal lymph node involvement is common, occurring in 80% of cases, and when the disease is bulky, might cause symptoms (chest pain, cough, and dyspnea)  ~5% of stages I–II patients present in infradiaphragmatic sites (e.g., inguinal, pelvic, or retroperitoneal lymph node regions)  B symptoms of night sweats, fever, and weight loss are reported in approximately 30% of patients  Other less frequent symptoms include pruritus and alcohol-induced pain localized over the involved lymph node

Diagnosis and Staging Figure 26.1 illustrates the diagnostic procedure of HL, including suggested examinations and tests.

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Hodgkin Lymphoma Suspected

Complete History and Physical Examination Including history of B symptoms

Excision biopsy (preferred) or core biopsy Consider further immunohistochemical studies

Hodgkin‘s Lymphoma diagnosed

CBC Erythrocyte sedimentation rate (ESR) Lactate dehydrogenase (LDH) Bilirubin Transaminases Creatine

Lab Studies

Recommended Computed tomography of the head and neck thorax, abdomen and pelvis Optional FDG-PET/CT

Fertillity preservation strategies Pregnancy test Lung function tests (for thoracic RT or bleomycin use) Ejection fraction measurement (for anthracycline use) Counseling

Imaging Studies

In Selected Cases

Multidisciplinary Discussion and Management

Bone marrow biopsy is rarely positive, not required in a typical patient with stages I–IIA disease. It should be done if the CBC is abnormal, if there is stages III and IV disease, or if B symptoms are present Staging laparotomy is unnecessary, as clinical staging aided by prognostic factors to arrive at a risk-adapted treatment approach is the standard

Figure 26.1 Proposed algorithm for diagnosis and staging of HL

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Tumor, Node, and Metastasis Staging Evaluating the extent and distribution of disease in HL has an important therapeutic implication, specifically in defining radiation treatment volume. The standard staging classification used is the Ann Arbor Staging System, detailed in Table 26.3. This staging system is widely adopted; it is incorporated into the American Joint Committee on Cancer (AJCC) cancer staging manual (7th edn., 2009). Table 26.3 Ann Arbor Staging Classification

a

Stage

Disease involvement

I

 Single lymph node region (I)  One extralymphatic site (IE)

II

 Two or more lymph node regions on the same side of the diaphragm (II)  Extralymphatic organ or site with regional lymph node involvement on the same side of diaphragm (IIE)

III

 Lymph node regions on both sides of the diaphragm (III)  May have local extralymphatic extension (IIIE)

IV

 Diffuse involvement of one or more extralymphatic organs or sites, with or without associated lymph node involvement; or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

A

 No B symptoms

B

 Presence of at least one of unexplained weight loss (>10% in 6 months prior to staging), unexplained fever >38°C, and/or recurrent night sweats

E

 Extralymphatic diseasea

X

 Bulky tumorb: either a single mass >10 cm, or more than a third of intrathoracic diameter for mediastinal mass

In the Ann Arbor system, an “E” lesion was originally defined as extralymphatic involvement. As Waldeyer’s ring, thymus, and spleen are considered to be lymphatic tissue, they do not constitute an E lesion. However, most clinicians consider these in the group of extranodal sites (E) because of their unique characteristics b The Cotwolds modification of the Ann Arbor Classification used the thoracic diameter defined at the level of T5–6, and also defines peripheral lymph nodes 10 cm or larger to be bulky. In clinical trials protocols, the definition of bulky disease may vary Sources: Edge SB, Byrd DR, Compton CC et al (eds) (2009) AJCC (American Joint Committee on Cancer) cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York; Tsang R, Connors J, Gospodarowicz MG (2008) Specific management problems posed by the primary extranodal presentations: part I – staging and response evaluation. In: Cavalli F et al (eds) Extranodal lymphomas pathology and management, 1st edn. Informa, London

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Lymph node regions described for staging purposes were defined by Kaplan et al and have been in use for over 40 years (Figure 26.2).

Waldeyer ring Cervical, supraclavicular, occipital and pre-auricular Infraclavicular Axillary and pectoral

Mediastinal

Epitrochlear and brachial

Spleen

Mesenteric

Paraaortic

Hilar

Figure 26.2 Lymph node regions. Reprinted with permission from Kaplan H, Rosenberg S (1966) The treatment of Hodgkin’s disease. Med Clin North Am 50:1591–1610, Copyright 1996, Elsevier

Iliac

Inguinal and femoral

Popliteal

Anatomical Regions for the Staging of Hodgkin‘s Disease

Prognosis Although the incidence of HL has been stable in the past two to three decades, the 5-year relative survival rates have improved significantly, from 74% in 1975–1977, to 79% in 1984–1986, and 86% in 1996–2004, likely due to the increasing success in treatments. Additional factors other than the clinical stage, which are important in selecting risk-adapted treatment, have been recognized to influence the outcome of patients with HL. For stages I and II patients, prognostic factors are listed in Table 26.4. By varying combinations of these factors, different groups will subclassify early-stage patients into favorable and unfavorable. For advanced-stage disease, an International Prognostic Score (IPS) has been used (Table 26.5).

EORTC

GHSG

NCIC

Favorable: Stages I–II without risk factors Unfavorable: Stages I–II with ≥1 risk factor(s) Favorable: Stages I–II without risk factors Unfavorable (or intermediate): Stages I–II with ≥1 risk factors (If stage IIB with bulky mass or extranodal disease: considered advanced stage) Favorable: Stages I–II without risk factors Unfavorable: Stages I–II with ≥1 risk factor(s)

Large mediastinal mass ESR ≥ 50 without B symptoms ESR ≥ 30 with B symptoms Age >50 ≥4 Nodal sites involved

Large mediastinal mass ESR ≥ 50 without B symptoms ESR ≥ 30 with B symptoms Extranodal disease ≥3 Nodal sites involved

Histology (MC, LD) ESR ≥ 50 Age ≥ 40 years ≥4 Nodal sites involved Note: Bulky mediastinal disease excluded from trial

HD6

HD7 HD8 HD10 HD11 HD13 HD14

H7 H8 H9 H10

Examples in this chapter

ESR: erythrocyte sedimentation rate; MC: mixed cellularity; LD: lymphocyte depleted; EORTC: European Organization for Research and Treatment of Cancer; GHSG: German Hodgkin’s Study Group, NCIC: National Cancer Institute of Canada Source: Specht L, Hasenclever D (2007) Prognostic factors in Hodgkin’s lymphoma. In: Hoppe R et al (eds) Hodgkin’s lymphoma, 2nd edn. Lippincott Williams & Wilkins, Philadelphia

Study group

Treatment groups

Prognostic (risk) factor

Table 26.4 Early-stage HL: prognostic factors and treatment groups

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Table 26.5 Advanced-stage HL: International Prognostic Score Risk factor

No. of risk factor

Freedom from progression at 5 years (%)

Serum albumin <40 g/l

0

84%

Hemoglobin <105 g/l

1

77%

Male gender

2

67%

Age ≥45 years

3

60%

4

51%

≥5

42%

Stage IV disease 9

White blood cell count ≥15 × 10 /l 9

Lymphocytopenia <0.6 × 10 /l Source: Hasenclever D, Diehl V, Armitage J et al (1998) A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339:1506–1514

Treatment Principle and Practice The management of Hodgkin’s lymphoma has evolved from extended-field radiation alone as the main therapy to a combined-modality approach with chemotherapy and radiation, or chemotherapy alone. As a majority of patients will be cured, there is interest in achieving the best therapeutic ratio by minimizing late toxicity while maintaining effectiveness. Second cancers and cardiac disease are the two main late effects to be considered. General guidelines for HL treatment and commonly used chemotherapy regimens are described in Tables 26.6 and 26.7. Table 26.6 General guidelines for Hodgkin’s lymphoma treatment Extent of disease or subtype

Treatment strategy

Early stage

Standard approach is combined-modality with short-course chemotherapy, followed by moderate-dose radiation targeting involved lymph nodes region(s)

NLPHL

The majority of these patients present at an early stage and have excellent prognoses with radiation alone

Advanced stage

Chemotherapy is the main modality and the focus recently has been on intensifying chemotherapy. There is a limited role for radiation

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Table 26.7 Chemotherapy regimens used for HL Regimen

Medication

Delivery

ABVD

   

Adriamycin Bleomycin Vinblastine Dacarbazine

Each agent is given intravenously on days 1 and 15 (1 cycle), each cycle repeated at 28 days

Stanford V

      

Adriamycin Bleomycin Vinblastine Vincristine Prednisone Mechlorethamine Etoposide

Each agent is given intravenously, except for prednisone

BEACOPP

      

Bleomycin Etoposide Adriamycin Cyclophosphamide Oncovin (vincristine) Procarbazine Prednisone

Each agent is given intravenously, except procarbazine and prednisone

Treatment of Early Favorable Disease The current standard approach is Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) (or equivalent) for two to three cycles, followed by involved-field radiation therapy (IFRT) at 20–30 Gy (Figure 26.3). Tables 26.8 and 26.9 list Stages I–II Favorable HL

ABVD x 2-3 cycles

3-4 weeks

Restaging optional

Options

Comments

ABVD × 2 restaging IFRT at 20 Gy

Based on GHSG HD10

Stanford V × 8 weeks + IFRT at 30 Gy

Stanford G4 trialb

ABVD × 2 cycles PET-CTa if CR, add ABVD × 2–4 cycles

If concerned with late RT toxicity

STLI (including spleen) with 35–40 Gy

If not a candidate for chemotherapy

IFRT 30 Gy a

b

Follow-Up

An integrated PET-CT or a PET with a diagnostic CT is recommended Source: Advani RH, Hoppe RT, Baer DM et al (2009) Efficacy of abbreviated Stanford V chemotherapy and involved field radiotherapy in early stage Hodgkin’s disease: mature results of the G4 trial. Blood 114: Abstract 1670

Figure 26.3 Treatment algorithm for stages I–II favorable HL

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important evidence that supports evolution of practice from extended-field radiation therapy (EFRT) alone to combined-modality therapy. Studies have shown superiority of combined-modality approach over EFRT (Table 26.8). In addition, clinical evidence has demonstrated that combined-modality treatment allows a safe decrease of radiation volume, leading to IFRT (Table 26.9).

Dose of Radiation for Favorable Early-Stage HL When radiation therapy (RT) alone was used, it was common practice to prescribe a dose ranging from 40 to 44 Gy. Further experience and clinical trial results have suggested IFRT of 30–35 Gy after chemotherapy, and more recently, 20 Gy, as supported by the European Organization for Research and Treatment of Cancer (EORTC) H9-F and German Hodgkin Lymphoma Study Group (GHSG) HD10 trials (Table 26.9). The published HD10 trial examined treatment intensity of both ABVD and IFRT, in early favorable-stage HL: 20 Gy after ABVD for two courses appeared to be optimal for early favorable disease. When all four arms were compared (median follow-up of 7,5 years), no significant differences in terms of overall survival (OS), freedom from treatment failure (FFTF), and progression-free survival (PFS) were noted.

Treatment of Early Unfavorable Disease The definition of unfavorable prognosis in the early stage (Figure 26.4) is variable among groups (Figure 26.4). Most of the patients are in this category because of bulky mediastinal masses. The standard treatment is combined modality, with ABVD (or equivalent) for four to six cycles, followed by IFRT to a total of 30 Gy (Table 26.10). Two studies have addressed the question of field size (i.e., IFRT versus EFRT) and showed that EFRT is not required for a combined-modality approach (Table 26.10) (EORTC H8U and GHSG HD8). Different chemotherapy regimens have been tested, and reduction in intensity has not been successful, unless in integrated protocols with radiation such as Stanford V (Table 26.10). The most commonly used chemotherapy regimen is ABVD, initially based on results from advanced HL trials. The optimal number of cycles of chemotherapy has been studied (EORTC H8U and GHSG H9U), and for a combined-modality approach, four cycles of ABVD is the standard, although it is still common practice to give six cycles. Stanford V is also another option. The concept is to use a larger number of effective drugs, each with less cumulative dose than with ABVD or MOPP, in combination with radiation (36 Gy) for disease bulk ≥5 cm in diameter. It was first evaluated in a nonrandomized study, but the recent ECOG 2496 is a phase III study.

348

333

617

SWOG-9133a

EORTC H7-Fb

GHSG HD7c

81% 96%

3-year EFS 3-year OS 10-year EFS 10-year OS 7-year FFTF 7-year OS 5-year EFS 10-year OS

STLI (36–40 Gy) AV ×3 plus STLI

STLI (36–40 Gy) EBVP ×6 plus IFRT (36–40 Gy)

EFRT 30 Gy (IFRT 40 Gy) ABVD ×2 plus EFRT 30 Gy (IFRT 40 Gy)

STLI 36 Gy (IFRT 40 Gy) MOPP/ABV ×3 plus IFRT 36 Gy

74% 92%

67% 92%

78% 92%

EFRT alone

Treatment arms

98% 97%

88% 94%

88% 92%

94% 98%

CT + RT

<0.001 0.001

<0.001 NS

0.01 NS

<0.001 NS

p-value

AV: Adriamycin and vinblastine; EBVP: epirubicin, bleomycin, vinblastine, prednisone; MOPP/ABV: mechlorethamine, vincristine, prednisolone, procarbazine, Adriamycin, vinblastine, bleomycin; EFRT: extended-field radiotherapy, STLI: subtotal lymphoid irradiation, IFRT: involved-field radiotherapy; EFS: event-free survival, OS: overall survival, FFTF: freedom from treatment failure a Source: Press OW, LeBlanc, Lichter AS et al (2001) Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin’s disease. J Clin Oncol 19:4238–4244 b Source: Noordijk EM, Carde P, Dupouy N et al (2006) Combined-modality therapy for clinical stage I or II Hodgkin’s lymphoma: longterm results of the European Organization for Research and Treatment of Cancer H7 randomized controlled trials. J Clin Oncol 24:3128– 3135 c Source: Engert A, Franklin J, Eich HT et al (2007) Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin’s lymphoma: final results of the GHSG HD7 Trial. J Clin Oncol 25:3495–3502 d Source: Ferme C, Eghbali H, Meerwaldt JH et al (2007) Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 357:1916–1927

EORTC/GELA H8-Fd 543

Patients (n)

Trial

Table 26.8 Randomized studies comparing radiotherapy alone (EFRT) versus combined-modality (CT + RT), for early favorable HL

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1370

619

133

Patients (n)

ABVD ×2 plus IFRT 30 Gy ABVD ×2 plus IFRT 20 Gy ABVD ×4 plus IFRT 30 Gy ABVD ×4 plus IFRT 20 Gy

EBVP ×6 plus IFRT 36 Gy EBVP ×6 plus IFRT 20 Gy EBVP ×6 (closed)

ABVD ×4 plus STLI 30 Gy (IFRT 36–40 Gy) ABVD ×4 plus IFRT 36–40 Gy

Treatment arms

98% 98% 8-year OS (NS) 94% 95% 94% 95%

8-year PFS (NS) 85% 87% 88% 90%

4-year OS (NS)

4-year EFS (p < 0.001) 87% 84% (70%)

96% 94%

12-year OS (NS)

OS (p-value)

87% 91%

12-year EFS (NS)

Outcome (p-value)

Source: Bonadonna G, Bonfante V, Viviani S et al (2004) ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol 22:2835 –2841 b Source: Noordijk EM, Thomas J, Ferme C et al(2005) First results of the EORTC-GELA H9 randomized trials: The H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable and unfavorable early stage Hodgkin’s lymphoma. J Clin Oncol 23:Abstract 6505 c Source: Engert A, Plutschow A, Eich HT et al (2010) Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. New Engl J med 363: 640-52

a

GHSG HD10c

EORTC/GELA H9-Fb

Milan favorable plus unfavorable patientsa

Trial

Table 26.9 Clinical evidence for the use of IFRT in combined-modality, early favorable HL

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Stages I–II Unfavorable HL

ABVD x 4–6 cycles

3–4 weeks

Options

Comments

Stanford V × 12 weeks + IFRT at 36Gy

RT to initial sites >5 cma

ABVD × 6 cycles

If concerned with RT toxicity (nonbulky disease). For stage IIB, this option is often considered

BEACOPP × 4 + IFRT at 20Gy or, ABVD x 4 + IFRT at 30 Gy

Based on GHSG HD11

Restaging optional

IFRT 30 Gy Consider 35 Gy for bulky site and/or significant residual mass >5 cm a

Follow-Up

Source: Horning SJ, Hoppe RT, Breslin S et al. (2002) Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: mature results of a prospective clinical trial. J Clin Oncol 20:630–637

Figure 26.4 Treatment algorithm for stages I–II unfavorable HL

A more intensive regimen with cyclophosphamide, doxorubicin, vincristine, bleomycin, etoposide, procarbazine, and prednisone (BEACOPP) is addressed in EORTC H9U and GHSG HD11. Recently, the GHSG has investigated BEACOPP (in escalated doses) for two cycles plus ABVD for two cycles (HD14). Previous studies mentioned for the early unfavorable group are listed in Table 26.10.

Chemotherapy as a Single Modality for Early-Stage HL Some groups have tested chemotherapy alone for early-stage patients, favorable and unfavorable. Combined-modality treatment remains the optimal therapy to achieve the highest control rate with an initial therapy, as mentioned in the National Cancer Comprehensive Network (NCCN) guidelines (Sources: NCCN guidelines for Hodgkin’s disease/lymphoma, v. 2.2009. http://www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf; Herbst C, Rehan F, Brillant C et al (2009) Combined modality treatment improves tumor control and overall survival in patients with early stage Hodgkin’s lymphoma: a systematic review. Haematologica 95:494–500; Meyer RM, Gospodarowicz MK, Connors JM (2005) Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin’s lymphoma: National Cancer Institute of

Patients (n)

1,064

995

808

1,395

Trial

GHSG HD8a

EORTC/ GELA H8Ub

EORTC/ GELA H9Uc

GHSG HD11d

ABVD ×4 plus IFRT 30 Gy ABVD ×4 plus IFRT 20 Gy BEACOPP ×4 plus IFRT 30 Gy BEACOPP ×4 plus IFRT 20 Gy

ABVD ×4 plus IFRT 30 Gy ABVD ×6 plus IFRT 30 Gy BEACOPP ×4 plus IFRT 30 Gy

MOPP/ABV ×6 plus IFRT 36–40 Gy MOPP/ABV ×4 plus IFRT 36–40 Gy MOPP/ABV ×4 plus STLI 36–40 Gy

COPP/ABVD ×2 plus EFRT 30 Gy (40 Gy to bulk) COPP/ABVD ×2 plus IFRT 30 Gy (40 Gy to bulk)

Treatment arms

Table 26.10 Clinical evidence with combined-modality, early unfavorable HL

85% 81% 87% 87%

94% 94% 95% 95%

OS 5-year

6

OS 4-year (NS)

EFS 4-year (NS)

FFTF 5-year

88% 85% 84%

84% 88% 87%

95% 96% 93%

OS 10-year (NS)

EFS 5-year (NS)

89% 94% 91%

91% 92%

OS 5-year (NS)

FFTF 5-year (NS) 86% 84%

OS (p-value)

Outcome (p-value)

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OS (p-value)

COPP/ABV: cyclophosphamide, Oncovin, procarbazine, prednisone; BEACOPPesc: escalated dose of BEACOPP; NS: not significant a Source: Engert A, Schiller P, Josting A et al (2003) Involved-field radiotherapy is equally effective and less toxic compared with extendedfield radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: results of the HD8 trial of German Hodgkin’s Lymphoma Study Group. J Clin Oncol 21:3601–3608 b Source: Ferme C, Eghbali H, Meerwaldt JH et al (2007) Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 357:1916 –1927 c Source: Noordijk EM, Thomas J, Ferme C et al (2005) First results of the EORTC-GELA H9 randomized trials: The H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable and unfavorable early stage Hodgkin’s lymphoma. J Clin Oncol 23:Abstract 6505 d Source: Eich HT, Diehl V, Gorgen H et al (21010) Intensified chemotherapy and dose-reduced radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: Final analysis of the German Hodgkin study group HD11 trial. J Clin Oncol 28: published online ahead of print August 16, 2010

Closed

ABVD ×4 plus IFRT 30 Gy BEACOPPesc x 2 plus ABVD ×2 plus IFRT 30 Gy

Outcome (p-value)

GHSG HD14

Treatment arms

ABVD ×6 plus IFRT 36 Gy if massive mediastinal mass Stanford V for 12 weeks plus IFRT 36 Gy if ≥5 cm mass Closed or macroscopic splenic disease

Patients (n)

ECOG 2496 locally extensive stages I–II and advanced stage

Trial

Table 26.10 (continued)

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Canada Clinical Trials Group and Eastern Cooperative Oncology Group. J Clin Oncol 23:4634–4642). However, chemotherapy with ABVD alone is an option, with disease control for 85–90% of patients (minimum of four cycles; often six cycles are considered if the approach is to give two further cycles beyond achieving complete response) (Sources: Canellos G, Abramson J, Fisher D et al (2010) Treatment of favorable, limited-stage Hodgkin’s lymphoma with chemotherapy without consolidation by radiation therapy. J Clin Oncol 28:1611–1615; Strauss D (2009) The case for chemotherapy only for localized Hodgkin’s lymphoma. Oncologist 14:1225–1231). Using fluorodeoxyglucose/positron-emission tomography (FDG-PET) to select patients in complete remission after chemotherapy alone (or doing an interim FDG-PET scan after two cycles of chemotherapy) may provide a way to decide on eliminating radiation therapy, yet maintain an acceptable low risk of recurrence (risk-adapted therapy). These approaches are under active investigation in phase II and phase III clinical trials. Eliminating radiation in the initial therapy has been postulated to decrease second cancer and late cardiac risk. The trade-off consequences of substituting radiation with more chemotherapy, in terms of acute and late risks of therapy, should be considered for further study. At present, it is most sensible to consider chemotherapy alone when there is high risk expected for radiation late effects (e.g., young women with axillary disease in whom RT will expose significant breast tissue).

Treatment of NLPHL Most patients with NHPHL present in early stage, with disease often limited to a single peripheral site (neck, axilla, or inguinal region). The mediastinum is rarely involved. Stages I and II NLPHL have excellent prognoses after radiation alone. Retrospective data suggest that IFRT is adequate (compared with EFRT) (Tables 26.11 and 26.12). Despite high response rates, late relapse occasionally occurs at sites distant to the original regions of presentation. However, patients often respond to salvage treatment and have a good outcome.

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Table 26.11 Clinical evidence for the treatment of NLPHL Trial

Details

ETFLa

 Treatment received for stages I–II NLPHL  Stage I: 88% RT alone, 12% combined modality  Stage II: 57% RT alone, 38% combined modality  Results for stages I–II  Stage I: FFTF 8 years: 85%, OS 8 years: 99%  Stage II: FFTF 8 years: 71%, OS 8 years: 94%

GHSGb

 Stage IA NLPHL  Treatment options: EFRT, IFRT, or combined modality (CMT)  Results for EFRT/IFRT/CMT  EFRT: 2-year FFTF: 100%, OS: 94%  IFRT: 2-year FFTF: 92%, OS: 100%  CMT: 2-year FFTF: 97%, OS: 96%  Results for EFRT/IFRT/CMT at 4 years: FFTF 93%

a

Source: Diehl V, Sextro M, Franklin J et al (1999) Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin’s Disease. J Clin Oncol 17:776 –783 b Source: Nogova L, Reineke T, Eich HT et al (2005) Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin’s Study Group (GHSG) Ann Oncol 16:1683 –1687 Table 26.12 Treatment options for NLPHL Type

Description

Standard

Comments

IFRT 30 –36 Gy alone

 For stage IA, without risk factors  If gross disease has been completely excised, 30 Gy is sufficient

Options: ABVD ×2–3  IFRT 30 Gy Chemotherapy alone (e.g., ABVD ×6) Observation post-excision

 Considered if stage I with risk factors (bulky, B symptoms) or stage II  For stages III–IV  For highly selected patients with no residual bulk

Treatment of Advanced-Staged Disease Treatment of Stages III–IV Disease The current standard treatment for stages III–IV HL is anthracycline-based chemotherapy with ABVD. It has been shown to be superior to MOPP, and

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other variants of MOPP-containing regimens such as alternating courses of MOPP and ABVD, or a MOPP–ABV hybrid regimen. Among other multidrug regimens tested, BEACOPP has the best results to date, although it is associated with a higher incidence of hematologic toxicity and gonadal damage, compared with ABVD. Therefore, ABVD for six to eight cycles is still the standard treatment, with the alternative approach of Stanford V being acceptable; the BEACOPP regimen holds promise of better disease control, particularly in patients with adverse prognosis, though at the expense of increased treatment toxicity. The Role of Consolidation RT When a complete response has been obtained with ABVD chemotherapy, or its equivalent, there is no role for consolidation RT (Table 26.13). Prior to the routine use of PET for response assessment, it was common practice to recommend consolidation RT for residual abnormalities detected by imaging, or for initially bulky disease.  The use of RT (30–40 Gy) was common practice in the clinical trials examining different chemotherapy regimens. RT enhances local control but has little or no impact on overall survival (Table 26.13).  A meta-analysis and multiple representative trials demonstrated no significant benefits of consolidative RT for disease-free survival (DFS), or OS (Table 26.13). The exception is the trial reported by Lasker et al, from India. However, the patients in this trial included stages I–II patients (58%), and two thirds were of mixed cellularity histology, different from a typical Western population. At present, after a complete response as assessed by FDG-PET scan, there is no definite need for consolidation radiation. Patients with partial response (residual abnormality present on PET) should be considered for biopsy to prove residual disease, and for eligible patients, salvage chemotherapy and autologous stem cell treatment (ASCT). Other Consolidation Therapy Three European trials (conducted by Scotland/Newcastle Group, European Intergroup, and Groupe Ouest-Est d’étude des Leucémies Aigues et autres Maladies du Sang [GOELAMS] in France) tested consolidation ASCT postchemotherapy for selected high-risk HL patients. They showed no improvement in DFS or OS (data not shown). At present, high-dose therapy with ASCT consolidation remains an investigational approach.

Tata Memorial Hospitald

EORTCc

SWOGb

179

250

ABVD ×6 ABVD ×6 plus RT Note: Patients randomized to observation versus RT after CR from chemotherapy

PR patients after CT: MOPP-ABV ×6 plus RT (30 –40 Gy)

421

Note: Patients randomized to observation versus RT after CR from chemotherapy

MOPP-ABV ×8 MOPP-ABV ×8 plus RT (24 Gy) Note: Patients randomized to observation versus RT after CR from chemotherapy

278

CMT versus CT: additional RT (same CT) CMT versus CT: RT versus additional CT

1,740 (14 trials)

Meta-analysisa

MOP-BAP ×6 MOP-BAP ×6 plus RT (20 Gy)

Treatment arms

Patients (n)

Trial Same (NS)

−8% for RT (0.045) OS 5 years (NS)

11% better for RT (0.0001) Same (NS) RFS 5 years (NS)

89% 100%

OS 8 years (0.002)

EFS 8 years (0.01) 76% 88%

87%

91% 85%

OS 5 years (NS)

79%

84% 79%

EFS 5 years (NS)

Subgroup analysis showed RT associated with longer remission duration in NS histology and bulky disease

79% 86%

OS 10 years

Tumor control 10 years

66% 74%

OS (p-value)

Outcome (p-value)

Table 26.13 Representative randomized trials of consolidation radiation therapy after chemotherapy for advanced HL

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1,449

GHSG HD12f

BEACOPP ×8 BEACOPP ×8 plus RT 30 Gy Note: 4-arm study, BEACOPP was increased dose in 4 cycles, or 8 cycles Residual disease if judged to be active by a panel were given RT (in 13% of reviewed patients)

OS 5 years (0.01*) 85% 94% 88% 78%

88% 95%

FFTF 5 years (NS)

92% (all patients) Not reported separately

OS 5 years (NS)

*Compared ABVPP ×8 versus ABVPP ×6 plus RT

74% 67% 78% 66%

EFS 5 years (NS)

Source: Loeffler M, Brosteanu D, Hasenclever D et al (1998) Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin’s disease. J Clin Oncol 16:818 –829 b Source: Fabian CJ, Mansfield CM, Dahlberg S et al (1994) Low-dose involved field radiation after chemotherapy in advanced Hodgkin’s disease. Ann Int Med 120:903 –912 c Source: Aleman BMP, Raemaekers JMM, Tirelli U et al (2003) Involved-field radiotherapy for advanced Hodgkin’s lymphoma. New Engl J Med 348:2396 –2406 d Source: Lasker S, Gupta S, Vimal MA et al (2004) Consolidation radiation after complete remission in Hodgkin’s disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: Is there a need? J Clin Oncol 22:62–68 e Source: Fermé C, Sebban C, Hennequin C et al (2000) Comparison of chemotherapy to radiotherapy as consolidation of complete or good partial response after six cycles of chemotherapy for patients with advanced Hodgkin’s disease: results of the Groupe d’études des Lymphomes de l’Adulte H89 trial. Blood 95:2246 –2252 f Source: Eich H, Gossmann A, Engert A et al (2007) A contribution to solve the problem of the need for consolidative radiotherapy after intensive chemotherapy in advance stages of Hodgkin’s lymphoma – analysis of a quality control program initiated by the radiotherapy reference center of the German Hodgkin’s Study Group. Int J Radiat Oncol Biol Phys 69:1187–1192

a

418

GELA H89e

MOPP/ABV ×8 ABVPP ×8 MOPP/ABV ×6 plus RT ABVPP ×6 plus RT Note: Patients with CR and PR ≥ 75% after 6 cycles of CT were randomized to 2 more cycles of CT, or STNI 30 –40 Gy

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PET for Therapy Response Assessment Posttreatment Response Evaluation After completion of therapy, computed tomography (CT) scans often reveal residual mass. Accurate assessment of the presence of residual disease is important because complete response (CR) is required for a curative outcome. PET has ability to distinguish between viable tumor and fibrosis in residual mass, with specificity of 90–95%. In fact, changes in tissue function often predate volume changes. For this reason, information provided by PET has been recently incorporated in the lymphoma guidelines for response evaluation after completion of the initial treatment program. Revised response criteria are detailed in Table 26.14. Table 26.14 Response criteria for lymphoma, based on initial International Workshop Criteria (IWC) and more recent revised response criteria with PET Outcome

IWCa

Revised IWCb,c

Complete response (CR)

No detectable disease; LN >1.5 cm must decrease to ≤1.5 cm

CR, CRu, PR, or SD by IWC and PET negative Bone marrow negative

Unconfirmed complete response (CRu)

LN >1.5 cm, SPD decrease >75% Indeterminate bone marrow

No longer exists

Partial response (PR)

SPD regressed >50%

CR, CRu, or PR by IWC and PET positive in ≥1 previously affected site

Stable disease (SD)

SPD decrease ≤50%, but not progressive disease

SD by IWC and PET positive in previously affected sites

Progressive disease (PD)/ relapse

New lesion or SPD increase >50% from nadir of any LN

PD by IWC and PET positive on the new or increased lesion if >1.5 cm

LN: lymph node; SPD: sum of products of the greatest diameters a Source: Cheson BD, Horning SJ, Coiffier B et al (1999) Report of an International Workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17:1244 –1253 b PET is considered positive if uptake is greater than mediastinum blood pool (for lesion >2 cm) or if uptake greater than local background (for lesion < 2 cm) c Cheson BD, Pfistner B, Juweid ME et al (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 5:579 –586

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Many studies have demonstrated that PET performed after conventional treatment is highly predictive of PFS and OS in HL. Two examples (among many) are detailed in Table 26.15. The role of PET in response assessment studies has been done after completing conventional treatment. Therefore, modifying initial treatment plan by abbreviating CT or omitting RT, based on a PET obtained before the end of the planned treatment, is still considered an experimental approach. Table 26.15 Selected studies on PET in HL (response assessment) Study

Stage

Details

Weihraucha All stages

 Question: assess diagnostic and prognostic value of PET in HL patients with residual mediastinal masses after completed therapy  28 patients with a residual mediastinal mass after chemotherapy, at least 2 cm  19 patients after initial therapy and 9 patients after salvage CT  Negative predictive value (PET negative and remission) at 1 year: 95%  Positive predictive value (PET positive and relapse) at 1 year: 60%

GHSG HD15b

 Question: assess negative predictive value of PET in advanced stage  817 patients with stage IIB (extranodal or bulky), III, or IV included  Randomization between different regimen of BEACOPP-based CT  3 arms (BEACOPP ×8, BEACOPPesc ×6, BEACOPP14 ×6)  311 patients had PET to assess residual mass (≥2.5 cm)  PET done after 6 –8 cycles of CT  Local RT only for patients with PR and PET+ (n = 63)  PFS: 96% for PET negative and 86% for PET positive  NPV for PET: 94%  Definition NPV: PET negative and no progression/relapse/RT for 12 months ▶

Advanced stage

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Table 26.15 (continued) Study

Picardic

Stage

Details

Early stage, bulky

 Question: role of consolidation RT in patients with residual mass posttreatment that is PET negative  260 patients received VEBEP ×6, median follow-up of 40 months  160 patients had residual mass (median: 2.2 cm) with a PET negative  PET done after 6 cycles of CT  Randomization for those 160 patients  RT 32 Gy to initial bulky site  No RT  Treatment failure  RT: 11/80 (14%), in involved bulky site, within 18 months  No RT: 2/80 (2.5%)  PET accuracy to exclude relapse in patients not receiving RT: 86%  PET false-negative results: 14%  The study suggested that the addition of RT improved event-free survival (EFS)

VEBEP: vinblastine, etoposide, bleomycin, epirubicin, prednisone; BEACOPPesc: cyclophosphamide, doxorubicin, vincristine, bleomycin, etoposide, procarbazine, prednisone, filgrastin (G-CSF) a Source: Weihrauch M, Re D, Scheidhauer K et al (2001) Thoracic positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin’s disease. Blood 98:2930 –2934 b Source: Kobe C, Dietlein M, Franklin J et al (2008) Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin’s lymphoma. Blood 112:3989 –3994 c Source: Picardi M, De Renzo A, Pane F et al (2007) Randomized comparison of consolidation radiation versus observation in bulky Hodgkin’s lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymph 48:1721–1727

Early-Interim-Response Assessment There is evidence that early PET (done after few cycles of CT) is prognostic in early- and advanced-stage HL, implying a high negative predictive value (Table 26.16). However, there is no randomized evidence that having response-adapted treatment, according to the results of early-interim PET, will result in superior outcomes.

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Table 26.16 Selected studies on PET in HL (early-interim assessment) Study

Hutchingsa

Gallaminib

Stage

Details

All stages

 Question: assess value of early-interim PET for PFS in HL  85 patients, planned to receive CT alone or combined-modality, according to stage, median follow-up of 3.3 years  PET done after 2–3 cycles of chemotherapy (mostly ABVD)  Relapse  62% for PET-positive patients (8/13)  6% for PET-negative patients (4/72)  5-year PFS: 38.5% for PET positive and 91.5% for PET negative  Majority of early-stage patients early-interimPET positive remained in remission, while all advanced-stage patients early-interim-PET positive relapsed within 2 years

All stages

 Question: assess prognostic role of early-interim PET and IPS in advanced-stage HL  260 patients (190 stages IIB–IVB and 70 stages IIA plus adverse prognosis factors), median follow-up of 2.2 years  PET done after ABVD ×2  No treatment changes according to results of interim PET  Treatment failure  86% for PET-positive patients (43/50)  5% for PET-negative patients (10/210)  2-year PFS: 12.8% for PET positive and 95% for PET negative  In multivariate analysis, prognostic value of interim PET was superior to IPS ▶

The concept of response-adapted therapy is attractive. It represents a further progressive approach from making treatment decision on well-established and validated prognostic factors, mentioned in Tables 26.4 and 26.5. Response to treatment is likely an important prognostic factor, as well, for the individual patient.

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Table 26.16 (continued) Study

Terasawac

Stage

Details

Advanced stage

 Question: to review the prognostic accuracy of PET in interim response assessment of patients with advanced HL or DLBCL  13 studies involving 360 advanced-stage HL met inclusion criteria  Few unfavorable-risk patients (<10% with IPS >3)  PET done mostly after 2 cycles of ABVD  Sensitivity/specificity were calculated, based on PET results and whether they experienced treatment failure  Results for HL: PET sensitivity of 81% (95% CI 0.72 –0.89) and PET specificity of 97% (95% CI of 0.94 –0.99)  PET performed after few cycles of standard chemotherapy suggested that it is a reliable prognostic test to identify poor responders

IPS: International Prognostic Score a Source: Hutching M, Mikhaeel NG, Fields PA et al (2005) Prognostic value of interim FDG-PET after two or three cycles of chemotherapy in Hodgkin’s lymphoma. Ann Oncol 16:1160 –1168 b Source: Gallamini A, Hutchings M, Rigacci L et al (2007) Early interim 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian–Danish study. J Clin Oncol 25:3746 –3752 c Source: Terasaw T, Lau J, Bardet S et al (2009) Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin’s lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 27:1906 –1914

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Until mature results from ongoing trials with early-interim-PET response assessment are available for early-stage (Table 26.17) and advanced-stage HL, modification of treatment (decreasing number of CT cycles if PET−, or switching for a more aggressive protocol of PET+) should be regarded as experimental.

Table 26.17 Selected studies on PET in HL (ongoing trials in early stage) Study

Stage

Details

UK NCRI phase IIIa

Early-stages IA/IIA, not bulky

 Question: assess the role of treatment modification with early-interim PET  PET done after ABVD ×3  Randomization for PET-negative patients  RT  No RT  If PET positive: 4th ABVD plus IFRT

GHSG HD16, ongoing phase III

Early-stages I–II without risk factor, such as: Extranodal ≥3 sites

 Question: assess the role of treatment modification with early interim PET (performed after ABVD ×2)  Randomized patients to  Standard arm: 2ABVD plus IFRT  Experimental arm: – If PET positive: 2 ABVD, plus IFRT 30 Gy – If PET negative: 2 ABVD no RT

Early stage Favorable group (F) Unfavorable group (U)

 Question: assess the role of treatment modification with early interim PET (performed after ABVD ×2)  Randomized patients to  Standard arm  F: 3 ABVD plus INRT 30 Gy  U: 4 ABVD plus INRT 30 Gy  Experimental arm: treatment adapted based on PET results  UF if PET negative after 2 cycles: 2 more cycles, no RT  UF if PET negative after 2 cycles: 4 more cycles, no RT  F or UF if PET positive after 2 cycles: 2 BEACOPPesc plus INRT 30 Gy

EORTC H10/GELA ongoing phase III

BEACOPPesc: cyclophosphamide, doxorubicin, vincristine, bleomycin, etoposide, procarbazine, prednisone, filgrastin (G-CSF); F: favorable; UF: unfavorable a Source: Radford JA, Barrington SF, O’Doherty MJ et al (2007) Interim results of a UK NCRI randomized trial comparing involved-field radiotherapy with no further treatment after 3 cycles ABVD and a negative PET scan in clinical stages IA/IIA Hodgkin’s lymphoma. Haematologica 92:Abstract C023

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Treatment of Refractory and Relapsed HL Definition  Refractory HL progression of disease during initial therapy or within 3 months of completion of treatment  Relapsed HL disease progression after a CR to primary treatment (early relapse is further defined as within 12 months of CR)  Initial treatment for HL results in good tumor control, but a significant number of patients experience either a tumor refractory to therapy or subsequent relapse. Second-line therapy is usually required for:  10–15% of patients with initial localized disease  25–40% of patients with initial advanced-stage disease Prognostic factors for this group of patients are listed in Table 26.18. Patients relapsing after a first complete remission still have the opportunity of being cured with adequate salvage treatment. Different options exist depending on the first-line therapy received:  Conventional chemotherapy (if initial treatment was RT alone)  RT alone as salvage therapy  Salvage high-dose chemotherapy (HDT) plus ASCT (Figure 26.5): standard of care if initially treated with chemotherapy. DFS rate at 5 years ranges from 35 to 55% after HDT with ASCT. Table 26.18 Prognostic factors for outcome after high-dose chemotherapy and stem cell transplantation for refractory or recurrent disease Factor

Description Interval between initial therapy and relapse

Sensitivity of the disease

Response to salvage therapy Number of failed prior regimens

Disease burden before salvage treatment

Disease stage at the time of recurrence Bulky disease at salvage Extranodal relapse

Constitutional symptoms

Presence of symptom B

Other factors

Low hemoglobin, serum albumin, low performance status

Source: Josting A, Franklin J, May M et al (2002) New prognostic score based on treatment outcome of patients with relapsed Hodgkin’s lymphoma registered in the database of the German Hodgkin’s lymphoma study group. J Clin Oncol 20:221–230

Chapter 26 Hodgkin’s Lymphoma

Second-line therapy for cytoreduction (e. g. with DHAP)

Chemosensitive disease? Yes Salvage high-dose therapy (HDT) with chemotherapy (no role for TBI)

Stem cell collection

799

Figure 26.5 Typical schema for a salvage treatment regimen with HDT and ASCT. DHAP dexamethasone, cytosine arabinoside, cisplatin. Sources: Linch DC, Winfield D, Goldstone AH et al (1993) Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomized trial. Lancet 341:1051–1054; Schmitz N, Pfistner B, Sextro M et al (2002) Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomized trial. Lancet 359:2065–2071

Autologgous stem cell transplant (ASCT)

Follow-Up

Radiation Incorporated into HDT plus ASCT When HDT and ASCT is the salvage approach used, RT can still be incorporated in order to enhance disease control. Timing of radiation (pre-ASCT or post-ASCT), extent of radiation field, and dose vary among institutions. For example, Memorial Sloan Kettering Cancer Center gives pre-ASCT radiation therapy as follows:  IFRT at 18 Gy, followed by total nodal irradiation (TNI) to a further 18 Gy, twice a day, within a 2-week period before ASCT  If previous RT, TNI not administered  DFS 50% at 6.5–10 years (Source: Yahalom J (1995) Integrating radiotherapy into bone marrow transplantation programs for Hodgkin’s disease. Int J Radiat Oncol Biol Phys 33:525–528).

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Other institutions will consider RT post-ASCT. RT will be given if previous disease ≥5 cm, disease responding incompletely to salvage CT, or residual PET positive lesions after ASCT. RT given 2–3 months after ASCT, the volume individualized according to patient’s characteristics and previous treatment (range, 25–35 Gy), with DFS of 30–55% at 5 years.

Role of Radiation as Salvage Treatment HL tends to recur in previously involved sites, especially if it was bulky. Before the routine use of HDT and ASCT, selected patients who failed initial CT were treated with salvage RT. Radiation techniques used varied from involved field to extended field, such as mantle field or even total lymphoid irradiation (TLI). Salvage RT results (Table 26.19) cannot be compared with ASCT outcomes, but they do illustrate that judicious use of RT remains a salvage option for selected patients, especially for:  Patients not eligible for ASCT because of age or comorbidities  Patients with favorable clinical characteristics with long disease-free interval, predominantly nodal distribution of disease, and absence of systemic symptoms Table 26.19 Largest published experience of salvage RT, from GHSG GHSG protocols

Refractory/ recurrent patients

RT as salvage treatment (n = 100)

Response rate

5-year FFTF/OS

From 1988 to 1999 n = 4,754

n = 624 (after initial therapy)

RT median dose: 40 Gy IFRT: 37% EFRT: 63% (Mantle: 43%, inverted Y: 8%, TLI: 12%)

81% (CR 77%)

FFTF: 28% OS: 51%

Source: Josting A, Nogova L, Franklin J et al (2005) Salvage radiotherapy in patients with relapsed and refractory Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 23:1522–1529

Radiation Therapy Technique Different types of radiation fields used in HL are listed in Table 26.20. Dose of RT is detailed for individual subtypes in previous sections.

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Table 26.20 Radiation therapy technique definitions Field

Definition

Extended field (EFRT)

Implies inclusion of multiple involved and uninvolved LN regions

Total lymphoid irradiation (TLI)

Includes all LN regions on both sides of diaphragm

Sub-total lymphoid irradiation (STLI)

Includes all LN regions on both sides of diaphragm, except pelvic LNs (iliac/inguinal/femoral LN)

Mantle

Includes all LN regions above the diaphragm: bilateral cervical/supraclavicular/submental/axillary nodes, mediastinal and bilateral hilar nodes

Inverted-Y

Includes all LN regions below the diaphragm: para-aortic, bilateral iliac/inguinal-femoral nodes, with or without spleen

Regional

Includes the involved LN region plus at least one adjacent clinically uninvolved region If extranodal: includes the involved organ plus uninvolved adjacent LN region

Involved-field (IFRT)

Includes involved nodes before chemotherapy and its entire nodal region If extranodal: includes the involved organ alone, if no LN involvement

Includes the originally involved nodes before chemotherapy. Concept recently introduced by the EORTC. Preliminary data Involved LN (INRT) available Requires FDG-PET before and after chemotherapy for RT planning, with reproducible patient positions Sources: Yahalom J, Hoppe R, Mauch P (2007) Prognostic factors in Hodgkin’s lymphoma. In: Hoppe R et al (eds) Hodgkin’s Lymphoma, 2nd edn. Lippincott Williams & Wilkins, Philadelphia; Girinski T, van der Maazen R, Specht L et al (2006) Involvednode radiotherapy (INRT) in patients with early Hodgkin’s lymphoma: concepatients and guidelines. Radiother Oncol 79:270 –277

Involved-Field RT As mentioned previously, IFRT is the most commonly used technique. It is implicit that IFRT targets an area smaller than the classical extended field. However, there was heterogeneity among experts regarding volumes and field-borders definition. Yahalom and Mauch have developed guidelines, published in 2002, for the Cancer and Leukemia Group B (CALGB).

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Table 26.21 lists the main IFRT treatment areas, and Table 26.22 details the set-up and treatment steps of RT for HL.

Table 26.21 Main IFRT treatment regions and radiation treatment coverage Region or organ

Field coverage

Supraclavicular

Unilateral or bilateral cervical/supraclavicular region

Mediastinum

Including bilateral medial supraclavicular LNs and lung hila

Axilla

Including the supraclavicular and infraclavicular LNs

Spleen

Spleen

Para-aortic LNs

Para-aortic LNs

Pelvis

Inguinal/femoral/external iliac regions

Source: Yahalom J, Mauch P (2002) The involved field is back: issues in delineating the radiation field in Hodgkin’s disease. Ann Oncol 13:79 –83

IFRT for Mediastinal Disease In HL, the mediastinum is the most frequent site of treatment for IFRT. Figure 26.6 illustrated a “modified mantle field” for mediastinal disease. A common IFRT target volume for mediastinal disease would have included bilateral cervical lymph nodes and the mediastinum, including the lung hila. Therefore, two-dimensional (2D) limits for this patient would have been:  Superior border: above the lower tip of mastoid process  Inferior border: 5 cm below the carina However, since the subclinical disease can usually be addressed by chemotherapy, entire nodal region coverage is superfluous, and the coverage, or this specific case in Figure 26.6, can be modified as follows:  Exclude the left upper cervical lymph nodes  Do not irradiate the entire right nodal region by excluding the highest right cervical nodes when disease is located in supraclavicular fossa only – Superior border: larynx level  Exclude subcarinal lymph node, when disease is confined to superior mediastinum (as in this case) – Inferior border: according to prechemotherapy volume – Lung hila intentionally not targeted Rationales of such arrangement include reducing salivary gland and oral cavity toxicity, sparing the heart and lungs, and limiting the dose to breast tissue.

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Table 26.22 Steps for radiation therapy planning  Evaluation before RT  Dental evaluation if upper neck treated (above larynx)  Sperm banking if pelvic nodes treated (if fertility issue)  Pulmonary function test (if clinically indicated)  Position: supine  Head in hyperextension if upper neck treated  Head in neutral position otherwise  Arms akimbo if axilla treated (option: arms up)  Arms at sides otherwise  Frog leg position if inguinal nodes treated  Immobilization: Device may vary between institutions  Mask for head and neck  Body immobilization system for pelvis  Planning: CT-based simulation  If mediastinum treated, both lungs need to be scanned (for DVH)  Pre-chemotherapy and post-chemotherapy information from CT and PET is important  Option: fusion with FDG-PET (before/after CT)  Intravenous contrast optional  Volumes  GTV: Usually not present post chemotherapy, if complete response – Some residual thickening is often noted with HL (sclerosis)  CTV: In general, include prechemotherapy disease plus the whole nodal region(s) that contained the involved LN – For a mediastinal mass, post-CT transverse diameter is used – For para-aortic disease, post-CT transverse diameter is also used  PTV: varies between institutions – Depends on immobilization, reproducibility, organ motion – Example: 10-mm margin, CTV to PTV  Beam arrangement: often parallel opposed pair fields (anterior plus posterior field)  Field can be shaped with multileaf collimation  Use of intensity-modulated radiation therapy (IMRT) can be considered for more conformal therapy  Respiratory gating can be an option for special cases (e.g., a wide mediastinal target) – Dose: may vary according to the clinical situation – Plan evaluation based on ICRU 50 and 62; PTV should receive a dose between 95 and 107% of prescribed dose – However, because of difference with patient separation within the field, dose homogeneity may be as high as 10% – Tolerance of organs at risk should be respected

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a

b

Norm. Volume

c Dose Volume Histogramm 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

500

1000

1500 2000 Dose (cGy)

2500

3000

3500

ROI Statistics

Line Type ROI Both lungs Breast left Breast right CTV Heart PTV

Trial

Min.

Max.

Mean

Std. Dev.

% Outside crid

O. Final O. Final O. Final O. Final O. Final O. Final

6.5 2.0 2.6 649.8 13.4 640.8

3194.1 3103.5 3192.5 3202.5 2982.1 3205.4

778.8 94.5 276.2 3017.2 466.7 3000.5

1091.5 299.3 658.0 59.6 776.7 82.9

0.00 % 0.00 % 0.00 % 0.00 % 0.00 % 0.00 %

Figure 26.6 a–c Radiation treatment field for a 33-year-old woman with unfavorable stage II HL. She had presented with bulky mediastinal mass and a right supraclavicular node. Post-ABVD × 6, with CR, and minor anterior mediastinal thickening. a Digitally reconstructed radiograph (DRR), showing the IFRT field with coverage of mediastinum, bilateral supraclavicular area and inferior neck (upper limit is larynx level). The clinical target volume (CTV) is in blue, planning target volume (PTV) is in green and carina is in light blue. b Dose distribution of this same field (axial view, at the level of carina), for a prescribed dose of 3,000 cGy. The minimum target dose of 2,850 cGy is illustrated by the yellow isodose line (−5%). Right and left breast are in pink and purple, respectively. c Dose–volume histogram (DVH) for CTV, PTV, and organs at risk. Note that 20% of bilateral lungs receive a dose of over 20Gy

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IFRT for Cervical Disease Typical IFRT field for cervical lymph adenopathy from HL is to treat the ipsilateral cervical/supraclavicular region with an anterior–posterior/posterior–anterior (AP/PA) beam arrangement. For lesions positioned close to critical normal organs (e.g., parotid gland), the intensity-modulated RT (IMRT) technique can be used to reduce dose to the uninvolved right parotid and limit higher-dose exposure to the oral cavity. However, the IMRT technique will increase the amount of normal tissues receiving lower doses. Figure 26.7 illustrates a case of cervical lymph nodal disease treated with IMRT. Other situations where IMRT considered in HL may include:  Mediastinal mass with significant lateral extension along chest wall  Recurrent disease at or near a previous irradiated area

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Figure 26.7 a–d Radiation treatment field for a 20-year-old man with favorable stage I HL, right cervical region. Initial disease was high in his neck, just below the parotid. He was treated with 3 cycles of ABVD and was planned for RT. Diagnostic CT scan showing right-neck Hodgkin’s lymphoma, axial perspective, at level of parotids gland a and hyoid bone b. Malignant lymph nodes in black and right parotid in white. c-d Dose distribution in axial perspective, at level of parotid c and hyoid bone d, for a prescribed dose of 30 Gy. CTV is in color wash blue. Right and left parotids are in red and pink, respectively. The oral cavity is in color wash light blue. Those organs at risk are contoured to limit the dose they receive

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e Dose Volume Histogramm

1.0 0.9

Norm. Volume

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

500

1000

1500

2000

2500

3000

3500

4000

Dose (cGy) ROI Statistics

Line Type ROI CTV Oral Cavity PTV Parotid left Parotid right Spinal Cord

Trial

Min.

Max.

Mean

Std. Dev.

% Outside crid

O. Final O. Final O. Final O. Final O. Final O. Final

1856.7 208.5 449.1 22.1 341.8 882.9

3437.4 3227.8 3463.7 125.6 3182.7 1984.2

3118.3 1558.2 3062.3 65.9 1938.0 1613.8

80.9 596.8 154.8 18.5 637.2 154.6

0.00 % 0.00 % 0.00 % 0.00 % 0.00 % 0.00 %

Figure 26.7 e DVH for CTV, PTV, and organs at risk. With IMRT, the dose to right parotid can be reduced, with a mean of 19.38 Gy

Normal Tissue Tolerance and Side Effects Radiation doses used in combined-modality protocols are well within the tolerance of normal tissues in virtually all supradiaphragmatic areas.

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Follow-Up Response to treatment is documented 6–12 weeks after completion, with repeat imaging and clinical evaluation. The regression of disease may be slow, and a residual fibrotic mass may persist after treatment. FDG-PET/CT is used as a standard test to document CR, although thymic rebound or subclinical radiation pneumonitis may lead to abnormalities on FDG-PET after mediastinal RT if done too early (<12 weeks from RT). The yield of routine tests in asymptomatic patients is low for subsequent follow-up. Relapse of HL is usually detected because of patients presenting with symptoms, rather than by routine screening, so greater emphasis should be placed on patient education rather than on routine tests. Routine CT or PET imaging for follow-up has not been shown to be cost-effective. Table 26.23 summarizes the follow-up schedule. Table 26.23 Follow-up schedule and examinations Schedule

Frequency

Years 0–2

 Every 3–4 months

Years 3–5

 Every 6 months

Years 5+

 Annually

Examinations History and physical

 History and physical: focus on lymphatic tissues

Laboratory tests

 CBC, ESR, TSH (if thyroid gland radiated)

Imaging

 Chest x-ray

Annual counseling

 Physical and psychological health, including physical activity, reproduction, cardiovascular fitness, and risk of second malignancy

Annual multidisciplinary care

 Ensure appropriate advice and care from family physician or cardiologist regarding: cardiac risk factors and strategies to minimize risk (smoking cessation, blood pressure control, cholesterol, lipids, exercise, weight control), particularly for patients who received mediastinal RT. Consider cardiac stress test for 10-year survivors

Annual screening for second cancer

 Screening for: colorectal cancers, lung cancers (particularly if patient uses tobacco) For women who had RT to breast tissue: mammography and/or MRI (at recommendation of radiologist or ACR guideline) starting 7–8 years posttreatment

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Table 26.24 Commonly observed acute, subacute, and late toxicities in RT for HL Side effect type

Manifestation

Acute

 Fatigue, nausea, skin reaction, esophagitis, laryngitis, and possible myelosuppression  Most symptoms will be mild and always reversible

Subacute

 Lhermitte’s syndrome (electric shock–like sensation from the neck, radiating down the spine, or upper extremities), which can start 2–4 months after RT and may last up to 6 –8 months  Prolonged fatigue  Radiation pneumonitis is uncommon, unless large volume of lung tissue is exposed  For situations where V20 > 36–40%, and/or median lung dose >15 Gy, the risk of pneumonitis is approximately 5 –10%

Delayed toxicity

 The most common delayed toxicity is hypothyroidism  Other significant late effects of therapy include cardiac disease and primary second malignancies  Second malignancies are particularly important for patients treated for limited stage at a young age, with an expected high cure rate for the HL, hence putting them at risk for the development of second cancers  Overall, breast, lung, and colorectal cancers account for approximately half of the excess risk of second cancers

Commonly observed treatment induced adverse effects are listed in Table 26.24. A detailed discussion of late effects of therapy is beyond the scope of this chapter, but it is likely that with present reduction of radiation volumes and dose, the actual risk of second cancers from IFRT will be lower than what is reported in the literature thus far. For patients who are at risk, a screening program should be implemented in the follow-up schedule.

27

Multiple Myeloma and Plasmacytoma Wee Joo Chng1 and Ivan W.K. Tham2

Key Points  Multiple myeloma is the second most common hematological malignancy.  In almost all cases of myeloma, there is a preceding monoclonal gammopathy of undetermined significance phase.  Diagnosis of multiple myeloma requires demonstration of monoclonal proteins or clonal plasma cells, with symptomatic manifestation.  Mainstay of multiple myeloma treatment remains high-dose therapy with stem cell transplantation. Therefore, the first therapeutic decision point is whether the patient is a transplant candidate.  Over the last decade, three novel agents, thalidomide, lenalidomide, and bortezomib have been approved by the US Food and Drug Administration (FDA) for treatment of multiple myeloma.  The use of novel agents prior to transplantation and as maintenance therapy has greatly improved outcome of myeloma patients. Similarly, for non–transplant-eligible patients, the incorporation of novel agents into their treatments has greatly improved survival.  Radiation therapy is useful in treating symptomatic bone disease and plasmacytomas.

1

Wee Joo Chng, MD () Email: [email protected]

2

Ivan W.K. Tham, MD Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_10, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Multiple myeloma (MM) is a clonal plasma cell proliferative disorder. Approximately 19,900 new MM cases and 10,700 MM deaths occur in the USA annually. Almost all cases of MM are preceded by a premalignant condition called monoclonal gammopathy of undetermined significance (MGUS). MM is about two- or threefold more common in African-Americans as compared with Caucasians, with an Asian prevalence about half that of the Caucasians. There is a 1.7-fold significantly increased risk for MM in relatives of MM cases as compared with relatives of controls. In addition, compared with relatives of controls, relatives of MGUS patients were found to have a significantly increased risk of MGUS (RR = 2.8) and MM (RR = 2.9) (Table 27.1).

Table 27.1 Relative risk of MM and MGUS in first-degree relatives of patients with MM or MGUS Study

Relative risk of MM among first-degree relatives

Relative risk of MGUS among first-degree relatives

Swedish study

1.67

2.96

Mayo Clinic study

ND

2.00

Swedish study

2.90

2.80

Mayo Clinic study

ND

3.30

MM patients

MGUS patients

Sources: Landgren O, Linet MS, McMaster ML et al (2006) Familial characteristics of autoimmune and hematologic disorders in 8,406 MM patients: a population-based case-control study. Int J Cancer 118:3095–3098; Landgren O, Kristinsson SY, Goldin LR et al (2009) Risk of plasma cell and lymphoproliferative disorders among 14,621 first-degree relatives of 4,458 patients with MGUS of undetermined significance in Sweden. Blood 114:791–795; Vachon CM, Kyle RA, Therneau TM et al (2009) Increased risk of monoclonal gammopathy in first-degree relatives of patients with MM or MGUS of undetermined significance. Blood 114:785–790

MGUS MGUS is one of the most common premalignant disorders in Western countries, with a prevalence of 3.2% in the Caucasian population, 50 years of age or older. It is characterized by the presence of a monoclonal immunoglobulin (Ig) (M protein) without evidence of MM or other lymphoproliferative malignancies. MGUS patients have an average 1% annual risk of developing a lymphoproliferative malignancy. A risk stratification model for MGUS pro-

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gression has been developed based on the high-risk factors as presented in Table 27.2. Table 27.2 Risk of progression from MGUS to MM Number of risk factora

Risk of progression at 20 years (%)

0

5%

1

21%

2

37%

3

58%

a

Risk factors include abnormal serum free light chain ratio, non-IgG MGUS, and an elevated serum M-protein value >15 g/l Source: Rajkumar SV, Kyle RA, Therneau TM et al (2005) Serum free light chain ratio is an independent risk factor for progression in MGUS of undetermined significance. Blood 106:812–817

Smoldering MM The probability of progression to MM or amyloidosis has been reported to be 54% at 5 years, 66% at 10 years, and 73% at 15 years of follow-up, with a median time to progression of 4.8 years. The overall risk of progression was 10% per year for the first 5 years, 3% per year for the next 5 years, and only 1% per year beyond 10 years of follow-up. A risk-stratification model based on three risk factors has been proposed (Table 27.3). Table 27.3 Risk of progression from SMM to MM Number of risk factora

Median time to progression (years)

1

10

2

5

3

2

Risk factors include bone marrow plasma cells 10%, serum M protein 3 g/dl, and serum Ig-free light chain ratio either <0.125 or >8 Source: Dispenzieri A, Kyle RA, Katzmann JA et al (2008) Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 111:785–789 a

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Pathology MM is characterized by clonal expansion of plasma cells, which secrete monoclonal protein. The most common monoclonal protein is IgG (52%), followed by IgA (21%). IgD myeloma is rare (2%). Sixteen percent of patients have light chain–only myeloma, and only 3% have non-secretory MM. There is often an accompanying immunoparesis (91%). Four disease-initiating genetic abnormalities define the main genetic subtypes of myeloma. These include t(4;14) in 15%, t(11;14) in 15%, t(14;16) in 5%, and hyperdiploidy in 60% of cases. Solitary plasmacytomas of bone and extramedullary plasmacytomas are tumors with clonal plasma cells within or outside the bone, respectively.

Diagnosis, Staging, and Prognosis Clinical Presentation The clinical presentation of MM is summarized in Table 27.4, with the myeloma-related organ or tissue impairment listed in Table 27.5. Figure 27.1 presents a patient with a plasmacytoma.

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Table 27.4 Clinical features of MM and plasmacytoma Feature

Description

MM

Bone disease

Bone pain is most common presenting symptom (58%), with X-ray changes in almost 80% of patients, with vertebral column and ribs being most common sites of disease X-rays may show lytic lesions and generalized osteoporosis Pathological fractures of vertebrae or long bones may occur Bone scan not sensitive because osteoblast activity inhibited; radiological skeletal survey more appropriate

Renal failure

Creatinine levels elevated in about 50% of patients, most commonly due to Bence–Jones proteins Multiple causes, including:  Hypercalcemia Infection  Dehydration  Amyloid deposition  Hyperuricemia  Nonsteroidal anti-inflammatory drug use

Anemia

Present in 73% of patients

Others

Fatigue (32%) Weight loss (24%) Bacterial or viral infections, especially in the chest Primary amyloidosis, especially in the kidneys, leading to proteinuria and nephrotic syndrome Peripheral neuropathy Hyperviscosity syndrome, e.g., headache, visual disturbance, and loss of concentration

Solitary plasmacytoma

Bone

Typically affects axial skeleton, though any bone may be involved Pain, nerve root, or cord compression are common presenting symptoms

Extramedullary

Commonly arises from upper respiratory passages as a mass

Source: Adapted from: Kyle RA, Gertz MA, Witzig TE et al (2003) Review of 1,027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78:21–33

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Table 27.5 Myeloma-related organ or tissue impairment (ROTI) Impairment

Criteria

Hypercalcemia

Serum calcium >0.25 mmol/l above the upper limit of normal or >2.75 mmol/l

Renal

Creatinine >173 mmol/l

Anemia

Hemoglobin 2 g/dl below the lower limit of normal or hemoglobin <10 g/dl

Bone

Lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify)

Others

Symptomatic hyperviscosity, amyloidosis, and recurrent bacterial infections (> 2 episodes in 12 months)

Source: International Myeloma Working Group (2003) Criteria for the classification of MGUS, MM and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121:749–757

Figure 27.1 a, b a Plain X-ray of a patient complaining of neck ache, showing no gross lesions. b Sagittal gadolinium-enhanced T1-weighted fat suppressed MRI of the same patient demonstrating cord compression at C7–T2 levels by a plasmacytoma

Diagnosis and Staging Diagnosis of MM should be differentiated from smoldering myeloma and MGUS, according to criteria of the International Myeloma Working Group (Table 27.6). The diagnostic process for plasma cell neoplasms is summarized in Figure 27.2.

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Table 27.6 Spectrum of monoclonal gammopathies Gammopathy

Criteria

MGUS

M protein in serum <30 g/l Bone marrow clonal plasma cells <10% and low level of plasma cell infiltration in a trephine biopsy (if done) No evidence of other B-cell proliferative disorders No ROTI

Asymptomatic MM

M protein in serum ≥30 g/l and/or Bone marrow clonal plasma cells ≥10% No ROTI

Symptomatic MM

M protein in serum and/or urine Bone marrow (clonal) plasma cells* or plasmacytoma ROTI present, though patient may be asymptomatic

No M protein in serum and/or urine with immunofixation Bone marrow clonal plasmacytosis ≥10% or plasmacyNon-secretory MM toma ROTI present

Solitary plasmacytoma of bone

No M protein in serum and/or urine** Single area of bone destruction due to clonal plasma cells Bone marrow not consistent with MM Normal skeletal survey (and MRI of spine and pelvis if done) No ROTI other than solitary bone lesion

Extramedullary plasmacytoma

No M protein in serum and/or urine** Extramedullary tumor of clonal plasma cells Normal bone marrow Normal skeletal survey No ROTI

*If flow cytometry is performed, most plasma cells (> 90%) will show a ‘neoplastic’ phenotype ** A small M-component may sometimes be present (serum IgG<3.5 g/dl; serum IgA <2.0 g/dl; urine monoclonal kappa or lambda <1.0g/24h) MGUS: monoclonal gammopathy of unknown significance; MM: multiple myeloma; MRI: magnetic resonance imaging; ROTI: related organ or tissue impairment Source: International Myeloma Working Group (2003) Criteria for the classification of MGUS, MM and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121:749–757

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Plasma Cell Neoplasm Suspected

Complete History and Physical Examination for Local Symptoms and ROTI

CBC - Blood smear Serum Chemistry - Renal function - Ca++ - Albumin, β-2 microglobulin M-component measurement - Serum and urine protein electrophoresis & immunofixation - Quantification of immunoglobulins

Bone marrow aspirate & trephine biopsy, or biopsy of mass if solitary lesion (clonality, immunophenotype & cytogenetics)

Skeletal survey CT scan to visualize ambiguous or soft tissue lesions MRI for spine lesions and if clinical suspicion of cord compression

Biopsy Studies

Imaging Studies

Lab Studies

Monocional Protein Increased clonal PCs in BM Plasmacytoma

Symptomatic (ROTI)?

Yes

MM

No

Plasmacytoma

Yes

Solitary MM Plasmacytoma

No BM PC% >10% M-Protein >30 g/L?

No

MGUS

Yes

SMM MM

Figure 27.2 Investigations performed to prognosticate patients include serum β-2 microglobulin and albumin, cytogenetics and FISH for high risk genetics including t(4;14) and 17p13 deletion ROTI: related organ and tissue impairment; PC: plasma cells; BM: bone marrow; MM: multiple myeloma; SMM: smouldering MM; MGUS: monoclonal gammopathy of unknown significance

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Staging An international staging system for multiple myeloma is in use and is described in Table 27.7. Table 27.7 International staging system for MM Stage

Diagnostic criteria

Prognosis (months)

I

Serum β-2 microglobulin <3.5 mg/l Serum albumin ≥3.5 g/dl

62

II

Neither stage I nor stage III

45

III

Serum β-2 microglobulin ≥5.5 mg/l

29

Source: Greipp P, San Miquel J, Durie B et al (2005) International staging system for multiple myeloma. J Clin Oncol 23:3412–3420

Prognostic Factors Prognostic factors for MM are summarized in Table 27.8. Table 27.8 Prognostic factors for MM Factor

Description

Disease related

ISS stage High-risk genetics (17p13 deletion, t(4;14)) Hypodiploid by cytogenetics High-risk gene expression signature

Patient related

Age

Treatment related

Complete remission Minimal residual disease (MRD) negative (by flow cytometry) remission

Sources: Stewart AK, Bergsagel PL, Greipp PR et al (2007) A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia 21:529–534; Ludwig H, Bolejack V, Crowley J et al (2010) Survival and years of life lost in different age cohorts of patients with multiple myeloma. J Clin Oncol 28:1599–1605; Harousseau JL, Attal M, Avet-Loiseau H (2009) The role of complete response in multiple myeloma. Blood 114:3139–3146

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Treatment of MM Principles and Practice The two main objectives of MM treatment include:  Manage the acute problems (Table 27.9), and  Achieve disease control with the deepest level of response possible High-dose therapy is the mainstay of treatment for disease control, and the first clinical decision is whether the patient is eligible for high-dose therapy and stem cell transplantation. Risk stratification based on high-risk genetics is possible due to poor efficacy of conventional treatment and the ability of novel agents, such as bortezomib, to overcome the adverse prognosis. The therapeutic aim is to achieve complete remission (CR), as there is a strong association between CR and survival advantage. Table 27.9 Managing acute complications of MM Complication

Description

Cord compression

A medical emergency should be investigated exigently with MRI of the spine A dose of dexamethasone at 8 mg or more should be delivered immediately to reduce edema Orthopedic referral for surgical stabilization, followed by RT is the treatment of choice

Pain

Pain should be controlled by analgesia. In more severe cases, vertebroplasty will offer symptomatic relief as well as restore vertebral height to some extent Radiotherapy may be useful in reducing bone pain if surgery is contraindicated

Hypercalcemia

Should be managed with hydration and bisphosphonates

Renal failure

May require dialysis The use of plasma exchange is controversial

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Management of Newly Diagnosed Transplant-Eligible Patients Patients are usually given 4 to 6 cycles of induction treatment to reduce the initial tumor load. Regimens incorporating novel agents such as thalidomide and lenalidomide are the current standard, producing good depth of responses prior to high dose therapy. There are no randomized studies comparing these regimens, so the choice is dependent on comorbid conditions. A detailed discussion about the supporting clinical evidence is out of the scope of this chapter. A proposed treatment algorithm based on genetic risk stratification is appended (Figure 27.3).

High Risk Yes

No

4 to 6 Cycles of Bortezomib-containing Regimen

4 to 6 Cycles of Rd or Bortezomib-containing Regimen

Collect Stem Cells

Collect Stem Cells

If not in CR, consider ASCT

Maintenance until progression

ASCT

Continue Rd

If not in CR/VGPR after 1st ASCT consider consolidation (e.g. 2nd ASCT or IMiD)

Figure 27.3 Treatment stratification of transplant-eligible patients. Rd Revlimid (lenalidomide)/dexamethasone; ASCT autologous stem cell transplant, CR/VGPR complete response/very good partial response

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Management of Newly Diagnosed Transplant-Ineligible Patients For patients who are not transplant candidates, recent studies have suggested melphalan, prednisone, and thalidomide (MPT) or melphalan, prednisone, and Velcade (MPV) should be the standard of care. Again, the choice should depend on comorbidities. A proposed treatment algorithm based on genetic risk stratification for this group of patients is appended (Figure 27.4).

High Risk No Yes

MP + Bortezomin*

MP + Thalidomide* or Rd (Bortezomib-containing Regimen may be preferred for patients with renal failure

Observation

Observation

* In patients in whom administration of thalomide or bortezomib is of concern, consider MP or Rd

Figure 27.4 Treatment stratification for transplant-ineligible patients. Rd Revlimid (lenalidomide)/dexamethasone MP melphalan, prednisone

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Maintenance Therapy and Treatment for Recurrences Maintenance thalidomide at a dose of 50–100 mg with or without alternateday prednisolone prolongs survival. Re-treatment with similar agents used for induction therapy is possible if the relapse occurs more than 1 year after completion of initial treatment and response to initial treatment is at least a very good partial remission. Several regimens have been shown to be effective in relapsed disease, based on randomized studies.

Supportive Treatment Patients with lytic lesions or osteopenia on skeletal survey should be treated with bisphosphonates (pamidronate, zolendronate, or clodronate) for not more than 2 years. Patients with symptomatic anemia due to myeloma may benefit from erythropoietin treatment. However, anemia generally improves in response to myeloma treatment, and the use of erythropoietin may potentially increase the risk of thromboembolism. Patients treated with thalidomide or lenalidomide in combination with steroids or chemotherapy should receive thromboembolic prophylaxis in the form of low-molecular-weight heparin or aspirin, depending on coexisting risk factors.

Response to Treatment Response is assessed according to the International Myeloma Working Group Uniform Response Criteria (Table 27.10).

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Table 27.10 International Myeloma Working Group uniform response criteria Response or relapse subcategory

Criteriaa

Stringent complete response (sCR)

 CR plus  Normal free light chain ratio and  Absence of clonal cells in bone marrowb by immunohistochemistry or immunofluorescence

CR

 Negative immunofixation on serum and urine  Disappearance of any soft tissue plasmacytomas  ≤5% plasma cells in bone marrowb

Very good partial response (VGPR)

 Serum and urine M protein detectable by immunofixation but not on electrophoresis or  90% or greater reduction in serum M-protein plus urine M-protein levels <100 mg/24 h

PR

 ≥50% reduction of serum M protein and reduction in 24-h urinary M protein by ≥90% or <200 mg/24 h  If serum and urine M protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved field light chain (FLC) levels is required  If serum, urine M protein and serum free light chain are all unmeasurable, ≥50% reduction in bone marrow plasma cells is required, provided baseline bone marrow plasma cells percentage was ≥30%  In addition, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is required

SD

Not meeting criteria for CR, VGPR, PR, or progressive disease

Progressive disease

 Requires increase of ≥25% from baseline in one or more of the following  Serum M protein (absolute increase must be ≥0.5g/dl) and/or  Urine M protein (absolute increase must be ≥200 mg/24 h) and/or  In patients without measurable serum and urine M proteins, the difference between involved and uninvolved FLC levels (absolute increase must be ≥10 mg/dl)  Bone marrow plasma cells percentage (absolute increase must be ≥10%)  Definite increase in size or development of new bone lesions or plasmacytomas  Development of hypercalcaemia (corrected serum calcium >11.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell disorder

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Table 27.10 (continued) Response or relapse subcategory

Criteriaa

Clinical relapse

Requires one or more of  Development of new soft tissue plasmacytomas or bone lesions   Increase in size (at least 50%) of existing plasmacytomas or bone lesions  Hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.65 mmol/l)  Decrease in hemoglobin of ≥2 g/dl  Rise in serum creatinine by 2mg/dl (177μmol/l) or more

Relapse from CR

Any one or more of the following  Reappearance of serum or urine M protein by immunofixation or electrophoresis  Development of ≥5% plasma cells in marrow  Appearance of any other signs of clinical progression as above

a

Requires two consecutive assessments made at any time Confirmation with repeat bone marrow not needed Source: Durie BGM, Harrousseau JL, Miguel JS et al (2006) International Uniform Response Criteria for Multiple Myeloma. Leukemia 20:1467–1473 b

Radiation Therapy for MM Radiation therapy (RT) is an important palliative treatment modality, with approximately 40% of patients requiring it during the course of their disease. The key points regarding RT in multiple myeloma are listed in Table 27.11.

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Table 27.11 Radiation therapy in multiple myeloma Aspect

Description

Indications

 Bone pain  Spinal cord or other neurological compression  Pathologic fracture  Impending pathologic fracture after surgical stabilization  Symptomatic soft tissue mass

RT techniques

 Simulation is site specific  Involved-field approach is generally recommended to minimize bone marrow toxicity, especially in patients planned for stem cell transplant  For disease in long bones: 2-cm margins to radiographic lesion sufficient and not shown to be inferior to wholebone irradiation  For diseases of vertebral bodies: involved level with 1 or 2 vertebral bodies above and below

 Dose of radiation depends on disease factors (e.g., indication for treatment), patient factors (e.g., performance status), and treatment factors (surgical or systemic options)  Typical schedule for MM radiation therapy is 25 Gy in 10 fractions. Other schedule used includes 8 Gy in 1 fraction, 20 Gy in 5 fractions, 30 Gy in 10 fractions, and 37.5 Gy in 15 fractions Dose fractionation  Subjective pain relief may be experienced with low-dose radiation (8–15 Gy)  Some studies suggest that healing of lytic lesions may require a higher dose (≥20 Gy), with no objective responses seen at about 10 Gy  Spinal cord compression may benefit from a higher dose (30–37.5 Gy) instead of ≤20 Gy, based on a multicenter retrospective series

Side effects

 Severe toxicity is uncommon due to the low doses commonly used  Bone marrow toxicity (anemia, leukopenia) may occur in large-field irradiation

Sources: Bosch A, Frias Z (1988) Radiotherapy in the treatment of multiple myeloma. Int J Radiat Oncol Biol Phys 15:1363 –1369; Catell D, Kogen Z, Donahue B et al (1998) Multiple myeloma of an extremity: must the entire bone be treated? Int J Radiat Oncol Biol Phys 40:117–119; Rades D, Hoskin PJ, Stalpers LJ et al (2006) Short-course radiotherapy is not optimal for spinal cord compression due to myeloma. Int J Radiat Oncol Biol Phys 64:1452–1457

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Treatment of Solitary Plasmacytoma Principles and Practice The main treatment modalities for solitary bone plasmacytoma and solitary extramedullary plasmacytoma are presented in Tables 27.12 and 27.13 respectively. Table 27.12 Treatment modalities for solitary bone plasmacytoma Type

Description

Radiation therapy

Indications

Mainstay of treatment High rate of local control (83–96%) with RT, but frequent progression to MM Patients presenting as SBP, but found on MRI to have disease more extensive, should be considered as having MM. Nevertheless, RT to SBP may be appropriate for palliation

Techniques

Recommended dose of 40–50 Gy, based on small studies on radiation dose response For large SBP (>5 cm), a higher dose (50 Gy in 25 fractions) should be offered MRI recommended to delineate bony lesions Involved-field RT to gross disease with 2-cm margins recommended for long bones to minimize bone marrow toxicity For vertebral involvement, treatment volume includes the entire bone, with a margin of 1 uninvolved vertebra above and below

Surgery

Indications

Important in cases of structural instability or neurological compromise, especially involving the spine Where surgery is required, RT should also be given Surgery is generally offered before RT, but the timing should be individualized

Techniques

Posterior pedicle screw instrumentation generally performed for spinal instability Decompression may also required to relieve neurological compromise Reconstruction of the anterior column may be beneficial in some cases ▶

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Table 27.12 (continued) Type

Description

Systemic therapy

Indications

 Adjuvant chemotherapy may be useful in delaying the progression to MM, with 1 small randomized trial of 53 patients, suggesting improved survival with 3 years of adjuvant melphalan and prednisolone  Patients not responding to RT should be offered chemotherapy

Medications

 Chemotherapy appropriate for MM may be offered, when indicated  Limited evidence-based recommendations for use of thalidomide or bisphosphonates for SBP

RT: radiation therapy; MM: multiple myeloma; SBP: solitary bone plasmacytoma Sources: Knobel D, Zouhair A, Tsang RW et al (2006) Prognostic factors in solitary plasmacytoma of the bone: a multicenter Rare Cancer Network study. BMC Cancer 6:118; Mill WB, Griffith R (1980) The role of radiation therapy in the management of plasma cell tumors. Cancer 45:647–652

We propose a treatment algorithm for solitary plasmacytoma in Figure 27.5.

Radiation Therapy Techniques Simulation and Target Volume Delineation Either conventional or computed tomography (CT) simulation may be utilized for target localization, with CT simulation preferred for more complex cases or if a soft tissue component is present. Particularly for treatment to the long bones, the choice of immobilization device and position must be made carefully, with due consideration of the eventual field arrangement, as well as the stability and comfort of the patient. The gross tumor is usually best visualized on a diagnostic magnetic resonance image (MRI) examination, and should be encompassed with a field margin of at least 2 cm for long bones and one vertebra for spinal lesions.

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Table 27.13 Treatment modalities for solitary extramedullary plasmacytoma Modality

Description

RT

Indications

SEP are highly radiosensitive tumors, with local control rates of 80–100% reported with moderate doses of RT Primary treatment modality may depend on site of disease  Head and neck SEP patients should be offered radical RT rather than surgery to minimize loss of function

Techniques

No established dose–response relationship, but optimal dose range likely to be 40–50 Gy in 2 Gy fractions, with 50 Gy recommended for bulky (>5 cm) SEPs Treatment volume should encompass the gross disease, with a margin of at least 2 cm Elective cervical nodal irradiation is controversial for head and neck primary disease, but can be avoided to reduce toxicity, except in high-risk primary sites, e.g., Waldeyer’s ring, where the first-echelon nodes may be included

Surgery Indications

May be offered if complete excision is feasible Should not be offered for head and neck SEP, where radical RT may be more appropriate

Techniques

Excision with clear margins is recommended  Adjuvant RT may be offered for inadequate margins No recommendation for adjuvant RT can be made for complete excision with clear margins

Systemic therapy

Indications

Adjuvant chemotherapy may be considered in patients with tumors larger than 5 cm and those with high-grade tumors Chemotherapy is indicated for patients with refractory disease or relapsed disease

Medication

Chemotherapy appropriate for MM may be offered, when indicated

SEP: solitary extramedullary plasmacytoma; RT: radiation therapy; MM: multiple myeloma Sources: Tournier-Rangeard L, Lapeyre M, Graff-Caillaud P et al (2006) Radiotherapy for solitary extramedullary plasmacytoma in the head-and-neck region: a dose greater than 45 Gy to the target volume improves the local control. Int J Radiat Oncol Biol Phys 64:1013 –1017; Liebross RH, Ha CS, Cox JD et al (1999) Clinical course of solitary extramedullary plasmacytoma. Radiother Oncol 52:245 –249

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Solitary Bone Plasmacytoma

Structural instability or neurological compromise

Solitary Extramedullary Plasmacytoma

Yes

Surgery for MM stabilisation or decompression

Head & neck site

No

Consider surgery if MM complete resection feasible

Yes

No Radical MM RT 40 – 50 Gy

Radical MM RT 40 – 50 Gy

Yes

Margins involved?

No

Assessment of Response (International Myeloma Working Group Uniform Response Criterial)

Progression of Disease? Yes

Restage Figure 27.5 Treatment algorithm for solitary plasmacytoma

No

Follow-Up MM

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Dose and Treatment Delivery Typical doses are detailed in Tables 27.11 to 27.13. Field arrangements are individualized, with an example of an axillary treatment demonstrated in Figure 27.6.

Figure 27.6 Two-field plan encompassing a large, solitary extramedullary plasmacytoma of the left axilla. Prescribed dose was 50 Gy in 25 fractions over 5 weeks. The red contour denotes the gross tumor volume, and the blue contour denotes the planning target volume. The 90% isodose is in red color wash. The dose-volume histogram is presented in the top right panel

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Normal Tissue Tolerance The doses delivered for radiation treatment of plasmacytoma or MM are typically below the tolerance for most organs at risk. Nevertheless, doses to normal tissue should be minimized, with site-specific dose constraints respected, e.g., spinal cord tolerance of 45 Gy.

Follow-Up Active follow-up after definitive radiation treatment for solitary plasmacytoma is recommended, as progression to MM can occur (Table 27.14). Acute and late side effects secondary to radiation treatment are site specific and generally self-limiting. Severe long-term adverse effects are rare, and may include radiation-induced organ dysfunction (e.g., radiation nephropathy, chronic pneumonitis, and myelopathy) and second malignancies. Table 27.14 Proposed follow-up schedule and examinations Schedule Years 0–2

Every 3–6 months

Years 2+

Every 6–12 months

Examinations History and physical Complete history and physical examination

Imaging studies

Consider cross sectional imaging (CT, MRI, or positronemission tomography [PET]/CT) as clinically indicated or annually Consider skeletal survey as clinically indicated or annually Other imaging tests based on clinical indication

Laboratory tests

Complete blood count Serum chemistry for creatinine, calcium, albumin, lactate dehydrogenase, β-2 microglobulin 24-h urine for total protein, urine protein electrophoresis, urine immunofixation electrophoresis Serum quantitative immunoglobulins, serum protein electrophoresis, serum immunofixation electrophoresis Consider bone marrow biopsy as clinically indicated

Adapted from the National Comprehensive Cancer Network (NCCN). Practice guidelines in oncology: multiple myeloma, v.2.2010. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

28

Cutaneous T-Cell Lymphoma Ivan W.K. Tham1

Key Points  Primary cutaneous lymphomas are rare, accounting for 2% of all lymphomas. About 75% are T-cell lymphomas.  There are two major subgroups within the cutaneous T-cell lymphomas (CTCL) spectrum: mycosis fungoides (MF) and Sézary syndrome (SS).  MF is the prototype of CTCL. It is defined as a peripheral, epidermotropic nonHodgkin’s T-cell lymphoma of low-grade malignancy, typically presenting in the skin initially, and proceeding in clinical progression from patches to plaques and tumors.  MF exhibits distinct histological (except in early stages), phenotypic, and genotypic features.  SS is a distinct variant of CTCL, characterized by exfoliative erythroderma, lymphadenopathy, lymphocytosis, pruritus, circulating Sézary cells, and a poor prognosis.  Primary cutaneous lymphoma is staged with the American Joint Committee on Cancer and the International Union against Cancer (AJCC/UICC) tumor, node, and metastasis (TNM) grouping and staging classification (7th edn.).  MF usually responds to skin-directed therapy first, with systemic treatments reserved for refractory, recurrent, or advanced disease. SS may respond to skindirected or systemic therapies.

1

Ivan W.K. Tham, MD () Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_11, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Table 28.1 describes some features specific to CTCL. Table 28.1 Epidemiology and etiology of cutaneous lymphoma Type

Description

Epidemiology

 Cutaneous T-Cell Lymphoma (CTCL) is more common than are other forms of cutaneous lymphoma, e.g., mature B-cell or immature hematopoietic malignancies  MF accounts for 60% of new cases of CTCL, with an incidence of 0.36/100,000 persons per year in the USA (1973–1992)  SS accounts for <5% of new cases of CTCL  Incidence increases with age, peaks at the fifth and sixth decades of life  Male:female ratio is about 2:1

Risk factors

 Etiology of CTCL is largely unknown  Various factors implicated for MF, including industrial exposure to chemicals, familial predisposition, and viral infection

Anatomy and Pathology Lymphoma may involve the skin primarily, or spread to the skin as a secondary site of disease. Cutaneous lymphomas can have some unique clinical aspects, such as presenting only in the skin, but not usually in other nodal or extranodal sites, or having a similar histological picture but different clinical behavior compared with nodal disease.

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Table 28.2 summarizes the classification and prognosis of the main subtypes of CTCL, the predominant form of cutaneous lymphoma. The chapter focuses mainly on MF and SS, the more common subtypes of CTCL. Table 28.2 Main subtypes of the WHO/EORTC classification of cutaneous mature T-cell and NK-/T-cell lymphomas Description

Prognosis

 Mycosis fungoides

5-year overall survival (OS) is 27–100%

 Sézary syndrome

Median survival (MS) is 2–4 years

 CD30+ T-cell lymphoproliferative disorders of the skin  Lymphomatoid papulosis  Primary cutaneous anaplastic large cell lymphoma

5-year OS is 100% 5-year OS is 90%

 Primary cutaneous peripheral T-cell lymphoma (PTL), unspecified

5-Year OS is <20 –80%

 Extranodal NK-/T-cell lymphoma, nasal type

MS is <15 months

 Extracutaneous lymphomas frequently involving the skin as a secondary site  Adult T-cell leukaemia/lymphoma  Angioimmunoblastic T-cell lymphoma  Systemic anaplastic large cell lymphoma

Depends on clinical subtype

Adapted from: LeBoit PE, Burg G, Weedon D, Sarasin A (eds) (2006) Pathology and genetics: skin tumors (WHO classification). IARC Press, Lyon, France

Histopathology The histologic diagnosis of MF is based on several subtle changes, which may also be present in many inflammatory and neoplastic cutaneous conditions. The most significant criteria, which may not always be present in early disease, include Pautrier microabscesses, exocytosis of lymphocytes, and disproportionate epidermotropism. Haloed lymphocytes are reported to be the most robust discriminator of MF from non-MF. In patch, plaque, and erythrodermic lesions of CTCL, the cellular infiltrate is located mainly in the superficial part of the dermis, though it may extend into deeper regions around hair follicles and eccrine glands. With tumor formation, the infiltrate penetrates between the collagen bundles of the reticular dermis and into the subcutaneous fat, up to several centimeters in depth.

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Lymph node involvement may be underestimated by routine methods because early nodal involvement cannot be easily differentiated from dermatopathic lymphadenitis or other nonspecific changes. Currently, either the National Cancer Institute (NCI) or Dutch grading system may be utilized, both of which assess “abnormal” cells and nodal architecture to assign a grade.

Routes of Spread MF is a systemic disease with preferential homing and proliferation of neoplastic lymphocytes into the skin. A leukemic phase may arise in advanced cases, as well as spread to other extracutaneous organs, e.g., lymph nodes, liver, spleen, gastrointestinal tract, and bone marrow.

Diagnosis, Staging, and Prognosis Clinical Presentation Table 28.3 summarizes the main clinical features of MF and SS. Table 28.3 Clinical features of MF and SS Type

MF

SS

Features  MF is characterized by a stepwise evolution, with sequential appearance of patches, plaques, and tumors  All parts of the skin may be involved without any predilection site  Patches are circumscribed lesions with discoloration with or without scaling, without palpable infiltration of the skin  Plaques usually evolve out of patches and present with palpable infiltration of varying degrees  Tumours have an exophytic growth and tend to ulcerate  In advanced stages, there may be spread into the peripheral blood, and involvement of lymph nodes, bone marrow, and internal organs  SS may have been preceded by clinically typical MF and is then designated SS preceded by MF or secondary SS  SS comprises a clinical triad of pruritus, erythroderma, and lymphadenopathy. Other features include alopecia, ectropion, nail dystrophy, palmoplantar keratoderma, and leonine facies  Bacterial skin infection is common and may lead to a marked deterioration of cutaneous disease  Secondary malignancies, both cutaneous and systemic, are reported to be more common in SS and are attributed to the immunoparesis associated with loss of normal circulating CD4 cells

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Diagnosis and Staging MF and SS are evaluated with methods listed in Table 28.4. The current staging system is presented in Tables 28.5 and 28.6. Table 28.4 Recommended initial evaluation of MF and SS Diagnostic tool

Description

History and complete physical examination

 Type(s) and extent of skin lesions (percent of body surface area)  Firm, irregular, clustered, fixed, or enlarged (>1.5 cm) lymph nodes, or organomegaly

Skin biopsy with dermatopathology review

 Pick most indurated area if only one biopsy taken  Consider immunophenotyping, e.g., CD2, CD3, CD4, CD5, CD7, CD8, CD20, and CD30  Consider evaluation for clonality of TCR gene rearrangement

Blood tests

 Complete blood count with manual differential  Comprehensive chemistries including liver function tests and lactate dehydrogenase levels  TCR gene rearrangement and relatedness to any clone in skin  Analysis for abnormal lymphocytes by either Sézary cell count with determination of absolute number of Sézary cells and/or flow cytometry (including CD4+/CD7− or CD4+/CD26 −)

Radiology

 Chest X-ray alone for T1, limited T2, N0, B0 patients  CT chest, abdomen, pelvis with or without PET scan for all others

Lymph node biopsy

 Excisional biopsy indicated for suspicious nodes  Pathologic assessment by light microscopy, flow cytometry, and TCR gene rearrangement

CBC: complete blood count; TCR: T-cell receptor; CT: computed tomography; PET: positron-emission tomography

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Table 28.5 TNMB classification and staging of MF and SS Organ

Primary tumor (T) skin

Classification TX

 Primary tumor cannot be assessed

T1

 Limited patchesa, papules, and/or plaquesb covering <10% of the skin surface. May further stratify into T1a (patch only) versus T1b (plaque with or without patch)

T2

 Patches, papules, or plaques covering ≥10% of the skin surface. May further stratify into T2a (patch only) versus T2b (plaque with or without patch)

T3

 One or more tumorsc (≥1 cm diameter)

T4

 Confluence of erythema covering >80% body surface area

NX

 Clinically abnormal peripheral lymph nodes; no histologic confirmation

N0

 No clinically abnormal peripheral lymph nodesd; biopsy not required

N1

 Clinically abnormal peripheral lymph nodes, histopathology Dutch grade 1 or NCI LN0 –2  N1a: clone negativee  N1ab: clone positivee

N2

 Clinically abnormal peripheral lymph nodes, histopathology Dutch grade 2 or NCI LN3  N2a: clone negativee  N2b: clone positivee

N3

 Clinically abnormal peripheral lymph nodes, histopathology Dutch grades 3–4 or NCI LN4; clone positive or negative

M0

 No visceral organ involvement (no pathologic M0, use clinical M to complete stage group)

M1

 Visceral involvement (must have pathology confirmationf and organ involved should be specified)

Regional lymph nodes

Distant metastasis (M) visceral

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Table 28.5 (continued) Organ

Classification

B0

 Absence of significant blood involvement: ≤5% of peripheral blood lymphocytes are atypical (Sézary) cells  Clone negativee  Clone positivee

B1

 Low blood tumor burden: >5% of peripheral blood lymphocytes are atypical (Sézary) cells but does not meet the criteria of B 2  Clone negativee  Clone positivee

B2

 High blood tumor burden: ≥1,000/μl Sézary cellsg with positive clonee

Blood

a

For skin, patch indicates any size skin lesion without significant elevation or induration. Presence/absence of hypo-or hyperpigmentation, scale, crusting, and/or poikiloderma should be noted b For skin, plaque indicates any size skin lesion that is elevated or indurated. Presence or absence of scale, crusting, and/or poikiloderma should be noted. Histologic features such as folliculotropism or large cell transformation (>25% large cells), CD30−, or CD30 −, and clinical features such as ulceration are important to document c For skin, tumor indicates at least one 1-cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also, note if histologic evidence of large cell transformation has occurred. Phenotyping for CD30 is encouraged d For node, abnormal peripheral lymph node(s) indicate(s) any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed, or 1.5 cm or larger in diameter. Node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically e A T-cell clone is defined by PCR or Southern blot analysis of the T-cell receptor gene f For viscera, spleen and liver may be diagnosed by imaging criteria g For blood, Sézary cells are defined as lymphocytes with hyperconvoluted cerebriform nuclei. If Sézary cells are not able to be used to determine tumor burden for B2, then one of the following modified ISCL criteria along with a positive clonal rearrangement of the TCR may be used instead:  Expanded CD4+ or CD3+ cells with CD4/CD8 ratio of 10 or more  Expanded CD4+ cells with abnormal immunophenotype including loss of CD7 or CD26 Source: Edge SB, Byrd DR, Compton CC et al (eds) (2009) American Joint Committee on Cancer (AJCC) cancer staging manual 7th edn. Springer, Berlin Heidelberg New York

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Table 28.6 Clinical staging/classification of MF and SS Stage

T

N

M

B

Estimated 5-year OS (%)

IA

1

0

0

0, 1

96–100%

IB

2

0

0

0, 1

73–86%

II

1–2

1, 2

0

0, 1

49–73%

IIB

3

0 –2

0

0, 1

40–65%

III

4

0 –2

0

0, 1

IIIA

4

0 –2

0

0

IIIB

4

0 –2

0

1

IVA1

1–4

0 –2

0

2

IVA2

1–4

3

0

0 –2

IVB

1–4

0 –3

1

0 –2

40–57%

15–40% 0–15%

B: blood Source: Edge SB, Byrd DR, Compton CC et al (eds) (2009) American Joint Committee on Cancer (AJCC) cancer staging manual 7th edn. Springer, Berlin Heidelberg New York

Prognostic Factors While MF and SS are often considered incurable conditions, majorities of patients have indolent disease and live for many years. Approximately 65–85% of patients with MF have stage IA or IB disease, of whom many do not progress to a more advanced stage. Patients presenting with isolated patch or plaque disease (T1–T2) have a median survival of more than 12 years, and patients with stage IA disease appear to have a comparable survival in an age-, gender-, and race-matched population. Main prognostic factors are listed in Table 28.7.

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Table 28.7 Adverse prognostic factors of MF and SS Factor

Disease related (MF)

 Advanced-stage patients with advanced-stage disease (stages IIB, III, and IVA) with tumors, erythroderma, and lymph node or blood involvement, but no visceral involvement have a median survival of 5 years from time of presentation  Survival <1 year expected for extracutaneous involvement or high-grade transformation  Patients with tumors (T3) appear to have an inferior outcome compared with those with erythroderma (T4)  Some histologic variants of classical MF, e.g., folliculotropic

Disease related (SS)

 High absolute Sézary cell count  Lymph node involvement  Large cell transformation

Patient related

 Age >60 years

Treatment related

 Aggressive up-front treatment not superior to sequential topical therapy

Treatment Principles and Practice The general approach is to minimize disease symptoms while limiting toxicity. A randomized trial has shown no difference in long-term outcome whether patients are treated aggressively with total skin electron-beam therapy (TSEBT) and polychemotherapy or sequential topical treatment (Source: Kaye FJ, Bunn PA Jr, Steinberg SM et al (1989) A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 321:1784 –1790).

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Early-stage disease (IA–IIA) generally involves skin-directed therapy, whereas recalcitrant early-stage disease or advanced-stage disease (IIB–IV) might benefit from systemic treatment. Table 28.8 summarizes the common treatment options.

Table 28.8 Commonly utilized treatment modalities for MF/SS Therapy

Description

Skin-directed therapies

Topical

 Emollients with or without topical steroids can produce good but short-lived response  Topical nitrogen mustard (NM) 0.01–0.02% (avoided during pregnancy) in aqueous solution or ointment base can give sustained response  Topical carmustine (BCNU) has less hypersensitivity reaction than NM, with similar efficacy. Requires regular CBC monitoring due to myelosuppression risk, and maintenance therapy is contraindicated  Topical bexarotene 1% gel indicated for stage I MF/SS resistant/intolerant to other topical treatments, with response rate of about 60%

Phototherapy

 Psoralen plus ultraviolet A (PUVA) has response rate of >80% for stage IA, with no response for tumor stage disease  Treatment given 2–3 times weekly until best response is achieved  Maintenance treatment avoided to minimize accumulated UVA dose and risk of non-melanomatous skin cancer  Ultraviolet B (UVB) also may be useful

Local RT

 CTCL is very radiosensitive and can be effectively palliated with low-dose superficial orthovoltage photons or electrons  Re-treatment even with overlapping fields often possible due to low doses used  Often used in combination with other therapies

Total skin electron beam

 Therapy where ionizing radiation is delivered to the entire skin surface with limited adverse systemic effects  Complete response rate up to 96% for stages IA–IIA, 60% for erythroderma and 36% for stage IIB, with some patients with long relapse-free survival

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Table 28.8 (continued) Therapy

Description

Systemic

Oral bexarotene

 Novel synthetic retinoid with selectivity to retinoid X receptor and shown in phases II–III trials to be effective for early (response rate of 54%) or advanced disease (response rate 45%)  Transient side effects include hyperlipidemia and central hypothyroidism

IFN-α

 IFN-α may enhance antitumor host response, with overall response rate of 45–74%  Higher response rate with higher dose

HDACi

 HDACi, e.g., vorinostat, romidepsin, have a response rate of 30%  Toxicities include gastrointestinal or constitutional symptoms, or hematological abnormalities

ECP

 Extracorporeal photopheresis is a form of apheresis, in which blood is treated with 8-methoxypsoralen, which is then activated with ultraviolet light  Systemic review of ECP in erythrodermic disease shows a complete response rate of 14–26%

Denileukin diftitox

 Intravenously administered recombinated fusion toxin that can inhibit protein synthesis in tumor cells expressing the IL-2 receptor  Response rate of 30% with 7-month median duration of response for heavily pretreated patients  Toxicity includes constitutional symptoms, acute hypersensitivity, and vascular leak syndrome

Chemotherapy

 MF/SS relatively chemoresistant with responses often short-lived  Liposomal doxorubicin and gemcitabine are first-line options  Chlorambucil, methotrexate, and etoposide also used as single agents

RT: radiation therapy; IFN-: interferon-; HDACi: histone deacetylase inhibitors; ECP: extracorporeal photopheresis

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Figures 28.1 to 28.3 illustrate possible treatment pathways for early stage (IA–IIA), stage IIB, and stage III disease, respectively. Stage IV with SS may be treated according to the algorithm illustrated in Figure 28.3. Patients with nodal or visceral disease may be treated with the systemic agents listed in Table 28.6, with the addition of TSEBT or local RT Early Stage (IA-IIA)

Symptomatic or Decision to Treat?

No

Expectant MM Management

First-Line Treatment

Yes

Lacalized, thin

Widespread, thin

Lacalized, thick

Widespread, thick

Solitary

Topical Steroids

PUVA/UVB

Palliative Local RT

Consider TSEB

Radical Local RT

Other possible first-line treatment options: Topical Bexarotene or NM

Progression of Disease?

No

Expectant MM Management

Yes

Second-Line Treatment

Early Stage (IA-IIA)

Combination or alternate 1st line therapy Oral Bexarotene IFN-α HDACi (Vorinostat) Low-Dose MTX Denileukin Diftitox

Upstaged or Transformed

See Algorithms 10.2 and 10.3

Figure 28.1 Proposed treatment algorithm for early-stage (IA–IIA) MF

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for palliation of skin disease. In general, interferon-α (IFN-α), bexarotene, histone deacetylase inhibitors (HDACi), and denileukin diftitox are considered before administering systemic chemotherapy, though for the rare patient with stage IVB disease and good performance status, aggressive chemotherapy, including transplantation strategies, can be considered early.

Stage IIB

First-Line Treatment

Limited Tumor Disease

Extensive Tumor Disease

Palliative Local RT +/Other Skin Directed Therapies

Prior therapy availability, patient‘s choice

TSEB +/Local RT

Progression or Relapse?

IFN-alpha

PUVA

No

Expectant MM Management

Yes

Refractory or Transformed

Skin-Directed Therapy

Second-Line Treatment

Mainly skin disease

Combination of first-line therapy Oral Bexarotene HDACi (Vorinostat) Denileukin Diftitox Novel agents Chemotherapy

Figure 28.2 Proposed treatment algorithm for stage IIB MF

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First-Line Treatment

Stage III or SS

B0

B1

+/Skin Directed Therapies

Extracorporeal photophoresis

IFN-alpha

PUVA + IFN-alpha

Progression or Relapse?

Mainly Skin disease

Second-Line Treatment

Prior therapy, availability, patient‘s choice

Bexarotene HDACi Denileukin diftitox Alemtuzumab Novel agents Chemotherapy

Figure 28.3 Proposed treatment algorithm for stage III MF

MTX

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Radiation Therapy for CTCL Radiation therapy (RT) plays a major role in the management of many patients with MF. While complete response (CR) rates are high, permanent eradication of all disease using RT is uncommon. Thus, treatment is usually aimed at palliating symptoms and improving cosmesis. Pruritus, scaling, discharge, and ulceration are some of the troublesome symptoms that may be alleviated by RT. The duration and likelihood of a CR decreases with increasing stage. While patients with T1 disease enjoy >80% CR rate and 5-year relapse-free survival (RFS) of 40–60%, patients with T4 have only a 20–30% CR rate and <10% 5-year RFS. Additionally, there is a small subgroup of patients with solitary MF lesions who may be offered “curative” RT to about 30 Gy, with the expectation of excellent disease control. Many patients can benefit from at least one course of TSEBT at some time over their clinical course, with some benefiting from durable remission, and others receiving significant palliation. It should be considered once a diagnosis of MF is made, as well as when a therapeutic decision is considered. TSEBT has been used sequentially with other treatments, especially for resistant or extensive disease. Adjuvant psoralen plus ultraviolet A (PUVA), nitrogen mustard (NM), or extracorporeal photopheresis (ECP) have been shown to improve disease-free survival, but not overall survival. Evidence describing the use of radiation is summarized in Table 28.9.

Radiation Therapy Techniques Target Volumes For most patients, the target volume is the epidermis and dermis. The skin thickness may vary in depth from 2 mm on the trunk to 4.5 mm at the extremities; the maximum depth of interest is only a few millimeters from the skin surface unless there are tumors or deep ulcers. Hence, the main modalities of treatment would be superficial X-rays (50–145 kVp) or 4–9 MeV electrons, with the European Organization for Research and Treatment of Cancer (EORTC) TSEBT consensus panel recommending that the 80% isodose line reaches4 mm deep. Nodal or visceral disease requiring palliative RT can be treated by using standard RT techniques.

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Table 28.9 Treatment strategies using radiation for CTCL and supporting evidence

a

Issue

Key results

Dose-response of RTa

 Of 110 lesions irradiated with 6–40 Gy total dose. In the complete responders, local in-field recurrence rate of 42% seen for group receiving ≤10 Gy, 32% in group receiving 10.1–20 Gy, 21% in group receiving 20.1–30 Gy, and 0% in group receiving >3,000 Gy

Low-dose palliative RTb

 65 symptomatic MF sites treated with 8 Gy in 2 fractions, with CR rate of 92%, without toxicity. 17 lesions treated with 4 Gy in 2 fractions, with response rate of only 30%

Minimal stage IA diseasec

 Radical RT with median dose of 22 Gy given to 15 patients, with 95% CR rate and 94% 5-year local progression-free rate was 94%, but 10-year overall relapse-free rate of 51%

TSEBT for erythrodermad

 Median TSEBT dose of 32 Gy delivered to 45 patients with erythrodermic MF/SS with 100% response rate, 60% CR, and 26% progression-free at 5 years. Radiation may be most efficacious in stage III MF, with no blood involvement

Adjuvant PUVA after TSEBTe

 114 patients with T1–T2 CTCL treated with adjuvant PUVA after TSEBT. Those who received PUVA had a 5-year disease-free survival (DFS) of 85% versus a 5-year DFS for the non-PUVA group of 50% (p < 0.02). PUVA can maintain remissions in patients with CTCL after TSEBT, with a significant benefit in 5-year DFS but no improvement in overall survival

TSEBT and ECPf

 44 patients with erythrodermic MF received TSEBT with or without concurrent and adjuvant extracorporeal photopheresis (ECP). CR rate for TSEBT was 73%. Of the complete responders, 3-year DFS was 49% for TSEBT only patients versus 81% for TSEBT plus ECP

Source: Cotter GW, Baglan RJ, Wasserman TH et al (1983) Palliative radiation treatment of cutaneous mycosis fungoides – a dose response. Int J Radiat Oncol Biol Phys 9:1477 –1480 b Source: Neelis KJ, Schimmel EC, Vermeer MH et al (2008) Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys 74:154 –158 c Source: Piccinno R, Caccialanza M, Percivalle S (2009) Minimal stage IA mycosis fungoides. Results of radiotherapy in 15 patients. J Dermatolog Treat 20:165–168 d Source: Jones GW, Rosenthal D, Wilson LD (1999) Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome). Cancer 85:1985–1895 e Quirós PA, Jones GW, Kacinski BM et al (1997) Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38:1027–1035 f Source: Wilson LD, Jones GW, Kim D et al (2000) Experience with total skin electron beam therapy in combination with extracorporeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides. J Am Acad Dermatol 43:54 –60

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Radiation Doses There appears to be dose response relationship for complete remission, especially in the context of TSEBT. A dose of 30 Gy may confer a CR rate of >90%, compared with a CR rate of only 55% for 10–20 Gy. The duration of response also appears to be lengthened with increasing dose. Nevertheless, a wide range of doses are commonly used, with doses of <20 Gy often being effective in palliating symptoms.

Limited Superficial RT T1 disease can usually be treated with a single radiation field, though abutting fields may be required in some convex surfaces, e.g., scalp. The junction of the abutting fields may be shifted to improve dose homogeneity. Lead cutouts of appropriate thickness may be used to delineate field margins, which may be 1–2 cm away from clinically evident disease. Either superficial Xrays or low-energy electrons (with bolus) may be utilized to encompass thin lesions with a margin at depth. Higher-energy electrons (6–16 MeV) may be required for tumors or ulcers. Given that many patients will require repeat local RT or TSEBT, a low dose per fraction is preferred, with a total dose ranging from 20 to 30 Gy. Fewer fractions, e.g., 8 Gy in 2 fractions, may also be appropriate palliation for selected patients to minimize treatment burden.

TSEBT The main objectives of TSEBT are to deliver an adequate dose to the skin in the most efficient manner possible while minimizing toxicity and accommodating repeated administration as required. Table 28.10 describes some key points for delivery of TSEBT, with Figure 28.4 demonstrating the patient in six standing treatment positions. Figure 28.5 illustrates the dual-field treatment technique.

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Table 28.10 Treatment technique for TSEBT Type

Description

Target volumes

 The targets include the epidermis, adnexal structures, and dermis, to a depth of ≥4 mm

Correction for dose heterogeneity

 Dose heterogeneity minimized by using 6 standing positions, with maximal unfolding of the skin (Figure 28.4)  Top-up treatments to under-dosed regions, e.g., patch treatment for soles, inframammary, perianal, buttocks/ thighs, perineum, and vertex regions

Technical tolerance

 Optimal source–patient distance is 3–8 m  Rotation of accelerator head 17.5–20°C above and below horizontal produces dual fields for dose homogeneity in vertical dimension (Figure 28.5)  At treatment distance, distribution of dose in air should be homogenous to 10% across dimensions of beam  Photon contamination at bone marrow should be <0.7 Gy for full course of TSEBT

Dose homogeneity

 There should be circumferential and radial dose homogeneity of 80% isodose  Dose at 20-mm depth should be <20% of maximum skin dose

Boost treatment

 Boost treatment to sites of infiltrating disease before start of TSEBT may reduce symptoms  Single 4 - to 6-Gy dose with 6 –12 MeV

Prescription

 Typical prescription of 35–36 Gy in 30 –36 fractions over 6–10 weeks  A cycle of TSEBT should be within 2–3 days (e.g., alternate beams for 6-beam technique over 2 days)  Goal to deliver ≥26 Gy at 4-mm depth in truncal skin along primary axes  With effective electron energies of 4–5.5 MeV, surface dose is 31–36 Gy  Patch treatments should top-up dose to 26 Gy

Shielding

 Globe of eye should receive <15% prescribed skin dose, achievable with internal and external eye shields  Regions of curvature (e.g., nose, wrists, forearms, penis, scrotum) should receive <120% of dose with selective shielding

Adapted from: Jones GW, Kacinski BM, Wilson LD et al (2002) Total skin electron radiation in the management of mycosis fungoides: consensus of the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group. J Am Acad Dermatol 47:364 –370

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Figure 28.4 Typical patient orientation for TSEBT using the six-dual-field technique. Upper row (left to right): right anterior oblique (RAO), anteroposterior (AP), and left anterior oblique (LAO). Lower row (left to right): right posterior oblique (RPO), posteroanterior (PA), and left posterior oblique (LAO). A typical 2-day cycle would treat in the AP/RPO/LPO positions on day 1 and the PA/RAO/LAO positions on day 2 Source: Smith BD, Wilson LD (2003) Management of mycosis fungoides: part 2, treatment. Oncology (Williston Park). 2003 17:1419–428; discussion 1430, 1433. Figure used with permission 3 meters Treatment plane

Beam center line y Calibration point

+ 20°

x

- 20° Scatter and degrader

2

132 cm

Floor

Figure 28.5 Geometrical arrangement of the symmetrical dual-field treatment technique. Equal exposures are given with each beam. The calibration point dose is at (x = 0, y = 0) in the treatment plane. Source: Li Y, Lu JJ (2008) Cutaneous T-cell lymphoma and NK/T-cell lymphoma. In: Lu JJ, Brady LW (eds) Radiation oncology: an evidence-based approach. Springer, Berlin Heidelberg New York

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Toxicity Limited superficial RT is well tolerated. Some patients treated with higher doses may experience mild radiation dermatitis. The main toxicities of TSEBT are summarized in Table 28.11. Table 28.11 Toxicities of TSEBT Frequency

Description

Common (50–100%)

 Skin erythema, especially over areas of prior UV exposure  MF lesions become erythematous, then pigmented before resolution  Temporary alopecia  Temporary nail stasis  Some hand and feet edema

Rare (3–10%)

     

Very rare (<1%)

 Corneal tears from internal eye shields  Chronic nail dystrophy, chronic xerosis, partial permanent alopecia, fingertip dysesthesia

Minor epistaxis Blisters on fingers and feet Anhidrosis Parotiditis Gynacomastia Male infertility (related to perineum boost)

Follow-Up Active follow-up should be carried out by a multidisciplinary specialized team. Continued skin surveillance and biopsy of suspicious areas may be required to document relapse, to rule out transformation to a large cell variant, or to detect treatment-related skin cancers. Patients may also require longterm social and psychological support.

29

Primary Central Nervous System Lymphoma Marnee M. Spierer1 and Evan M. Landau 2

Key Points  Primary central nervous system lymphoma (PCNSL) is a rare malignancy that accounts for 2.5% of all brain tumors. This entity can involve the eyes and the entire central nervous system (CNS).  PCNSL presents with focal neurological deficits, neuropsychiatric symptoms, and increased intracranial pressure. Systemic symptoms are uncommon.  The initial diagnosis is based on brain magnetic resonance imaging (MRI) findings, and histological confirmation is needed via either vitreous biopsy, cerebral spinal fluid sampling (CSF), or a stereotactic brain biopsy.  Prognosis is highly dependent on patient age (>50 years) and performance status. Overall survival will vary and can be greater than 5 years for young patients with excellent performance status and less than 1 year for the elderly patients, with poor performance status.  PCNSL is a very radiation-sensitive malignancy; however, long-term survivors are rare in those who receive radiation alone. Great strides have been made with high-dose methotrexate (MTX)-based chemotherapy, with current median survival greater than 40 months.  Combination of MTX-based chemotherapy and whole-brain radiation therapy (WBRT) can yield devastating neurotoxicity, with some series reporting greater than 80% incidence in patients older than 60 years of age.  The current data for treatment are limited, with only two fully accrued randomized trial, and many heterogeneous phase II and retrospective series.  One recently presented abstract of a randomized trial of high dose MTX plus or minus WBRT demonstrated a benefit in progression free survival for WBRT but no overall survival benefit.  Current treatment trends include integration of newer chemotherapeutic/targeted agents with MTX-based chemotherapy and response-based indications for radiation therapy with possible dose de-escalation.

1

Marnee M. Spierer, MD () Email: [email protected]

2

Evan M. Landau MD Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_12, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Primary central nervous system lymphoma (PCNSL) is a rare malignancy. It is the sixth most common central nervous system (CNS) malignancy and it represents ~2.5% of all brain tumors and ~1% of all Non-Hodgkin’s lymphoma. There has been a threefold increase in incidence from 1973 to 1997. However, after peaking to an incidence of 10.2 per million in 1995, the incidence has decreased to 5.1 per million. The change in incidence parallels that of the AIDS epidemic. PCNSL patients are separated into two groups, immunocompetent and immunocompromised. Congenital or acquired immunodeficiencies are the only established risk factors (Table 29.1). Table 29.1 Risk factors of PCNSL Factor

Description

Age and gender

The overall incidence of diagnosis increases with age from 1 per 100,000 in the 55- to 64-year age group to a peak of 2.13 per 100,000 in the 75- to 84-year age group. The male to female ratio is 1.4:1

Immunodeficiency: HIV/AIDS

Prior to the advent of highly active retroviral therapy, HIV increased the incidence by 3,600 times AIDS-related PCNSL patients presents at younger ages than do immunocompetent patients

Solid tumor transplants

Chronic immunosuppression has been linked to PCNSL

Source: Jellinger KA, Paulus W et al. (1995) Primary central nervous system lymphoma - New pathological developments. J Neurooncol 24:33-36

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Anatomy PCNSL can involve any part of the leptomeninges, brain, spinal cord, or eyes, without visceral or lymph node involvement (Figure 29.1). Arachnoid Granulation Dural Sinus (Venous Blood) Sub Arachnoid Space Chorroid Plexus (Site of CSF Production) Lateral Ventricle Eye

Fourth Ventricle

Papilledema

Spinal Cord

Sub Arachnoid Space

Sub Arachnoid Space (Spinal Canal)

Optic Foramen Pituitary Gland

Figure 29.1 Anatomical structures involved in PCNSL Source: http://www.ihrfoundation.org/intracranial/hypertension/info/C16 Accessed on Aug. 22.2010

Pathology More than 90% of PCNSL are B-cell lymphoma (predominately diffuse large B-cell variant [DLBCL]) and <10% are T-cell lymphoma. The tumor likely arises from an extra neural site and migrates to the CNS, as systemic DLBCL is morphologically indistinguishable from the PCNSL variant. Most PCNSL DLBCL lesions are non-germinal center subtype with CD10-positive and/or Bcl-6-positive and negative MUM1 on immunohistochemical stating. However, this subclassification has not been shown to affect prognosis. (Source: Hattab EM, Martin SE et al (2010) Most primary central nervous system diffuse large B-cell lymphomas occurring in immunocompetent individuals belong to the nongerminal center subtype: a retrospective analysis of 31 cases Modern Pathology 23, 235-243; Raoux D, Duband S et al (2010) Primary central nervous system lymphoma: Immunohistochemical profile and prognostic significance, Neuropathology 30(3):232-40)

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Pattern of Spread PCNSL is a local disease that involves the leptomeninges, brain, eyes, and cerebral spinal fluid (CSF). Systemic involvement is uncommon (Table 29.2).

Table 29.2 Routes of spread of PCNSL Route

Description

Local extension

 Two thirds of patients will have a single lesion, which is  supratentorial 87% of the time  Twenty percent of patients will have ocular involvement  at presentation  16–40% of patients will present with leptomengeal in volvement  Of recurrences, 84% are at the primary site. However, the  entire CNS tract (eyes, CSF, and leptomeninges) is at risk for failure

Systemic and lymphatic spread

 Systemic disease and lymphatic disease is an uncommon event (<5%) at presentation  The testicular chemotherapy “sanctuary” may make testicular recurrence more common

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Clinical Presentation The most common presenting symptoms of PCNSL include focal neurological deficits, neuropsychiatric symptoms, or symptoms related to increased intracranial pressure (Table 29.3). B symptoms are uncommon. Table 29.3 Common presentations of PCNSL Area

Brain

Ocular region

Particulars     

Focal deficit (70%) Neuropsychiatric symptoms (43%) Increased intracranial pressure (33%) Seizures (14%) Systemic illness (febrile respiratory or gastrointestinal symptoms) (7%)

Vitreous involvement (4%), i.e., “floaters,” blurred vision, diminished visual acuity, and painful, red eyes

Source: Bataille B, Delwail V, Menet E et al (2000) Primary intracerebral malignant lymphoma: a report of 248 cases. J Neurosurg 92:261–266

Diagnosis Once suspected on a magnetic resonance imaging (MRI) scan, there are two parts to the workup of PCNSL. First, a pathological diagnosis needs to be established, and second, a baseline evaluation for treatment direction needs to be performed (Figure 29.2).

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If possible, hold corticosteroids*

Diagnosis CSF sampling Vitreous biopsy (if slit-lamp positive) Stereotactic brain biopsy**

Baseline Evaluation Complete medical, neurological, ophthalmologic (dilated eye and slit lamp), lymph node, and testicular exams Record prognostic factors (age and ECOG PS) Serial cognitive assessment mini mental exam

1. CBC 2. Serum chemistry 3. LFT 4. HIV 5. LDH 6. 24 hour urine collection for creatinine**** 7. CSF Fluid -cell count, protein levels, cytology, flow cytometry, immunoglobulin heavy chain rearrangement studies, and IgH PCR

Recommended Brain T1 and T2-weighted MRI with Gadolinium. CT C/A/P with contrast and testicular ultrasound in elderly males. Optional CT (if MRI contradicted) PET/CT (may replace CT C/A/P and ultrasound)*** MRI spine if CSF positive

Pathology Bone marrow biopsy Lab and Pathology Studies

Imaging Studies

Multidisciplinary Treatment * Steroids before biopsy may obscure diagnosis. ** If the CSF or vitreous biopsy is positive, then stereotactic brain biopsy is not needed *** PET may increase diagnosis of systemic disease **** Assessment of 24-h urine collection for creatine is important for a patient undergoing high-dose methotrexate

Figure 29.2 Clinical presentation and MRI suggestive of PCNSL

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Staging PCNSL is stage IE according to the Ann Arbor Staging System (Chap. 25, “Non-Hodgkin’s Lymphoma,” Table 25.7).

Prognosis The median survival is 1.5–2 months without treatment. The overall prognosis of this illness has improved significantly with the advent of effective MTX-based chemotherapy. Two major prognostic scoring systems have been developed for patients treated with MTX-based chemotherapy (Table 29.4). However, these scoring systems are derived from patients on clinical trials, and they likely perform better than do the overall population.

Table 29.4 Scoring systems for prognosis of PCNSL System MSKCCa

IELSG a

b,c

Factor and criteria

Survival (years)

Class 1: Age <50

5.2 years

Class 2: Age ≥ 50 and KPS > 70

2.1 years

Class 3: Age ≥50 and KPS < 70

0.9 years

Low (0 –1)

2 years, 85%

Moderate (2–3)

2 years, 57%

High (4 –5)

2 years, 24%

Source: Abrey LE, Ben-Porat L, Panageas KS et al (2006) Primary central nervous system lymphoma: the Memorial Sloan–Kettering Cancer Center prognostic model. J Clin Oncol 24:5711–5715 b International Extranodal Lymphoma Study Group (IELSG) uses (1) age >60, (2) ECOG >1, (3) elevated LDH, (4) elevated CSF, and (5) involvement of the deep structures of the brain c Source: Ferreri AJM, Blay JY, Reni M et al (2003) Prognostic scoring system for primary CNS lymphomas: the international extranodal lymphoma study group experience. J Clin Oncol 21:266 –272

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Response Criteria Response to initial therapy determines subsequent treatment of PCNSL. An international workshop designed a response criteria in order to standardize care and help clinical decision making (Table 29.5). Table 29.5 Radiological response after initial treatment Response

Detail

CR

No contrast enhancement

CRu

Minimal abnormality

PR

50% decrease in enhancing tumor

POD

25% increase in lesion or new disease

Source: Abrey LE, Batchelor TT, Ferreri MG et al (2005) Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034 –5043

Treatment PCNSL is a very radiation-responsive disease, which was historically treated with radiation alone, with few cures and overall poor outcome. However, significant strides have been made in overall survival with a MTX-based chemotherapy regime (Table 29.6; Figures 29.3 and 29.4). Secondary to concerns of radiation-induced toxicity, the role of radiation has been decreasing, and current trends include response-based treatment, dose de-escalation, and withholding of radiation. Only two fully accrued randomized trial has been performed, and current recommendations are based on phase II single-arm trials, which have inherent heterogeneity (Tables 29.7 and 29.8). Definitive evidence-based guidelines are still lacking. These guidelines are written for the immunocompetent patients. Table 29.6 Treatment modalities for PCNSL Type

Description

Surgery Indications

 No survival benefit to surgical resection  Surgical debulking for patient with large, single space– occupying lesion with medical refractory deteriorating neurological status

Facts

 PNCSL is a multifocal disease and the entire CNS is at risk

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Table 29.6 (continued) Type

Description

Chemotherapy/targeted therapy Indications

 Standard of care for definitive treatment (with or without WBRT)  Salvage therapy for progression or recurrent of disease  Definitive treatment for ocular lymphoma

Facts

 High dose MTX (>1 g/m2) can overcome the blood–brain barrier and provided cytotoxic levels for effective tumor kill. MTX-based chemotherapy is indicated for all patients with KPS > 40 and creatinine clearance >50 ml/min  In a comparison of prospective series, this regimen has led to improvement in median survival of patient (>30 months) over WBRT alone (<12 months)  MTX (3.5 g/m2) plus cytarabine (2 g/m2) statistically improves freedom from failure with a trend toward improved survival compared with MTX alone  Multiple MTX-based combination chemotherapy regimens are is currently employed, and active agents include cytarabine, procarbazine, vincristine, carmustine, teniposide, methylprednisolone, idarubicin, and thiotepa  MTX >3 g/m2 has adequate concentration in the CSF for leptomeningeal coverage. However, if the CSF is positive, then intrathecal MTX is needed  Salvage chemotherapy and targeted agents have shown a response rate of 53 to 31%. Active agents include topotecan, rituximab, and temozolomide  Ocular lymphoma can respond to intraocular chemotherapy

Radiation therapy Indications

 Definitive treatment following chemotherapy  Definitive treatment alone in patients not candidates for MTX-based chemotherapy  Salvage therapy  Definitive treatment for ocular lymphoma

Treatment

 WBRT with or without boost to target  Response-based doses of radiation: non CR does of 45 Gy (1.8–2 Gy), and CR dose of 23.6 –36 Gy (1.5–2 Gy)  Older patients (>60 years) when treated with MTX and WBRT have reported grade 5 neurotoxicity, as such, consider lowering the total dose or withholding radiation

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Definitive Treatment KPS ≥ 40 Creatinine clearance <50 ml/min

Induction Chemotherapy High-dose MTX-based chemotherapy regimen plus cytarabine If CSF positive or spinal MRI positive, then intrathecal MTX

CR

Yes

No

WBRT of 24-36 Gy (1.5-2 Gy) Consider withholding treatment for patients older than 60 years of age

WBRT 23-36 Gy (1.8-2 Gy) Boost to gross residual disease to 45 Gy (1.8-2 Gy) RT to globe if positive after induction chemotherapy

Recommend Follow-Up: History and Physical Mini-Mental Status Exam MRI Scans

Figure 29.3 Proposed algorithm for treatment using methotrexate

Definitive Treatment KPS ≤ 40 and/or Creatinine clearance <50 ml/min

WBRT to 45 Gy (1.8–2 Gy) RT to Globe (if positive on slit lamp) Non-MTX Chemotherapy

Recommend Follow-Up: History and Physical Mini-Mental Status Exam MRI Scans

Figure 29.4 Proposed algorithm for treatment without methotrexate

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Table 29.7 Clinical evidence of definitive treatment of PCNSL Trial

Results

G-PCNSL-SG1 MTX +/- WBRTa

 Multi-institutional non inferiority study of 551 patients who received MTX (4 g/m2) (before 2007) and MTX+ Ifosamide (1.5 g/m2) (2007-9). Randomized before treatment to WBRT (A) arm or not (B) arm. If CR then A arm 45 Gy (1.5 Gy) vs. B arm watch and wait. If no CR then A arm 45 Gy versus B arm HD-ara-c.  318 for per protocol analysis, overall survival showed no difference. (32.4 (A) vs. 37.1 months (B) p=0.7)  Progression free survival showed a benefit for WBRT for CR 36.3 (A) vs. 21.5 months (B) (p=0.038) and for non CR 5.6 (A) vs. 3 months (B) (p=0.003)  Critique of this trial include 25% of patients were removed from all analysis only 318 out of 551 were treated per protocol. Treatment groups appeared unbalanced as CR group 56 A vs. 96 B and in non CR 98 A vs. 68 B.

RTOG 8315: WBRT aloneb

 Multi-institutional phase II trial of 41 patients treated with WBRT 40 Gy with a 20-Gy boost (tumor + 2 cm). No MRIs were performed  Of the 26 patients with posttreatment CT scan, a 61% CR rate was noted  Median survival as 11.6 months, and 61% recurred locally  Of local recurrences, 88% occurred in the 60-Gy region

RTOG 93-10: MPV c

 Multi-institutional phase II trial of 102 patients treated with 5 cycles of MTX (2.5 g/m2), vincristine IV (1.4 mg/m2), procarbazine (100 mg/m2/day), intrathecal MTX, leucovorin (20 mg/10 mg), and Decadron. Chemotherapy was followed by sequential WBRT and cytarabine (3 mg/m2/day)  Initially, WBRT dose was 45 Gy for all patients, but was adjusted for CR to 36 Gy in 1.2 Gy twice daily  If ocular lymphoma was present, both eyes were included in the RT field to 36 Gy at 1.8 Gy per fraction  Of the patients who did not have a complete surgical resection, there was a 58% CR rate to chemotherapy  At 56 months follow-up, 29% had a relapse (95% were local), progression-free survival of 24 months, and overall survival of 36.9 months  For patients older than 60 years of age as compared with younger patients, overall median survival of 21.8 versus 50.4 months (p < 0.001), respectively ▶

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Table 29.7 (continued) Trial

Results

Abrey: MPV plus WBRT d

 Single-institution study of 52 patients treated with 5 cycles of MTX (3.5 gm/m2), intrathecal MTX, procarbazine (100 mg/ m2/day), and vincristine (1.4 mg/m2) (MPV), followed by sequential WBRT of 45 Gy and cytarabine (3 g/m2)  48 patients were assessed for response, with a CR rate of 87%  Overall median survival of 60 months  83% of patients >60 years of age who received WBRT developed late neurotoxicity, of which 90% died. Of patients ≤60 years of age who received WBRT, 6% developed late neurotoxicity  No difference in survival was noted for patients > 60 years of age who did not receive WBRT versus those who did receive WBRT.

Shah and Correa: R-MPV plus WBRT e

 Single-institution trial of 30 patients treated with 5–7 cycles of rituximab (500 mg/m2), MTX (3.5 gm/m2) (intrathecal MTX if CSF positive), procarbazine (100 mg/m2/day), and vincristine (1.4 mg/m2) (R-MPV)  WBRT if CR at 23.4 Gy, and others at 45 Gy, and treated patients >60 years of age. Eyes were included if positive for lymphoma. Followed by cytarabine (3 g/m2/day)  90% completed treatment, of which a 77% CR rate was recorded  Relapse rate for CR was 67%, and the local control in CNS for 23.4 Gy was 85%.  2-year overall median survival was 67%, and progressionfree survival was 57%  No incidence of neurotoxicity or significant cognitive decline for patients with 23.4 Gy at 2-year follow-up

Bessel: CHOD/ BVAM plus WBRT, 45 versus 30.6 Gyf

 Two consecutive multi-institutional phase II trials with a total of 57 patients with identical chemotherapy of cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), vincristine (1.4 mg/m2), dexamethasone (4 mg), carmustine (100 mg/m2), vincristine (1.4 mg/m2), MTX (1.5 g/m2), and cytarabine (3 g/m2) (CHOD/BVAM)  Followed by in the 1st trial, 45 Gy with boost and in the 2nd trial, CR of 30.6 Gy for 17 fractions if no CR 45 Gy with boost. Spinal RT if CSF was positive  Both trials had similar patient characteristics, except trial II had more patients with multiple lesions  CR rate of 68 and 77% in trials I and II, respectively  The lower dose arm had a 70% incidence of relapse versus the higher dose arm 29% incidence (p = 0.02)  No evidence of neurotoxicity in low dose, but the high dose had 60% rate of late mild cognitive dysfunction

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Table 29.7 (continued)

a

Trial

Results

Poortmans: MBVP g

 Phase II multicenter trial of 52 patients treated with 2 cycles of MTX (3 g/m2), teniposide (100 mg/m2) carmustine (100 mg/m2) methylprednisolone (60 mg/m2), two intrathecal MTX, cytarabine (40 mg), and hydrocortisone (25 mg) (MBVP)  WBRT of 40 Gy (eyes included if positive)  Response rate of 77% after chemotherapy and 81% after WBRT  32% failed, and 25% failed in the brain  Overall median survival was 17 months  10% incidence of episodes of toxic death during treatment and 1 episode of late leukoencephalopathy death

Ferreri: MATILDE plus WBRT h

 Phase II trial of 41 patients treated with 3 cycles of MTX (3.5 g/ m2), cytarabine (1.7–2 g/m2), idarubicin (13–15 mg/m2), thiotepa (20–25 mg/m2) (MATILDE), followed by WBRT CR of30 Gy, PR of 36 Gy, SD/POD of 45 Gy with a 9 Gy boost  Response rate of 76% before chemotherapy and 83% after WBRT  58% failed and 88% of tumors were at primary site  Overall median survival was 49 months

Batchelor: NABTT 96-07, MTX alonei

 Phase II multicenter trial of 25 patients treated with 8 g/m2 of MTX until CR  No adjuvant WBRT  52% CR rate and total response rate was 74%  Progression-free survival was 12.8 months, and overall median survival was 55.4 months  High rate (26%) of total failures was systemic  No grade 5 MTX-related toxicity

Source: Thiel E, Korfel A et al (2010) Should whole brain radiotherapy be considered standard of care in newly diagnosed primary central nervous system lymphoma? The GPCNSL-SG1 randomized phase IV trial. J Clin Oncol 28:155 (suppl; abstract 2008); Ferreri AJM, Reni M, Foppoli M et al (2009) High-dose cytarabine plus high dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma a randomised phase 2 trial. Lancet 374:1512–1520 b Source: Nelson DF, Martz KL, Bonner H et al (1992) Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 23:9–17 c Source: DeAngelis LM, Seiferheld W, Schold SC et al (2002) Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20:4643–4648 d Source: Abrey LE, Yahalom J, DeAngelis LM (2000) Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18:3144 –3150 ▶

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Table 29.7 (continued) e Sources: Shah GD, Yahalom J, Correa DD et al (2007) Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25:4730–4735; Correa DD, Rocco-Donovan M, DeAngelis LM et al (2009) Prospective cognitive follow up in primary CNS lymphoma patients treated with chemotherapy and reduced dose radiotherapy. J Neurooncol 91:315–321 f Source: Bessell EM, Lopez-Guillermo A, Villa S et al. Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol 20: 231–236 g Source: Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H et al (2003) High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group phase II trial 20962. J Clin Oncol 21:4483–4488 h Source: Ferreri AJM, Dell’Oro S, Foppoli M et al (2006) MATILDE regimen followed by radiotherapy is an active strategy against primary CNS lymphomas. Neurology 66:1435–1438 i Source: Batchelor T, Carson K, O’Neill A et al (2003) Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 21:1044–1049 Table 29.8 Clinical outcomes of definitive treatment of PCNSL Trial

RTOG 83-15 WBRT RTOG 93-10 MTX V P WBRT

Patients Follow(n) up (months)

Response Survival Local Neurorate (CR + (months) control toxicity PR) (%)

41

80%

102

54

56

94%

11.6

37

39%

5 CNS toxicities on CT imaging

46%

15%lLeukoencephalopathies 66% fatalities

IELSG 20 MTX WBRT MTX C WBRT

79

30

40% 69%

3 years 32% 46%

40%

In patients without recurrence or death, MMSE improvement of 1+

Shah RMTXVP +WBRT

30

37

93%

37

70%

No neurotoxicity for 23.4 Gy

NABTT 96-07 MTX

25

78

74%

23

NA

5%

WBRT: whole-brain radiation; MTX: methotrexate; V: vincristine; P: procarbazine; C: cytarabine; R: rituximab

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Salvage Treatment Approximately 35–60% of patients will fail first-line therapy and require salvage treatment (Figure 29.5). In patients who have not received wholebrain radiation therapy (WBRT) as part of the initial therapy, WBRT in the salvage setting has an excellent response rate. Multiple chemotherapy agents show promise including temozolomide, rituximab, topotecan, and high-dose chemotherapy with stem cell rescue (Table 29.9). The presented data are from phase II and retrospective trials (Table 29.10).

Salvage Treatment

Prior WBRT Yes

No

Chemotherapy-Targeted Agents Stem Cell Transplant

WBRT 45 Gy Chemotherapy-Targeted Agents Stem Cell Transplant

Figure 29.5 Proposed algorithm for salvage treatment

Table 29.9 Outcome after salvage treatment Treatment

Response rate (CR + PR) (%)

OS (months)

WBRT

74 –79%

11–16

Rituximab and temozolomide

53%

14

Topotecan

40%

33

High-dose chemotherapy plus stem cell rescue

50%

18

Results based on clinical trials detailed in Table 29.10

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Table 29.10 Salvage treatment

a

Trial

Results

Nguyen et al (WBRT)a

 Single institution study of 27 patients who failed MTX of 3.5 or 8 g/m2 alone with no prior WBRT (10 with tumor relapse and 17 with refractory tumor). Salvage treated with WBRT with mean dose of 36 Gy, and 7 patients received a boost of 10 Gy  74% response rate and overall median survival after WBRT was 10.9 months.  In patients with a mean dose of WBRT > 36 Gy, 4 patients developed late neurotoxicity, and no neurotoxicity was noted at ≤36 Gy (p = 0.04)

Hottinger et al (WBRT)b

 Single-institution retrospective review of 48 patients initially treated with MTX-based chemotherapy. 50% received a CR and 50% had a refractory disease. Salvage treatment with WBRT median dose of 40 Gy  79% response rate and median survival from WBRT was 10 months  10 patients developed neurotoxicity with significant KPS decline, but incidence was significantly lower if greater than 6 months elapsed since MTX

Enting et al (rituximab and temozolomide)c

 Single-institution retrospective review of 15 patients who had refractory or recurrent disease treated with temozolomide at 100 –200 mg/m2 and rituximab at 750 mg/m2  53% response rate and overall median survival of 14 months  No grade 4 toxicity was noted

Voloschin et al (Topotecan)d

 Prospective phase II trial of 15 patients with refractory or relapsed disease treated at two institutions, with topotecan at 1.5 mg/m2  40% response rate and overall median survival was 33 months. However, progression-free survival was 60 days  12/15 patients were salvaged with radiation (SRS or WBRT)

Soussain et al (high-dose chemotherapy plus stem cell rescue)e

 Prospective phase II trial of 43 patients who had failed MTXbased chemotherapy. The regimen consisted of cytarabine at 2 g/m2/day, and etoposide at 200 mg/m2/day (CYVE), followed by peripheral blood stem cell harvest. Chemosensitive patients then received intensive chemotherapy of thiotepa at 250 mg/m2/day plus busulfan at 10 mg/kg and cyclophosphamide. Hematopoietic stem cells were re-infused (IC+HCR)  Overall median survival was 18.3 months and there was a 50% response rate  5 patients had late neurotoxicity after IC+HCR

Source: Nguyen PL, Chakravarti A, Finkelstein DM et al (2005) Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol 23:150715–13

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Radiation Therapy Technique Radiation Therapy for Definitive and Salvage Treatment The target volume is the whole brain from C2 to C3 interspace and including the posterior third of the orbit. For incomplete responders to induction chemotherapy, a smaller boost volume to the gross residual tumor may be used. However, in a patient receiving radiation without chemotherapy, WBRT to full dose is preferred. A head immobilization device with thermoplastic mask should be used, and radio-opaque markers should be placed at the ocular canthi. A computed tomography (CT) scan simulation with 2.5- to 5-mm cuts should be performed to the bottom of C6.

Dose and Treatment Delivery The entire brain should be treated to 24 –36 Gy in 1.8- to 2-Gy fractions. For a patient with an incomplete response to induction chemotherapy, a boost is needed to gross disease. In a patient with ocular involvement after induction chemotherapy, both eyes should be included in the field for a total dose of 36 Gy in 2 to 1.8-Gy fractions. In a patient receiving radiation without chemotherapy, 45 Gy should be given to the entire brain. For the WBRT, laterally, equally weighted opposed fields should be used. Photon energy can range from 6 to 10 MV, and custom made blocks or multileaf collimator should be used. Care should be taken to properly cover the anterior temporal bone and cribriform plate. The anterior field edges of the lateral beams should be coplanar to minimize divergence into the eyes. For the boost plan, the patient should be treated with a conformal threedimensional (3D) or intensity-modulated radiation therapy (IMRT) plan using three to five fields. T1- and T2-weighted MRI with contrast should be fused with the planning CT. The Gross residual tumor on MRI and CT scans

b

Source: Hottinger AF, DeAngelis LM, Yahalom J et al (2007) Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 69:1178 –1182 c Source: Enting RH, Demopoulos A, DeAngelis LM et al (2004) Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology 63:901–903 d Source: Voloschin AD, Betensky R, When PY et al (2008) Topotecan as salvage therapy for relapsed or refractory primary central nervous system lymphoma. J Neurooncol 86:211–225 e Source: Soussain C, Hoeng-Xuam K, Taillandier L et al (2008) Intensive chemotherapy followed by hematopoietic stem cell rescue for refractory and recurrent primary CNS and intraocular lymphoma societe francaise de greffe de moelle osseuse-therapie cellulaire. J Clin Oncol 26:2515 –2518

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should be contoured as gross tumor volume (GTV). The lesion may extend beyond the imaging findings, and as such, large, uniform clinical target volume (CTV) expansion of 1–1.5 cm should be used for microscopic disease. The planned target volume (PTV) margin should account for setup uncertainty.

Normal Tissue Tolerance The dose prescribed for PCNSL is below the normal tissue tolerance for almost all organs at risk (OAR) in the brain, and the necessity to treat the entire brain allows for minimal flexibility in sparing. Neurotoxicity of leukoencephalopathy remains the feared toxicity, and the OAR likely responsible for this toxicity is the entire brain. As such, in boost planning, the normal brain should be spared. OARs in radiation therapy for brain tumor are detailed in Chap. 31, “Adult Glioma,” Table 31.5.

Follow-Up Long-term follow-up is indicated in all PCNSL patients. Disease recurrence and neurotoxicity should be the focus of follow-up. Effective salvage treatment exists necessitating diligent follow-up (Table 29.11). Table 29.11 Suggested follow-up protocol for posttreatment PCNSL Schedule

Frequency

First follow-up

 2–4 weeks posttreatment 

Year 1

 Every 3 months 

Year 2

 Every 4 months 

Years 3–5

 Every 6 months 

Years 5+

 Annually 

Examinations History and physical

 Complete history and physical including a MMSE

Imaging study

 MRI with gadolinium

Pathology

 For patients with initial positive vitreous or CSF, repeat lumbar puncture and ophthalmologic examination should be repeated as needed

MMSE: mini-mental state examination Source: Abrey LE, Batchelor TT, Ferreri MG et al (2005) Report of an international work shop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034 –5043

Section IX Tumors of the Central Nervous System

IX 30

Meningioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873 Allison M. Quick, Eric L. Chang and Simon S. Lo

31 Adult Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895 Bernadine Donahue 32 Pituitary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923 Keith H. C. Lim and Simon S. Lo

30

Meningioma Allison M. Quick1, Eric L. Chang2 and Simon S. Lo3

Key Points  Meningiomas are the most common benign intracranial tumor in adults and tend to be slow growing, and usually have favorable long-term prognoses.  The majority of meningiomas are benign, but 5–10% of cases are atypical or malignant, carrying an unfavorable long-term outcome.  Many meningiomas are found incidentally on imaging, but they can present with symptoms such as headaches, vision changes, or cranial nerve impairment.  The treatment of choice for meningiomas is maximal surgical resection.  Many meningiomas cannot be completely resected, or are unresectable because of their location adjacent to critical structures.  There are no randomized trials to determine the standard treatment for meningiomas, but retrospective studies have demonstrated improved local control with gross total resection over subtotal resection.  Adjuvant radiation is recommended after subtotal resection of benign meningiomas and for all atypical and malignant meningiomas.  Radiation can be delivered definitively for unresectable tumors and recurrent meningiomas to reduce local recurrence rates.  Optic nerve sheath meningiomas represent 1–2% of all meningiomas, and radiation therapy is an alternative treatment option because of the risk of morbidity with surgery.  Stereotactic radiosurgery (SRS), intensity-modulated radiation therapy (IMRT), fractionated stereotactic radiotherapy (FSRT), and proton-beam therapy are new radiation technologies with promising outcomes for treatment of meningioma.  Metastatic dissemination is rare but has been reported.

1

Allison M. Quick, MD Email: [email protected]

2

Eric L. Chang, MD Email: [email protected]

3

Simon S. Lo, MD () Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_13 © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology The incidence of meningiomas is approximately 6 per 100,000 individuals in the USA, and there are approximately 33,000 meningioma cases worldwide per year. Meningiomas make up 20–30% of all intracranial tumors and are the most common intracranial tumor in adults. While most meningiomas arise sporadically, several risk factors have been implicated in the etiology of meningiomas (Table 30.1). Table 30.1 Risk factors of meningioma Type

Description Age and gender: peak incidence in the 6–7th decade of life then continues to rise; twice as common in females than males Past medical history: females with a history of breast cancer have an increased risk of developing meningiomas

Patient related

Ionizing radiation: after cranial irradiation, actuarial risk of meningioma is 0.53% at 5 years and 8.18% at 25 years; typically arise 20–30 years after exposure to low- or high-dose radiation Hormone factors: progesterone and estrogen receptors identified in 70 and 30% of all meningiomas; androgen receptors found in 40% Genetic predisposition: associated with neurofibromatosis type 2, multiple endocrine neoplasia type1, and deletion of chromosome 22

Anatomy Meningiomas are intracranial or intraspinal tumors that arise from the meningeal coverings. Ninety percent of meningiomas occur intracranially, and the remaining 10% occur in the spine. The most common intracranial locations include the following: cerebral convexity, falx cerebri/parasagittal sinus, sphenoid wing, base of skull, and posterior fossa.

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Pathology Meningiomas arise from arachnoid cap cells, which are the epithelial cells of the arachnoid villi. They are macroscopically well circumscribed, firm, and tan or gray. Microscopically, they have a bland, whorled appearance, with or without psammoma bodies. Benign meningiomas have little mitoses or anaplasia. There are several histological variants including fibrous, transitional, clear cell, chordoid, rhabdoid, and angiomatous. The tumors are graded according to the World Health Organization (WHO) classification (Table 30.2). Table 30.2 World Health Organization grading of meningioma Grade (%)

Type

Characteristics

Benign

 Slow growing, recurrence risk  low  <4 Mitoses per HPF   Excludes clear cell, chordoid,  papillary, or rhabdoid type

 10-year PFS  approximately 80%

II (15– 25)

Atypical

 More aggressive than benign   Characterized by ≥4 mitoses  per HPF, brain invasion, clear cell or chordoid type, or 3 of 5 of the following: sheeting architecture, high N/C ratio, macronucleoli, hypercellularity, spontaneous necrosis

 7–8 × increased  recurrence risk compared to grade 1  10-year DFS  40–60%

III (1–4)

Anaplastic/ malignant

 Highly invasive; worse prog nosis  ≥20 mitoses HPF, anaplasia, or  papillary or rhabdoid type

 Median RFS  <2 year

I (70– 85)

Long-term outcomes

HPF: high-power fields, PFS: progression-free survival, DFS: disease-free survival, N/C: nuclear/cytoplasmic, RFS: recurrence-free survival

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Routes of Spread Meningiomas spread via local extension, regional lymph nodes, and cerebrospinal fluid. Hematogenous spread to distant sites is rare (Table 30.3). Table 30.3 Routes of spread in meningioma Type

Description

Local extension

 Meningioma can invade pia mater, dural venous sinus,  brain, or bone (particularly the sphenoid wing)

Regional lymph nodes

 Lymphatic spread can occur from skull or scalp involvement or from lymph nodes around the cranial nerves

Distant metastasis

 Distant metastases are rare in benign tumors but occur in 5% of atypical and up to 30% of malignant meningiomas (most common in papillary histology)  Sites of metastasis include the lung (most common), bone, liver, and abdominal viscera  Access to cerebral spinal fluid (CSF) occurs with dural venous sinus or cranial nerve invasion and can result in drop spinal metastasis and/or hematogenous spread.

Diagnosis, Staging, and Prognosis Clinical Presentation Meningiomas may be asymptomatic and are often discovered as incidental findings on a head computed tomography (CT) or brain magnetic resonance images (MRIs). Other meningiomas cause signs and symptoms, depending on their location of origin (Table 30.4). Large tumors can lead to increased intracranial pressure. The most common symptoms are headache and hemiparesis. Diagnosis is typically made radiographically. On CT scan, meningiomas appear extra-axial, and they are well circumscribed with homogenous contrast enhancement. On MRI, they appear isointense on T1-weighted sequence and isointense to hyperintense on T2 with homogenous contrast enhancement. Migration of cells along dura appears as tail of enhancement and is characteristic but not pathognomonic. Malignant meningiomas are diagnosed both based on clinical features, such as aggressive growth or recurrence, and histopathologic features.

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Table 30.4 Commonly observed signs and symptoms of meningioma, based on location of origin Location of origin

Sign/symptom

Cerebellopontine angle

Cranial nerve symptoms

Cerebral convexity

Headache or seizure

Sphenoid wing or optic nerve

Vision loss

Prognosis Prognosis depends on the location of the meningioma, extent of surgical resection, and histopathology (benign or malignant). Patients with gross total resection (GTR) and benign histology have better prognosis than have those with subtotal resection (STR) and atypical or malignant histologies. Benign meningiomas have a recurrence rate of approximately 7–20%, as compared with 40% for atypical and 50–80% for malignant histologies. The survival after diagnoses of a malignant meningioma is about 2 years (Table 30.5). Table 30.5 Local control and survival rates for GTR versus STR in retrospective studies Author

Extent of resection

Local control rate (%)

Survival (%)

5 years

10 years

15 years

5 years

10 years

15 years

Condraa

GTR STR

93% 53%

80% 40%

76% 30%

95%b 83%

93 66

88% 51%

Mirimanoffc

GTR STR

93% 63%

80% 45%

68% 9%

83%d

77

69%

Stafforde

GTR STR

88% 61%

75% 39%

– –

88%f 61%

75 39

– –

GTR: gross total resection, STR: subtotal resection a Source: Condra KS, Buatti JM, Mendenhall WM et al (1997) Benign meningiomas: primary treatment selection affects survival. Int J Radiat Oncol Biol Phys 39:427–436 b Cause-specific survival c Source: Mirimanoff RO, Dosoretz DE et al (1985) Meningioma: analysis of recurrence and progression following neurosurgical resection. J Neurosurg 62:18 d Absolute survival e Source: Stafford SL, Perry A, Suman VJ et al (1998) Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988. Mayo Clinic Proc 73:936–942 f Progression-free survival

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Treatment Surgical resection is the initial treatment of choice for meningiomas (Table 30.6). GTR is attempted as definitive treatment for all benign meningiomas (Table 30.7). STR is correlated with increased recurrence rates and worse long-term outcomes. Because of the richly vascular nature of meningiomas, preoperative angiography and embolization may be utilized. Some meningiomas are located in areas that are surgically unresectable or that carry high risk of morbidity if aggressive resection is attempted. Surgeons must weigh the risks of surgical morbidity of a GTR in these areas against the risk of local recurrence with incomplete surgical resection.

Table 30.6 Treatment modalities used in meningioma Type

Description

Surgical resection Indication

 Initial treatment of choice if located in a surgically resectable location

Facts

 ≈ 1/3 of meningiomas are unresectable or incompletely resected due to location (skull base, cavernous sinus, CPA) or size  Surgery involves resection of tumor, involved dura mater, and any involved soft tissue or bone  85–90% of tumors in the cerebral convexity or parasagittal falx region will have GTR, whereas tumors in the sella, sphenoid ridge, posterior fossa, cavernous sinus, clivus, and CPA carry a higher risk of morbidity with attempted GTR  GTR often difficult for grades II and III tumors because of involvement of dura mater or brain invasion  Surgery is recommended over radiation if significant mass effect is present

Radiation therapy

Indications

 Adjuvant therapy after subtotal resection of benign meningioma and for all atypical or malignant histologies  Definitive treatment for unresectable or recurrent tumors after surgery or if unresectable  Optic nerve sheath meningiomas

Techniques

 EBRT with 3DCRT  SRS, IMRT, FSRT, and proton-beam therapy are new advances with promise for treatment of meningiomas

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Table 30.6 (continued) Type

Description

Systemic therapy

Indications

 No clear role for systemic therapy  Systemic therapy been used for recurrent or progressive tumors after radiation  Several emerging therapies are being investigated

Medications

 Cyclophosphamide/adriamycin/vincristine and interferon α-2b have demonstrated modest benefit, and hydroxyurea has had conflicting efficacy in trials  Hormonal therapy, such as tamoxifen and RU486 (mifepristone) have been studied because of the high expression of hormone receptors. Anti-estrogen therapy has been mostly ineffective, but anti-progesterone therapy has resulted in greater than a 50% response to therapy  EGFR inhibitors and other molecularly targeted therapy are currently being investigated in clinical trials

CPA: cerebellopontine angle tumors, GTR: gross total resection, STR: subtotal resection, EBRT: external-beam radiation therapy, 3DCRT: three-dimensional conformal radiation therapy, SRS: stereotactic radiosurgery, IMRT: intensity-modulated radiation therapy, FSRT: fractionated stereotactic radiotherapy, EGFR: epidermal growth factor receptor

Table 30.7 Grading of surgical resection with the Simpson criteria and corresponding recurrence rates Simpson grade

Extent of resection

Recurrence rate (%)

I

Complete tumor resection and removal of dural attachments and abnormal bone

II

Complete tumor resection and coagulation of dural attachment

19%

II

Complete tumor resection without removal or coagulation or dural attachment or extradural extensions

29%

IV

Partial tumor resection

40%

V

Decompression with or without biopsy

NA

9%

NA: not applicable Source: Simpson D (1957) The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 20:22–39

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Retrospective studies support the use of adjuvant radiation after STR and for aggressive histologies, but there have been no randomized trials to determine indications for radiation therapy (RT). A treatment algorithm based on our current clinical evidence is shown in Figure 30.1.

Meningioma

Asymptomatic and in noncritical location

Observation/serial imaging every 4-6 months

Symptomatic, progressive, in critical location

Operable

GTR

Inoperable or patient refuses surgery

STR

Grade I

Grade II/III

Observation

Adjuvant RT

Grade I

ONSM

Definitive RT

Grade II/III

Adjuvant RT

GTV = enhancing tumor on contrast enhanced MRI (Figure 30.3) CTV = GTV PTV = CTV plus 0.3–0.5 cm (Figure 30.4) Smaller PTV margins may be appropriate when using fractionated stereotactic radiation therapy (FSRT), depending on the setup accuracy of the stereotactic system (typically 0.2 cm) PTV = GTV in SRS NSM = Optic nerve sheath meningioma

Figure 30.1 A proposed treatment algorithm for meningioma

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Treatment of Benign Meningioma Maximal surgical resection is the primary treatment for benign meningioma. The local recurrence rate at 10 years for benign histology is approximately 20–25% with complete surgical resection, and 60% after STR without adjuvant radiation. Adjuvant radiation for STR has resulted in improved local control and progression-free survival rates (Table 30.8). Table 30.8 Selected retrospective studies supporting postoperative RT after subtotal resection of benign meningioma Author

Description

Glaholma

 186 patients with intracranial meningiomas including   117 benign, 28 aggressive benign, 41 other  32 inoperable; 23 total tumor resection, 82 subtotal resection (microscopic disease) and 46 partial resection (gross residual disease)  EBRT dose: 50–55 Gy in 30–33 fractions to preoperative tumor  volume plus 2- 4-cm margin  Benign 5-/10-/15-year CSS: 87/78/67%   Benign 5-/10-/15-year DFS: 84/74/68% 

Soyuerb

 92 patients with benign meningiomas   Initially treated with surgery (48 GTR, 44 STR); EBRT given as ad juvant (12) or salvage (28) in 40  EBRT dose: median 54 Gy in 1.8 Gy per fraction; 4 had salvage  SRS to median dose of 12 Gy prescribed to 89–90% line  5- to 10-year PFS: GTR, 77–61% versus STR, 52–37%   5-year PFS: STR plus adjuvant EBRT, 91% versus STR alone or de layed EBRT, 38%  Median time to progression: STR plus adjuvant EBRT, 8.4 years  versus SRS alone, 4.1 years  No 5- to 10-year OS difference: GTR (97–83%), STR plus EBRT  (90–77%), STR (90–85%)

Miralbellc

 36 patients with benign meningiomas   Received adjuvant EBRT (17) after STR or salvage EBRT (19) at  time of recurrence  Control group: 79 patients previously reported from same insti tution with STR alone  Primary therapy 8-year PFS: STR plus EBRT, 88% versus STR alone,  48%  Salvage therapy 8-year PFS: STR plus EBRT, 78% versus STR alone,  11% ▶

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Table 30.8 (continued) Author

Goldsmithd

Nuttinge

Taylorf

Condrag

Description  117 patients with benign meningioma   All underwent STR plus postoperative EBRT   Median EBRT dose: 54 Gy to postoperative tumor plus 1- to 2-cm margin   5-year PFS/OS: benign, 89–85%   Improved PFS with higher EBRT dose  >52 Gy, 93%; ≤52 Gy, 65% (p = 0.04)   82 patients with benign meningiomas of skull base   62 with primary surgery and EBRT; 20 had salvage surgery plus EBRT   EBRT: 55–60 Gy in 33 fractions; 2- to 3-cm margin plus preoperative tumor volume   5- to 10-year PFS: surgery plus EBRT, 92–83%   132 patients with benign intracranial meningioma   Treatment: STR alone, STR plus EBRT, GTR alone   10-year local control: STR alone, 18%; STR plus EBRT, 82%; GTR, 77%   10-year survival rates: 49, 82, and 93%, respectively   216 with benign meningioma   Primary therapy: surgery, 87%; surgery and EBRT, 8%; EBRT, 5% (7 × EBRT, 5 SRS)   Median EBRT tumor dose  Postoperatively: 53.3 Gy in 1.8 Gy per fractions  EBRT alone: 51.7 Gy in 1.8 Gy per fraction; SRS: 15 Gy prescribed to 70–90% isodose line   15-year LCR, CSS: 71, 86%   15-year LCR for S: 66% (76% for GTR and 30% for STR)   15-year LCR for STR plus EBRT: 87%

EBRT: external-beam radiation therapy, CSS: cause-specific survival, DFS: diseasefree survival, PFS: progression-free survival, GTR: gross total resection, STR: subtotal resection, OS: overall survival, LCR: local control rate a Source: Glaholm J, Bloom HJ, Crow JH (1990) The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients. Int J Radiat Oncol Biol Phys 18:755–761 b Source: Soyuer S, Chang EL, Selek U et al (2004) Radiotherapy after surgery for benign cerebral meningioma. Radiat Oncol 71:85–90 c Source: Miralbell R, Linggood RM, de la Monte S et al (1992) The role of radiotherapy in the treatment of subtotally resected benign meningiomas. J Neurooncol 13:157–164 d Source: Goldsmith BJ, Wara WM, Wilson CB et al (1994) Postoperative irradiation for subtotally resected meningiomas. J Neurosurg 80:195–201 e Source: Nutting C, Brada M, Brazil L et al (1999) Radiotherapy in the treatment of benign meningioma of the skull base. J Neurosurg 90:823– 27 f Source: Taylor BW Jr, Marcus RB Jr, Friedman WA et al (1988) The meningioma controversy: postoperative radiation therapy. Int J Radiat Oncol Biol Phys 15:299–304 g Source: Condra KS, Buatti JM, Mendenhall WM et al (1997) Benign meningiomas: primary treatment selection affects survival. Int J Radiat Oncol Biol Phys 39:427–436

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Treatment of Atypical and Malignant Meningiomas Atypical and malignant meningiomas are more aggressive than are benign histologies, and they recur more frequently after complete or incomplete resections. Table 30.9 displays evidence from retrospective studies supporting the use of radiation for atypical and malignant tumors. Table 30.9 Selected retrospective studies with RT for atypical or malignant meningiomas Author

Description

Goldsmitha

 23 patients with malignant meningioma  All underwent STR and postoperative EBRT  Median EBRT dose was 54 Gy to preoperative tumor volume plus 1- to 3-cm margin  5-year PFS and OS: malignant, 48 and 58%  Improved PFS with higher EBRT dose >53 Gy, 63%; ≤53 Gy, 17%

Condrab

 47 atypical meningioma  Primary therapy: 35 surgeries (21 GTR, 14 STR); 9 surgeries plus EBRT; 2 EBRT alone  Median EBRT tumor dose  Postoperative: 53.3 Gy in 1.8 Gy per fraction  EBRT alone: 51.7 Gy in 1.8 Gy per fraction  15-year LCR was 55%  77% GTR, 43% STR, 75% GTR + EBRT, 60% STR + EBR, and 50% for EBRT alone  15-year CSS was 57%

Glaholmc

 186 patients with intracranial meningiomas  117 benign, 28 aggressive benign, 9 malignant, and 32 other  32 inoperable; 23 total tumor resection, 82 subtotal resection (microscopic disease) and 46 partial resection (gross residual disease)  EBRT dose: 50–55 Gy in 30–33 fractions to preoperative tumor  volume plus 2- to 4-cm margin  Aggressive benign 5- to 10-year CSS and DFS : 66–20% and  44–13%  67% with malignant histology died within 5 years  ▶

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Table 30.9 (continued) Author

Hugd

Goyale

Milosevicf

Description   31 meningiomas (15 atypical, 16 malignant)   16 treated with primary EBRT (63% malignant), 15 salvage EBRT (60% atypical)  8 GTR, 21 STR, 2 unresected   Photon or proton/photon EBRT  Mean dose: 62.5 Gy/CGE for atypical and 58 Gy/CGE for malignant in 1.8–2 Gy per fraction   5- to 8-year LCR: 38–19%, atypical; 52–17% malignant   5- to 8-year OS: 89–89%, atypical; 51–51%, malignant   Improved LCR and OS with protons versus photon only and with dose ≥60 CGE   22 atypical meningiomas   Surgery was GTR (15), STR (4), or unknown (3)   8 treated with EBRT (2 postoperative EBRT after GTR [3], STR [2], or unknown [3]; 6 salvage EBRT)   Median EBRT dose was 54 Gy   Overall 5- to 10-year LCR and OS: 71–55% and 91–76%, respectively   5- to 10-year LCR improved in GTR (87–87%) versus STR or unknown (51–17%)   STR without EBRT associated with worse LCR and trend toward worse OS   59 atypical (17) or malignant (42)   All received EBRT (24 primary surgery and EBRT, 33 salvage surgery plus EBRT, 2 salvage EBRT alone)   Surgery was GTR (31), STR (22), biopsy (3) or unknown (3)   Most common EBRT dose was 50 Gy in 25 fractions to tumor plus 3- to 4-cm margin   LRR for GTR 47% and for STR 72%   Overall 5-year OS and CSS: 28% and 34%, respectively   Factors associated with improved CSS: age ≤58 years, EBRT dose ≥50 Gy (trend for atypical histology, immediate EBRT, and GTR)

CGE: cobalt Gray equivalent, LRR: local recurrence rate a Source: Goldsmith BJ, Wara WM, Wilson CB et al (1994) Postoperative irradiation for subtotally resected meningiomas. J Neurosurg 80:195–201 b Source: Condra KS, Buatti JM, Mendenhall WM et al (1997) Benign meningiomas: primary treatment selection affects survival. Int J Radiat Oncol Biol Phys 39:427–436 c Source: Glaholm J, Bloom HJ, Crow JH (1990) The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients. I Int J Radiat Oncol Biol Phys 18:755–751 d Source: Hug EB, DeVries A, Thornton AF et al (2000) Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy. J Neurooncol 48:151–160 e Source: Goyal LK, Suh JH, Mohan DS, Prayson RA, Lee J, Barnett GH (2000) Local control and overall survival in atypical meningioma: a retrospective study. I Int J Radiat Oncol Biol Phys 46:57–61 f Source: Milosevic MF, Frost PJ, Laperriere NJ et al (1996) Radiotherapy for atypical or malignant intracranial meningioma. Int J Radiat Oncol Biol Phys 34:817–822

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Treatment of Unresectable or Recurrent Meningioma External-beam radiation can be used for definitive treatment of unresectable meningiomas or if a patient refuses or cannot undergo surgery. In addition, recurrent tumors may be treated with definitive or adjuvant radiation (Table 30.10). Outcomes for both unresectable and recurrent tumors are in general less favorable (Table 30.11). Because of the risk of blindness from surgery or progressive disease, optic nerve sheath meningiomas (ONSM), which constitute 1–2% of all meningiomas, are typically treated with RT, which may preserve or improve vision and prevent intracranial growth. Table 30.10 RT for treatment of meningiomas Author

n

Treatment

Grade(s) RT dose (Gy)

Outcomes

I and II

NA

8-year LC: 81% (all recurrent)

8-year PFS: 11% for S and 78% for S + EBRT

S S + EBRT

I

50–63 in 1.8–2 Gy per fraction

5-year PFS: 30% for S and 88% for S + EBRT

5-year OS: 45% for S and 90% for S + EBRT

S + EBRT

50–61.2 in I, II, or III 1.7–2 Gy per fraction

LC: 5-year, 36%; 8-year, 27%

OS: 5-year, 45%; 8-year, 33%

CSS: 5-year, 58%; 10-year, 46%; 15-year, 46%

DFS: 5-year, 53%; 10-year, 47%; 15year, 47%

RT for recurrent meningiomas

Miralbella

Taylorb

Kokubuc

19

10

20

S S + EBRT

RT for unresectable meningioma

Glaholmd

Condrae

32

7

EBRT

EBRT or SRS

50–55 in I, II, or III 30–33 fractions

I or II

51.7 in 1.8 Gy per fraction EBRT LC: 86% (median); 15 to 70–80% IDL SRS

– ▶

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Table 30.10 (continued) Author

n

Treatment

Grade(s) RT dose (Gy)

Outcomes

RT for unresectable meningioma Pourelf

9

56 Gy (median) 5-year RFS: I, II, or III in 1.8 -2Gy per 80% fraction

EBRT

–

S: surgery, EBRT: external-beam radiation, NA: not available, RFS: relapse-free survival, IDL: isodose line, LC: local control, CSS: cause-specific survival, PFS: progression-free survival a Source: Miralbell R, Linggood RM, de la Monte S et al (1992) The role of radiotherapy in the treatment of subtotally resected benign meningiomas. J Neurooncol 13:157–164 b Source: Taylor BW Jr, Marcus RB Jr, Friedman WA et al (1988) The meningioma controversy: postoperative radiation therapy. Int J Radiat Oncol Biol Phys 15:299–304 c Source: Kokubo M, Shibamoto Y, Takahashi JA et al (2000) Efficacy of conventional radiotherapy for recurrent meningioma. J Neurooncol 48:51–55 d Source: Glaholm J, Bloom HJ, Crow JH (1990) The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients. Int J Radiat Oncol Biol Phys 18:755–761 e Source: Condra KS, Buatti JM, Mendenhall WM et al (1997) Benign meningiomas: primary treatment selection affects survival. Int J Radiat Oncol Biol Phys 39:427–436 f Source: Pourel N, Auque J, Bracard S et al (2001) Efficacy of external fractionated radiation therapy in the treatment of meningiomas: a 20-year experience. Radiother Oncol 61: 65–70

Table 30.11 Selected retrospective studies utilizing 3DCRT for optic nerve sheath meningiomas Author

n

RT dose (Gy)

Outcomes

39 (15 primary, FSRT 24 secondary)

Median follow-up was 35.5 months; 54 (Convention- all patients without recurrence; 43% al fractionation) with primary ONSM with improvement in visual fields

b

Narayan

14

3DCRT

50.4 to 56 (conventional fractionation)

Median follow-up was 51.3 months; 0% with radiographic progression; 36% had vision improvement; 50% had stable vision

Baumertc

23

FSRT

45–50 (conventional fractionation)

Median follow-up was 20 months; 95% had visual control; 70% had improved vision; 22% had stable vision

a

Becker

a

Treatment

Source: Becker G, Jeremic B, Pitz S et al (2002) Stereotactic fractionated radiotherapy in patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 54:1422–1429 b Source: Narayan S, Cornblath WT, Sandler HM et al (2003) Preliminary visual outcomes after three-dimensional conformal radiation therapy for optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 56:537–543 c Source: Baumert BG, Villà S, Studer G et al (2004) Early improvements in vision after fractionated stereotactic radiotherapy for primary optic nerve sheath meningioma. Radiother Oncol 72:169–174

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RT Techniques Simulation and Target Volume Delineation Planning CT scans obtained with proper head immobilization is fused with a diagnostic T1-weighted MRI for optimal target delineation, as illustrated in Figures 30.2, 30.3, and 30.4. No consensus exists for inclusion of the dural tail, or areas of hyperostosis or involved bone in target volumes. For stereotactic radiosurgery (SRS), the contrast-enhancing tumor (GTV) is treated without margin.

Figure 30.2 Treatment planning CT–MRI (axial T1 with contrast) fusion. GTV is outlined in cyan and PTV in red

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Figure 30.4 PTV (red) = GTV (cyan) plus 0.5 cm

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Treatment Planning Technique In this modern era, three-dimensional conformal radiotherapy (3DCRT) is the minimum required treatment technique to minimize toxicities to various critical structures including the eyes, brainstem, optic pathway, and normal brain parenchyma. If 3DCRT is used, the above goals can be better achieved by using multiple nonopposing and noncoplanar beams. Typically, 4- to 6-MV beams are used, but higher energy may be used in certain beams, with a large depth to enhance coverage of the target volume distal to the isocenter in the beam path, and to avoid hotspots because of tissue lateral effect. Typically, a 0.7- to 1-cm margin around the PTV is used to account for the penumbra. Figure 30.5 shows a typical 3DCRT plan using multiple nonopposing and noncoplanar beams.

Figure 30.5 A six-field 3DCRT plan for a meningioma

When intensity-modulated radiation therapy (IMRT) is used, inverse planning is utilized and constraints are set for various critical structures (see Sect. “Normal Tissue Tolerance,” below). SRS can be delivered with a linear-accelerator-based unit, a gamma knife unit, a CyberKnife unit, or a proton-beam machine. Regardless of the device used, the goal is to deliver an ablative dose of radiation to the GTV while sparing the surrounding normal brain parenchyma. Figure 30.6 shows the gamma knife plan for a cerebellopontine angle meningioma. When gamma knife is used for SRS, the utilization of smaller shots will improve the conformality and steepen the dose gradient beyond the GTV.

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Allison M. Quick, Eric L. Chang and Simon S. Lo Figure 30.6 A dose of 12 Gy is delivered to a cerebellopontine angle meningioma

Dose and Treatment Delivery Radiation for meningiomas can be delivered with 3DCRT, IMRT, SRS, fractionated stereotactic radiotherapy (FSRT), or proton-beam therapy. Overall, 5- to 10-year progression-free survival (PFS) rates are similar for externalbeam RT ([EBRT] 80–100%) and SRS (75–100%), with similar local control rates. Recommended doses:  Grade 1: 50–54 Gy in 25–30 fractions  Grades 2–3: 60 Gy in 30–33 fractions  ONSM: 50–54 Gy in 25–30 fractions  SRS: 12–20 Gy in 1 fraction, typically 12 Gy for tumors close to critical structures such as the brainstem, and 15–20 Gy for meningiomas not close to critical structures  ONSM: optic nerve sheath meningioma (Sources: Lo SL, Chang EL, Suh JH (2008) Recent advances in therapeutic radiation: an overview. In: JH Lee (ed) Meningiomas – diagnosis, treatment and outcomes. Springer, Berlin Heidelberg New York, pp 253–258; Simon SL, Tinnel B, Suh JH (2008) Conventional radiation for meningiomas. In:

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JH Lee (ed) Meningiomas – diagnosis, treatment and outcomes. Springer, Berlin Heidelberg New York, pp 259–265; Lo SL, Samuel Chao, John H. Suh (2008). 3D Conformal RT. In: B Jeremic, S Pitz (eds) Optic nerve sheath meningioma. Springer, Berlin Heidelberg New York, pp 85–94). In a randomized dose-escalation trial (by Harvard University) comparing 55.8 cobalt Gray equivalent (CGE) and 63 CGE (Table 30.12), there was no difference in local control. For aggressive meningiomas, some data have suggested improved local control with higher doses, but this has not been verified. (Source: Lopes VV, Chan A, Loeffler J et al (2003) A randomized radiation dose escalation trial in patients with recurrent or incompletely resected benign meningiomas treated with proton–photon radiation. Int J Radiat Oncol Biol Phys 57:S323–324). Table 30.12 Technological advances for treatment of meningiomas Type

Description

IMRT

 Allows sparing of critical structure, due to steep dose gradient   Local control rates ranging from 93.6 to 100%   Avoid beams passing through eye or lacrimal gland   Higher non-target integral dose, with potential risk for 2nd ma lignancy  Dose constraints: chiasm and optic nerve, <54 Gy; lacrimal  glands, <32 Gy; lens, 10 Gy; brainstem, <54 Gy

PBRT

 More conformal and homogenous than photon therapy is, due  to Bragg peak dose deposition  Decreased integral nontarget dose   Can be used alone or in combination with photons   Local control rates ranging from 87 to 98% 

SRS

 Meningiomas appropriate for SRS: up to 3–4 cm, distinct margin,  away from critical structures  Suggested dose based on size of tumor: 18 Gy (<1 cm), 16 Gy (1–3  cm), 12–14 Gy (>3 cm)  12–16 Gy for tumors along skull base in posterior fossa   Keep optic nerve <8 Gy, brainstem <15 Gy (lower to 12 Gy for  acoustic tumors)

FSRT

 For tumors that are not amenable to SRS but require precise tu mor localization with critical structure sparing  Uses stereotactic positioning with conventional fractionation   PTV required (as opposed to only GTV for SRS) for daily set up  error

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Normal Tissue Tolerance Dose constraints for organs at risk vary, depending on the radiation treatment technique used (Table 30.13). The tolerance of several critical structures is given in Table 30.14. Table 30.13 FSRT versus SRS for meningiomas Author

Technique

n

Dose (Gy)

Local control

Late toxicity

Loa

FSRT SRS

18 35

54 in 30 fractions 14 to 75% IDL

92.9% 91%

1 (6%) 2 (6%)

Torresb

FSRT SRS

77 79

48.4 in 1.8 Gy per fraction 15.7 to 67% IDL

97.2% 92%

4 (5%) 4 (5.2%)

Metellusc

FSRTd SRSd

38 36

53 in 1.9 Gy per fraction 15 to 50% IDL

97.4% 94.4%

2.6% 0%

a

Source: Lo SS, Cho KH, Hall WA et al (2002) Single dose versus fractionated stereotactic radiotherapy for meningiomas. Can J Neurol Sci 29:240–248 b Source: Torres RC, Frighetto L, De Salles AA et al (2003) Radiosurgery and stereotactic radiotherapy for intracranial meningiomas. Neurosurg Focus 14:e5 c Source: Metellus P, Regis J, Muracciole X et al (2005) Evaluation of fractionated radiotherapy and gamma knife radiosurgery in cavernous sinus meningiomas: treatment strategy. Neurosurgery 57:873–886 d Cavernous sinus meningiomas

Toxicities While fatigue, focal alopecia, and skin erythema may be acute toxicities associated with radiation for meningioma, serious side effects are uncommon. Potential rare toxicities include cranial neuropathies, cerebral or brainstem necrosis, encephalomalacia, cerebrovascular events, second malignancies, and edema. Treatment for ONSM carries a risk of orbital pain, visual defects, cataracts, eye dryness, or pituitary dysfunction.

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Table 30.14 Tissue tolerance of critical structures to radiation

Structure

Optic nerve

TD 5/5 for critical structures

RTOG 0539

QUANTEC

Dose (Gy)

Dose (Gy)

Dose (Gy)

50

50 (Intermediate risk) 55 (High risk)

<55 in < 2-Gy fractions ≤8–12 (point dose) in 1 fraction in SRS

Optic chiasm

50

54 (Intermediate risk) 56 (High risk)

<55 in < 2-Gy fractions ≤8–12 (point dose) in 1 fraction in SRS

Retina

45

45 (Intermediate risk) 50 (High risk)

NA

Lens

10

5 (Intermediate risk) 7 (High risk)

NA

55 (Intermediate risk) 60 (High risk)

54 (Whole) 59 in ≤2-Gy fractions (1–10 ml) 12.5 (Point dose) in 1 fraction in SRS

Brainstem

50

TD: 5/5 the probability of 5% complication within 5 years from treatment, RTOG: Radiation Therapy and Oncology Group, QUANTEC: Quantitative Analyses of Normal Tissue Effects in the Clinic, NA: not available Sources: Emami B, Lyman J, Brown A et al (1991) Tolerance of normal tissue to therapeutic radiation. Int J Radiat Oncol Biol Phys 21:109–22 ; http://rtog.org/members/ protocols/0539/0539.pdf. Mayo C, Martel MK, Marks LB et al (2010) Radiation dose– volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 76:S28–S35; Mayo C, Yorke E, Merchant TE. Radiation-associated brainstem injury. Int J Radiat Oncol Biol Phys 76:S36–S41

Follow-Up Routine follow-up is important after definitive treatment because of the risk of local recurrence. MRI of the brain should be performed every 3–4 months for the first 2 years, every 6 months for the next 3 years, then annually.

31

Adult Gliomas Bernadine R. Donahue1

Key Points  Anaplastic gliomas (including anaplastic oligodendrogliomas and anaplastic oligoastrocytomas) and glioblastoma multiforme (GBM) account for about half of all high-grade primary brain tumors in adults.  Median survival of patients with GBM is 1–1.5 years; with anaplastic astrocytomas (AA), it is 2–3 years; and with anaplastic oligodendrogliomas (AO) and anaplastic oligoastrocytomas (AOA), it is 5–7 years.  Clinical prognostic factors for both GBM and AA include age at diagnosis, Karnofsky performance status (KPS), histology, extent of resection, duration of symptoms, and neurologic functional/mental status.  More recently, molecular markers such as O6 -methylguanine-DNA methyltransferase (MGMT) methylation status, and chromosomes1p/19q deletions in tumors with oligodendroglioma features have been identified as important prognostic factors.  Surgery, radiation therapy, and chemotherapy, particularly the oral alkylator temozolomide, are important therapeutic modalities in the curative treatment of high-grade gliomas.  Low-grade gliomas account for approximately 10% of all primary intracranial tumors in adults and are generally categorized as pilocytic astrocytoma (World Health Organization [WHO] grade I) or diffusely infiltrating low-grade gliomas (WHO grade II).  Low-grade gliomas in adults are usually treated with surgery and/or radiation therapy, although the subtype of oligodendroglioma may be considered for treatment with chemotherapy.

Epidemiology and Etiology The annual incidence of malignant primary brain tumors in the United States is 22,000 cases. More than two thirds of these are glioblastoma multiforme (GBM), which remains an almost uniformly fatal tumor in adults. Various genetic alterations leading to primary GBM, secondary GBM, and anaplastic oligoastrocytomas (AOA) have been identified (Figure 31.1). In addition, all 1

Bernadine R. Donahue, MD Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_14, © Springer-Verlag Berlin Heidelberg 2011

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high-grade gliomas express vascular endothelial growth factor (VEGF) and oligodendrocyte lineage transcription factor 2 (OLIG2). Heritable disorders associated with central nervous system (CNS) tumors include neurofibromatosis, Li-Fraumeni syndrome, von Hippel-Lindau disease, and Turcot’s syndrome. Multiple studies have addressed the association of cell phone use with the rise of primary brain tumors but to date, cell phone use in adults has not been shown to cause malignant glioma.

PTEN deletion p53 mutations RB mutations

p53 mutations PDGFR overexpression LOH 10q RB mutation P16 deletion

EGFR amplification/ mutations LOH 10q PTEN deletion P16 deletion

AO

AA & Secondary GBM

Primary GBM

Figure 31.1 Genetic alterations associated with high-grade gliomas (Source: Wen PY, Kasari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507)

Pathology Histology is critical in guiding treatment, and diagnosis can be obtained during definitive surgical resection or biopsy. Advances in image-guided stereotactic biopsy has allowed access to even eloquent locations in the brain, and with the rare exception of infiltrating pontine gliomas and some optic gliomas, a tissue diagnosis is imperative prior to instituting treatment; rarely, is “empiric” treatment indicated. Treatment and prognosis will vary, depending on the grade and subtype of glioma identified. Table 31.1 illustrates the typical pathological findings. Table 31.1 Pathologic features of gliomas Tumor type

Histologic findings

Glioblastoma multiforme

Nuclear atypia, mitotic activity, vascular proliferation, and necrosis

Anaplastic gliomas

Nuclear atypia, mitotic activity

Oligodendroglioma

“Fried-egg” appearance

Pilocytic astrocytoma

Glioma matrix with Rosenthal fibers

Low-grade fibrillary astrocytoma

Well-differentiated and lack mitoses, nuclear pleomorphism, anaplasia, vascular proliferation, and necrosis

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Diagnosis, Staging, and Prognosis Clinical Presentation Patients present with signs and symptoms relevant to the location of the tumor and the resulting mass effect. These are summarized in Tables 31.2 and 31.3. Table 31.2 Clinical presentation Signs and symptoms of gliomas Alteration in mental status

Ataxia

Headache

Motor deficits

Visual changes

Sensory deficits

Speech deficit

Gait disturbance

Cranial nerve palsies

Table 31.3 Signs/symptoms related to tumor location CNS location

Signs/symptoms

Frontal lobe

Hemiparesis, seizures, alteration in mental status, urinary incontinence

Occipital lobe

Visual changes, seizures

Parietal lobe

Seizures, language disturbances (if a tumor is in the dominant hemisphere), difficulty with reading and calculations, spatial disorientation

Temporal lobe

Aphasia, seizures, emotional disturbance, difficulty with depth perception, altered sense of time

Basal ganglia

Hemiparesis

Thalamus

Impaired judgment and memory, behavioral changes , altered motor and sensory integration

Hypothalamus

Alteration in thirst, urination, sleep, eating patterns, temperature, and blood pressure; emotional changes

Optic tract

Abnormal pupil reactions, impaired vision, eye movement disorders

Posterior fossa

Headaches, nausea, vomiting, blurry vision, ataxia, dizziness, coordination problems, double vision, neck pain, head tilt

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Diagnosis Table 31.4 details the examination and tests used in the diagnosis of adult gliomas. Some MRI findings are detailed in Table 31.5. Table 31.4 Examination and tests used in the diagnosis of adult glioma Examination and tests

Signs/symptoms

Physical examination

Complete history and physical examination with a thorough neurological examination including a baseline mini-mental status examination Particular attention to ophthalmological and endocrine findings, depending on the tumor location Malignant gliomas cause high incidence of deep venous thrombosis and subsequent risk of pulmonary embolism; thus, attention to associated symptoms or physical findings is required

Imaging studies

MRI, with and without gadolinium, is the imaging modality of choice for evaluation of malignant brain tumors T1-weighted images are useful for defining anatomy and should be obtained pre- and postcontrast T2-weighted images and fluid attenuation inversion recovery (FLAIR) aid in detecting edema or infiltration of brain parenchyma, including infiltration across the corpus callosum, a not-infrequent finding in malignant gliomas The pattern of enhancement is useful in the differential diagnosis of the lesion (Table 31.5) CT scan is utilized when patients cannot undergo MRI (implanted pacemaker/defibrillator or other non-MRIcompatible implanted devices, surgical clips, or metals, etc.) or are unable to tolerate MRI CT is useful for identifying calcifications, such as those seen in oligodendrogliomas

Advanced imaging studies

MR spectroscopy, perfusion MRI, and PET can help provide further information regarding functional brain tissue or tumor Diffusion tensor imaging has illustrated the white matter tracts along which malignant gliomas can infiltrate and may be useful for guiding surgical approaches or RT planning. High-grade gliomas rarely metastasize to the spine, but neuroaxis imaging using MRI of spine (with or without gadolinium) should be considered in symptomatic patients or in the presence of ventricular dissemination of tumor Low-grade gliomas can disseminate to the neuroaxis, and spine imaging should be obtained if clinically indicated

MRI characteristics

Peripheral enhancement and a central necrotic region with surrounding FLAIR/T2 signal change indicative of vasogenic edema or tumor infiltration

Infiltrative, mass effect may or may not enhance

Non-enhancing; calcifications on CT

Tumor type

Glioblastoma multiforme

Anaplastic gliomas

Oligodendroglioma

Table 31.5 MRI findings in glioma Example

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MRI characteristics

Well-circumscribed, vividly enhancing lesions, often with a cystic component

Hypointense and non-enhancing on T1-weighted images, hyperintense on FLAIR images

Tumor type

Pilocytic astrocytoma

Low-grade fibrillary astrocytoma

Table 31.5 (continued) Example

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Staging The American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) staging system is not widely used in the staging of malignant gliomas. Tumor histology, location, and biology have proven to be more important in predicting outcome. The CNS Tumor Task Force of AJCC recommended that a formal classification/staging system not be included in the staging manual in 1997. The Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) divides patients with GBM and anaplastic astrocytoma (AA) into classes, i.e., groups with similar outcomes (Table 31.6). There is not a widely recognized staging system for low-grade gliomas; however, in practical terms, they can be thought of as disseminated or non-disseminated. Table 31.6 Radiation Therapy Oncology Group Recursive Partitioning of malignant gliomas Class

Patient characteristics

Median survival (months)

I–II

 Anaplastic astrocytomas with age <50 years and normal mental status or age >50 years and KPS >70, and symptom duration >3 months

III–IV

 Anaplastic astrocytomas with age <50 years and abnormal mental status or age ≥50 years, KPS ≥70, and symptom duration <3 months 11–18  GBM with age <50 years or age ≥50 years, KPS ≥70, surgical resection, and good neurologic function status

V–VI

 GBM with age ≥50 years, KPS <70 or GBM with age ≥50 years, KPS ≥70 surgical resection but a poor neurologic function status or GBM with age ≥50 years, KPS ≥70 biopsy only

40–60

5–9

Prognosis The prognosis of patients with high-grade gliomas is generally poor, although the median and overall survival rates vary by histologic subtype. In general, an oligodendroglial component confers an improved survival. Table 31.7 lists the clinical prognostic factors for high and low-grade gliomas, respectively, and Table 31.8 summarizes survival. Molecular markers have been increasingly identified as important prognostic factors in high-grade gliomas (see Table 31.8). Five-year results from the landmark European Organization for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) study evaluating the

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impact of temozolomide added to radiation therapy (RT) in the treatment of GBM, have shown that O6 -methylguanine-DNA methyltransferase (MGMT) methylation status was the most important prognostic factor for survival. MGMT codes for a repair enzyme, and when methylated, it is defunctionalized, thus impairing the tumor cell’s ability to repair the damage caused by the alkylator temozolomide. Recently, an additional molecular marker that may affect the prognosis and predict response to therapy in patients with GBM is isocitrate dehydrogenase 1 (IDH1). So-called triple-positive GBMs (MGMT methylated, phosphatase and tensin homolog [PTEN], and p53 positive) are uncommon but may be associated with a better prognosis than are other GBMs. Molecular markers have also been identified as prognostic factors in oligodendrogliomas (Table 31.9). Allelic loss of chromosomes 1p and 19q has been identified as a good prognostic factor in oligodendrogliomas. MGMT methylation may also influence the outcome in these tumors. Table 31.7 Clinical prognostic factors High-grade gliomas

Low-grade gliomas

Age at diagnosis (age >50 years is associated with poorer prognosis)

Age at diagnosis (age >40 years is associated with poorer prognosis)

KPS

Size of the tumor

Extent of resection

Extent of resection

Duration of symptoms

Extension across midline

Neurologic status

Mental status

Table 31.8 Survival by tumor type Tumor type

Median survival (months)

5-year overall survival (%)

Glioblastoma multiforme

12–16

5–10%

Anaplastic gliomas

24

25–30%

Anaplastic oligodendroglioma

60

50–60%

Oligodendroglioma

120

80%

Pilocytic astrocytoma

NA

95%

Low-grade fibrillary astrocytoma

84

60%

NA not applicable

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Table 31.9 Impact of molecular markers on survival Tumor

Marker

Status

Survival Median (months)

MGMT GBM IDH1

AOA

2-year (%)

5-year (%)

Methylated

15.3–23.4

5.2– 13.8%

Unmethylated

11.8–12.6

0–8.3%

Mutated

30

Wild type

12

Co-deleted

>84

65.4– 71.7%

Non-deleted

33.6

31.3– 46.7%

1p/19q

Sources: Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC–NCIC trial. Lancet Oncol 10:459–466; Weller M, Felsberg J, Hartmann C et al (2009) Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol 27:5742–5750; Cairncross G, Berkey B, Shaw E et al (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group trial 9402. J Clin Oncol 24:2707–2014; van den bent MJ, Dubbink HJ, Sanson M et al (2009) MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Study 26951. J Clin Oncol 27:5881–5886

Treatment Principles and Practice The treatment of high-grade gliomas involves the multimodality approach of surgery, RT, and chemotherapy. In general, for GBMs, all three modalities are used at initial diagnosis. For other high-grade gliomas, the sequencing of these modalities remains controversial. When possible, maximal safe surgical resection is the treatment of choice for low-grade gliomas. Pilocytic astrocytomas are usually approached with surgery alone, whereas infiltrating low-grade gliomas frequently require RT.

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Treatment of High-Grade Gliomas The Brain Tumor Cooperative Group trials of the 1960s and 1970s established the role of RT and nitrosoureas in the treatment of GBM, and for many years, this was the standard treatment for high-grade gliomas after surgical resection. However, temozolomide is the current standard chemotherapy drug of choice, and more recently, targeted agents are being explored in the treatment of high-grade gliomas. See Tables 31.10, 31.11, 31.12, and 31.13 for different modalities of treatment and various trial results, and Figure 31.2 for and a proposed treatment algorithm for high-grade gliomas.

Table 31.10 Different modalities for treatment of glioma Modality

Description

Surgery

Indications

Facts

   

Biopsy for diagnosis Resection with definitive intent Palliative debulking for management of mass Shunting to relieve symptoms caused by increased intracranial pressure or hydrocephalus  Resection of recurrent disease in selected patients  Maximal surgical resection appears related to outcome  Biopsy versus resection is a node in the RTOG recursive partitioning analysis (RPA) class  Glioma Outcomes Project: North American prospective observational database involving 52 centers evaluated the influence of resection versus biopsy on length of survival in patients with malignant glioma, from 1997 to 2001. On multivariate analysis, resection rather than biopsy was associated with a prolonged survival time for patients with GBM (p < 0.0001)a  bis-Chloronitrosourea (BCNU)-impregnated biodegradable polymer (GLIADEL wafer) may be considered for intraoperative placement if frozen section reveals highgrade glioma  Phase III randomized trial of the wafer compared to placebo showed an improvement in median survival from 11.6 months to 13.9 months (p = 0.03) but for patients with GBM, the wafer was not measured against systemic chemotherapy, but rather RT alone  Role with temozolomide is not clearb

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Table 31.10 (continued) Modality

Description

Radiation therapy

Indications

Definitive treatment (with concurrent and adjuvant chemotherapy) after resection or biopsy Palliative treatment to primary or metastatic foci RT usually started within 5 weeks of definitive resection

Techniques

 EBRT using 3D-CRT or IMRT  Stereotactic radiosurgery (SRS)  Interstitial brachytherapy may have a role in selected patients

Chemo-/targeted therapy

a

Indications

 Concomitant treatment with RT after surgery Adjuvant treatment after RT Mainstay treatment for salvage palliative therapy

Medications

Temozolomide, an oral alkylator that crosses the blood brain barrier, is the chemotherapy of choice in glioma, and it significantly improves treatment outcome in patients with GBM The use of temozolomide, or other chemotherapy including BCNU or procarbazine, lomustine, and vincristine (PCV), in newly diagnosed AA is controversial (although temozolomide first received US Food and Drug Administration (FDA) approval for use in the treatment of recurrent AA) Temozolomide plays a major role in the treatment of oligodendrogliomas Bevacizumab, an antiangiogenic agent, with or without Camptothecin (CPT)11, is used for recurrent GBM and is being evaluated as part of the initial treatment of GBM with RT and temozolomide

Source: Laws ER, Parney IF, Huang W et al (2003) Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes project. J Neurosurg 99:467–473 b S ource: Westphal M, Hilt DC, Bortey E et al (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (GLIADEL wafers) in patients with primary malignant glioma. Neuro Oncol 2:79–88

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Table 31.11 Treatment strategies for glioblastoma multiforme and supporting clinical evidence Trial

Results

RTOG 9006: Established conventional fractionation as the standard RT fractionationa

 Randomized 712 patients with high-grade glioma to partial brain RT at conventional fractionation of 2.0 Gy per fraction daily to 60 Gy versus 1.2 Gy per fraction bid to 72 Gy  Patients in both arms received BCNU  Median survival time in the control arm was 13.2 months versus 11.2 months in the hyperfractionated arm  No survival advantage for hyperfractionated RT (HFRT) in any subgroup (median survival time was statistically better for all patients under the age of 50 with conventional fractionation)

 573 patients with GBM randomized to radiotherapy alone (60 Gy in 30 daily fractions) versus concomitant daily temozolomide (75mg/m2 daily) with standard radiotherapy, followed by 6 cycles of maintenance temozolomide (150–200 mg/m2 daily on days 1 to 5 every 28 days)  Significant survival benefit in the temozolomide arm: meEORTC dian survival was 14.6 months with radiotherapy plus te26981/22981-NCIC: mozolomide versus 12.1 months with radiotherapy alone Established RT + temozolomide  2-year survival rate was 26.5% with radiotherapy plus temozolomide and 10.4% with radiotherapy alone (p < as the standard 0.0001) treatment regimenb  Recent update reported the 4-year survival rate to be 12.1% in the combined arm and 3% in the RT alone arm. Toxicity with chemoradiotherapy was acceptable with 7% grade 3 or 4 hematologic toxicity  MGMT methylation important prognostic factor (see Table 31.9) RTOG 0525: Compared RT + conventional adjuvant temozolomide versus dose intensive temozolomidec

 Phase III, 2006–2008  All patients received standard RT and concurrent temozolomide  The adjuvant temozolomide was randomized to conventional schedule versus 21-day course  Results pending (2009 American Society of Clinical Oncology [ASCO] presentation reported an approximately 33% methylation rate, which is lower than in the EORTC trial)

RTOG 0825: Evaluates the role of bevacizumab in newly diagnosed GBMd

 Phase III randomized study of standard RT and temozolomide with or without bevacizumab  Bevacizumab starts during the 4th week of RT and continues during adjuvant temozolomide cycles on the experimental arm

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Pathologic Confirmation * (all patients should be considered for enrollment on clinical trial) * include molecular markers such as MGMT, 1p19q, etc.

GBM

Concurrent chemoradiation 6,000 cGy per 30 fractions, involved field with temozolomide, 75mg/m2

AO AOA

AA

Concurrent treatment

Sequential treatment

Adjuvant temozolomide, 150 – 200 mg/m2 Figure 31.2 Proposed algorithm for the treatment of high-grade glioma

a

Source: Scott C, Curran W, Yung W et al (1998) Long-term results of RTOG 9006: a randomized trial of hyperfractionated radiotherapy (RT) to 72.0 Gy and carmustine vs. standard RT and carmustine for malignant glioma patients with emphasis on anaplastic astrocytoma (AA) patients. J Clin Oncol 16:S384 b Source: Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC–NCIC trial. Lancet Oncol 10:459–466 c Sources: RTOG Web site closed trial; Aldape KD, Jones G, Wang M et al (2009) MGMT methylation testing in RTOG 0525: a phase III trial of newly diagnosed glioblastoma. J Clin Oncol 27:Abstract 2051 d Sources: RTOG Web site open trials

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Table 31.12 Treatment strategies for anaplastic astrocytomas and supporting clinical evidence Trial

Results

NCOG 6G61: Compared RT + BCNU versus RT + PCVa

 Phase III randomized trial  37 and 36 patients with anaplastic astrocytoma treated on each arm, respectively  Hydroxyurea was given daily with RT  Median survival was approximately 1.5 versus 3 years (p = .021)  PCV was found to be associated with an improved outcome; however, in contrast, a retrospective review of patients from the RTOG database with newly diagnosed AA, showed no improvement in survival with PCV, as compared with BCNU

RTOG 9813: Compared RT + BCNU versus RT + temozolomideb

 The phase III portion of this study opened in 1999 (AOA was included if pathology showed a dominant astrocytic component)  Temozolomide 200 mg/m2 was given daily on days 1–5 of the 1st week of radiotherapy on the experimental arm  The phase III portion of the study closed in 2007 and results are pending

EORTC 6053_22054/ RTOG 0834 (The CATNON Intergroup Trial): Evaluates RT alone versus RT + temozolamide in non-1p/19q deleted anaplastic gliomac

 Recently opened international study that may help clarify the role of temozolomide in the setting of AA  Patients with non–1p/19q–deleted anaplastic glioma are randomly assigned to concomitant RT and temozolomide versus RT alone  There is also a random assignment to adjuvant temozolomide or observation  The primary end point is overall survival; enrollment of more than 800 patients is planned

Historically, AA were treated with RT and either BCNU or PCV, although data establishing the superiority of chemoradiation over RT alone for this histology are lacking. The current National Comprehensive Cancer Network (NCCN) guidelines leave chemotherapy as an option. Many people have extrapolated the experience of temozolomide in GBM to the setting of AA; however, this remains controversial a Source: Levin VA, Silver P, Hannigan J et al (1990) Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 18:321– 324 b Source: Chang S, Seiferheld W, Curran W Jr et al (2004) Phase I study pilot arms of radiotherapy and carmustine with temozolomide for anaplastic astrocytoma (Radiation Therapy Oncology Group 9813): implications for studies testing initial treatment of brain tumors. Int J Radiat Oncol Biol Phys 59:1122–1126 c Sources: EORTC Web site; Stupp R, Hegi ME, Gilbert MR et al (2007) Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 25:4127–4136

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Table 31.13 Treatment strategies for anaplastic oligodendroglioma/oligoastrocytoma and supporting clinical evidence Trial

Results

RTOG 9402: RT alone versus neoadjuvant PCV, followed by RTa

Phase III randomized 289 patients with newly diagnosed AO and AOA: RT alone or neoadjuvant PCV (4 cycles), followed by radiotherapy Median survival was 4.9 years in the combined arm, and 4.7 years in the RT alone arm radiotherapy alone (p = 0.26); no difference in overall survival Progression-free survival was better in the combined arm, 2.6 versus 1.7 years with RT alone (p = 0.008) Grade 3 or 4 toxicity was observed much more frequently with PCV It is important to note that 57% of patients treated with RT alone received salvage chemotherapy with PCV or temozolomide at the time of recurrence thus confounding interpretation of the survival data 1p/19q loss of heterozygosity (LOH) was identified in 46% of the patients, and these patients survived significantly longer regardless of treatment arm

EORTC 26951: RT alone versus RT followed by PCVb

368 patients were randomized to receive either radiotherapy alone or radiotherapy, followed by 6 cycles of adjuvant PCV No statistically significant difference in median survival: 40.3 months in the combined arm and 30.6 months in the RT alone arm (p = 0.23) Median progression-free survival was 23 months in the combined arm, as compared with 13.2 months in the RT alone arm (p = 0.0018) It is important to note that in this study, PCV was given at recurrence to 65% of patients in the RT alone arm; thus, this trial investigating the use of sequential chemoradiotherapy, like the above RTOG trial, failed to show any overall survival advantage of PCV chemotherapy over radiotherapy alone. However, it is important to note the high number of patients who received chemotherapy at the time of progression: the lack of benefit observed in these trials may reflect the effect of salvage therapy 25% of patients were identified as having both 1p and 19q loss, and these patients survived longer on both arms ▶

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Table 31.13 (continued) Trial

Results

 Multicenter German trial included patients with AO, AOA, and AA  Patients randomized to RT versus PCV or temozolomide NOA-04: evaluated  PFS and OS similar on both arms (AA did worse than AO sequential and AOA); however, the findings are suggestive that an radiation and c “RT first approach” might be better (at 4.5 years, nearly chemotherapy 80% of the patients on the chemotherapy arm had received salvage RT, but on the RT arm only 50% had received salvage chemotherapy) Current NCCN guidelines leave chemotherapy as an option; however, most neuro-oncologists incorporate chemotherapy at some point in the treatment of AO and AOA, although the sequencing of the modalities remains controversial. In a survey of The Society of Neuro-Oncology members, the majority of whom practiced at academic medical centers, the most common recommendation for the treatment of anaplastic oligodendroglioma, regardless of molecular status, was temozolomide with RT, followed by adjuvant temozolomide (Source: Abrey LE, Louis DN, Paleologos N et al (2007) Survey of treatment recommendations for anaplastic oligodendroglioma. Neuro Oncol 9:314–318) a Source: Cairncross G, Berkey B, Shaw E et al (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendrogliomas: Intergroup Radiation Therapy Oncology Group 9402. J Clin Oncol 24:2707–2714 b Source: Van den Bent MJ, Carpentier AF, Brandes AA et al (2006) Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organization for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715–2722 c Source: Wick W, Hartmann C, Engel C et al (2009) NOA-04 randomized phase III trial of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolamide. J Clin Oncol 27:5874–5880

Palliation A palliative approach is warranted for patients with high-grade glioma with poor performance status and who are unable to tolerate a prolonged course of RT, or those with comorbidities that preclude them from definitive chemoradiation, particularly the very elderly. This may include palliative debulking, but there are no data to show that this improves survival. Steroids and anticonvulsants may be employed as indicated, and referral to hospice may be appropriate.

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Treatment of Low-Grade Gliomas The timing of intervention for patients with low-grade tumors remains controversial. The clinical course is variable, with some patients having long survival even without treatment, and others suffering from progressive deterioration despite treatment. In general, early intervention is indicated for patients with increasing symptoms, radiographic progression, and high-risk features suggestive of transformation to a higher-grade tumor. Pilocytic Astrocytoma Pilocytic astrocytoma is a rare tumor in adults, and when it does occur, it is thought to have a relatively benign course. The median age at presentation is in the early 30s, and the most common symptom is headache. In general, adults with pilocytic astrocytoma appear to have a favorable prognosis with regard to survival and neurologic function. See Tables 31.14 and 31.15 for treatments for pilocytic astrocytoma, and trial results.

Table 31.14 Treatments available for low-grade gliomas Modality

Description

Surgery Gross total resection should be performed when feaIndications

sible, as this is the definitive treatment Shunting to relieve symptoms caused by increased intracranial pressure or hydrocephalus Resection of recurrent disease

Radiation therapy

Indications

RT can be used in the setting of residual symptomatic or progressive disease, particularly when re-resection is not feasible The use of RT for pilocytic astrocytoma in adults is not well defined

Techniques

EBRT using 3D-CRT or IMRT Stereotactic radiosurgery (SRS) If RT is to be utilized, the dose and volumes treated are those described for pilocytic astrocytoma in children

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Table 31.15 Treatment strategies for pilocytic astrocytomas and supporting clinical evidence

a

Trial

Results

German trial: Described outcome in adults treated with surgerya

 45 patients over the age of 16 years underwent surgery for primary or recurrent tumor  18% of patients died from disease, at a mean follow-up of >6 years  It is important to note that in this particular series, slightly more than a quarter of the patients had pathologic features of increased proliferation or anaplasia, and without these features, survival would be expected to parallel the excellent 95% survival in pediatric series

NCCTG 86-72-51/ RTOG 9110/ECOG 2389: Described outcome in adults treated with surgery and/or RTb

 Prospective trial for low-grade gliomas with different treatments based upon histology and extent of resection  Included 20 adults with supratentorial PA treated between 1986 and 1994  Patients who had subtotal or gross total resection were observed  Patients with biopsy only were treated with postoperative RT 50.4 Gy in 28 fractions  11 patients underwent complete resection, 6 had incomplete resections, and 3 had biopsy only, with median follow-up of 10 years; the 5-year progression-free and overall survival rates were >90%  Neurologic function remained high

Source: Stuer C, Vilz B, Majores M et al (2007) Frequent recurrence and progression in pilocytic astrocytoma in adults. Cancer 110:2799–2808 b Source: Brown PD, Buckner JC, O’Fallon JR et al (2004) Adult patients with supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial. Int J Radiat Oncol Biol Phys 58:1153–1160

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Infiltrating Low-Grade Gliomas It is not always clear as to when to proceed to surgery in a patient with a suspected low-grade glioma. Most patients undergo some type of surgery at presentation in order to establish the diagnosis and to determine histology, grade, and molecular characteristics, which affect treatment. The most controversial issue in the management of the adult patient with a low-grade glioma is whether to administer RT immediately or at the time of progression. See Tables 31.16 and 31.17, and Figure 31.3 for treatment modalities, trial results, and an algorithm for proposed treatment, respectively.

Table 31.16 Treatment modalities for infiltrating low-grade gliomas Modality

Description

Surgery

Indications

Maximal safe surgical resection is the treatment of choice when possible Shunting to relieve symptoms caused by increased intracranial pressure or hydrocephalus Resection of recurrent disease in selected cases

Facts

These tumors are often diffusely infiltrative and involve of eloquent regions, making complete surgical resection difficult Many studies have found total or subtotal (>90%) resection to be associated with improved outcome Aggressive resection may result in more accurate histopathologic diagnosis

Radiation therapy

Indications

NCCN recommendation for a maximally resected tumor is observation for patients under the age of 45, and observation or RT for patients over the age of 45. Many of the cooperative group trials have identified 40 years of age as a cutoff RT can be used in the setting of residual symptomatic or progressive disease

Technique

EBRT using 3D-CRT or IMRT

Chemo/targeted therapy Indication

Chemotherapy may be considered in oligodendrogliomas, particularly those with 1p or combined 1p/19q deletion

Medications

Temozolomide, an oral alkylator that crosses the blood brain barrier, is the mainstay medication for chemotherapy in gliomas Its use in low-grade gliomas remains undefined

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Table 31.17 Treatment strategies for infiltrating fibrillary astrocytomas and supporting clinical evidence Trial

Results

NCCTG 86-72-51/ RTOG 9110/ECOG 2389: Compared low-dose RT with high-dose RT a

 Prospective trial for low-grade gliomas, with different treatments based on histology and extent of resection  Phase III portion of the study included 203 patients who were randomized to 50.4 Gy in 28 fractions or 64.8 Gy in 36 fractions  No difference in progression-free survival or overall survival  Grades 3–5 neurotoxicity occurred in 5% of patients in the high-dose arm, as compared with 2.5% of patients in the low-dose arm  No role for high-dose RT

 Phase III trial in which 379 patients were randomized to EORTC 22844: receive 45 Gy in 5 weeks or 59.4 Gy in 6.5 weeks Compared low There was no difference in progression-free survival or dose RT with highoverall survival in either arm (50 and 60%, respectively) b dose RT  No role for high-dose RT

RTOG 9802: Evaluated phase II and phase III prospective treatment strategies in adultsc

 Phase II study of observation in favorable low grade  Phase III study of RT with or without PCV in unfavorable low-grade glioma (age >40 or subtotal resection/biopsy)  In the 111 favorable patients who were observed, the 5-year PFS was 50%, and the 5-year OS was 94%  For the 251 unfavorable patients, there was no difference in OS at 5 years: 61% with RT alone and 70% with RT plus PCV (p = 0.72); the 5-year PFS was only 39, and 61% respectively (p = 0.38)  Analysis of outcome by 1p/19q status is pending

EORTC 22845: Compared immediate RT with deferred treatment at the time of progressiond

 314 patients with low-grade gliomas were randomized to receive postoperative radiotherapy to 54 Gy in fractions of 1.8 Gy (n = 157) or radiotherapy at progression (n = 157)  Median progression-free survival was significantly better with immediate RT, 5.3 versus 3.4 years (p < 0.0001); however, there was no difference in median survival, 7.4 versus 7.2 years (p = 0.872)  Seizure control was reported as being better in the immediate RT group, but it is important to recognize that there was no in-depth quality of life–adjusted analysis  It appeared that immediate RT results in improved progression-free survival, but withholding radiotherapy until tumor progression does not jeopardize overall survival

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Table 31.17 (continued) Trial

Results

Evaluated concurrent temozolomide with RT (54 Gy in 30 fractions) for high-risk patients RTOG 0424:  High-risk patients are patients with supratentorial WHO Evaluated the role grade II astrocytoma, oligodendroglioma, or oligoasof RT + concurrent trocytoma, with at least 3 of the following risk factors: temozolomide in age ≥40, largest preoperative diameter of tumor ≥6 cm, selected subsets tumor crossing midline, tumor subtype of astrocytoma of adults with low(astrocytoma dominant) or preoperative neurological e grade glioma function status >1 Closed in 2009, results pending Phase III randomized trial comparing radiotherapy (50.4 EORTC 22033: Gy in 28 fractions) versus temozolomide Evaluating the role of Eligible patients have supratentorial WHO grade II gliotemozolomide in mas and at least 40 years of age or have radiographic progression or new or worsening neurological sympselected subsets toms (other than seizures only) or intractable seizures of adults with lowgrade gliomaf Stratified by 1p and 19q allele status a

Source: Shaw E, Arusell R, Scheithauer B et al (2002) Prospective randomized trial of low-versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol 20:2267–2276 b Source: Karim AB, Maat B, Hatlevoll R et al (1996) A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 36:549–556 c Source: Shaw EG, Berkey BA, Coons SW et al (2006) Initial report of Radiation Therapy Oncology Group (RTOG) 9802: prospective studies in adult low-grade glioma (LGG). J Clin Oncol 24:S1500 d Source: Van den Bent MJ, Afra D, de Witte O et al (2005) Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366:985–990 e Source: RTOG Web site, http://www.rtog.org/ f Source: RTOG Web site, http://www.rtog.org/

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Pathologic Confirmation * * may not be feasible for such tumor as optic glioma or brainstem glioma

Pilocytic astrocytoma

Observation Radiation therapy can be used in the setting of residual symptomatic or progressive tumor, particularly when resection is not feasable

Infiltrating gliomas oligodendrogliomas

Maximally resected tumor under the age of 40 – 45: observation

Maximally resected tumor over the age of 40 – 45: observation or RT

Radiation therapy can be used in the setting of residual or progressive disease. Consider open trials evaluating chemotherapy especially if 1 p 19 deleted

Figure 31.3 Proposed algorithm for the treatment of low-grade gliomas

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Radiation Therapy Techniques Definitive Radiation Therapy Dose and Fractionation For high-grade gliomas (GBMs, AA, anaplastic oligodendrogliomas [AO], AOA) external-beam RT to a total dose of 60 Gy at 2 Gy per fraction (or 59.4 Gy at 1.8 Gy per fraction) is delivered to an initial field. A cone down is performed after 46 Gy (or 45 Gy). (Some physicians treat the tumor volume and a 2- to 3-cm margin to 60 Gy without a cone down [this was the volume treated on the landmark EORTC 26981 study for GBM]). For low-grade gliomas, the RT dose that should be delivered is approximately 50.4 Gy at 1.8 Gy per fraction daily. Simulation and Planning Computed tomography (CT)-based treatment planning with magnetic resonance (MR) fusion is used for defining gross tumor volume (GTV) and partial tumor volume (PTV) (Figure 31.4).

Figure 31.4 Fusion of treatment-planning CT with MRI and PET scan

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In the future, there may be a role for incorporating perfusion imaging, spectroscopy, diffusion tensor imaging (DTI), or positron-emission tomography (PET) into RT planning, but to date these are not routinely used. Emerging awareness of the location of neural stem cells in the subventricular zone adjacent to the lateral ventricles and in the subgranular zone of the dentate gyrus may affect RT planning in the future. Individualized immobilization device (e.g., headrest, Aquaplast, tilt boards) should be used during planning and treatment (Figure 31.5). Treatment-planning CT should be obtained in the treatment position. The head position depends on the location of the tumor and the patient’s ability to tolerate positioning. Slices, no more than 1.25 mm thick, should be obtained from the level of above the head (i.e., into air) through the shoulders. Thicker slices may not allow adequate visualization of structures such as optic nerves, chiasm, cochlea, etc. Figure 31.5 Angled headrest and facemask for reproducible setup

Volumes for Gliomas Most cooperative group protocols originally specified volumes based on the preoperative imaging. However, recently there has been a trend to plan from postoperative images, and to account for anatomic shifts that occurred after surgery. In anatomic regions in the brain where natural barriers would likely preclude microscopic tumor extension, such as the cerebellum, the contralateral hemisphere, the tentorium cerebri, and the ventricles, the margins may be modified (see Figure 31.6).

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Figure 31.6 Volumes outlined from MRI displayed on fused treatment-planning CT

High-Grade Gliomas  GTV1: contrast-enhancing lesion, the surgical resection cavity and surrounding edema  PTV1: GTV1 plus 2.0-cm margin (PTV1 is treated to 46 Gy in 23 fractions, and after that there is a cone down to PTV2, which is treated for an additional 14 Gy in 7 fractions)  GTV2: contrast-enhancing lesion and surgical cavity  PTV2: GTV2 plus 2.5-cm margin Pilocytic Astrocytomas  GTV: contrast-enhancing lesion and any associated cyst  PTV: GTV plus 1–1.5 cm Infiltrating Low-Grade Gliomas  GTV: fluid-attenuated inversion recovery (FLAIR)/T2 abnormality and any contrast enhancement  PTV: GTV plus 1–1.5 cm Isodose distributions for the PTVs should be generated and evaluated for homogeneity and normal tissue tolerance. It also may be helpful to look at

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composite isodose lines in absolute dose when evaluating a plan (see Figure 31.7). The inhomogeneity within the target volume should be kept to ≤10%, and the minimum dose to the target volume should be kept within 5–10% of the dose at the center of the volume.

Figure 31.7 Isodoses and beam arrangement displayed on the treatment-planning CT

Field Arrangements Treatment should be delivered with multiple fields in an attempt to achieve homogeneity throughout the volume and to spare dose to uninvolved brain (see Figure 31.7). This can be accomplished by using three-dimensional (3D) conformal techniques or intensity-modulated RT (IMRT). In general, parallelly opposed portals are not used; however, in cases where tumor is infiltrating across midline through corpus callosum, this may be a very reasonable field arrangement for PTV1. On-board imaging techniques with kV images or cone-beam CT can be used for daily treatment verification and setup adjustment (see Figure 31.8).

Normal Tissue Tolerance Organs at risk (OAR) in RT of gliomas include eyes, optic nerves, optic chiasm, brainstem, cochlea, spinal cord, and perhaps the pituitary/hypothalamus. Dose limitations are suggested in Table 31.18.

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Figure 31.8 Treatment-planning CT fused with the cone-beam CT acquired on the treatment table

Table 31.18 Recommended dose constraints Organ at risk

Dose (Gy)

End point

Brainstem

Dmax < 54

Permanent neuropathy

Spinal cord

Dmax < 45–50

Myelopathy

Optic nerves

Dmax < 50

Optic neuropathy

Chiasm

Dmax < 54

Optic neuropathy

Retina

Mean dose < 45

Blindness

Cochlea

Mean dose < 45

Sensorineural hearing loss

Dmax maximum dose Modified from: Marks LB, Yorke ED, Jackson, A et al (2010) Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 76:S10–S19 Source: active or recently closed RTOG protocols

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Follow-Up Although high-grade and low-grade gliomas have vastly different outcomes, both require follow-up, with emphasis on the importance of serial imaging. At least 25% of patients with high-grade gliomas treated with RT and temozolomide will develop pseudoprogression on the initial posttreatment images. This must be taken into consideration when planning a therapeutic intervention. Additional imaging, such as perfusion, PET, DWI, and/or spectroscopy may be useful. Patients should also be followed with physical examinations, with attention to neurologic findings and screening for late effects. MRI schedule during follow-up is presented in Table 31.19. Table 31.19 Follow-up MRI schedule and examinations Schedule

Frequency

High-grade glioma First follow-up

  3–6 weeks after RT ends

Year 1–3

 Every 2–3 months 

Year 4–5

 Every 3–6 months 

Years 5+

 Annually 

Examinations Low-grade glioma First follow-up

 1–3 months after RT

Years 1–5

 Every 3–6 months

Years 5+

 Annually

Modified from: NCCN Guidelines 2009, http://www.nccn.org/professionals/physician_ gls/f_guidelines.asp

Common radiation-induced adverse effects include alopecia, fatigue, anorexia, erythematic/soreness of the scalp, irritation of the external auditory canal, serous otitis, nausea, vomiting, headaches, seizures, and exacerbation of focal neurologic deficits. Xerostomia or altered taste may be reported by patients. Due to the poor prognosis, reports on long-term complications, other than radiation necrosis, in high-grade glioma are rare; however, late effects are recognized in low-grade glioma and include radiation necrosis, endocrine dysfunction, neurocognitive deficits, hearing impairment, visual damage (including retinopathy, cataracts, optic neuritis), and radiationinduced neoplasms.

32

Pituitary Tumors Keith H. C. Lim1 and Simon S. Lo2

Key Points  Pituitary adenoma is the most common type of pituitary tumor and accounts for 10 –15% of all intracranial tumors.  The natural history of pituitary adenoma is long in most cases.  Approximately 10% of cases are diagnosed incidentally from magnetic resonance images (MRIs) of the brain for other conditions.  Surgery is the mainstay modality for microadenoma.  Medical treatment is indicated to control hormonal dysfunction and reduce the size of tumor in functioning pituitary adenomas. Choices of medication depend on the endocrine function of the disease.  Radiation therapy (RT) is usually not indicated in completely resected microadenoma unless the disease is persistent.  Adjuvant RT is recommended for incompletely resected and unresectable lesions, recurrent disease, or tumors with extrasellar extension.  Both fractionated RT and stereotactic radiosurgery (SRS) have been effectively used in the treatment of pituitary adenoma. Dose of fractionated RT ranges between 45 and 54 Gy, and dose of SRS ranges between 15 and 18 Gy for nonfunctioning and 18 and 30 Gy for functioning tumors.  Outcome after treatment is usually measured by symptomatic relief and control of hormone hypersecretion. Improvement of hormone abnormalities is gradual and may take up to 10 years to achieve.  Long-term disease control after surgery or surgery followed by RT is approximately 60, 75, and 50% for prolactinoma, Cushing’s disease, and acromegaly, respectively.

1

Keith H. C. Lim, MBBS FRANZCR Email: [email protected]

2

Simon S. Lo, MD () Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_15, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Epidemiology statistics and risk factors of pituitary tumors are detailed in Table 32.1. Table 32.1 Statistics and risk factors of pituitary cancer Type

Description

Statistics

Incidence: accounts for 10 –15% of all primary brain tumors, and occurs in 7 in 100,000 (female) and 3 in 100,000 (male) people annually worldwide ~70% are hormone-secreting tumors 20 –25% of apparently normal pituitary glands removed at autopsy contain adenoma Age: usually occurs in patients aged 30 –60 years, with a median age of 52 years Gender: the overall male:female ratio is ~2–3:1. Females have more prolactin and ACTH-releasing tumors; male have more nonfunctioning and GH-releasing tumors The etiology of pituitary adenoma or adenocarcinoma is unknown

Risk factors

Genetic predisposition: autosomal dominant multiple endocrine neoplasia type 1 (MEN-1) syndrome (tumors of pituitary, parathyroid, and pancreatic islet cells) accounts for 3% of pituitary tumors

There is no effective strategy for prevention of pituitary adenoma, and active screening using magnetic resonance imaging (MRI) or computed tomography (CT) is not recommended.

Anatomy The pituitary gland, or hypophysis, rests in sella turcica. It is surrounded by optic nerves/chiasm and cerebral arteries superiorly, cavernous sinuses laterally, and sphenoid sinus inferiorly (Figure 32.1). The anterior lobe (adenohypophysis) of the pituitary produces prolactin, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH); the posterior lobe (neurohypophysis) secrets oxytocin and antidiuretic hormone (ADH).

Chapter 32 Pituitary Tumors Anterior commissure

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Optic recess Infundibulum

Lamina terminalis

Circular sinus Ant. cerebral artery

Cerebral peduncle

Optic chiasma

Corpus mammillare

Anterior lobe of hypophysis

Post. cerebral artery

Posterior lobe

Pons

Basilar artery

Figure 32.1 Pituitary gland and its surrounding structures. Adapted from Gray’s anatomy

Pathology Most of the pituitary adenomas arise from the anterior lobe, which is derived from Rathke’s pouch, and are benign in nature. Pituitary adenoma can be categorized as secretory or nonsecretory tumors, with a ratio of 2:1, and further classified according to function (Table 32.2). Tumors that hypersecrete prolactin, corticosteroids, and GH account for 50, 25, and 20% of pituitary adenomas, respectively. In patients who previously have bilateral adrenalectomy, 20 –40% may develop Nelson’s syndrome, manifesting as very rapid growth of the pituitary adenoma.

Table 32.2 Pathology types of pituitary adenomas and clinical manifestations Disease

Manifestation

Prolactinoma

 More common in females  Males with disease more advanced (macroadenoma)  Prolactin hypersecretion caused by loss of inhibition from  hypothalamus from mass effect on infundibulum  Elevated serum prolactin level   Symptoms mostly caused by mass effect or hyperprolac tinemia  Hypopituitarism may occur   Symptoms include amenorrhea, galactorrhea, decreased  libido, impotence, and infertility ▶

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Table 32.2 (continued) Disease

Manifestation

 Caused by GSH pituitary adenoma  Male:female ratio of ~1:1  Elevated GH and insulin-like growth factor (IGF-1)  Symptoms mostly caused by mass effect or GH hypersecretion Acromegaly  Gigantism if occurs in childhood  Acromegaly in adults: enlargement of hands and feet, coarse facial features, visual impairment (20% of patients), weight gain, arthritis, organomegaly, heat intolerance, glucose intolerance, oily skin, skin tags, and colon polyps  Caused by ACTH-secreting pituitary adenoma  More common in females  Most are microadenomas  Elevated serum and urine cortisol, nonsuppressible with low-dose dexamethasone and partially suppressed with Cushing’s disease high-dose dexamethasone  Serum ACTH can be normal to moderately elevated  Symptoms mostly caused by hypersecretion of ACTH: truncal obesity, hypertension, psychologic changes, skin striae, diabetes, hirsutism, and Nelson’s syndrome  Rarely diagnosed pituitary adenoma  ~70% secrete TSH alone, and ~30% secrete GH, PL, and FSH/LH in addition TSH-secreting adenoma  Most are macroadenoma and invasive  Symptoms mostly caused by hypersecretion of TSH: goiter and features of hyperthyroidism  Usually diagnosed as macroadenoma  Can be undifferentiated cell types (mixed cell or oncocytoma) or hormonally inactive glycoprotein-producing adenoma Nonfunctioning  Symptoms mostly caused by mass effect: headache, visual  adenoma field deficits, and endocrine deficiencies (hypogonadism, hypothyroidism, hypoadrenalism or panhypopituitarism) due to compression of normal pituitary  Often incidental finding during MRI of head and neck region  Hypersecretion of both prolactin and growth hormones Mixed growth hormone/  Clinical symptoms caused by hypersecretion of both horprolactin mones (see above) and mass effect (see above) Gonadotropin Hypersecretion of FSH, LH, and α-subunit secreting Clinical symptoms caused by a nonfunctioning sellar mass adenoma  Very rapid enlargement of pituitary adenoma, leading to mass effect Nelson’s  Hyperpigmentation may be present syndrome  High ACTH levels

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Malignant pituitary neoplasms accounts for ~1% all pituitary tumors, and have no unequivocal histopathologic features of carcinoma. Hence, the diagnosis of malignancy is reserved for pituitary neoplasms with metastases to remote areas of the central nervous system (CNS) or distantly.

Routes of Spread Most of the pituitary tumors are benign in nature but can locally invade bone and soft tissues. CNS and distant metastases can occur in malignant pituitary neoplasms.

Diagnosis, Staging, and Prognosis Clinical Presentation The presenting symptoms and signs in patients with pituitary adenoma are caused by local tumor extension (mass effect and neuro-ophthalmic manifestation) or hormonal dysfunction (endocrine syndromes) (Table 32.2 and Table 32.3). The initial presenting symptom of a malignant pituitary tumor is usually a secreting, invasive macroadenoma, with ACTH and prolactin being the most common hormones secreted. Table 32.3 Commonly observed signs and symptoms in pituitary adenoma Type

Description

General

 Usually present with long-term history (varies from days to years)  Most general symptoms are secondary to mass effects, which are more common in nonsecreting adenoma cases  Common symptoms: headache, extraocular palsies, and visual symptoms (bitemporal hemianopia, homonymous hemianopia)

Endocrine function related

 ~75% of pituitary adenomas are functional and present with hormone hypersecretion  Symptoms associated with hormone hypersecretion are detailed in Table 32.2

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Diagnosis and Staging Figure 32.2 illustrated the diagnostic algorithm for pituitary tumors, including suggested examination and tests. Laboratory tests used in the diagnosis and evaluation of pituitary tumors are detailed in Table 32.4.

Pituitary Tumor Suspected

Complete History and Physical Examination with Neuro-ophthalmic Examination

Recommended Enhanced MRI with Gadolinium-DTPA

CBC Serum Chemistry Urine Analysis

Optional CT of Brain Skeletal Survey

Prolactin and Other Baseline Endocrine Tests

Imaging Studies

Baseline Lab Studies

Recommended Tests for Prolactinoma Acromegaly Cushing‘s Disease (Table 31.5)

Specific Lab Tests

Multidisciplinary Treatment

≈ 10% of cases are diagnosed incidentally by MRI for other diseases Neuro-ophthalmic examination should focus to cranial nerve dysfunction and include a formal visual field test High-resolution CT can be used if enhanced MRI is contraindicated or unavailable Baseline endocrine tests include ACTH, cortisol, estradiol, testosterone, GH, somatomedin-C, FSH, LH, TSH, and thyroxine are required to determine the functionality and cell origin of tumor

Figure 32.2 Proposed algorithm for diagnosis of pituitary tumor

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Table 32.4 Laboratory tests in the evaluation of pituitary tumors Disease/target of test

Test(s)

Prolactinoma

Prolactin

Acromegaly

Baseline growth hormone, somatomedin-C, or IGF-1, glucose suppression and insulin tolerance, thyrotropin-releasing hormone stimulation Serum ACTH, urine 17-hydroxy-corticosteroids, and free cortisol, response to dexamethasone suppression

Cushing’s disease

Selective bilateral simultaneous venous sampling of ACTH from inferior petrosal sinuses (in Cushing’s disease with negative neuroimaging studies)

Thyroid function

TSH and free thyroxin index

Gonadal function

FSH and LH Estradiol and testosterone

Adrenal function

Basal plasma or urinary steroids Cortisol response to insulin-induced hypoglycemia Plasma ACTH response to metyrapone administration

Staging Pituitary tumors can be categorized by their sizes into microadenomas (<1 cm) and macroadenomas (1 cm) (Figure 32.3). Hardy’s radiographic classification for pituitary adenoma and schema for suprasellar extension is detailed in Table 32.5.

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Figure 32.3 Microadenoma and macroadenoma of the pituitary. Courtesy of the Department of Neurosurgery, UCLA Health System, Los Angeles

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Table 32.5 Hardy’s radiographic classification for pituitary adenomas and grading schema for suprasellar extension Stage/grade

Diagnostic criteria

0

Normal pituitary appearance

I

Enclosed within the sella, microadenoma, <10 mm

II

Enclosed within the sella, macroadenoma, ≥10 mm

III

Invasive, locally, into the sella

IV

Invasive, diffusely, into the sella

A

0- to 10-mm suprasellar extension occupying the suprasellar cistern

B

10 - to 20-mm extension, evaluation of the third ventricle

C

20 - to 30-mm extension, occupying the anterior third ventricle

D

Greater than 30-mm extension, beyond the foramen of Monro, or grade C with lateral extensions

Source: Huang D, Halberg FE. Pituitary tumors. In: Leibel SA, Phillips TL (2004) Textbook of radiation oncology, 2 edn. Saunders, Philadelphia, pp 533 –548

Prognosis Independent prognostic factors of pituitary adenoma correlating with outcome are detailed in Table 32.6. Table 32.6 Prognostic factors of pituitary adenoma Type

Description

Disease related

 Stage (i.e., invasiveness) of the disease   Functioning pituitary adenomas may have worse outcomes  compared with nonfunctioning adenoma, because radiotherapy controls tumor growth in over 90% of patients with pituitary adenomas but is less effective in control of hormone hypersecretion  Free from recurrence 

Patient related

Factors such as age, gender, performance status, or presence of visual deficits have not been found to be of prognostic significance

Diagnostic or treatment related

 Success in normalizing endocrine activity or relieving pressure  effects with treatment  No difference in overall survival after surgery, surgery plus ra diation therapy, or radiation alone  A radiation dose of 45 Gy or higher is associated with higher  local control rates

Source: Huang D, Halberg FE. Pituitary tumors. In: Leibel SA, Phillips TL (2004) Textbook of radiation oncology, 2 edn. Saunders, Philadelphia, pp 533 –548

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Outcomes after treatment for pituitary adenoma are usually measured by the control of tumor growth and hormone hypersecretion, especially after medical and radiation therapy, and can be achieved in the majority of patients. Improvement of visual symptoms occurs in ~50% of cases. Survival after metastasis is poor, and the 1-year overall survival is <66%.

Treatment Principles and Practice The aims of treatment for pituitary tumor include symptomatic control (due to mass effect or hormone hypersecretion), removal of tumor, and restoration of pituitary function, without injury to surrounding structures. Commonly utilized modalities include medical therapy, surgery, radiation therapy, and their combination (Table 32.7). Table 32.7 Treatment modalities for pituitary adenoma Type

Description a

Surgery

Indications

Outcome

Techniques

a

 Usually considered the mainstay of treatment  Provides rapid relief of tumor mass and hormone hypersecretion  Compression of optic chiasm, leading to visual field deficits  Cure rate of 80–90% for functioning tumors, without involvement of the cavernous sinus, suprasellar region, or clivus  Cure rate of ~60 and ~25% at 5 years after complete resection of microprolactinoma or subtotal resection of macroprolactinoma  Cure rate of ~75 and 50% for Cushing’s disease and acromegaly, respectively  Trans-sphenoidal approach is usually the technique of choice  Ideally, the entire tumor is removed with normal pituitary tissue intact. In patients without identifiable microadenoma and fertility is not a concern, the majority of the gland is removed  Adjuvant radiotherapy is usually needed after surgery for macroadenoma (usually invasive tumor and incomplete resection, or persistent elevated hormone level)

Source: Molitch ME. Prolactinoma. In Melmed S (ed) (2002) The pituitary, 2nd edn. Blackwell Publishing, Malden MA, pp 455 –495 b Source: Grigsby et al (IJROBP 1999) – surgery plus RT: 10-year OS/DFS 85.1% and 89.4% Grigsby et al (Cancer 1999) – RT alone vs immediate post-op RT: post-op RT arm had better PFS c Source: Huang D, Halberg FE. Pituitary tumors. In: Leibel SA, Phillips TL (2004) Textbook of radiation oncology, 2 edn. Saunders, Philadelphia, pp 533–548

Chapter 32 Pituitary Tumors

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Table 32.7 (continued) Type

Description

Radiation therapyb

Indications

 Definitive treatment for inoperable, invasive, or recurrent pituitary tumor if optic chiasm is at risk of compression but without symptoms  Radiation therapy is deemed not to be appropriate for patients with visual field deficits, because quick and dramatic tumor shrinkage is not expected  Adjuvant treatment for large tumors, after incomplete resection (when MRI at 6 –12 months postoperation demonstrate residual tumor), or with persistent hormone hypersecretion  Not indicated after complete resection of microadenoma unless with persistently raised hormone levels

Outcome

 Controls hypersecretion in 80% of patients with acromegaly, 50–80% of those with Cushing’s disease, and one third of those with hyperprolactinemia  Normalization of hormone level may take months to years

Techniques

 Fractionated RT (e.g., conventional RT, 3D-CRT, and IMRT) and SRS/SRT (for small tumors) can be used  Common dose scheme in fractionated RT: 45–54 Gy in 1.8–2.0 Gy per daily fraction  Common dose scheme in SRS: 15–30 Gy to edge of tumor  Common dose of SRT is 45–54 Gy in 1.8–2.0 Gy per daily fraction

Medical treatmentc

Indications

 Drug therapy can be offered for secretory tumors and choice of drug depends on tumor pathology  Can be primary treatment (in prolactinoma) but usually noncurative  Usually indicated to treat hormone dysfunction and reduce the size of the tumor

Medications

 Prolactinoma: dopaminergic agents (bromocriptine and cabergoline)  Acromegaly and TSH-producing tumors: somatostatin analogues (octreotide [~50% response rate] and lanreotide)  Cushing’s disease: Ketoconazole, metyrapone, and mitotane interfere in steroid biosynthesis in adrenal glands

RT: radiation therapy; CRT: conformal radiation therapy; IMRT: intensity-modulated radiation therapy; SRS: stereotactic radiosurgery; SRT: fractionated stereotactic radiotherapy

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The optimal treatment for individual cases depends on the type and size of the tumor, symptoms, and patient preference. Incidentally diagnosed nonfunctioning tumors can be managed with watchful-waiting strategy. Treatment algorithms for more commonly diagnosed prolactinoma, Cushing’s disease, and acromegaly are detailed in Figures 32.4 and 32.5.

Diagnosis of Prolactinoma

Symptomatic?

No

> 1 cm (macro)?

Yes

No

Yes

Medical Treatment (bromocriptine, pergolide, cabergoline)

Progression

Active Surveillance with Prolactin and MRI

Uncontrolled or Intolerance Surgery

Uncontrolled Adj. Radiotherapy

Active Follow-Up Figure 32.4 Proposed treatment algorithm for prolactinoma (radiation therapy to young females with prolactinoma may cause hypopituitarism, and is not the optimal initial treatment)

Radiation Therapy Techniques Simulation and Target Volume Delineation CT planning should be done with the patient in the supine position, with head flexed and fixed with thermoplastic mask. MRI fusion is highly recommended for delineation of target volumes. Selection and delineation of gross tumor volume (GTV), clinical target volume (CTV), and planning target volumes (PTV) are as follow (Figure 32.6):

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Diagnosis of Cushing‘s Disease/Acromegaly

Surgery Candidate? Yes

No Uncontrolled

Surgery

Uncontrolled

Adj. Radiotherapy

Controlled Medical Treatment (Ketoconazole for Cushing‘s Disease, Octerotide, DOPA adonists or pegvisomant for Acromegaly)

Active Surveillance with Cortisol or Somatomedin C

Active Follow-Up Somatostatin or octreotide is needed after adjuvant RT until normalization of GH secretion Octerotide is 40-fold more potent than somatostatin is

Figure 32.5 Proposed treatment algorithm for Cushing’s disease or acromegaly

 GTV: Contrast enhances gross tumor on MRI (axial T1 with gadolinium sequence)  CTV: GTV plus 0- to 0.5-cm margin (additional margin may be needed for pituitary adenocarcinoma, and the amount is dependent on the extent of tumor infiltration)  PTV: CTV plus 0.3- to 0.5-cm margin (for three-dimensional conformal radiation therapy [3DCRT] or intensity-modulated radiation therapy [ IMRT]) or 0.2 cm (when a Gill–Thomas–Cosman head frame is used for SRT)

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Figure 32.6 a–c Contrast-enhanced pituitary adenoma demonstrated on axial T1 MRI a; treatment-planning CT showing GTV (cyan) b; fusion of MRI and treatment-planning CT c showing PTV (red) (the mismatch of the soft tissue contours was caused by resolution of soft tissue edema at the time treatment planning was performed); in this case, a CTV expansion was not performed because the GTV was very well demarcated

Field Arrangement and Treatment Techniques Conventional radiation technique using three fields (two angled, wedged lateral fields and one noncoplanar anterior/superior field [exiting through occiput] to avoid irradiation to the eyes) with the isocenter set at the center of sella is commonly used (Figure 32.7). For 3DCRT, to achieve a conformal dose distribution, multiple noncoplanar and nonopposing beams are used. If the technology is available, IMRT can provide a better isodose distribution (Figure 32.8). Overall, 3D-CRT and IMRT can yield isodose distributions delivering lower doses to the temporal lobes, including bilateral hippocampi, which are responsible for memory.

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Figure 32.7 Three-field technique for pituitary irradiation

Figure 32.8 Isodose distribution of an eight-field IMRT plan for pituitary adenoma

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Dose and Treatment Delivery Dose of fractionated radiation therapy range from 45 to 50 Gy for both nonfunctioning and functioning tumors (1.8 Gy/day) (Table 32.8). Table 32.8 Commonly used dose and fractionations for EBRT for pituitary tumors, based on pathology Tumor type

Dose and fractionation

Prolactinoma

45 Gy in 25 fractions (1.8 Gy per fraction)

GH secreting

45 Gy in 25 fractions (1.8 Gy per fraction)

Endocrine inactive, postoperative

45 Gy in 25 fractions (1.8 Gy per fraction)

ACTH secreting

50.4 Gy in 28 fractions (1.8 Gy per fraction)

TSH secreting

50.4 Gy in 28 fractions (1.8 Gy per fraction)

Nelson’s syndrome

45–50.4 Gy in 28 fractions (1.8 Gy per fraction)

Source: Huang D, Halberg FE. Pituitary tumors. In: Leibel SA, Phillips TL (2004) Textbook of radiation oncology, 2 edn. Saunders, Philadelphia, pp 533 –548

Doses for SRS depend on the function of the disease. Lower doses of 15 –18 Gy and higher doses of 18–30 Gy are recommended for nonfunctioning and functioning tumors, respectively (Figure 32.9). An effort should be made to limit the radiation dose to the optic chiasm to <8 Gy. For prolactinomas and GH-secreting tumors, stopping antisecretory medications 2–4 months

Figure 32.9 Isodose distribution of Gamma Knife–based stereotactic radiosurgery for a patient with macroscopic pituitary adenoma; prescription dose was 15 Gy (yellow isodose line) to the edge of tumor while keeping the dose to optic chiasm to below 8 Gy (green isodose line)

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prior to SRS may improve chances of endocrine cure. The optimal timing is unclear, and there is a risk of tumor enlargement during the time when the anti-secretory medication is stopped (Source: Sheehan JP, Niranjan A, Sheehan JM et al (2005) Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 102:678 –691; Witt T (2003) Stereotactic radiosurgery for pituitary tumors. Neurosurg Focus 14: e10).

Normal Tissue Tolerance Organs at risk in fractionated radiation therapy for pituitary tumor and their dose limitations are detailed in Chap. 30, “Meningioma,” Table 30.14. Significant radiation optic neuropathy develops in <2%, with a median maximum single dose of 10 Gy to the optic nerve/chiasm (Source: Stafford SL, Pollock BE, Leavitt JA et al (2003) A study on the radiation tolerance of the optic nerves and chiasm after SRS. Int J Radiat Oncol Biol Phys 55:1177–11781).

Follow-Up Active follow-up after definitive treatment for pituitary tumor is recommended. Schedule and suggested examinations for follow-up are detailed in Table 32.9. Table 32.9 Follow-up schedule and examinations Schedule

Frequency

Years 0–2

 Annually every 4–6 months

Year 3–5

 Every 6–12 months

Year 6 and beyond  Annually Examination History and physical

 Complete history and physical examination  Formal visual field testing

Imaging study

 MRI every 6 months in the first 2 years, then annually

Laboratory tests

 Endocrine tests are recommended every 6 months  Tests include GH, TSH/T3/T4, gonadal function and adrenal function tests, and hypersecreted hormone prior to treatment

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Toxicities Acute and late side effects secondary to radiation treatment are similar to those observed in other brain tumor treatments. Acute side effects may include alopecia, skin reaction, and fatigue. Severe long-term adverse effects are uncommon, except for pituitary hypofunction (especially for growth hormone). Radiation-induced optic neuropathy, brain necrosis, and neuropsychological dysfunction can occur but are rare with modern radiotherapy techniques. Secondary malignancy may occur rarely (~2% at 20 years) (Source: Huang D, Halberg FE. Pituitary tumors. In: Leibel SA, Phillips TL (2004) Textbook of radiation oncology, 2 edn. Saunders, Philadelphia, pp 533 –548).

Section X Skin Cancers and Soft Tissue Sarcoma

X

33 Soft Tissue Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . 943 Heather McCarty, Colleen Dickie and Brian O’Sullivan 34

Cutaneous Malignant Melanoma . . . . . . . . . . . . 977 José A. Peñagarícano and Vaneerat Ratanatharathorn

35

Basal and Squamous Cell Carcinoma of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995 José A. Peñagarícano and Vaneerat Ratanatharathorn

33

Soft Tissue Sarcoma Heather McCarty1, Colleen Dickie2 and Brian O’Sullivan3

Key Points  Soft tissue sarcoma (STS) is a relatively rare malignancy.  The median age of onset of STS is from 50 to 55 years of age.  Deep lesions with history of growth or any superficial/deep abnormalities with prior radiation exposure require careful evaluation.  Approximately 50% arise in the extremities, 40% in the trunk and retroperitoneum, and 10% in the head and neck.  STS are characterized by wide heterogeneity in anatomical site, pathologic subtype, and clinical behavior.  Histologic confirmation is necessary, with careful planning of initial core-needle or incisional biopsy to avoid compromising curative resection.  Prebiopsy cross-sectional imaging (computed tomography [CT] and/or magnetic resonance imaging [MRI]) of primary lesion should be done.  Prognosis depends on a patient’s age, and the size, histologic grade, and stage of the tumor.  Review of biopsy tissue, staging, and treatment planning should be undertaken by a multidisciplinary team of specialists experienced in sarcoma management.  Low-grade, superficial, small tumors (<5 cm) are usually curable by surgery alone.  High-grade tumors usually require a combined-modality approach of preoperative or postoperative radiation therapy in combination with function-preserving surgery.  Role of chemotherapy is less well defined. Anthracycline-based chemotherapy is the mainstay of adjuvant and metastatic regimes.  The most commonly observed metastatic site is lung.  Treatment of metastatic disease includes surgery for patients with optimal underlying biologic behavior and pulmonary metastases.  Gastrointestinal stromal tumors are a different entity and require a different management approach with surgery and molecularly-targeted therapies.

1

2 Heather McCarty, MD Colleen Dickie, MSc, MRT (T) (MR) 3 Brian O’Sullivan, MD Email: Email: Email: [email protected] [email protected] [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_16, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Soft tissue sarcomas (STS) are malignant tumors derived from mesenchymal tissue and contribute to approximately 1% of adult cancers in the the USA. The incidence of adult STS is 6.5/100,000 in the USA, and in 2010, approximately 10,660 new cases of STS will be diagnosed in the USA, of which 5,780 will be men and 4,880 women. A number of risk factors have been identified for STS (Table 33.1). However, screening in high-risk patients using imaging or laboratory tests is not supported by clinical evidence, due to low incidence and prevalence of this disease. Table 33.1 Risk factors of STS Type

Description Age: median age is 50–55 years Lifestyle: The significance of prior injury to the site of presentation is not confirmed Family medical history: not specifically related apart from genetic predisposition

Patient related

Past medical history: lymphedema associated with lymphangiosarcoma, past radiation exposure Genetic predisposition: associated with p53 mutations (LiFraumeni syndrome), neurofibromatosis (von Recklinghausen disease), retinoblastoma, Gardner’s Syndrome, Carney’s triad, Werner’s syndrome, Gorlin’s syndrome, tuberous sclerosis, and basal cell nevus syndrome

Environmental

Industrial chemicals: workers in manufacturing thorotrast, vinyl chloride and arsenic (hepatic angiosarcomas), phenoxyherbicides, chlorophenols, dioxins, phenoxyacetic acids, and certain herbicides

Anatomy The majority of STS arise in individual muscle groups in the extremities; the thigh is the most common site. Expansion tends to be longitudinal within the muscle and confined to the compartment of origin. There is generally an area of edema surrounding the tumor, particularly in the craniocaudal direction. Tumors that arise in the subcutaneous tissues are separated from the muscles by the superficial investing fascia, and maintenance of this plane is impor-

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tant; surgical disruption during an unplanned sarcoma resection may result in deep tumor contamination. Retroperitoneal tumors, by definition, arise in the tissues of the retroperitoneum and commonly grow to a large size before being clinically detected. They initially displace but eventually invade adjacent organs and tissues.

Pathology STS arise from the mesoderm and on occasion, from ectoderm. There are many subtypes, with varying biological behavior (Table 33.2). While malignant fibrous histiocytoma (MFH) has been the most frequent pathological diagnosis of the past two decades (40%), these tumors are now considered part of a heterogeneous group, with undifferentiated pleomorphic sarcoma the most common subtype. Liposarcoma is the second most commonly encountered STS (25%) and has a more favorable outcome than do the other histological subtypes. Welldifferentiated myxoid liposarcoma (MLS) is the most prevalent variant. These tumors can have a multifocal presentation and develop an unusual pattern of metastases, which includes a predilection for the retroperitoneum, mediastinum, and bone. MLS is a radiosensitive tumor and may have favorable local control after adjuvant radiotherapy. Angiosarcoma’s natural history is inconsistent with the general behavior of STS. Superficial angiosarcoma tends to occur more frequently in the head and neck region (50%) of older male patients, with a multifocal radial growth pattern within the dermis of the scalp and facial tissues, which frequently results in satellite lesions. Gastrointestinal (GI) stromal tumors are primary GI malignancies and are described in more detail later. Table 33.2 Commonly diagnosed histology types of STS and differentiation score Tumor type

Description

Fibrous

 Fibromatoses: superficial and deep  Fibrosarcoma

Fibrohistiocytic

 Dermatofibrosarcoma protuberans  Malignant fibrous histiocytoma

Lipomatous

 Atypical lipoma  Liposarcoma

Smooth muscle sarcomas

 Leiomyosarcoma  Epithelioid leiomyosarcoma

▶

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Table 33.2 (continued) Tumor type

Description

Skeletal muscle sarcomas

 Rhabdomyosarcoma

Malignant tumors of blood and lymph vessels

 Epithelioid hemangioendothelioma  Angiosarcoma and lymphangiosarcoma  Kaposi’s sarcoma

Malignant perivascular

 Malignant glomangiosarcoma  Malignant hemangiopericytoma

Malignant neural

 MPNST (neurofibrosarcoma)  Primitive neuroectodermal tumor

Extraskeletal cartilaginous and osseous

 Extraskeletal chondrosarcoma  Extraskeletal osteosarcoma

Paraganglionic

 Malignant paraganglioma

Pluripotential malignant mesenchymal

 Gastrointestinal stromal tumor (GIST)  Synovial sarcoma  Clear cell sarcoma  Epithelioid Sarcoma  Desmoplastic small cell tumor

MPNST: malignant peripheral nerve sheath tumor Source: Fletcher CDM, Unni K, Mertens K (eds) (2002) World Health Organization Classification of tumors: pathology and genetics of tumors of soft tissue and bone. IARC Press, Lyon, France

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Routes of Spread Local extension is the major route of spread in sarcoma (Table 33.3). Regional lymphatic spread is less common, and distant hematogenous metastases are present in 10% of cases at initial diagnosis. Table 33.3 Routes of spread of STS Route

Description

Local extension

 Spread longitudinally within the muscle groups from which they originate  May invade contiguous structures, muscle, and envelope major neuro-vasculature  For extremity lesions, barriers to spread such as bone and major fascial planes prevent axial spread of disease beyond originating compartments  Non-extremity lesions have similar patterns of spread, and therefore, fascial planes should be recognized and accounted for in surgical and/or radiation target volumes

Regional lymph node metastasis

 Lymph node metastasis is uncommon for STS except for epithelioid sarcoma, clear cell sarcoma, angiosarcoma, and rhabdomyosarcoma  Has been associated with an adverse prognosis  Isolated lymph node metastasis may not be as deleterious a factor

Distant metastasis

Present in 10% of cases at diagnosis Most common site of metastasis is to the lungs  Spread to bone may follow lung metastases or may be the first site of relapse for MLS histologies  MLS may also develop isolated soft tissue metastases  For intra-abdominal visceral sarcomas and retroperitoneal sarcomas, the liver is a more common site of first metastasis

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Diagnosis, Staging, and Prognosis Clinical Presentation Signs and symptoms of STS depend on the location of the primary tumor (Table 33.4). The most commonly observed symptom of extremity and superficial torso STS includes a painless mass. The average interval between onset of symptoms and diagnosis is shorter for extremity and head and neck lesions than for abdominal or retroperitoneal tumors. Some tumors may be asymptomatic with rapid growth, and could be large at presentation. Table 33.4 Commonly observed signs and symptoms in STS Type

Description

General

 Pain on presentation suggests origin from or invasion of neurovascular structures  Superficial lesions are usually smaller than those in the retroperitoneum and those originating deep to fascia  Erythema and warmth may be evident  Large, slow-growing lesions may restrict joint motion  Larger tumors may ulcerate skin or invade adjacent compartment and bone, leading to fracture

 Growth rate determinant of clinical response   Low grade may grow at a slow rate without symptoms  and may be large at presentation (i.e., retroperitoneal Intraliposarcomas) abdominal and  Nonspecific abdominal pain or a palpable mass  retroperitoneum  Anorexia and chronic subacute intestinal obstruction  with subsequent weight loss appear late with large tuDiagnosis and Staging mors  Nasal obstruction

Figure 33.1 illustrates the diagnostic pathway for initial evaluation of an STS Cranial nerve dysfunction patient, including suggested examination and tests. Head and neck

Proptosis  Associated mass effect in sensitive locations including pain, odynophagia, pharynx obstruction, and airway compromise

Figure 33.1 Proposed algorithm for diagnosis and staging of STS

Chapter 33 Soft Tissue Sarcoma

Soft Tissue Sarcoma Suspected

Complete History and Physical Examination

Recommended MRI or CT prior to biopsy Avoid 'Unplanned excision' situation Pre Biopsy

Recommended Core preferable incisional biopsy where needed Biopsy and Pathology Assessment

Chest CT or chest X-ray for Low grade T1 lesions

MRI preferred or CT of primary site

CT for intraabdominal lesions

Routine Imaging Studies

CSF bone marrow in certain cases (e.g. rhabodomyosarcoma)

CT retroperitoneum in myxoid liposarcoma of extremity

Additional Imaging in selected cases

Metastasis?

Yes

Assess for potential cure

No

Multidisciplinary Treatment All soft tissue masses deep to the investing fascia should be considered sarcoma until proven otherwise Emphasis needed on type of biopsy and pathological assessment Cerebrospinal fluid (CSF) analysis for tumor cytology is indicated in parameningeal rhabdomyosarcoma

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Tumor, Node, and Metastasis Staging Diagnosis and clinical staging depends on history and physical examination, imaging, and laboratory tests. Pathological staging depends on findings during surgical resection and pathological examination. The 7th edition of the tumor, node, and metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC) is presented in Table 33.5. The grade of a tumor is more important in STS than in many other tumors and contributes to the stage grouping (Table 33.6). Table 33.5 AJCC TNM classification of carcinoma of STS Stage

Description

Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1a

Superficiala tumor ≤5 cm in greatest dimension

T1b

Deepa tumor ≤5 cm in greatest dimension

T2a

Superficiala tumor >5 cm in greatest dimension

T2b

Deepa tumor >5 cm in greatest dimension

Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

Distant metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Grade (G)

a

GX

Primary tumor cannot be assessed

G1

Well differentiated

G2

Moderately differentiated

G3

Poorly or undifferentiated

Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer (AJCC) cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

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Table 33.6 Stage grouping of STS Group

Stage (group)

T

N

M

G

IA

1a plus 1b

0

0

1

IB

2a plus 2b

0

0

1

IIA

1a plus 1b

0

0

2 or 3

IIB

2a plus 2b

0

0

2

2a plus 2b

0

0

3

Any T

1

0

Any G

Any T

Any N

1

Any G

III IV

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer (AJCC) cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

Certain subtypes of STS are not included in the TNM classification, due to widely differing natural history. These include fibromatosis (desmoid tumor), Kaposi’s sarcoma, and infantile fibrosarcoma. Rhabdomyosarcoma has two classifications, with the preoperative staging system being more in keeping with a TNM approach.

Prognosis The expected survival of STS at 5 years is 60%, with the majority of patients achieving local control (other than certain sites, e.g., retroperitoneum). The most important prognostic factors include anatomic site, size, depth, and pathologic characteristics (Table 33.7). Table 33.7 Five-year survival rates in patients with extremity STS Stage

Freedom from local failure (%)

Disease-free survival (%)

Overall survival (%)

I

88.0%

86.1%

90.0%

II

82.0%

71.7%

80.9%

III

83.4%

51.8%

56.3%

Source: Data from Memorial Sloan–Kettering Cancer Center for the period of 1 July 1982 to 30 June 2000

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Treatment Principles and Practice Surgical excision is the primary treatment of STS. Adjuvant radiation is recommended for deep tumors or if surgical margins are positive (Table 33.8). Chemotherapy is reserved for certain chemosensitive tumors or high-risk cases. A proposed treatment algorithm based on the best available clinical evidence is presented in Figure 33.2. Table 33.8 Treatment modalities used in STS Modality

Description

Surgical management Indications

 The main curative treatment modality  May need re-excision if margins involved or close  Adequate alone in superficial <5-cm tumors

Facts

 Local recurrence is <10% in experienced centers  Preoperative plan to spare critical structure, with resulting positive margin has LRR of 3.6% with use of RT  Unplanned excision (“whoops” operation) with positive margin has LRR of 31.6%

Radiation therapy

Indications

 Adjuvant treatment after complete resection for deep or  >5-cm tumors  Adjuvant treatment when margins close or involved   Palliative treatment to primary or metastatic foci 

Techniques

 EBRT using 3D-CRT or IMRT   Interstitial brachytherapy has a role in experienced cen ters  IORT has been used for retroperitoneal tumors 

Chemo-/targeted therapy

Indications

 Limited benefits for most patients  Potential adjuvant treatment for chemosensitive myxoid or round cell liposarcoma or synovial sarcoma  Used in treatment of rhabdomyosarcoma and GIST

Medications

 Anthracycline based regimes are mainstay in adjuvant and palliative setting  Gemcitabine–Paclitaxol has role as second-line therapy  Imatinib has transformed management of GIST

LRR: local recurrence rate; EBRT: external beam radiation therapy; 3D-CRT: 3D conformal radiation therapy; IORT: intraoperative radiation therapy

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Diagnosis of Soft Tissue Sarcoma

Clinical Staging of Soft Tissue Sarcoma

Low Grade

High Grade

Conservative Resection

Conservative Resection

Large (> 10 cm) lesions

Consider Adjuvant Chemotherapy (Gemcitabine)

Amputation (5% of cases)

(95% of cases)

Clear Margins

Positive Margins

RT Unusual

Reexcisiom +/Radiation Therapy Adjuvant Treatment

Clear Margins

Usually Radiation Therapy(50 Gy/ 25 Fractions If Preoperative, 60-66 Gy in 30-33 Fractions If Postoperative

Adjuvant Treatment

Positive Margins

Reexcisiom +/-

+/-

Radiation Therapy Unusual in This Setting

Radiation Therapy Adjuvant Treatment

Active Follow-Up

Figure 33.2 Proposed treatment algorithm based on the best available clinical evidence

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Treatment of Localized Superficial Small (<5 cm) STS (T1a, N0, M0) Surgical excision alone is sufficient provided the fascia boundaries are not compromised intraoperatively and margins are wide (Table 33.9). If margins are involved or close (<2 cm), re-excision or adjuvant radiation should be considered. Table 33.9 Surgical evidence Trial

Results

Surgery alone for selected cases MDACC, Houston

 Prospective data base of 88 patients with T1 STS deemed suitable for a R0 surgical alone  68% T1a, 58% high grade, 68% extremity  84% had R0 excision. 14% had R1, followed by 64 Gy  5-year LRR 7.9% for R0. 42.9% for R1  Demonstrated carefully selected T1 tumors can be treated adequately by gross total resection alone  Results pertain to highly specialized sarcoma surgical practice in a multidisciplinary environment

STS: soft tissue sarcoma; R0: negative surgical margin; MDACC: MD Anderson Cancer Center Source: Pisters PWT, Pollock RE, Lewis VO et al (2007) Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg 246:675–681

Treatment of Localized Deep and/or Large (>5 cm) STS (T1b–2b, N0, M0) Surgery is the main curative treatment modality, with the aim being to achieve negative margins. Radiation may be used either pre- or postoperatively to reduce the risk of local failure.

Surgery The goal of surgery is to resect the entire lesion with an adequate margin of normal tissue to reduce the risk of microscopic residual disease. Unplanned or “non-sarcoma” operations in which tumor margins are not considered preoperatively should be avoided. Amputation was the historical means of achieving adequate clearance but limb-sparing techniques are now standard of care (Table 33.10).

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Table 33.10 Surgical interventions for the treatment of STS Type of surgery

Description

Intralesional

 Piecemeal operation transects lesion  Macroscopic residual disease

Marginal

 Shell out of tumor  Surgical margin close or positive

Wide local excision

 Intracompartmental en bloc resection with cuff of normal tissue  Intact fascial plane  Margin adequate (>20 mm)

Radical

 En bloc resection of entire compartment including fascia

Amputation

 When impossible to achieve adequate surgical clearance due to major neurovascular or multicompartmental involvement  Or when significant radiation complications anticipated  On occasion, below-knee amputation gives better functional outcome compared with extensive surgery and RT

The size of an adequate surgical margin is not well defined. The quality should also be considered. Natural barriers to spread such as periosteum, muscular fascia, epineurium, and vascular adventitia allow for smaller margins, though may need adjuvant radiotherapy. Inadequate margins require additional treatment either re-excision or adjuvant radiation. Having positive margins nearly doubles the risk of local recurrence and increases distant recurrence and disease-related death (Table 33.11). Table 33.11 Clinical evidence of surgical treatment effectiveness in STS Trial

Results

Amputation or limb sparing plus RT NCI, Bethesdaa

 Randomized (1:2) 43 cases of high-grade extremity sarcoma to amputation (at/above joint proximal to tumor) or to limb-sparing surgery plus RT  Adjuvant RT: 50 Gy to entire at risk area plus 10–20 Gy to tumor bed  Local recurrence 4/27 (RT arm) versus 0/16 (p = 0.06)  However less aggressive approach provided no difference in survival: 5-year OS, 83 versus 88% (p = 0.99) ▶

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Table 33.11 (continued) Trial

Results

Surgical margins Roswell Park Buffalob

 Single-center 7-year experience of patients operated on  with attempt to achieve wide margins  If margins <2 cm: given adjuvant RT (60 Gy if extremity,  other areas 45–50 Gy)  85 extremity STS patients: 5-year LRR of 17% for surgery  alone (i.e., margins> 2 cm) and 7% for surgery plus RT

Surgical extent impacting on local failure and survival Istituto Nazionale Tumori Milanc

 Prospective database of 21-year single-center experience 997 extremity patients: 874 R0 excisions 10-year LRR: 10% for R0, and 30% for R1 (p < 0.0001) 10-year disease-specific mortality: 19% R0 and 38% R1 17% of deaths in R1 group due to local disease  Concluded that surgical approach important as local relapse may directly impact survival

Planned positive margins PMH, Torontod

 Prospective single-center data set: 87 extremity STS patients with positive margins  LRR varied with classification of positive margins: small low-grade liposarcomas (4.2%), planned positive due to critical structures (3.6%), positive after re-excision of unplanned excision (31.6%), unplanned positive (37.5%)  Confirms a management philosophy that accepts carefully planned deliberate marginal excision when combined with radiation therapy

Expert sarcoma centers University of Miami Miller School of Medicine, Miamie

 4,205 patients operated on in 256 centers in Florida  7 so-called high-volume centers, treated 32.2% with significantly more high grade (53.8 versus 44.3%) and >10cm tumors (40.7 versus 28.7%)  Despite of this, median survival was 40 months at highvolume centers and 37 months at lower-volume centers (p = 0.002)

OS: overall survival; RT: radiotherapy; NCI: National Cancer Institute; PMH: Princess Margaret Hospital a Source: Rosenberg SA, Tepper J, Glatstein E et al (1982) Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196:305–314 b Source: Karakousis CP, Emrich LJ, Rao U et al (1986) Feasibility of limb salvage and survival in soft tissue sarcomas. Cancer 57:484–491 c Source: Gronchi A, Vullo SL, Colomob C et al (2010) Extremity soft tissue sarcoma in a series of patients treated at a single institution: the local control directly impacts survival. Ann Surg 251:506–511 d Source: Gerrand CH, Wunder JS, Kandel RA et al (2001) Classification of positive margins after resection of soft-tissue sarcoma of the limb predicts the risk of local recurrence. J Bone Joint Surg Br 83:1149–1155 e Source: Gutierrez JC, Perez EA, Moffat FL et al (2007) Should soft tissue sarcomas be treated at high-volume centers? An analysis of 4,205 patients. Ann Surg 245:952–958

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Radiotherapy Treatment With the advent of limb-sparing surgical techniques, adjuvant use of radiotherapy has been shown to improve local control without affecting survival. External-beam and brachytherapy have both been used. Clinical evidence for adjuvant external-beam radiation therapy (EBRT) is presented in Table 33.12.

Brachytherapy Brachytherapy allows delivery of treatment in the perioperative period over a shorter time course than EBRT does. It can be used alone or in combination with EBRT, particularly when one modality may result in higher than normal probability of complication. Various methods are used including low-dose rate (LDR), fractionated high-dose rate (HDR), and intraoperative HDR. Evidence supporting brachytherapy use is limited to small case series, and comparisons are difficult due to nonstandardization of target volumes, dose prescription points, and delivered dose. In particular, there are no robust large series evaluating HDR brachytherapy (Table 33.13). Concern remains over reduced local control, particularly in proximally located tumors. Brachytherapy dose optimization remains unknown and depends on dose rate and whether treatment is combined with EBRT (Table 33.14; Figure 33.3).

Cathetera 1-2 cm Cathetera 2-5 cm

TUMOR BED

2-5 cm

Cathetera

Cathetera

1-2 cm

Figure 33.3 American Brachytherapy Society guidelines for catheter positions. Source: Nag S, Shasha D, Janjan N et al (2001) The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys 49:1033–1043

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Table 33.12 Treatment strategies for use of adjuvant radiation and supporting clinical evidence Randomized Trial

Results

RT versus observation NCI, Bethesdaa

 Randomized 141 cases of extremity sarcoma after limbsparing surgery (and chemotherapy if high grade), to adjuvant RT or surgery alone  RT: 45 Gy plus 18 Gy boost to tumor bed  ~20% Cases did not receive adjuvant CRT as planned  At 9.6-year follow up, 1.4% (RT arm) versus 24% (surgery alone) LRR (p = 0.003)  No difference in OS  Summary: LC favored adjuvant RT arm

RT alone for unresectable sarcoma MGH Bostonb

 112 patients in single institution   43% extremity patients. 89% grade 2 or 3. 20% had che motherapy  5-year local control 51, 45, and 9% for tumors measuring  <5 cm, 5–10 cm, and >10 cm.  Those who received <63 Gy had 5-year LCR, DFS, and OS  rates of 22, 10, and 14%, compared with 60, 36, and 52% for those with >63 Gy  Increased radiation complication with dose > 68 Gy (28  versus 8% < 68 Gy)

Timing of RT NCIC CTG Canadac

 Randomized 190 cases of extremity sarcoma to pre- or postoperative RT. Both arms received 50 Gy to 5-cm expansion. All postoperative patients had phase 2 (16–20 Gy to 2-cm tumor bed expansion), whereas only positive margins of preoperative group got phase 2  Primary end point of wound complication: 35% preoperative versus 17% postoperative at median follow-up of 3.3 years (p = 0.01). Lower limbs at higher risk  2-year fibrosis rates of 31.5% (preoperative) versus 48.2% (p = 0.07)  No difference in 5-year local recurrence rate or OS (7 % preoperative EBRT versus 8 % postoperative EBRT LRR)

DFS: disease-free survival; MS: median survival time; LC: local control; DSS: diseasespecific survival; MGH: Massachusetts General Hospital; NCIC CTG: National Cancer Institute of Canada Clinical Trials Group; CRT: Chemotherapy a Source: Yang JC, Chang AE, Baker AR et al (1998) Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16:197–203 b Source: Kepka L, DeLaney TF, Suit HD et al (2005) Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 63:852–859 c Sources: O’Sullivan B, Davis AM, Turcotte R et al (2002) Preoperative versus postoperative RT in STS of the limbs: a randomised trial. Lancet 359:2235–2241; Davis AM, O’Sullivan B, Turcotte R et al (2005) Late radiation morbidity following randomization to preoperative versus postoperative RT in extremity STS. Radiother Oncol 75:48–53

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Table 33.13 Clinical evidence of brachytherapy for treatment of STS Trial

Results

ABS guidelinesa

 After complete resection of intermediate- or high-grade lesions with negative margins  Avoid as sole treatment when (1) CTV not fully encompassable, (2) critical organ proximity precludes delivery of meaningful dose, (3) skin involvement

Brachytherapy versus observation MSKCC, New Yorkb

 Intraoperative randomization after complete excision of superficial trunk or extremity tumors to brachytherapy or observation  164 patients (40% of those eligible) had catheters inserted with treatment, starting at day 6 postoperatively  Iridium 192 wires delivering 42–45 Gy over 4–6 days  5-year LCR: 82 (RT arm) versus 69% (p = 0.04)  5-year DSS: 84 versus 81% (p = 0.65)  No significant difference in low-grade tumors  Increased wound complication (p = 0.03) when brachytherapy commenced within 5 days of surgery. No significant difference when RT start changed to >5 days post surgery (p = 0.67)

LDR brachytherapy alone MSKCC, New Yorkc

 202 patients with gross total resection (18% microscopic positive margin) of high-grade extremity STS  Median dose of 45 Gy delivered over 5 days  5-year LCR (84%) and OS (70%)

ABS: American Brachytherapy Society; CTV: clinical target volume; MSKCC: Memorial Sloan-Kettering Cancer Center a Source: Nag S, Shasha D, Janjan N et al (2001) The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys 49:1033–1043 b Source: Pisters PW, Harrison LB, Leung DH et al (1996) Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 14:859–868 c Source: Alektiar KM, Leung D, Zelefsky MJ et al (2002) Adjuvant brachytherapy for primary high-grade soft tissue sarcoma of the extremity. Ann Surg Oncol 9:48–56

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Table 33.14 Brachytherapy doses Mode

Description

LDR monotherapy

 Total dose: 45–50 Gy  Dose rate: ~0.45 Gy/h  Time: 4–5 days

LDR with EBRT

 Total dose: 15–25 Gy (plus 45–50 Gy EBRT)   Dose rate: ~0.45 Gy/h   Time: 2–3 days 

Fractionated HDR

 Total dose: 32–50 Gy  Dose rate: ~twice daily, every 6 h  Time: 4–7 days

Fractionated HDR with EBRT

 Total dose: 12–18 Gy (plus 45–50 Gy EBRT)  Dose rate: ~twice daily, every 6 h  Time: 3 days

IORT (HDR)

 Total dose: 8–15 Gy  Time: 15–50 min

Source: Ballo MT, Lee AK (2003) Current results of brachytherapy for soft tissue sarcoma. Curr Opin Oncol 15:313–318

Treatment with Chemotherapy The role of adjuvant chemotherapy remains unproven in most STS subtypes. Several large trials have been reported recently in abstract form, and peer reviewed publications are awaited (Table 33.15). There is a consensus that certain subtypes of high-grade tumor benefit most from adjuvant chemotherapy, and use is at the treating physician’s discretion. Neoadjuvant treatment has been explored often in combination with radiation therapy (RT), but toxicity concerns outweigh any small benefits obtained. Extraosseous Ewing sarcoma and rhabdomyosarcoma have different biology, and chemotherapy is an integral part of their management.

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Table 33.15 Adjuvant chemotherapy Meta-analysis/trial Results

Sarcoma Meta-analysis Collaboration, (IPD)a

 14 Doxorubicin-based trials with 1,568 individual patient data (IPD)  No histology available on 18%  Heterogeneity in inclusion criteria  27% reduction in risk of local recurrence with 6% absolute benefit at 10 years  No significant difference in OS (p = 0.12)

2008 metaanalysis (literature based), Ontariob

 Included 18 trials with 1,953 patients (did not review individual patient data)  5 trials used a combination of Doxorubicin and Ifosfamide  Mean follow up was 4.9 years  The absolute improvement for OS was 6% in favor of the chemotherapy (40 versus 46%, p = 0.003)  Chemotherapy reduced LRR 4% (19 versus 15%) and DRR reduced 9% (37 versus 28%)

Neoadjuvant chemoradiation therapy, RTOG 9413c

 Multicenter study of 64 patients with high-grade extremity or body wall sarcoma >8 cm  44 Gy in 22 fractions preoperative RT split between 3 cycles of MAID chemotherapy, followed by surgery then 3 further cycles of modified MAID and 16-Gy boost (if margins positive)  Preoperative chemotherapy completed in 79%. Grade 4 hematology toxicity in 78%  5% treatment-related deaths  3-year LFR of 17.6% and 3-year OS of 75.1%

MAID: modified mesna, doxorubicin, Ifosfamide, and dacarbazine a Source: Sarcoma Meta-analysis Collaboration (1997) Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 350:1647–1654 b Source: Pervaiz N, Colterjohn N, Farrokhyar F et al (2008) A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 113:573–581 c Source: Kraybill WG, Harris J, Spiro IJ et al (2006) Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol 24:619–625

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Locally Recurrent STS Despite optimal primary combined modality treatment, 10–25% of STS will recur locally. The goal of management remains to regain local control while preserving normal tissue function. Salvage options depend on location and up-front treatment and include radical surgical resections (including amputation) or limited re-excisions with or without adjuvant therapy. Radiation should be used if not done previously, and re-irradiation can be considered on an individual basis. Brachytherapy to resected tumor bed has potential to limit re-irradiation of normal tissues.

Advanced STS (Unresectable T1–2/N1/M1) Pulmonary metastasectomy is potentially curative with a 5-year survival rate of 32 ± 7%. The decision to resect depends on disease free interval, histology, and patient age. For metastatic disease, anthracycline-based chemotherapy has been standard of care for many years. Multidrug regimens, particularly with the addition of Ifosfamide, have been shown to increase response rate but do not provide a survival benefit. Second-line therapies have been used with limited success. Subset analyses of several trials have shown the importance of histological diagnosis on response rates, though again, this does not always confer an improvement in survival outcomes (Table 33.16).

Retroperitoneal STS This heterogeneous group represents 10–15% of STS. All pathological subtypes can occur, though liposarcoma (30–60%) and leiomyosarcoma (20– 30%) are most common. Complete en bloc surgical resection is the main treatment. Treatment is summarized in Table 33.17 and Figure 33.4. Unlike extremity tumors, retroperitoneal STS have a greater propensity to recur locally than at a distant site. The rate of local relapse of these often biologically indolent tumors is high (40–50% at 5 years). Adequate margins can be difficult to obtain due to anatomical considerations, and surgical recommendations are to resect organs with evidence of direct invasion. More extensive surgery has been advocated though remains investigational. Outside of palliation of local symptoms, there is no advantage to macroscopically incomplete resections.

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Table 33.16 Treatment strategies for advanced disease Mode

Description

Gemcitabine plus Docetaxol Groupe Sarcome Françaisa

 Retrospective review of multi-institutional use of chemotherapy in advanced disease  133 patients; 21 had no prior chemotherapy  Days 1 and 8, 900 mg/m2 Gem plus day 8, Doc 100 mg/ m2, every 21 days  Overall response rate: 18.4%, leiomyosarcoma response rate: 24.2%  Median survival of 12.1 months

Trabectedin International multi-institutional coalitionb

 Multi-institutional review of 51 myxoid liposarcoma patients after failure of conventional chemotherapy  1.1–1.65 mg/m2 Trabectedin every 21 days until progression or unacceptable toxicity. Median of 10 cycles  Overall tumor control rate of 51%  Median progression-free survival of 14 months

Pulmonary metastasectomy MDACC Houstonc

 Single-institution retrospective review of bone and soft tissue pulmonary metastases management  5.6% of those with pulmonary metastases had surgery  115 STS patients with only pulmonary recurrence  Median survival of MFH, synovial sarcoma, leiomyosarcoma, and other sarcoma types grouped was 16.7, 30.2, 41.8, and 45.3 months respectively  A subgroup analysis of predictors for survival found disease-free interval of >24 months, maximum number of pulmonary nodules and age at diagnosis to be significant

Gem: Gemcitabine; Doc: Docetaxel a Source: Bay J-O, Ray-Coquard I, Fayette J et al (2006) Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis. Int J Cancer 119:706–111 b Source: Grosso F, Jones RL, Demetri GD et al (2007) Efficacy of Trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 8:595–602 c Source: Blackmon SH, Shah N, Roth JA et al (2009) Resection of pulmonary and extrapulmonary sarcomatous metastases is associated with long-term survival. Ann Thorac Surg 88:877–884

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Table 33.17 Clinical evidence for management of RPS Trial

Results

Surgical extent MSKCC, New Yorka

 Single-center prospective review of 500 patients  231 patients deemed resectable: R0 MS 103 months, R2 MS 18 months  No difference between MS of R2 and unresectable disease  Concluded that R2 surgery of no benefit

Post op Radiation RCT NCI, Bethesdab

 1980s, single-institution RCT comparing postoperative EBRT with IORT and EBRT  15 patients received 20 Gy IORT with electron fields, followed by 35- to 40-Gy postoperative EBRT  20 received 35–40 Gy extended-field EBRT with 15-Gy EBRT boost  40 versus 80% LRR (p < 0.001) in favor of adding IORT  At expense of significantly higher radiation enteritis and neuropathy in IORT arm  No significant difference in median survival (45 versus 52 months)  Small numbers, high toxicity and higher than expected LRR in control arm have limited the impact of this trial

Preoperative RT PMH, Torontoc

 55 patients, 33% with recurrent disease, followed prospectively  46 patients had R0 resection, 41 had preoperative EBRT and 23 had postoperative brachytherapy  Median EBRT dose of 45 Gy, brachytherapy dose to 25 Gy  All radiation acute GI toxicity RTOG scores of <2  Surgical and/or brachytherapy led to RTOG scores >3 in 39%  5% wound complications  2-year OS was 96.7% (primary), 74.1% (recurrent)

 2 centers, 74 intermediate-/high-grade patients treated Pre op RT with median of 45-Gy preoperative RT PMH, Toronto plus  75% primary, 25% recurrent disease MDACC, Houstond 54 patients had R0 surgery: 5-year DFS of 46%, OS of 61%

Surgical extent French Association of Surgerye

 Retrospective review of 382 primary RPS patients  121 patients received radiation and 145 received chemotherapy  32% had “complete compartmental resection” with resection of uninvolved organs to obtain rim of normal tissue  3-year LRR: 10 versus 50% for those with “standard surgery”  No difference in OS though 81% of recurrences had reresection

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Table 33.17 (continued) Trial

Results

Surgical extent Istituto Nazionale Tumori Milanf

 Single-center retrospective review of 288 patients   Median follow up: 120 months “standard surgery” and 32  months “aggressive surgery”  Aggressive approach: resection of tissues/organs if within  1–2 cm of tumor surface  30% of patients in each surgical group received RT   5-year LRR 29% for aggressive surgery versus 48% for  standard surgery (p = 0.0074)  OS: 60 versus 51% (p = NS) 

Use of RT Huntsman Cancer Hospital Utahg

 Retrospective review of a merged database of tumor reg istries from 150 US institutions  261 patients treated with curative intent surgery from  1982 to 2003  54.8% had local removal of tumor only. 28% had RT   5-year LFFS 69% (79% RT versus 64% no RT, p = 0.05) 

MS: Median Survival; RCT: randomized control trial; LFFS: local failure-free survival a Source: Lewis JJ, Leung D, Woodruff JM et al (1998) Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg 228:355–365 b Source: Sindelar WF, Kinsella TJ, Chen PW et al (1993) Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Arch Surg 128:402–410 c Source: Jones JJ, Catton CN, O’Sullivan B et al (2002) Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 9:346–354 d Source: Pawlik TM, Pisters PWT, Mikula L et al (2006) Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediateor high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol 13:508–517 e Source: Bonvalot S, Rivoire M, Castaing M et al (2009) Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. J Clin Oncol 27:31–37 f Source: Gronchi A, Lo Vullo S, Fiore M et al (2010) Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol 27:24–30 g Source: Sampath S, Hitchcock YJ, Shrieve DC et al (2010) Radiotherapy and extent of surgical resection in retroperitoneal soft-tissue sarcoma: Multi-institutional analysis of 261 patients. J Surg Oncol 101:345–550

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Suspected Primary Retroperitoneal Sarcoma

Contrast Enhanced CT scan of abdomen and pelvis + Ensure Unaffected Kidney Function Adequate (e.g. Differential renal scan)

Core Biopsy if Neo-adjuvant Treatment Considered

Soft Tissue Ewings, Rhabdomyosarcoma or GIST

Soft Tissue Sarcoma

Benign or Not SarcomaTreat as Appropriate

Multidisciplinary Meeting

R0, R1 Resection possible

No

Consider Neoadjuvant RT or Chemotherapy +/- RT

Unresectable

Resectable

Palliative/ Supportive Care

R2 Resection

Palliative Treatment

Local Recurrence

Yes

Consider Neoadjuvant RT +/- Neoadjuvant Chemotherapy

En bloc Resection

R0, R1 Resection

Consider Post op RT If Not Given Preop

Definitive Treatment

Active Follow-Up

Figure 33.4 Proposed treatment algorithm based on the best available clinical evidence for retroperitoneal STS

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Radiation use in the preoperative, intraoperative, and postoperative settings has been explored but randomized prospective evidence is lacking. Chemotherapy (alone or concurrent with RT) has been evaluated in several phase I trials and shown to be tolerable. However, there is as of yet no survival benefit of chemotherapy in this or the adjuvant setting. As a result, chemotherapy use is currently limited to high grade, locally advanced, unresectable, or metastatic disease. Unfortunately, an American College of Surgeons Oncology Group (ACOSOG) randomized control trial designed to evaluate the role of (neo)adjuvant RT and a phase II Radiation Therapy Oncology Group (RTOG) trial of combined-modality preoperative treatment both closed early due to slow accrual.

Gastrointestinal Stromal Tumors Primary GI sarcomas represent <3% of all GI malignancies but 14% of all STS. The response to Imatinib mesylate, an oral selective molecular inhibitor of the KIT and platelet-derived growth factor receptor-alpha (PDGFR-α) tyrosine kinases, has transformed management. Surgical excision remains the main treatment modality for operable disease, though evidence is emerging for Imatinib use in the adjuvant setting (Table 33.18). European and US guidelines now recommend a minimum of 1 year of adjuvant treatment after complete resection. Trials exploring optimal duration of therapy are underway. Table 33.18 Clinical evidence for Imatinib use in GIST Trial

Results

Adjuvant use ACOSOG Z9001a

 Multicenter, randomized trial  714 patients randomized to 400 mg Imatinib or placebo for 12 months after surgical resection  1-year recurrence-free survival 98 versus 83% (p < 0.0001)  No difference in OS though median follow-up only 19.7 months and cross-over allowed, i.e., those in observation arm given Imatinib when relapsed

Metastatic disease EORTC 62005b

 946 patients with advanced or metastatic GIST  Randomized to 400 or 800 mg/day until progression or grade 3/4 toxicity  ITT analysis: CR in 5 and 6% and PR, in 45, and 48% of once a day and twice daily, respectively  40-month median follow-up: no difference in PFS. Overall median PFS: 22 months  2-year OS: 69 versus 74%  Serious adverse reactions in 37 versus 38%

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Table 33.18 (continued) Trial

Results

Metastatic disease SWOG0033c

 746 metastatic or locally advanced GIST patients randomized to 400 or 800 mg/day  At progression, low-dose patients were crossed to 800mg treatment (133)  CR: 5 and 4%, and PR: 40 and 42%, for low and high dose, respectively  PFS: 18 versus 20 months  2-year OS: 76 versus 72% (p = 0.83)

Sunitinib after imatinib failure International multi-institutional coalitiond

 312 patients with Imatinib-resistant unresectable disease  Median TTP of 27.3 weeks for those on 50 mg Sunitinib versus 6.4 weeks placebo (p < 0.0001)  Tolerable side effects: 9 versus 8% withdrawal due to adverse events

ITT: intention to treat; CR: complete response; PR: partial response; PFS: progressionfree survival; TTP: time to progression a Source: Dematteo RP, Ballman KV, Antonescu CR et al (2009) Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373:1097–1104 b Sources: Verweij J, Casali PG, Zalcberg J et al (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134; Casali PG, Verweij j, Kotasek D et al (2005) Imatinib mesylate in advanced gastrointestinal stromal tumours (GIST): survival analysis of the intergroup EORTC/ISG/AGITG randomized trial in 946 patients. Eur J Cancer 3:S201 (Abstract 711) c Source: Blanke CD, Rankin C, Demetri GD et al (2008) Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626–632 d Source: Demetri GD, van Oosterom AT, Garrett CR et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338

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Imatinib at 400 mg/day is standard of care for locally advanced, recurrent, and metastatic gastrointestinal stromal tumors (GIST). Dose escalation may benefit some patients on progression and a second tyrosine kinase receptor inhibitor, Sunitinib has shown efficacy post-Imatinib progression.

RT Techniques RT for Adjuvant Therapy Simulation and Volume Definition Radiation fields should encompass tumor bed plus areas at risk of subclinical spread to achieve local control. The preoperative imaging, biopsy approach, location of scars or drains, and the anatomical compartment involved are all helpful in delineating this “at-risk” area. Magnetic resonance imaging (MRI) T2 high signal has been demonstrated surrounding many STS, in keeping with peritumoral edema that may contain microscopic disease, and should be included within the clinical target volume (CTV). A computed tomography (CT) simulation scan (3- to 5-mm cut) can be fused with any preoperative imaging, particularly MRI. Organs at risk (OAR) including bone should be delineated. There is limited randomized evidence supporting CTV margins and practice varies. A 4-cm margin on imaging abnormalities including peritumoral edema and sites of surgical disruption is used, based on randomized trial evidence of outcome. The shrinking-field technique is often used in the postoperative setting when margins are reduced to 2 cm surrounding the tumor bed after 50 Gy. When patients are treated with intensity-modulated RT (IMRT), there is an opportunity to treat simultaneously all volumes in a single phase, with an infield boost of the volume at highest risk of recurrence (Figure 33.5). Dose and Treatment Delivery For extremity sarcomas, conventional fractionation using photons to a total dose of 50 Gy is recommended preoperatively, with a boost of 16 Gy to tumor bed with a 2-cm margin recommended postoperatively if margins are involved. In the postoperative setting, 66-Gy total dose is delivered in 2-Gy fractions with a shrinking-field technique surrounding the tumor bed after 50 Gy. An ongoing prospective randomized clinical trial is currently investigating CTV margins for postoperative treatment (Figure 33.6).

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b

Norm. Volume

a

c

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

d

DVH Calculation Dose Axis Display Cumulative Absolute Dose

0

1000 2000 3000 4000 5000 6000 7000 Dose (cGy)

Volume Axis Display Normalized Volume

ROI Statistics Line ROI Type Bone CTV66 CTV56 CTV63

Trial Min

Max

Mean

Std. Cev

% Outside grid

%> Max

Genralized CUD

66 66 66 66

6521.9 6880.3 6880.3 6880.3

2366.3 6740.3 6128.1 6521.1

1823.3 44.6 365.7 163.7

0.00 % 0.00 % 0.00 % 0.00 %

0.00 % 0.00 % 0.00 % 0.00 %

2366.12 6741.63 6132.35 6525.39

204.8 6595.1 3706.0 4831.9

Figure 33.5 a–d Example of a small synovial sarcoma treated postoperatively due to a close resection margin status, 66 Gy delivered in 33 fractions. a Diagnostic preoperative T1-weighted Coronal MRI; the tumor is contoured in red for the purpose of this text. b Diagnostic postoperative T2-weighted coronal MRI. The area where the original site of tumor was located is contoured in red as in a. This convention is used in our own institution to ensure that the original site of tumor is properly included within the clinical target volume (CTV). The CTV is identified in green and is enlarged substantially to encompass the area of surgical change in addition to the area of the original site of tumor. c Axial view of the area where the lesion was located preoperatively shown in red, the CTVs, and Planning Target Volume (PTV)s..This three-level dose fractionation plan can be treated in consecutive phases as described above or simultaneously in a single-IMRT phase treatment. d Corresponding dose–volume histogram (DVH) demonstrating the three CTV dose levels. The bone dose is represented by the purple line

Chapter 33 Soft Tissue Sarcoma

Eligibility

Control arm

Soft tissue sarcoma Post op with clear or microscopic positive margins Without prior radiation therapy

RANDOMIZATION

Histologically proven Extremity

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Conventional two phase Phase 1: 50 Gy Sup-inf = 5 cm margin on GTV/ 1 cm on scar Axial = minimum 2 cm Phase 2: 16 Gy Sup-inf = 2 cm margin on GTV Axial = minimum 2 cm Total dose: 66 Gy in 33 fractions

Research arm Single-phase treatment to only phase 2 volume of control arm Total dose: 66 Gy in 33 fractions

Figure 33.6 Ongoing Cancer Research UK Clinical Trials Unit trial on CTV margins (randomized trial of volume of postoperative radiotherapy given to adult patients with extremity soft tissue sarcoma: Vortex trial)

Retroperitoneal tumors require large volume fields and 45–50 Gy in 1.8to 2-Gy fractions can be given safely, particularly preoperatively when the in situ tumor acts to limit OAR dose (Figure 33.7).

Figure 33.7 a, b

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Norm. Volume

e Dose Volume Histogram

a

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Dose Absolute Dose Volume Axis Display Normalized Volume

0

1000

2000

3000

4000

5000

6000

Dose (cGy) ROI Statistics Line Type

ROI

Type

PTV PTV PTV Spinal Canal R Kidney Liver

Uniform Dose Max Dose Min Dose Max Dose Max Dose Max DVH

Target cGy 4500 4725 4275 4400 500 3000

Weight 10 10 10 1 1 1

Figure 33.7 c–e Field volumes for retroperitoneal sarcoma. Delineated in red is the GTV, green represents the CTV, and blue represents the PTV. a–c Preoperative CT simulation scan demonstrating a right-sided retroperitoneal sarcoma (RPS) shown in the coronal, sagittal, and axial views respectively. Preoperative radiotherapy is especially preferred on the right side due to the proximity of the liver. d Preoperative CT simulation coronal view of a left-sided RPS. Red arrow indicates bowel pushed out of treatment volume by tumor. e Corresponding DVH for the right-sided RPS shown in a–c. Note dose constraints for critical structures such as the kidney, liver, and spinal cord

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IMRT in the Adjuvant Setting The benefit of IMRT in adjuvant treatment has not been fully addressed (Table 33.19). Table 33.19 Use of IMRT Nonrandomized trial

MSKCC, New York

Results  41 extremity patients with primary STS were treated with limb-sparing surgery and adjuvant IMRT  Majority of patients had positive margins, tumors >10 cm, and high-grade disease  Median follow-up of 35 months  Preoperative RT given to 7, postoperative RT delivered to remaining 34  Overall 5-year actuarial LC rate was 94%  5-year distant control rate was 61%, and the overall survival rate was 64%  IMRT in STS of the extremity provides excellent local control in a group of patients with high-risk features

Source: Alektiar KM, Brennan MF, Healey JH, Singer S. Impact of intensity-modulated radiation therapy on local control in primary soft-tissue sarcoma of the extremity. J Clin Oncol 26:3440–3444

Simulation and Target Volume Delineation Definitions of gross target volume (GTV), CTV, and planning target volume (PTV) in three-dimensional conformational RT (3D-CRT) and IMRT are as follow:  GTV: Gross tumor on imaging studies  CTV: GTV + 4 cm  PTV: CTV + 0.5–1 cm Treatment Delivery Coplanar fields can be used according to the shape of PTV in both the preoperative and postoperative settings (Figure 33.8).

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Norm. Volume

e Dose Volume Histogram 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0

1000

2000

3000 4000 Dose (cGy)

5000

6000

ROI Statistics Line ROI Type CTV50 GTV bone PTV50

Min

Max

Mean

4346.6 4749.5 253.9 3767.3

5621.4 5526.2 4848.6 5621.4

5108.8 5064.7 2694.4 5067.4

Std. % OutCev side grid 162.9 0.00 % 157.1 0.00 % 1054.9 0.00 % 216.1 0.00 %

Figure 33.8 a–e a T2weighted fat-saturated coronal MRI demonstrating the tumor and surrounding edema. b CT simulation coronal view of the GTV (red), CTV (green), PTV (blue), and edema (pink). Sagittal CT simulation image of the target volumes used preoperatively. d Axial view of target volumes with corresponding T2 fat-saturated MRI simulation scan fused for planning purposes. e DVH of bone and target volumes. Note: for this case, special care was taken to protect the femur, as this patient suffers from polio and has limited use of the unaffected limb

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Normal Tissue Tolerance OARs in radiation therapy of STS depend on the site of disease. Bone is the major dose avoidance structure in extremity tumors, while abdominal organs including small bowel, liver, kidneys, and spinal cord (Table 33.20) need to be considered in retroperitoneal sarcoma. Table 33.20 Dose limitation of OARs in radiation therapy for retroperitoneal sarcoma OAR

Dose limitations

Bone

 Mean dose < 37 Gy   Max dose < 59 Gy   V40 < 67% 

Spinal cord

 TD5/5: 45 Gy   Maximal dose 45 Gy to any point 

Liver

 TD5/5: 30 Gy   V30 < 40% 

Small intestine

 TD5/5: 45 Gy   V45 < 10% 

Kidney

 TD5/5: 20 Gy   V20 < 50% for both kidneys, or   V20 < 1/3 of one kidney 

Follow-Up The potential for local or distal recurrence of STS requires close follow-up after completion of treatment. Schedule and suggested examination during follow-up is presented in Table 33.21.

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Table 33.21 Follow-up schedule and examinations Schedule

Frequency

First follow-up

 4 –6 weeks after radiation therapy

Years 0–1

 Every 3–4 months

Years 2–5

 Every 6 months

Years 5–10

 Annually

Examination History and physical

 Complete history and physical examination 

Laboratory tests

 Serum chemistry if retroperitoneal primary 

Imaging studies

 Chest X-ray   CT of the abdomen and pelvis (if retroperitoneal primary) 

34

Cutaneous Malignant Melanoma José A. Peñagarícano1 and Vaneerat Ratanatharathorn2

Key Points  Cutaneous malignant melanoma is the fourth leading cancer type in men and the fifth in women in the USA. It is readily curable in early stages but in the disseminated state, it carries a grave prognosis.  Melanoma occurs more frequently in white adults, with peak incidence during the fourth and fifth decades of life melanoma is rare in dark-skinned races.  Women have a survival advantage. Most melanomas arise de novo. They also may arise from preexisting nevi.  Diagnosis is established by excisional biopsies (1- to 2-mm margin), full-thickness incisional biopsies, or punch biopsies of the thickest portion of the tumor, selected according to tumor site and size. Biopsies should be made with consideration of future definitive treatment in mind.  Histological types include nodular, lentigo maligna, superficial spreading, and acral lentiginous.  Primary mode of treatment for cutaneous melanoma is surgery, with full-thickness excision serving as proper staging as well as treatment. Adjuvant chemotherapy, systemic biological therapy, and radiation therapy may be indicated.  Survival rates have increased between the years 1995 and 2000 as compared with the 1970s, in part due to increased awareness and screening programs.  Depth of invasion correlates with survival in cutaneous malignant melanoma. For stages I, II, III, and IV tumors, 15-year survival rates approximate 80, 50, 35, and 5%, respectively.  Other prognostic factors include mitotic rate, ulceration, regression, host immune response, satellitosis, angiolymphatic invasion, and status of regional nodal involvement.

1

José A. Peñagarícano, MD Email: [email protected]

2

Vaneerat Ratanatharathorn, MD Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_17 © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology The incidence of melanoma in the US population is approximately 15 per 100,000 cases. Cutaneous malignant melanoma is the fourth leading cancer type in men and fifth in women in the USA. A number of risk factors have been identified in cutaneous malignant melanoma (Table 34.1). Table 34.1 Risk factors of melanoma skin cancer Factor

Description Host: poor tanning ability, white race, red hair, blond hair, blue eyes, freckles Premalignant conditions: dysplastic nevi, congenital nevi (low risk if <1.5 cm, giant congenital nevi >20 cm carries 5–8% risk of developing malignant melanoma within the nevi), Spitz nevi ,or juvenile melanoma

Patient related

Past medical history: history of previous melanoma, family history of melanoma (8–12% positive family history but not all have hereditary melanoma syndrome), immunosuppression, sun exposure, sunburns Genetic predisposition: FAMMM, xeroderma pigmentosa. Susceptibility genes in familial melanoma include CDKN2A, p14ARF, CDK4, and MC1R. The major susceptibility gene is CDKN2A on chromosome locus 9p21. Patients with CDKN2A are also at risk for developing pancreatic carcinoma at early age

Environmental

Carcinogens: petroleum and its by-products, chemicals (polyvinyl chloride, polycyclic aromatic hydrocarbons, benzene, pesticides); some of these chemicals also are risk factors for other hematological or solid malignancies

FAMMM: familial atypical multiple mole–melanoma syndrome

Anatomy The anatomy of human skin is detailed in Chap. 35, “Basal and Squamous Cell Carcinoma of the Skin” (Table 35.2).

Pathology The cell of origin in cutaneous malignant melanoma is the melanocyte. Histological subtypes include nodular, lentigo maligna, superficial spreading, and acral lentiginous (Table 34.2).

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Table 34.2 Histological subtypes of cutaneous malignant melanoma and their clinical characteristics Subtype

Characteristic

Superficial spreading

 70% of melanoma cases, associated with sun exposure  Commonly develop from pre-existing nevi  Slow-growing radial phase with low metastatic potential (5%), followed several years later by rapid vertical-growth phase, carrying high metastatic potential (35–80%)

Nodular

 30% of all melanoma cases  Most malignant subtype of malignant melanoma

 4 –15% of all melanoma cases  Not associated with pre-existing nevi Lentigo malignant  Has the most benign behavior of all melanomas  Disease of the elderly

Acral lentiginous

 2–8% of all melanoma cases  35–90% of melanomas in African Americans, Asians, and Hispanics  Involves palms and soles or subungual regions  Seen in sixth decade of life  Commonly metastasizes

Desmoplastic

 1–3% of melanoma cases (uncommon variant)  Characterized by highly infiltrative growth notable for propensity toward perineural invasion and frequent, local recurrences  Occurs mostly in the head and neck regions of elderly men in the sixth and seventh decades  Often deep at the time of diagnosis due to the difficulty in making the diagnosis in these atypical and often unpigmented lesions  Survival is similar to melanoma of similar thickness

In 2005, a previously unrecognized variant, lentiginous melanoma, was described. It has peculiar growth patterns, and it may be misinterpreted as an atypical lentiginous nevus or a dysplastic nevus. It usually occurs in the elderly and has an invasive component. Lentigo maligna melanoma, superficial spreading melanoma, and acral lentiginous melanoma are curable during the indolent, radial growth phase. However, vertical growth of any histological subtypes indicates metastatic potential and poor prognosis.

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Routes of Spread Local extension, regional (lymphatic), and distant (hematogenous) metastases are the three major routes of spread in cutaneous malignant melanoma.

Local Extension Depth of invasion correlates with survival in cutaneous malignant melanoma. There is a strong relationship between tumor thickness and risk of nodal metastasis. Clark’s classification (Table 34.3) and Breslow thickness (Table 34.4) defines melanoma by depth of invasion and prognostic significance. Table 34.3 Clark level of invasion Level

Description

I

Confined to epidermis

II

Invasion into papillary dermis

III

Tumor into papillary dermis and pushing the reticular dermis

IV

Invasion of reticular dermis

V

Invasion of subcutaneous tissue

Sources: Breslow A (1970) Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 172:902–908; McMasters KM, Wong SL, Edwards MJ et al (2001) Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery 130:151–156; Rousseau DL, Ross MI, Johnson MM et al (2003) Revised AJCC staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients. Ann Surg Oncol 10:569–574

Table 34.4 Tumor thickness versus risk of lymph node metastasis Breslow tumor thickness (mm)

Risk of lymph node metastasis (%)

≤0.75

<5%

≥0.76 but ≤1.50

10%

≥1.51 but ≤4.00

20%

>4.00

30–50%

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Lymph Node Metastasis Pattern and probability of lymphatic spread in melanoma depends on the location and extent of invasion of the primary tumor (Table 34.4). In thin lesions (<1 mm) lymph node metastasis is rare. Cutaneous melanoma does not always progress in a predictable fashion from the primary lesion to the nodal draining stations. On occasion melanoma cells present at distant sites as metastasis.

Distant Metastasis Hematogenous spread to lungs, liver, bone, brain, and skin is not uncommon with more invasive or thicker lesions.

Diagnosis, Staging, and Prognosis Clinical Presentation Melanoma occurs more frequently in white adults, with peak incidence during the fourth and fifth decades of life. Melanoma is rare in dark-skinned races. Patients present with suspicious pigmented lesions, usually in sun-exposed areas, but may appear in non-exposed areas as well (i.e., acral lentiginous melanoma). Approximately 85% of melanoma patients present with localized disease, 15% with regional disease, and 5% with distant metastatic disease. Using the mnemonic ABCDE is helpful in identifying suspicious lesions.  Asymmetry  Borders that are irregular or diffuse  Color variation  Diameter >5 mm  Enlargement or evolution (Source: Friedman RJ, Rigel DS, Kopf AW (1985) Early detection of malignant melanoma: the role of physician examination and self-examination of the skin. CA Cancer J Clin 35:130–151).

Diagnosis and Staging Diagnosis is established by excisional biopsies (1- to 3-mm margin), fullthickness incisional biopsies, or punch biopsies of the thickest portion of the

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tumor, selected according to tumor site, size, and biopsies, and should be made with consideration of future definitive treatment in mind. For example, biopsies of lesions on extremities should be oriented longitudinally so the biopsy scar can be easily and completely incorporated in the definitive surgical volume. Excisional biopsies may be inappropriate for lesions on face, distal digit, palmar surface of hand, subungual locations, sole of foot, ear, or in very large lesions. The tumor thickness is objectively measured in micrometers from the top of the granular cell layer to the deepest tumor cell in the Breslow method. In cases of ulceration, tumor thickness measurement starts from the depth of the ulcer. Although tumor cells associated with skin adnexal structures are not considered in the measurement in the Breslow method, that involvement does predict for metastatic spread potential.

Tumor, Node, and Metastasis Staging For staging purposes, the American Joint Committee on Cancer (AJCC) 2009 staging system uses tumor thickness and ulceration to categorize tumor (T)1–4 (note: level of invasion was not used), uses number of nodal metastases and burden of nodal metastases for the node (N) categories, and uses the sites of distant metastases (soft tissues, lung, and other visceral) as well as serum LDH for metastasis (M) categories. T classification in melanoma depends on tumor thickness and level of invasion (Clark’s classification) and the presence or lack of ulceration. The 7th edition of the TNM staging system of AJCC is presented in Tables 34.5 and 34.6.

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Table 34.5 AJCC TNM classification cutaneous melanoma of the skin Stage

Description

Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Melanoma in situ

T1

Melanoma ≤1.0 mm in thickness with or without ulceration and <1/mm2 or ≥1mm2 mitoses

T1a

Melanoma ≤1.0 mm in thickness without ulceration and <1/mm2 mitoses

T1b

Melanoma ≤1.0 mm in thickness with ulceration or mitosis ≥1/mm2

T2

Melanoma 1.01–2.0 mm in thickness with or without ulceration

T2a

Melanoma 1.01–2.0 mm in thickness, no ulceration

T2b

Melanoma 1.01–2.0 mm in thickness, with ulceration

T3

Melanoma 2.01–4.0 mm in thickness with or without ulceration

T3a

Melanoma 2.01–4.0 mm in thickness, no ulceration

T3b

Melanoma 2.01–4.0 mm in thickness, with ulceration

T4

Melanoma >4.0 mm in thickness with or without ulceration

T4a

Melanoma >4.0 mm in thickness, no ulceration

T4b

Melanoma >4.0 mm in thickness, with ulceration

Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in one lymph node

N1a

Clinically occult (microscopic) metastasis

N1b

Clinically apparent (macroscopic) metastasis

N2

Metastasis in 2–3 nodes (microscopic) macroscopic or in transit/ satellites without metastasis nodes

N2a

Clinically occult (microscopic) metastasis

N2b

Clinically apparent (macroscopic) metastasis

N2c

Satellite or in-transit metastasis without nodal metastasis

N3

Metastasis in four or more regional lymph nodes, or matted metastatic nodes, or in-transit metastasis or satellite(s) with metastasis in regional node(s) ▶

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Table 34.5 (continued) Stage

Description

Distant metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

M1a

Metastasis to skin, subcutaneous tissue, or distant lymph nodes

M1b

Metastasis to lung

M1c

Metastasis to all other visceral sites or distant metastasis at any site associated with an elevated serum lactic dehydrogenase (LDH)

Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society (AJCC) cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York Table 34.6 Stage grouping of malignant melanoma Stage grouping T1a

T1b

T2a

T2b

T3a

T3b

T4a

T4b

N0

IA

IB

IB

IIA

IIA

IIB

IIB

IIC

N1-3

III

III

III

III

M1

IV

IV

IV

IV

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

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Table 34.7 Pathologic stage grouping, and 5- and 10-year OS rate as a function of stage Stage

T stage

NSTAGE

M0

5 year (%)

10 year (%)

IA

T1a

N0

M0

97.2%

92.7%

IB

T1b

N0

M0

93.6%

86.5%

T2a

N0

M0

91.3%

82.9%

T2b

N0

M0

81.8%

67.3%

T3a

N0

M0

79.0%

66.1%

T3b

N0

M0

67.8%

55.3%

T4a

N0

M0

70.9%

56.9%

IIC

T4b

N0

M0

53.3%

39.4%

IIIA

T1–4a

N1a

M0

78%

68%

T1–4a

N2a

M0

T1–4b

N1a

M0

59%

43%

T1–4b

N2a

M0

T1–4a

N1b

M0

T1–4a

N2b

M0

T1–4a

N2c

M0

T1–4b

N1b

M0

40%

24%

T1– 4b

N2b

M0

T1–4b

N2c

M0

Any T

N3

M0

Any T

Any N

M1

65, 1 year 32, 1 year

40, 2 year 18, 2 year

IIA

IIB

IIIB

IIIC

IV

Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society (AJCC) cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

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Prognosis Since the 1970s, 5-year relative survival rates have increase from 80 to 90%. The overall melanoma mortality has not increased dramatically over the last several years. It is readily curable in early stages, but has a grave prognosis in disseminated state. The most important prognostic factor is stage at presentation, including the number of positive lymph nodes (Tables 34.6 and 34.7). Histological subtype (nodular, acral, desmoplastic), thick lesions (>1 mm), deep Clark level invasion, positive lymph nodes, and tumor ulceration are considered poor prognostic factors. Table 34.8 Nine-year survival from cutaneous melanoma as a function of number of positive nodes Number of positive lymph node(s)

9-year survival (%)

1

40%

2–4

15%

5 or more

10% (5-year survival)

Source: Balch CM, Soong SJ, Murad TM et al (1981) A multi-factorial analysis of melanoma: III. Prognostic factors in melanoma patients with lymph node metastases. Ann Surg 193:377–388

Bleeding and ulceration occurs in ~10 and 55% of localized and advanced melanomas, respectively. Ulceration reduces disease-free survival (DFS) by ~10%, regardless of tumor thickness. Outcome of patients with familial melanoma syndrome appear to be the same as patients with sporadic melanoma. The biologic behaviors of familial and sporadic melanoma are the same.

Treatment A proposed treatment algorithm is presented in Figure 34.1.

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Histopathological Diagnosis of Cutaneous Malignant without Systemic Metastasis

cStage or Stage IA with no adverse features (+deep margins, angiolymphatic invasion and mitotic rate > 1 mm2

cStage IA with adverse features

cStage IB, cStage II

cStage III without clinically positive nodes

+ SNLB

If surgery is not feasible, alternative therapies include: radiation therapy, intralesional therapy, CO2 laser ablation,electroporation, systematic therapy, biological therapies, hyperthermic isolated limb perfusion and isolated limb infusion

Lymph node dissection (LND)

- LND

Follow-up

cStage III in-transit

Wide excision with clear margins if feasible is the preferred therapy. Consider SNLB

Sentinel Lymph node Biopsy (SNLB)

- SLNB nodal disease ≤ 0.1mm

cStage III with clinically positive nodes

+ LND

For + SNLB proceed according to final pathological nodal status pathway

Higher than N1a disease, nodes larger than 3cm multiple nodes, extranodal extension

Interferon α-2b for stage III*

RT

Figure 34.1 A proposed algorithm for treatment of nonmetastatic cutaneous malignant melanoma (stages I–III). C clinical, RT radiation therapy, + positive, − negative,* consider participation in clinical trials or active observation. High-dose interferon 2b for pathological stages IIb, IIc, and III. PEGylated interferon 2b for pathological stage III (EORTC 18991)

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Principles and Practice Initial treatment of the primary lesion is complete surgical excision. Adjuvant radiation therapy or systemic therapy is indicated in locally or regionally advanced disease, as detailed in Table 34.9.

Table 34.9 Treatment modalities used in cutaneous malignant melanoma Modality

Description

Surgery

Indications

 The mainstay definitive treatment modality   For lesions <1.0 mm in thickness, surgical excision is cura tive; no adjuvant therapy is indicated  For lesions ≥1.0 mm in thickness, sentinel lymph node  biopsies are recommended (Table 34.10). Positive sentinel lymph node biopsy indicates a dissection of the involved nodal basin  Indicated in highly selected cases with limited distant  metastatic disease such as solitary brain, lung, and subcutaneous tissue metastasis

Techniques

 Surgery involves a wide excision of the primary lesion,  and its use depends on the thickness of primary lesion  The recommended excision margin depends on the tu mor thickness (Table 34.10); however, optimal margin of surgical resection is unknown  Surgical and histological margins may not correspond 

Radiation therapy

Indications

 Adjuvant treatment after complete resection   Definitive treatment for unresectable disease   Palliation to primary, regional, or metastatic foci to treat  or prevent ulceration, bleeding, or pain

Technique

 External-beam radiation therapy

Chemo-/targeted therapy

Indications

 Adjuvant treatment after surgery   Adjuvant treatment with concurrent EBRT for unresect able disease  Mainstay treatment for palliative therapy 

Medications

 Dacarbazine (DTIC) remains most commonly used che motherapy agent in metastatic melanoma  Temozolomide with similar mechanism of action to DTIC  is equally effective

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Surgery for Definitive Treatment The margin size is a trade-off between cosmetic result and potential poorer long-term survival if it is too narrow. The comparison between narrow margin (1–2 cm) and wide margin (3–5 cm) in five large randomized trials showed no statistically significant overall survival benefits toward using wide margin. Therefore, the maximal surgical margin of resection recommended is up to 2 cm, depending on the thickness of the lesions (Table 34.10) (Cochrane Database of Systematic Reviews). Table 34.10 Surgical margins for wide excision of primary cutaneous melanoma Tumor thickness

Recommended surgical margins

In situ

0.5 cm

≤1.0 mm

1.0 cm

1.0–2.0 mm

1–2 cm

2.0–4.0 mm

2.0 cm

>4 mm

2.0 cm

Subungal

Amputation proximal to distal interphalangeal joint

Sources: Balch CM, Urist MM, Karakousis CP et al (1993) Efficacy of 2 cm surgical margins for intermediate thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218:262–267; Ringborg U, Andersson R, Eldh J et al (1996) Resection margins of 2 cm versus 5 cm for cutaneous malignant melanoma with tumor thickness of 0.8 to 2 mm: randomized study by the Swedish Melanoma Study Group. Cancer 77:1809–1814; Cohn-Cedermark G, Rutqvist LE, Anderson R et al (2000) Long term results of a randomized study by the Swedish Melanoma Study Group on 2 cm versus 5 cm resection margins for patients with cutaneous melanoma with tumor thickness of 0.8 to 2.0 mm. Cancer 89:1495–1501

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Sentinel Lymph Node Biopsy Sentinel lymph node(s) is (are) the first node(s) draining the primary tumor site along the lymphatic pathway. Sentinel lymph node biopsy (SLNB) spares patients from the complications associated with elective lymphadenectomy. Patients with cutaneous melanoma with the thickness of0.76 mm should undergo SLNB (Table 34.9). The false-negative rate of SLNB is <5% as compared with elective lymphadenectomy. When a sentinel node is negative, the probability of other nodes in the basin harboring metastases is very low. In patients with positive sentinel nodes, only 20% of non-sentinel nodes are positive. Patients with positive SLNB and immediate lymphadenectomy had a superior overall survival advantage as compared with patients with lymphadenectomy at the time of clinically evident nodal diseases. Furthermore, adjuvant radiation therapy and systemic therapy can be considered based on the result of positive SLNB. (Morton DL, Thompson JF, Cochran AJ et al (2006) Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 355:1307–1317). Treatment of Unresectable Recurrence and In-Transit Metastases of Extremity Melanoma In-transit metastases from extremity melanoma are subcutaneous or cutaneous deposits of melanoma distant from the primary site by >5 cm but not reaching the draining nodal basin. Subcutaneous or cutaneous deposits separated from the primary lesion but located within 5 cm are called satellitosis. Treatment options are outlined in Table 34.11. Table 34.11 Treatment of unresectable recurrence and in-transit metastasis Therapy/outcome

Description

 Therapeutic options are limited and vary according to the  disease volume and extent Treatment options  Surgery is the preferred treatment  for primary  For unresectable disease, RT, intralesional BCG injection,  disease carbon dioxide laser ablation, electroporation or electrochemotherapy using bleomycin or cisplatinum, biological therapy, and systemic therapy can be used Regional treatment modalities

Include hyperthermic isolated limb perfusion and isolated limb infusion

Outcome

Mimics that of advanced regional nodal disease

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Adjuvant Systemic Therapy Clinical evidence supporting adjuvant systemic therapy is detailed in Table 34.12. Table 34.12 Clinical evidence for adjuvant systemic therapy for melanoma Trial Metaanalysisa

EORTC 18991b

EORTC 18991 (QoL)c

Description  Second meta-analysis shows a statistically significant improve ment in overall and disease-free survival in patients with high risk cutaneous melanoma treated with IFN-α  Randomized 1,256 patients to observation (n = 629) or PEG-IFN-α 2b (n = 627)  8 Weeks induction, then weekly maintenance for an intended  duration of 5 years were given to the testing arm  With a median follow-up of 3.8 years, results showed 4-year RFS  benefit in the treated group (45.6 versus 38.9%), with no overall survival benefit  31% discontinued treatment due to toxicities, which include fa tigue (16%), hepatotoxicity (11%), and depression (6%)  The intended duration of the treatment was 5 years, but the me dian duration of treatment was 12 months  Longer-acting IFN-α-2b was approved by the US Food and Drug  Administration for adjuvant therapy for resected stage III melanoma, based on this report  Studied the health related quality of life (HRQOL) in patients ac crued to the EORTC 18991 trial  Demonstrated that PEG-IFN-α-2b decreased global HRQOL at  month 3 and year 2  Differences were found for 5 scales: 2 functioning scales (social and  role functioning) and 3 symptom scales (appetite loss, fatigue, and dyspnea), with the PEG-IFN-α-2b arm being the most impaired  The use of adjuvant PEG-IFN-α-2b does not seem to meet the need  of high-risk melanoma patients in terms of improved tolerability of treatment or improved feasibility of longer duration of treatment

PEG-IFN-α-2b: PEGylated interferon alph-2b; RFS: relapse-free survival a Source: Mocellin S, Pasquali S, Rossi C et al (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis; J. Natl Cancer Inst. 102(7): 493-501; Wheatley K, Ives N, Hancock B et al (2003) Does adjuvant interferon for high risk melanoma provide a worthwhile benefit? A meta-analysis of ranomizede trials. Cancer treat rev 29: 241-252 b Source: Eggermont AM, Suciu S, Santinami M et al (2008) Adjuvant therapy with PEGylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372:117–126 c Sources: Bottomley A, Coens C, Suciu S et al (2009) Adjuvant therapy with pegylated Interferon alfa-2b versus observation in resected stage III melanoma: a phase III randomized controlled trial of health-related QoL and symptoms by the EORTC Melanoma Group. J Clin Oncol 27:2916–2923; Glaspy J, Ribas A, Chmielowski B (2009) Interferon alfa in the postsurgical management of high-risk melanoma: is it worth it? J Cancer Oncol 27:2896–2897

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Adjuvant Nodal Irradiation Surgery is indicated in patients with positive nodal diseases. Indications for adjuvant regional nodal irradiation include:  Large lymph nodes (>3 cm)  2 positive nodes  Extranodal extension  Recurrent disease in the previously dissected nodal basin Adjuvant radiation therapy after total lymphadenectomy (TL) provides ~80% regional control. However, the distant metastases–free and the DFS remain at 44 and 49%, respectively (Sources: Guadagnolo BA, Zagars GK (2009) Adjuvant radiation therapy for high-risk nodal metastases from cutaneous melanoma. Lancet Oncol 10:409–416; Mac LA, McKinnon JG (2004) Controversies in the management of metastatic melanoma to regional lymphatic basins. J Surg Oncol 86:189–199; Agarwal S, Kane JM, Guadagnolo BA et al The benefits of adjuvant RT after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer 115: 5836–5844). There has been no randomized trial reported on the efficacy of adjuvant radiation therapy versus total lymphadenectomy alone in high-risk clinically advanced nodal metastatic melanoma. It is crucial that the critical structure radiation tolerance be carefully considered when hypofractionation is used to avoid causing irreversible radiation damage in late-reacting tissues. Chronic lymphedema is the major complication associated with total lymphadenectomy and adjuvant radiation therapy especially in the inguinal region.

Treatment of Metastatic Melanoma Most metastatic patients are not candidates for curative resection. Systemic and local palliative therapies are usually indicated for metastatic melanoma. However, in highly selected patients with good performance status, complete surgical resection may result in long-term survival, ranging from 5–25%. Brain metastases confer poor prognosis and contribute to mortality in ~95% of patients with brain lesions. However, complete resection may be indicated for solitary brain metastases. Stereotactic radiosurgery is a reasonable alternative to surgical resection. Other focal treatments that may be considered for metastatic lesions include stereotactic body radiation therapy and radiofrequency ablation. A more detailed discussion on surgery for metastatic disease is beyond the scope of this chapter.

Chapter 34 Cutaneous Malignant Melanoma

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Radiation Therapy Technique Simulation and Field Arrangement The radiation therapy portal design is generally confined to the involved nodal basin. Extended field treatment (i.e., treat one station beyond the involved nodal region) does not confer additional benefits but may increase complications (Source: Guadagnolo BA and Zagars GK (2009) Adjuvant radiation therapy for high-risk nodal metastases from cutaneous melanoma. Lancet Oncol 10:409–416).

Dose Fractionation For adjuvant radiation therapy, the dose fractionation varies from conventional fractionation of 2 Gy per fraction daily to hypofractionation of 6–7.5 Gy per fraction twice a week treatment. Total doses vary from 60 Gy with conventional fractionation scheme to 30–48 Gy, depending on the dose per fraction. For palliative radiation therapy, commonly used hypofractionated regimens to overcome radio resistant cell are 30 Gy in 10 fractions, 20 Gy in 5 fractions, or 6 Gy per fraction given weekly for 5–6 weeks.

Follow-Up Patients diagnosed with a skin melanoma have about a tenfold risk of developing a second melanoma as compared with the general population. Melanoma patients are also at increased risk of developing non-melanoma skin cancers. Therefore, life-long follow-up after completion of treatment is recommended for melanoma patients. A schedule and suggested examinations during follow-up is presented in Table 34.13. Patients with familial melanoma syndrome should be seen by age 10 or earlier if clinically indicated, using total skin photography every 3–6 months. In patients with CDKN2A tumor suppressor gene mutation, they should also be screened for pancreatic cancer starting at age 35 years, or at the age 10 years younger than the age of the diagnosis of family member with pancreatic cancer using endoscopic ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI), or serum tumor marker (CA 19-9).

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Table 34.13 Follow-up schedule and examinations Schedule

Frequency

First follow-up

 4 –6 weeks after radiation therapy

Years 1–2

 Every 3–6 months (most recurrences occur within first 2 years after treatment)

Years 2+

 Every 6–12 months

Examination

History and physical

 Complete history and physical examination  Education on self examination and sun protection  Lighting-controlled total skin photography to detect early skin cancers arising in pre-existing conditions secondary to extensive sun exposure or from underlying genodermatoses (such as xerodema pigmentosa)

Laboratory tests

 Complete blood counts (CBC) and Serum chemistry  Liver and renal function tests  LDH

Imaging studies

 Chest X-ray (stages I–III)  Other imaging studies depend on clinical finding

Patients with melanoma in situ need patient education and annual examination only. Patients with stage IV disease require individualized surveillance program

35

Basal and Squamous Cell Carcinoma of the Skin José A. Peñagarícano1 and Vaneerat Ratanatharathorn2

Key Points  Basal and squamous cell carcinomas of the skin are the most commonly diagnosed malignancies in the USA. Basal cell carcinoma accounts for approximately 80% and squamous cell carcinoma for 20% of all nonmelanoma skin cancers.  Exposure to sunlight is the most common cause of skin cancer.  Patients with nonmelanoma skin cancer have a 30–50% risk of developing additional skin cancers.  Poor prognostic factors in squamous cell carcinoma of the skin are tumor size of at least 4 cm, perineural invasion, and invasion beyond the subcutis.  Basal cell carcinoma of the skin rarely metastasizes but has a predilection for local invasion.  Squamous and basal cell carcinomas are most commonly treated with surgery, radiation therapy, or a combination of both. Selection of therapy is based on preservation of function and cosmesis, and patient preference.  T-classification at diagnosis correlates with local control in irradiated basal and squamous cell carcinoma of the skin. For T1, T2 and T3 tumors, local control rates are 95, 80, and 53%, respectively.  Local control rates of irradiated basal and squamous cell carcinomas of the skin smaller than 1 cm are 97 and 91%, respectively. For tumors between 1 and 5 cm, local control rates are 87 and 76%, respectively.

1

José A. Peñagarícano, MD Email: [email protected]

2

Vaneerat Ratanatharathorn, MD Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_18, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin are the most common histological types of skin cancer and the most commonly diagnosed malignancy. The incidence of nonmelanoma skin cancer in the USA in 2010 was more than 1 million cases, with mortality of less than 2,000 cases. A number of risk factors have been identified for BCC and SCC of the skin (Table 35.1). Table 35.1 Risk factors of nonmelanoma skin cancer Factor

Description Host : blonde or red hair, fair complexion, blue eyes, and a tendency to burn on sunlight exposure Pre-malignant conditions: actinic keratoses, Bowen’s disease, keratoacanthoma, lentigo maligna, and nevi Past medical history: immunosuppression, ultraviolet light exposure, genodermatoses, and cutaneous β-human papilloma virus infection

Patient related

Genetic predisposition: mutations that activate the Hedgehog intercellular signaling pathway genes, including PTCH (human homolog of the Drosophila patched gene), Sonic hedgehog (Shh), and Smoothened (Smo) play a significant role in cutaneous carcinogenesis Genetic syndromes: such as albinism, xeroderma pigmentosum, Turcot syndrome, Rothmund–Thomson syndrome, Fanconi anemia, and Gorlin or nevoid basal cell syndrome predispose individuals to nonmelanoma skin cancer (and other types of malignancies) formation

Environmental

Carcinogens: ultraviolet light, exposure to ionizing radiation, chemicals (inorganic arsenic, soot, polycyclic aromatic carbons), smoking (squamous cell carcinoma only)

Chapter 35 Basal and Squamous Cell Carcinoma of the Skin

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Anatomy The skin contains three layers: epidermis, dermis, and subcutis (Table 35.2). Table 35.2 Layers of skin and their composites Skin layer

Composites

Epidermis

Stratified squamous cells with variable thickness throughout the body. Shed and replaced by cells from the basal layer

Dermis

Papillary and reticular layers

Subcutis

Connective tissue and fat as support of larger nerves and vessels

The structural strength of the skin is due to connective tissue of collagen and elastin fibers, which contain nerves, blood and lymphatic vessels, and adnexal structures.

Pathology BCC BCC of the skin is the most common histological type of skin cancer. It is a nonkeratinizing neoplasm arising from the basal layer of the epidermis, with low metastatic potential and a predilection for invasion. Perineural invasion is uncommon but occurs in recurrent and aggressive lesions. The histological subtypes are detailed in Table 35.3. Table 35.3 Histological subtypes of BCC Type

Description

Nodular

Raised nodule with telangiectasia in sun-exposed areas

Superficial

Erythematous or eroded macule, which may mimic eczema or psoriasis

Morpheaform

Flat, firm lesion without well-defined margins

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SCC SCC of the skin is the second most common histological type of skin cancer. It is a neoplasm of keratinizing malignant cells.

Routes of Spread Local extension, regional (lymphatic), and distant (hematogenous) metastases are the three major routes of spread in SCC of the skin. BCC of the skin rarely metastasizes but prefers local invasion. Overall, nodal and distant metastases occur in ~10% of cases.

Lymph Node Metastasis Pattern of lymphatic spread in SCC of the skin depends on the location of the primary tumor. For example, the most commonly involved lymph nodes in SCC of the skin of the head and neck are the intraparotid lymph nodes, followed by the lymph nodes in the submandibular triangle and upper jugulodigastric regions.

Diagnosis, Staging, and Prognosis Clinical Presentation Commonly observed signs and symptoms in BCC and SCC are listed in Table 35.4.

Diagnosis and Staging Definitive diagnosis can only be made by biopsy (Table 35.5). Patients with poor prognostic factors or clinically evident metastasis should be given a workup for systemic disease.

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Table 35.4 Commonly observed signs and symptoms in skin cancer Carcinoma

Description

BCC

    

Smooth, raised “rodent ulcer” lesions with translucent borders Lesions can infiltrate deeply and can cause deformity Mainly occur in the head and neck region Rarely metastasize Rare in the palms or soles and are not seen on mucosa membranes

   

Lesions are irregular, nodular, or plaque-like Some lesions are covered by a keratotic scale Bleeding is common with minimal trauma Invasion is common in larger lesions and may involve the underlying muscle, bone, blood vessels, or lymphatic channels

SCC

Table 35.5 Types of skin biopsies Type

Description

Shave

Adequate for raised lesions

Punch

Adequate for flat lesions

Excisional

Used to sample deep dermal and subcutaneous tissue with postoperative margin assessment

Tumor, Node, and Metastasis Staging Diagnosis and clinical staging depends on findings from history and physical examination, imaging, and laboratory tests. Staging depends on clinical and pathological findings. The 7th edn. of the tumor, node, and metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC) is presented in Table 35.6.

1000 José A. Peñagarícano and Vaneerat Ratanatharathorn Table 35.6 AJCC TNM classification nonmelanoma carcinoma of the skin (excluding eyelid) Stage

Description

Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor 2 cm or less in greatest dimension

T2

Tumor larger than 2 cm in greatest dimension or tumor of any size with two or more high risk features

T3

Tumor with invasion of maxilla, mandible, orbit or temporal bone

T4

Tumor with invasion of skeleton (axial or appendicular) or peunemol invasion of skull base High risk features: >2 mm thickness Clark level ≥IV Peuneural invasion Primary site ear Primary site non-hair-bearing lip Poorly differentiated or undifferentiated

Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension

N2a

Metastasis in a single ipsilateral lymph node, >3 cm but ≤6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none >6 cm

N3

Metastasis in a lymph node more than 6 cm in greatest dimension

Distant metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Source: Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer (AJCC) cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York

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Table 35.7 Stage grouping of carcinoma of the skin (excluding eyelid) Stage Grouping T1

T2

T3

T4

N0

I

II

III

IV

N1

III

III

III

IV

N2

IV

IV

IV

IV

N3

IV

IV

IV

IV

M1

IV

IV

IV

IV

Prognosis Tables 35.8 and 35.9 outline local control rates based on treatment and classification of tumor. Table 35.8 Control rates for carcinomas of eyelid treated with radiation therapy Histologic subtype

Total (n)

Previously untreated (n)

Recurrent (n)

5-year local control rate

BCC

1,062

686

376

1,009/1,062 (95%)

SCC

104

62

42

Total

1,166

748

418

97/104 (92%) 1,106/1,166 (95%)

Source: Fitzpatrick PJ, Thompson GA, Easterbrook WM et al (1984) Basal and squamous cell carcinoma of eyelids and their treatment by radiotherapy. J Radiat Oncol Biol Phys 10449–454

Table 35.9 T-classification at diagnosis correlates with local control T-classification

10-Year local control (%)

T1

95%

T2

80%

T3

53%

When results are adjusted for tumor size, local control rates of irradiated skin BCC and SCC <1 cm are 97 and 91%, respectively; for tumors between 1 and 5 cm, local control rates are 87 and 76%, respectively. Local control rates seem to be slightly higher for BCC than for SCC (Table 35.9).

1002 José A. Peñagarícano and Vaneerat Ratanatharathorn

Treatment Principles and Practice Squamous and basal cell carcinomas are most commonly treated with surgery (Mohs surgery or postoperative margin assessment), radiation therapy, or a combination of the two (Table 35.10). Selection of therapy is based on preservation of function and cosmesis, and patient preference. Proposed treatment algorithms are summarized in Figures 35.1 and 35.2. Extensive lesions without distant metastases require extirpative surgery, including amputation in lesions involving extremities when limb salvage is not possible (Figure 35.3). Table 35.10 Adverse prognostic factors for recurrence Carcinoma

Description

BCC

 Histological subtypes (when margins of resection are <4 mm): morpheaform and nodular (when micronodules are present)  Tumor location: face, ears  Size: >2 cm  Pathology: perineural invasion, poorly defined tumor borders

SCC

   

Depth: >4 mm or invading the reticular dermis and subcutis Tumor size: >4 cm in diameter Treatment: resection margins of <6 mm Pathology: poorly differentiated tumors; perineural invasion is an indicator for local and/or regional recurrence or distant metastasis  Location: head and neck area, genitalia, mucosal surfaces, ear  Locally recurrent SCC of the skin has an overall metastatic rate of 30%

Chapter 35 Basal and Squamous Cell Carcinoma of the Skin

1003

Hispathological diagnosis of SCC of the skin

Local disease

Clinically postive lymph nodes

High-risk disease

- Margin and no poor prognostic factors

+ Margin and no poor prognostic factors Re-excise or RT

Low-risk disease

Poor prognostic factors

Margins +

Margins -

Fineneedle aspiration (FNA)

Re-excise or RT RT Follow-up

Follow-up + FNA

- FNA

Lymph node dissection

Open biopsy

+ Biopsy

- Biopsy

RT with or without systemic therapy

Follow-up

Figure 35.1 Proposed algorithm for treatment of SCC of the skin. SCC squamous cell carcinoma, High-risk disease tumor of at least 4 cm in diameter, perineural invasion, and subcutis invasion, RT radiation therapy, + positive, − negative

1004 José A. Peñagarícano and Vaneerat Ratanatharathorn

Hispathological diagnosis of BCC of the skin

High-risk disease

- Margin and no poor prognostic factors

Low-risk disease

+ Margin and no poor prognostic factors

Poor prognostic factors

Re-excise or RT

RT

Follow-up

Margins +

RT for non-surgical candidate

Margins -

Re-excise or RT

Follow-up

Figure 35.2 Proposed algorithm for treatment of BCC of the skin. BCC basal cell carcinoma, High-risk disease tumor of at least 2 cm in diameter, perineural invasion, subcutis invasion, poorly defined borders, nodular or morpheaform histologies, RT radiation therapy, + positive, − negative

Figure 35.3 Photographs of extensive SCC of the hand. For this patient with no distant metastasis, amputation of the hand was recommended

Chapter 35 Basal and Squamous Cell Carcinoma of the Skin

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Adjuvant Radiation Therapy Indications for adjuvant radiation therapy is listed in Table 35.11. Positive margins should have re-excision to achieve negative margins or receive adjuvant radiation therapy. Biopsy of potential regional disease (clinically or radiographically abnormal adenopathy) is indicated. A regional lymph node dissection is recommended, followed by adjuvant radiation therapy for positive lymph adenopathy; however, a patient can be followed-up after excision of the primary tu-

Table 35.11 Treatment modalities used to treat skin cancer Modality

Description

Surgery Indications

 Excision and Mohs micrographic surgery is indicated for primary  curative modality  Excision maybe used for palliative treatment 

Facts/ issues

 Surgery is indicated for small tumors that can be excised and  then the defect closed directly or with skin graft  For any extensive lesion without distant metastases, extirpative  surgery is indicated including amputation in lesions involving extremities when limb salvage is not possible (see Figure 35.3)  Key strength of Mohs surgery includes   Complete margin control during the removal of the cancers by  using frozen section histology  Uses a much smaller surgical margin and to precisely spare  healthy tissues  Used in the areas prone to recurrence such as the central area  of the face, auricular helix and canal  In the following cases margin assessments are more challenging:  positive margin in recent resection, recurrence, poorly defined borders, radiation induced skin cancers, skin cancers arising in old scars (Marjolin’s ulcer), and patients with genodermatoses  5-year local recurrence rate with Mohs surgery for primary BCC is  as low as 1% and slightly higher for SCC

Radiation therapy

Indications

  Commonly used in treating lesions on the face for better cosmetic and functional results  Primary curative modality mainly in the older-aged patient or if  surgery is contraindicated  Adjuvant therapy after surgery (positive or close margins, peri neural invasion, and/or positive nodes)  Mainstay palliative modality  ▶

1006 José A. Peñagarícano and Vaneerat Ratanatharathorn Table 35.11 (continued) Modality

Description

Radiation therapy (continued) Technique

EBRT using kV or electron-beam radiation

Facts

 Local control rate after definitive radiation therapy is ~90% for all sizes of BCC, which is comparable with surgery   Similar results after radiation therapy for both BCC and SCC, where reported retrospectively in which patients were treated with radiation for initial treatment or after failing initial surgical excision

mor if the lymph node biopsy is negative (Sources: Freeman RG, Knox JM, Heaton CL (1964) The treatment of skin cancer: a statistical study of 1,314 skin tumors comparing results obtained with irradiation, surgery, and curettage followed by electrodissecation. Cancer 17:535–538; Mazeron JJ, Chassagne D, Crook J et al (1988) Radiation therapy of carcinomas of the skin of the nose and nasal vestibule. A report of ,1676 cases by the Groupe Europeen de Curietherapie. Radiol Oncol 13:165–173; Lovett RD, Perez CA, Shapiro SJ et al (1990) External irradiation of epithelial skin cancer. Int J Radiat Oncol Biol Phys 19:235–242; Avril MF, Auperin A, Margulis A et al (1997) Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study. Br J Cancer76:100–106; Tierney EP, Hanke CW (2009) Cost effectiveness of Mohs micrographic surgery: review of the literature. J Drugs Dermatol 8:914–922).

Radiation Therapy Techniques Radiation therapy treatment volumes and definitive doses depend on the size and the extent of the disease, the need of irradiating any high-risk areas, and the expected cosmetic result. Superficial radiation therapy using kilovoltage (kV) radiation or electronbeam radiation therapy is usually used for definitive treatment of skin cancers. For kV radiation therapy, the dose is specified at the maximum dose (Dmax), and for electron at 100% on central axis, ensuring a minimum dose of 90–95% to the entire target (Table 35.12).

Chapter 35 Basal and Squamous Cell Carcinoma of the Skin

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Table 35.12 Parameters for kV and electron radiation therapy Carcinoma

Margins (kV RT)

Margins (electron)a

Low-risk BCC

5–8 mm

1.5–1.8 cm

High-risk BCC, large or poorly defined lesion, and SCC

1–1.5 cm

2–2.5 cm

a

With 0.5- to 1-cm bolus to pull 100% isodose to skin surface

Dose and Fractionation Dose of radiation for BCC is listed in Table 35.13. In the postoperative setting for BCC and SCC with adverse prognostic factors, the recommended radiation therapy dose is 60 Gy at 2 Gy per fraction. Higher doses are required for positive margins (66–70 Gy per fraction at 2 Gy per fraction). This course may be modified for small volumes, or when cosmesis is not an issue (i.e., 50 Gy in 15 fractions over 3 weeks). The use of standard fractionation (1.8–2 Gy per fraction) is expected to show an improved cosmetic result, whereas the use of a higher dose per fraction is associated with increased late effects of normal tissues. If the treatment volume is large, conventionally fractionated radiation therapy should be used instead of the hypofractionated regimens. When cosmetic result is not important or other patient related issues (transportation, performance status, etc.) preclude protracted course of treatment, shorter courses may be used (e.g., 50 Gy in 15 fractions over 3 weeks).

Table 35.13 Recommended doses for RT Extent of BCC

Dose of RT (Gy)

BCC lesions <1 cm

40

BCC lesion ≤3 cm or SCC <1 cm

45–50

BCC lesion > 3 cm, SCC >1 cm

60

Postoperative negative margin Postoperative positive margin

60 66–70

All treatment is given in 2.5-Gy fractions per day, 4 days/week, except in the postoperative setting where it is 2 Gy per fraction

1008 José A. Peñagarícano and Vaneerat Ratanatharathorn

Salvage Radiation Therapy Radiation therapy can be used as a salvage therapy for patients in whom initial radiation failed to control the disease. A local control rate of >50% after a second course of radiotherapy after local recurrence can be expected. In this setting, a combined biologic equivalent dose (BED) dose of 110 Gy to the skin/tumor and 55 Gy at a 0.5-cm depth has a cure rate of 78%. Tissue damage is a function of fraction size and total dose. SCC is more resistant to re-irradiation as compared with BCC (Sources: Mendenhall WM, Parsons JT, Mendenhall NP et al (1987) T2–T4 carcinoma of the skin of the head and neck treated with radical irradiation. Int J Radiat Oncol Biol Phys 13:975–981; Turesson I, Notter G (1984) The influence of fraction size in radiotherapy on the late normal tissue reaction. I: Comparison of the effects of daily and once-a-week fractionation on human skin. Int J Radiat Oncol Biol Phys 10:593–598; Locke J, Karimpour S, Young G et al (2001) Radiotherapy for epithelial skin cancer. Int J Radiat Oncol Biol Phys 51:748–755).

Follow-Up As 30–50% of patients will develop another nonmelanoma skin cancer, active follow-up after adjuvant or definitive treatment of BCC or SCC the skin is recommended (Table 35.14). Most recurrences of SCC of the skin occur within the initial 2 years after therapy, and ~85% recurrences were noted within 2 years of radiation therapy, and almost all cases within 5 years of treatment. Some patients may have extensive skin changes either from long-term extensive sun exposure or from genodermatoses. Patient should be educated about self-skin examination and sun protection. Table 35.14 Follow-up schedule and examinations Schedule

Frequency

First follow-up

 4 –6 weeks after radiation therapy

Years 0–1

 Every 3–6 months

Years 2–5

 Every 6–12 months

Examination History and physical

 Complete history and physical examination  Lighting-controlled total skin photography by dermatologists for detecting early skin cancers arising in these preexisting lesions

Section XI Pediatric Tumors

XI 36

Pediatric Brain Tumors . . . . . . . . . . . . . . . . . . . . . . 1011 Arnold C. Paulino

37 Retinoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037 David B. Mansur 38

Neuroblastoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053 Natia Esiashvili

39

Ewing Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073 Daniel Indelicato and Robert B. Marcus Jr.

40 Wilms’ Tumor and Other Childhood Renal Tumors . . . . . . . . . . . . . . . . . . . 1089 Arnold C. Paulino

36

Pediatric Brain Tumors Arnold C. Paulino1

Key Points  Brain tumors are the second most common group of malignancies in children.  For some pediatric tumors such as medulloblastoma, supratentorial primitive neuroectodermal tumor (PNET), ependymoma and germ cell tumors, leptomeningeal dissemination is a route of spread. Imaging of the entire neuraxis is performed in addition to cerebral spinal fluid (CSF) cytology from a lumbar tap.  For low-grade gliomas, surgery is the mainstay of treatment. Adjuvant therapy is not needed for patients who have gross total resections.  Diffuse pontine gliomas are the most common brainstem gliomas in children. Radiation to a dose of 54 Gy in 30 fractions over 6 weeks is the standard treatment.  Current treatment strategies in medulloblastoma, which include maximal safe resection, craniospinal irradiation (CSI) followed by primary site irradiation, and chemotherapy, have resulted in 5-year progression-free survivals of 80 and 70% for standard- and high-risk patients.  The extent of resection is the most important prognostic factor for ependymoma.  Adjuvant radiotherapy is currently recommended for ependymoma, regardless of extent of resection.  Germ cell tumors are divided into germinoma and nongerminomatous germ cell tumor (NGGCT), with the former having a better prognosis. Germinomas are highly curable with radiotherapy alone, while NGGCT is best managed with a combination of radiation and chemotherapy.  Late effects of radiotherapy in young children (<3 years of age) with medulloblastoma, ependymoma, and malignant glioma have prompted investigators to delay or possibly eliminate radiotherapy by using chemotherapy.  The current trend for treatment of craniopharyngiomas is limited surgery or biopsy followed by radiotherapy, as achieving a gross total resection may result in significant morbidity because of the proximity of critical structures such as the optic chiasm and nerves, circle of Willis, and hypothalamus to the tumor.

1

Arnold C. Paulino, MD Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_19 © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Brain tumors are the most common solid tumor and are second only to leukemia as the most common group of malignancy in children. The overall incidence rate of brain tumors in the USA is 18.16 per 100,000 people-years, and 7% were in individuals <20 years of age, and 93% for individuals 20 years or older at diagnosis. The incidences of commonly diagnosed pediatric brain tumor are illustrated in Figure 36.1 and Table 36.1. Ages 0-14 (n=4,959) All Other 29.4% Craniopharyngioma 2.4% Pituitary 19.7% Germ Cell 5.19% Nerve sheath 0.4%

Ages 15-19 (n=1,871) All Other 29.4%

Pilocytic 11.8%

Pilocytic 11.8% Craniopharyngioma 2.4%

All Other Astrocytoma 4.2%

All Other Astrocytoma 4.2%

Glioblastoma 4.2% Embryonal/ primitive/ Ependymoma/ medulloblastoma anaplastic 4.2% ependymoma Glioma malignant 3.6% 4.4%

Glioblastoma 4.2% Pituitary 19.7%

Germ Cell 5.19%

Nerve sheath 0.4%

Ependymoma/ anaplastic ependymoma 3.6% Glioma malignant 4.4%

Embryonal/ primitive/ medulloblastoma 4.2%

Figure 36.1 Distribution of brain tumors in children by histology and age group. Data are derived from the Central Brain Tumor Registry of the United States. Available at: www.cbtrus.org. Cited 1 February 2011

Table 36.1 Commonly diagnosed primary brain tumors in children, based on age at diagnosis Age at diagnosis (years)

a

Type and probability of brain tumorsa

0–14b

 Pilocytic astrocytoma (19%)   Malignant glioma (14%)   Embryonal tumors such as medulloblastomas (13%) 

15–19

 Pituitary tumors (20%)   Pilocytic astrocytoma (12%) (Figure 36.1) 

For children 2–2 years of age, there is propensity for infratentorial compared with supratentorial location of tumor b For children <15 years of age, the incidence is 4.47 per 100,000 person years

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In children, primary brain tumors are much more common than brain metastases (Table 36.2). Table 36.2 Probabilities of brain metastases in pediatric cancer cases Type of pediatric cancer

Probability of brain metastasis (%)

Neuroblastoma

8%

Rhabdomyosarcoma

6.7%

Ewing sarcoma

5.7%

Osteosarcoma

4.7%

Non-rhabdomyosarcoma soft tissue sarcoma

2.4%

Wilms’ tumor

1%

Source: Paulino AC, Nguyen TX, Barker JL Jr (2003) Brain metastasis in children with sarcoma, neuroblastoma, and Wilms’ tumor. Int J Radiat Oncol Biol Phys 57:177–183

Genetic predisposition has been reported in 2–5% of cases. Syndromes are associated with particular central nervous (CNS) tumors are listed in Table 36.3. Table 36.3 Syndromes associated with brain tumors Syndrome

Associated tumor

Neurofibromatosis type 1 (NF-1)

Optic pathway glioma

Neurofibromatosis type 2 (NF-2)

Vestibular schwannoma, ependymoma, and meningioma

Tuberous sclerosis

Subependymal giant cell astrocytoma, astrocytoma, ependymoma, glioblastoma

von Hippel-Lindau syndrome

Cerebellar hemangioblastoma, glioma, pheochromocytoma, paraganglioma, clear cell carcinoma of the kidney

Li-Fraumeni syndrome

Brain tumors (astrocytoma, glioblastoma), breast, bone, and lung cancer

Gorlin’s syndrome

Medulloblastoma, basal cell carcinoma

Turcot’s syndrome

Brain tumors (medulloblastoma, glioblastoma), colon cancer

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Nongenetic factors associated with the development of brain tumors have been described such as ionizing radiation and immunosuppressive therapy. Radiation-induced meningiomas and malignant gliomas have been described in childhood cancer survivors who have received previous radiation therapy to the brain, head and neck region, and scalp (Sources: Paulino AC, Mai WY, Chintagumpala M et al (2008) Radiation-induced malignant gliomas: is there a role for re-irradiation? Int J Radiat Oncol Biol Phys 71:1381–1387; Paulino AC, Ahmed IM, Mai WY et al The influence of pretreatment characteristics and radiotherapy parameters on time interval to development of radiation-associated meningioma. Int J Radiat Oncol Biol Phys 75:1408– 1414).

Brain Development During Childhood and Adulthood The human brain is most sensitive to the ill effects of radiation therapy in utero. After birth, it is most sensitive during the first few years of life, when rapid postnatal growth, synaptogenesis, and myelinization occur. Some capacity for neurogenesis continues in adults. Inhibition of hippocampal neurogenesis is involved in the pathogenesis of memory decline after cranial irradiation, and is mediated by perturbation of the neurogenic microenvironment by microglial inflammation. The age at time of irradiation has a significant effect on cognitive function in children with brain tumors (Table 36.4). Because of the concern for severe neurocognitive toxicity after cranial irradiation in the very young (<3 years), several groups have advocated chemotherapy after maximal resection for pediatric brain tumor patients (Sources: Duffner PK, Horowitz ME, Krischer JP et al (1993) Postoperative chemotherapy and delayed radiation in children less than 3 years of age with malignant brain tumors. N Engl J Med 328:1725–1731; Rutkowski S, Bode U, Deinlein F et al (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986).

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Table 36.4 Clinical evidences on the effect of radiation to brain according to age of radiation Studies

Age of RT

Results

CCGa

<7 years

Worse non-verbal IQ decline in children who received craniospinal RT for medulloblastoma

St. Judeb

<5 years

Reading scores deteriorated in children who received conformal RT for ependymoma

Merchant et alc

Adolescents

No significant decline in cognitive function between pre-and post-RT assessments (patients treated for intracranial germinoma)

RT: radiation therapy; CCG: Children’s Cancer Group: IQ: intelligence quotient; St. Jude: St. Jude Children’s Research Hospital a Source: Ris MD, Packer R, Goldwein J et al (2001) Intellectual outcome after reduceddose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a CCG study. J Clin Oncol 19:3470–3476 b Source: Conklin HM, Li C, Xiong X et al (2008) Predicting change in academic abilities after conformal radiation therapy for localized ependymoma. J Clin Oncol 26:3965–3970 c Source: Merchant TE, Sherwood SH, Mulhern RK et al (2000) CNS germinoma: disease control and long-term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 46:1171–1176

Pathology Division of pediatric brain tumors is listed in Table 36.5. Table 36.5 Nomenclature for brain tumors Type

Description

Glioma  Juvenile pilocytic astrocytoma (JPA) (WHO grade I)  Fibrillary astrocytomas (WHO grade II)  Pleomorphic xanthoastrocytomas (WHO grade II)  Anaplastic astrocytoma (WHO grade III)  Glioblastoma multiforme (WHO grade IV)

Astrocytoma

Ependymoma

 Subependymoma (WHO grade I)  Myxopapillary ependymoma (WHO grade I)  Classic ependymoma (WHO grade II)  Anaplastic ependymoma (WHO grade III)

Other

 Oligodendroglioma

a

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Table 36.5 (continued) Type

Description

Primitive neuroectodermal tumor (PNET) Medulloblastoma

 Most common PNET

Supratentorial PNET

 Histologically resembles medulloblastoma

Germ cell tumor Germinomab

 Pure germinomas are histologically identical to testicular seminoma and ovarian dysgerminoma

NGGTC

 Embryonal carcinoma  Endodermal sinus tumor  Choriocarcinoma  Mature or immature teratoma  Histology can be mixed or pure

Miscellaneous  Craniopharyngioma   Meningioma   Hemangiopericytoma   Hemangioblastoma   Choroid Plexus tumor  WHO: World Health Organization a Most of the intracranial childhood ependymomas are classified as “classic” or “anaplastic” subtype b The diagnosis of pure germinoma verified by histology should be accompanied by an absence of α-fetoprotein markers in serum and CSF samples. Minimal elevation of β-HCG (<2,000 mIU/ml) can occur with pure germinomas

Routes of Spread The pattern of tumor spread varies, depending on the histology of the brain tumor (Table 36.6). Most brain tumors spread locally into surrounding normal brain tissue. Metastasis in brain tumor includes neural axis spread and extraneural metastasis.

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Table 36.6 Routes of spread and disease progression Route

Description

Local invasion

 Mode of disease progression for craniopharyngiomas, pituitary adenomas and gliomas  Low-grade gliomas tend to behave in a more indolent pattern as compared with malignant gliomas, where microscopic tumor can be found in areas of edema surrounding the primary tumor

Neural axis spread

 Tumors with known propensity to spread throughout the neuraxis include medulloblastoma, ependymoma, germ cell tumor, and supratentorial PNET  ~30–40% of medulloblastoma will have dissemination beyond the primary site at initial diagnosisa  Ependymoma has a low incidence of neuraxis dissemination at initial diagnosis; leptomeningeal spread is related to location and grade of tumor  High-grade infratentorial ependymoma have ~15%, while low-grade supratentorial ependymoma have a ~3%, chance of neuraxis diseaseb  Juvenile pilocytic astrocytoma tend to spread locally but occasionally leptomeningeal dissemination in thalamic or hypothalamic tumors  MRI of the brain and spine for germinoma patients should be performed to rule out spread similar to medulloblastoma, supratentorial PNET, ependymoma, and NGGCT

Extraneural metastasis (ENM)

 An unusual pattern of tumor spread, which can be seen in medulloblastoma and germ cell tumors  1–2% of medulloblastoma at initiation diagnosis have ENM; 5–10% develop ENM throughout the course of their disease  Bone, bone marrow, lung, liver and lymph nodes metastases have been reported for medulloblastoma  ENM maybe occasionally iatrogenic and caused by placement of a VP shunt  The use of chemotherapy has lowered the chance of extraneural relapse in medulloblastoma

VP shunt: ventriculoperitoneal shunt; NGGCT: non-germinomatous germ cell tumor a Sources: Paulino AC (2002) Current multimodality management of medulloblastoma. Curr Probl Cancer 26:317–356; Tarbell NJ, Loeffler JS, Silver B et al (1991) The change in patterns of relapse in medulloblastoma. Cancer 68:1600–1604 b Source: Vanuytsel L, Brada M (1991) The role of prophylactic spinal irradiation in localized intracranial ependymoma. Int J Radiat Oncol Biol Phys 21:825–830 Source: Paulino AC (2003) Long-term survival in a child with extraneural metastasis from medulloblastoma treated with chemo-radiotherapy. Med Pediatr Oncol 40:396– 397

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Clinical Presentation, Diagnosis and Staging, and Prognosis Clinical Presentation Nausea/vomiting and constant headaches are commonly observed symptoms of pediatric brain tumors, due to increased intracranial pressure. Clinical presentations of children with brain tumors vary and depend on the pathology and location of disease (Tables 36.7 and 36.8; Figure 36.2). Table 36.7 Commonly observed signs and symptoms of brain tumors Location of tumor

Symptom(s)

Temporal lobe

Seizures

Brainstem or cerebellar process

Ataxia and dysmetria

Suprasellar

Endocrine dysfunction, resulting in growth disturbance, precocious puberty, amenorrhea, hypothyroidism, and/or diabetes insipidus

Optic pathway (e.g., glioma,) sellar (e.g., pituitary adenoma craniopharyngioma), and suprasellar (germ cell tumors)

Visual disturbances

Supratentorial lesion, spinal cord compression from leptomeningeal dissemination

Weakness of an extremity

Pressure on the quadrigeminal plate

Limited conjugated upward gaze as well as impaired pupillary response (Parinaud’s syndrome) as seen in patients with pineal region tumors

Diagnosis and Staging Diagnosis of Pediatric Brain Tumors For most pediatric brain tumors, magnetic resonance imaging (MRI) with gadolinium is the modality of choice in brain imaging at diagnosis, assessment of postoperative residual, and follow-up. Postoperative MRI of the brain is done within 48 h of surgery, as surgically induced changes can mimic residual tumor and may not resolve until ~2 weeks after resection. In tumors with known propensity to spread throughout the neuraxis (Table 36.6), MRI of the spine and CSF cytology from a lumbar tap may indicate tumor dissemination, and are used for staging (Table 36.8).

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For germ cell tumors, because tumors in the pineal region are in close proximity to various vascular and brain structures, initial reports on management of these tumors have not included obtaining tissue diagnosis and using radiation therapy to a local field as a method of “radiodiagnosis”: tumor response to 20 Gy of RT were diagnosed as germinoma; and nonresponding tumors were diagnosed as nongerminomatous tumor (NGGCT) or glioma. Currently, the risk of morbidity from stereotactic biopsy is ~1%; thus, tissue diagnosis is advocated. Serum and CSF markers for β-human chorionic gonadotropin (β-HCG) and α-fetoprotein may be useful in patients with pineal or suprasellar tumors with a diagnosis of germ cell tumor.

Table 36.8 Clinical characteristics of pediatric brain tumors Tumor type

Description  JPA is most commonly seen in the cerebellum. Region  of the hypothalamus, third ventricle, optic chiasm, suprasellar cistern and thalamus are other common sites  Optic pathway tumors in NF-1 patients are JPA until  proven otherwise  The classical description of a JPA in the cerebellum is a  tumor with a solid nodule and a large cyst

Low-grade astrocytoma

 Fibrillary astrocytomas tend to occur in the diencepha lon and cerebral hemispheres  The less common gemistocytic variant is more aggres sive and often undergoes malignant degeneration within years after diagnosis  Pleomorphic xanthoastrocytomas occur primarily in  cerebral hemispheres  Behave in a relatively benign fashion, although ap pears aggressive histologically

High-grade astrocytoma

 Include anaplastic astrocytoma (WHO grade III) and  glioblastoma (WHO grade IV)  Less common in children as compared with low-grade  astrocytoma  Although glioblastoma is more common than ana plastic astrocytoma, a higher proportion of anaplastic astrocytoma is seen in children compared with adults  Primarily in the supratentorial brain   These tumors usually have poorly defined margins,  with central necrosis and surrounding vasogenic edema ▶

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Table 36.8 (continued) Tumor type

Brainstem glioma (Figure 36.2)

Description  Diffuse intrinsic tumors account for 80% of all brainstem tumors and are primarily located in the pons  In the setting of the typical clinical presentation and MRI findings, a biopsy is not necessary  These children usually have a relatively short duration of symptoms, which may consist of multiple cranial nerve deficits, long tract signs, and ataxia  On MRI, they are usually hypointense on T1 sequence and hyperintense on T2 sequence  At autopsy, many of these tumors are high-grade gliomas  The other types of brainstem gliomas are more indolent and behave in a less aggressive fashion than diffuse intrinsic tumors do  Dorsally exophytic tumors may arise from the floor of the fourth ventricle, and are well delineated from surrounding structures  Cervicomedullary tumors arise in the upper cervical spinal cord and grow rostrally, above the foramen magnum.  Focal tumors <2 cm are most common in the medulla and the midbrain

Medulloblastoma

 Classically arise in the vermis; however, they can be found more frequently in the lateral cerebellar hemispheres of adolescents and young adults  Known to spread throughout the neuraxis, thus curative treatment has included CSI

Supratentorial PNET

Accounts for 2–3% of all childhood brain tumors  Tumors can be located in the cerebral hemispheres, suprasellar region, or pineal region (pineoblastoma)

Ependymoma

 Make up ~10% of all childhood brain tumors  2/3 of ependymomas in children are infratentorial

Germ cell neoplasms

 ~1–3% of pediatric brain tumors  Incidence can be as high as 5–9% of all childhood brain tumors (Taiwan and Japan)  ~2/3 are pure germinomas, with the rest being NGGCT  Germ cell tumors occur within the diencephalic structures in the midline  Pineal region tumors are the most common (50–60%), while suprasellar tumors occur in 30–35% of cases

Table 36.8 (continued)

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Tumor type

Description

Craniopharyngioma

 Benign tumor in the suprasellar region, thought to  arise from remnants of Rathke’s pouch  Usually associated with solid and cystic components   ~2/3 are retrochiasmatic   Although well circumscribed, usually adherent to sur rounding structures (optic chiasm/nerves, circle of Willis, hypothalamus, and tuber cinereum)

NGGCT: non-germinomatous germ cell tumors; CSI: craniospinal irradiation

Figure 36.2 a, b Different presentations of brainstem glioma. a Focal brainstem glioma and b diffuse pontine glioma

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Staging for Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumor Clinical staging for pediatric brain tumors are not commonly practiced. Prognoses are usually pathology and treatment dependent, including medulloblastoma and supratentorial primitive neuroectodermal tumor (PNET), for which the metastasis (M) staging system plays an important role in determining the risks after treatment (Table 36.9). Table 36.9 The Chang M staging system for medulloblastoma and supratentorial PNET Stage of disease

Description

M0

No evidence of subarachnoid metastasis

M1

Tumor cells in CSF cytology

M2

Intracranial tumor beyond the primary site

M3

Gross seeding in spinal subarachnoid space

M4

Extraneural metastasis

Source: Chang CH, Housepian EM, Herbert C Jr (1969) An operative staging system and a megavoltage RT technique for cerebellar medulloblastomas. Radiology 93:1351– 1359

Prognosis Factors and prognoses of pediatric brain tumors are detailed in Table 36.10. Table 36.10 Prognostic factors and outcome of patients with pediatric brain tumors Disease

Outcome

Low-grade glioma

 Long-term DFS and OS in 80–100% of cases after R0  resection  PFS after incomplete resection alone range from 33 to 67%   5- and 10-year OS with the addition of RT range from 67  to 100% and from 63 to 89%, respectivelya

Brainstem glioma

MS of diffuse intrinsic brainstem glioma is 8–10 months

Ependymoma

 The degree of surgical resection determined by a post operative MRI is the most important prognostic factorb  5-year LC rates were 82% after gross total resection, and  40% after subtotal resections  5-year OS was ~80%c 

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Table 36.10 (continued) Disease

Outcome

Medulloblastoma

 Maximal safe resection is important, which divides dis ease into standard-risk and high-risk categories  Standard-risk group: age ≥3 years old, M0 disease, and  <1.5-cm2 tumor residual on postoperative MRI. With a 5-year PFS of ~80%  High-risk category: age ≥3 years; M1–4 disease, and/or  >1.5-cm2 residual on postoperative MRI. With a 5-year PFS of ~70%d  Presence of neuraxis spread carries a worse outcome 

PNET

 Survival outcome of infratentorial is much better than  with supratentorial PNETse  3-year OS approximates 50% for supratentorial PNETf   In patients ≥3 years old with nonmetastatic (M0) supra tentorial PNET, tumors in the pineal region have a better prognosis as compared with other locations

Germinoma

 Long-term OS have exceeded 90–95% after RT or CRT 

NGGCT

 Has a worse outcome compared to pure germinoma:  OS of 60–80% CRT, and 40–50% after RT aloneg

Craniopharyngioma

 5- to 10-year PFS for gross total resection versus limited  surgery and postoperative RT are the same at 75–95%

MS: median survival; OS: overall survival; PFS: progression-free survival rates; RT: radiation therapy; CRT: chemoradiation therapy a Source: Freeman CR, Farmer JP, Montes J (1998) Low grade astrocytomas in children: evolving management strategies. Int J. Radiat Oncol Biol Phys 41:978–87 b Source: Healey EA, Barnes PD, Kupsky WJ et al (1991) The prognostic significance of postoperative residual tumor in ependymoma. Neurosurgery 28:666–672 c Source: Schroeder TM, Chintagumpala M, Okcu MF et al (2008) IMRT in childhood ependymoma. Int J Radiat Oncol Biol Phys 2008, 71:987–993 d Source: Zeltzer PM, Boyett JM, Finlay JL et al (1999) Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the CCG 921 randomized phase III study. J Clin Oncol 17:832–845 e Source: Paulino AC, Cha DT, Barker Jr JL et al (2004) Patterns of failure in relation to radiotherapy fields in supratentorial PNET. Int J Radiat Oncol Biol Phys 58:1171–1176 f Source: Timmermann B, Kortmann RD, Kuhl J et al (2002) Role of radiotherapy in the treatment of supratentorial PNET in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20:842–849 g Sources: Robertson PL, DaRosso RC, Allen JC et al (1997) Improved prognosis of intracranial NGGCT with multimodality therapy. J Neurooncol 32:71–80; Schild SE, Haddock MG, Scheithauer BW et al (1996) NGGCT of the brain. Int J Radiat Oncol Biol Phys 36:557–563

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Treatment Treatment of Low-Grade Astrocytoma Juvenile Pilocytic Astrocytoma Treatment for cerebellar Juvenile pilocytic astrocytoma (JPA) is gross total resection. Radiation therapy is used if complete resection cannot be performed, such as in the thalamus. Another option is observation if the site of tumor will not compromise neurologic function with slow growth, and re-resection is an option. If more immediate treatment is needed, such as in large unresectable tumors, chemotherapy has been used in younger children to delay radiotherapy. Carboplatin and vincristine are active agents for JPA (Packer RJ, Ater J, Allen J et al (1997) Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86:747– 754). In children with neurofibromatosis type 1 (NF-1), tumors are observed with serial MRI, as they can wax and wane for a long period without treatment. With clinical or definite radiographic progression, chemotherapy is preferred over radiation because radiotherapy in NF-1 patients has a higher risk of secondary primary tumors (SPT) and Moyamoya syndrome (Source: Desai SS, Paulino AC, Mai WY et al (2006) Radiation-induced moyamoya syndrome. Int J Radiat Oncol Biol Phys 65:1222–1227; Sharif S, Ferner R, Birch JM et al (2006) SPT in NF-1 patients treated for optic glioma: substantial risks after radiation. J Clin Oncol 24:2570–2575). Fibrillary Astrocytoma and Pleomorphic Xanthoastrocytomas Surgery is the mainstay treatment for these diseases, and radiation therapy and chemotherapy are reserved for unresectable sites or progressive disease after gross total and subtotal resection. Treatment of High-Grade Astrocytoma The surgical and radiotherapeutic management for high-grade astrocytomas are similar in adults and children. Maximal safe resection followed by postoperative RT is advocated. Whereas in adults, most would utilize chemotherapy consisting of temozolomide during and after RT, in children, it is controversial whether chemotherapy is needed, and the optimal regimen is less established.

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Treatment of Brainstem Glioma Diffuse Brainstem Glioma Radiation therapy is the mainstay treatment modality for diffuse brainstem glioma. Studies have focused on innovative ways of RT delivery and/or use of chemotherapy. Dose-escalated and hyperfractionated radiation (70.2 Gy in 1.17Gy fractions, twice daily) did not improve survival as compared with conventional strategy (54 Gy in 1.8-Gy fractions), according to a POG phase III trial (Source: Mandell LR, Kadota R, Freeman C et al (1999) There is no role for hyperfractionated RT in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a POG phase III trial comparing conventional vs. hyperfractionated RT. Int J Radiat Oncol Biol Phys 43:959–964). Other Types of Brainstem Glioma The management for dorsally exophytic, cervicomedullary, and focal brainstem glioma is surgery. These tumors are usually pilocytic astrocytomas, and most are controlled without adjuvant radiotherapy. In the rare case of a focal tectal plate glioma presenting with hydrocephalus, a CSF diversionary procedure may be the only treatment needed. Treatment of Medulloblastoma Several phase III studies comparing the use of postoperative radiotherapy with or without chemotherapy have shown a possible survival benefit in patients with more advanced disease (Table 36.11). Table 36.11 Randomized trials of postoperative radiotherapy with or without chemotherapy in medulloblastoma Studies SIOP-I

CCG

b

POGc

a

Treatment arms

Findings

30–45 Gy CSRT 50–55 Gy PFRT With or without vincristine and CCNU

Chemotherapy provides survival benefit if subtotal resection, brainstem involvement, or T3–T4 disease

35–40 Gy CSRT Chemotherapy provides 50–55 Gy PFRT survival benefit for T3–T4 With or without vincristine, lesions and M1 to M3 disease CCNU, prednisone 35 Gy CSRT 54 Gy PFRT With or without MOPP

Chemotherapy provides survival benefit if they were ≥5 years of age, female, and white ▶

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Table 36.11 (continued) Studies

Treatment arms

Findings

SIOP/UK Children’s Cancer Study Group PNET-3 Studyd

35 Gy CSRT 55 Gy PFRT With or without pre-RT vincristine, etoposide, carboplatin, cyclophosphamide

Chemotherapy improved EFS (only M0 and M1 patients were in this study)

RT: radiation therapy; CSRT: craniospinal radiotherapy; PFRT: posterior fossa radiotherapy; EFS: event-free survival; MOPP: nitrogen mustard, vincristine, prednisone and procarbazine; SIOP: International Society of Pediatric Oncology a Source: Tait DM, Thornton-Jones H, Bloom HGJ et al (1990) Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 26:464–469 b Source: Evans AE, Jenkin RDT, Sposto R et al (1990) The treatment of medulloblastoma. Results of a prospective randomized trial of RT with and without CCNU, vincristine and prednisone. J Neurosurg 72:572–582 c Source: Krischer JP, Ragab AH, Kun LE et al (1991) Nitrogen mustard, vincristine, procarbazine and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 74:905–909 d Source: Taylor R, Lucraft H, Robinson K et al (2003) Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: the ISPG/UK Children’s Cancer Study Group PNET-3 Study. J Clin Oncol 21;1581–1591

Based on the results of a phase II Children’s Cancer Group (CCG) study, it is felt that low-dose craniospinal irradiation (CSI) to 23.4 Gy CSI with chemotherapy is equivalent to, if not better, than 36-Gy CSI. Radiation dose used for CSI and total dose after boost radiation is listed in Table 36.12.

Table 36.12 Postoperative radiation dose (with chemotherapy) for medulloblastoma Risk

a

CSI dose

Low

23.4 Gy in 13 fractions

High

36–39.6 Gy in 20–22 fractions

Posterior fossa boost dose (Gy) a

54–54.8 Gyb 54–54.8 Gy

A phase II CCG study showed that reducing the CSI dose to 23.4 Gy with chemotherapy resulted in a 5-year PFS of 79% b Tumor bed irradiation only may not compromise local control Source: Packer RJ, Goldwein J, Nicholson HS et al (1999) Treatment of children with medulloblastoma with reduced-dose CSI and adjuvant chemotherapy: a CCG study. J Clin Oncol 17:2127–2136

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Chemotherapy using cyclophosphamide or lomustine (1-(2-chloroethyl)3-cyclohexyl-1-nitrosourea [CCNU]) (both with vincristine and cisplatin) resulted in similar event-free survival (Source: Packer RJ, Gajjar A, Vezina G et al (2006) Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24:4202–4208). Treatment of Supratentorial PNET The work-up and treatment for supratentorial PNET is similar to high-risk medulloblastoma. Treatment of Ependymoma Surgery is the mainstay treatment modality, and radiation therapy is considered the standard adjuvant therapy for intracranial ependymomas. Treatment options for ependymoma include surgery and postoperative radiation therapy (Table 36.13).

Table 36.13 Treatment modalities for ependymoma Type

Description

Surgery Indication

Mainstay treatment for ependymoma

Technique

Gross resection with imaging verification

Radiation therapy

Indications

 Adjuvant therapy after gross total resection of infratentorial disease  Adjuvant radiation is controversiala after imaging verified gross total resection for supratentorial lowgrade disease

Techniques

 External-beam radiation therapy  Target postoperative tumor bed and residual

Chemotherapy Indication a

 Has limited role as the only randomized clinical trial revealed no improvement in OS after adjuvant CCNU, vincristine, and prednisone

Recently closed COG ACNS0121 study did not use adjuvant RT in patients with WHO grade II disease after imaging-verified gross total resection. The result of this study is yet to be reported

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Clinical evidence for the use of gross total resection with or without radiation therapy is listed in Table 36.14. Table 36.14 Clinical evidence for the use of gross total resection with or without radiation therapy Researcher/study

Results

Paulino et al  Postoperative radiation improved OS to 40–68% from  17–21% (surgery alone) (literature review)a Hukin et al

 10 Children (8 supratentorial, 7 WHO grade II) had imag ing verified gross total resection treated with no adjuvant RT. 7 remained disease free, and 2 of 3 recurrent cases were salvaged by resection and postoperative RT

Rogers et alc

 Gross total resection of posterior fossa ependymoma  with postoperative RT may improve 10-year OS to 83 from 67% with gross resection alone

CCG-942 (Evans et al)d

 The only randomized trial comparing surgery, RT with  or without chemotherapy in patients with ependymoma  Randomized 36 children into 2 arms: surgery plus RT only  versus surgery plus RT plus chemotherapy (CCNU, vincristine, and prednisone)  The 10-year FFS was 36% in both arms 

b

OS: overall survival; RT: radiation therapy; FFS: failure-free survival a Source: Paulino AC (2002) Radiotherapeutic management of intracranial ependymoma. Pediatr Hematol Oncol 19:295–308 b Source: Hukin J, Epstein F, Lefton D et al (1998) Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 29:40–45 c Source: Rogers L, Pueschel J, Spetzler R et al (2005) Is gross total resection sufficient treatment for posterior fossa ependymomas? J Neurosurg 102:629–636 d Source: Evans AE, Anderson JR, Lefkowitz-Boudreaux IB et al (1996) Adjuvant chemotherapy of childhood posterior fossa ependymoma: craniospinal irradiation with or without adjuvant CCNU, vincristine and prednisone: a CCG study. Med Pediatr Oncol 27:8–14

Treatment of Germ Cell Tumors Pure Germinoma Treatment options include neoadjuvant chemotherapy, followed by radiation therapy or radiation alone. Whether the use of neoadjuvant chemotherapy can reduce radiation dose and volume hence minimize late toxicities as compared with radiation alone with higher dose and larger volume remains to be seen. The use of chemo-

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therapy such as cisplatin introduces another potential long-term toxicity – hearing loss – to these patients. Previous studies using CSI in pure germinoma have resulted in favorable cognitive and stable endocrine function (Source: Merchant TE, Sherwood SH, Mulhern RK et al (2000) CNS germinoma: disease control and longterm functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 46:1171–1176). NGGCT Patients with NGGCT require neoadjuvant chemotherapy followed by possible resection, and CSI with boost. Neoadjuvant chemotherapy consists of carboplatin and etoposide given DURING cycles 1, 3, and 5 alternating with ifosfamide and etoposide on cycles 2, 4, and 6 (COG ACNS0122 protocol). Treatment for Craniopharyngioma Treatment modalities for craniopharyngioma include surgery and postoperative radiation therapy. Chemotherapy has no major role in the treatment (Table 36.15).

Table 36.15 Treatment modalities for craniopharyngioma Type

Description

Surgery Indication

 Important treatment and diagnosis modality

Techniques

 Gross resection is indicated but difficult to achieve without morbidity  Subtotal resection and biopsy requires adjuvant radiation therapy

Radiation therapy Indication

 Adjuvant therapy after subtotal resection and biopsy

Techniques

 External-beam radiation therapy  Intracavitary radiation using 32P. Reserved primarily for tumors with solitary cystic lesion with a stable or nonproblematic solid component

Chemotherapy Indications

 Generally has no role in treatment  Exception is occasional use of bleomycin as intracavitary treatment

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Target volumes in radiation therapy, as well as radiation dose and fractionation based on diagnosis, are detailed in Table 36.16. Table 36.16 Target volumes in radiation therapy PTV

Dose/fractiona

0.3–0.5 cm

45–54 Gy in children >5 years and 45–50.4 Gy in <5 years

Tumor bed and residual (MRI T1 sequence)

CTV-1: 2 cm plus GTV/ edema (MRI T2 sequence) 0.3–0.5 cm CTV-2: 1 cm plus GTV (MRI T1 sequence)

CTV-1: 45–50 Gy CTV-2: 10–15 Gy

GTV (MRI T2 sequence)

1.5–2 cm

54 Gy

Tumor type

GTV

Low-grade astrocytoma

Enhanced GTV on MRI T1 sequence

0.5- to 1-cm margin

High-grade astrocytoma

Brainstem glioma

Medulloblastoma (Figures 36.3 and 36.4)

Supratentorial PNET

Ependymoma

Germinoma (Figure 36.5)

CTV

0.3–0.5 cm

Craniospinal irradiation (CSI): to include the entire neuraxis with special attention to the end of the thecal sac on MRI for the caudal border of the field Tumor bed and residual 1–2 cm boost CSI after maximal resection Tumor bed and residual 1 cm boost Postoperative tumor 1 cm bed and reb sidual

3–5 mm

3–5 mm

3–5 mm

Standard-risk: 23.4 Gy in 13 fractions High-risk: 36–39.6 Gy in 20–22 fractions 18–32. 4 Gy (total 54–55,8 Gy) 36 Gy 18–19.8 Gy to total of 54–55.8 Gy 54 Gy over 6 weeks to WHO grade II 59.4 Gy over 6.5 weeks for WHO grade III

Entire ventricular field includes the lateral, 3rd and 4th 3–5 mm ventricles on MRI with a 1-cm margin (or CSI if metastatic)

24 Gy in 16 fractions

Primary tumor boost

21 Gy in 14 fractions to a total of 45 Gy/30 fractions

1–1.5 cm

3–5 mm

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Table 36.16 (continued) Tumor type

GTV

CSI Primary NGGCT tumor (for boost) Solid and Craniopharyngioma cystic component on (Figure 36.6) MRIc

CTV

PTV

Dose/fractiona 36 Gy

1 cm

3–5 mm

18 Gy to a total of 54 Gy

1 cm

3–5 mm

54 Gy

CSI: cranial–spinal irradiation a Daily fractionation is 1.8 Gy if not otherwise indicated b CSI is not needed for localized ependymoma and is used only in leptomeningeal spread; irradiation to the entire posterior fossa is not needed for infratentorial ependymomas Source: Paulino AC (2001) The local field in infratentorial ependymoma: does the entire posterior fossa need to be treated? Int J Radiat Oncol Biol Phys 49:757–61 c Because cysts are known to change volume during the course of RT, serial weekly MRI during RT course may be required

CSI Techniques for Medulloblastoma The entire neuraxis is included in the CSI field, and special attention to the end of the thecal sac on MRI is necessary to determine the caudal border of the spinal field (Figure 36.3). A dose gradient of −5 to +7% of the prescribed dose is recommended for neuraxis irradiation for dose homogeneity. Feathering of the craniospinal and spinal–spinal junction is performed at least every five treatments to minimize under- or overdosing of the junction sites. The use of a cochlear-sparing intensity-modulated radiation therapy (IMRT) tumor bed boost approach resulted in POG grade 3–4 ototoxicity in 25% of patients, affecting 18.2% of 88 ears tested, less than those observed after parallel-opposed lateral fields for entire posterior fossa (Figures 36.4, 36.5, and 36.6) (Paulino AC, Lobo M, Teh BS et al (2010) Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma. Int J Radiat Oncol Biol Phys. Epub ahead of print).

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Figure 36.3 Field segment settings for patient requiring craniospinal irradiation. Left column shows multileaf collimator (MLC) settings for right lateral brain, middle column shows MLC settings for upper spine, and right column shows MLC settings for lower spine. Source: South M, Chiu JK, Teh BS et al (2008) Supine craniospinal irradiation using intrafractional junction shifts and field-in-field dose shaping: early experience at Methodist Hospital. Int J Radiat Oncol Biol Phys 71:477–483, 2008. Used with permission. Figure 36.5 a–d An adolescent male with pure germinoma of the pineal region. a MRI axial image, b MRI sagittal image, and c whole-ventricular irradiation using IMRT. Axial image showing PTV in blue covered by 25.2 Gy (red isodose line). d Same plan showing sagittal view and coverage of PTV with 25.2 Gy (red isodose line)

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Figure 36.4 IMRT tumor bed boost in a child with medulloblastoma. Red GTV, yellow CTV, purple PTV, olive green right cochlea, blue left cochlea. Note the “dipping” of isodose lines to spare the right and left cochlea

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Figure 36.6 Patient with craniopharyngioma treated with biopsy and IMRT. PTV (pale orange) is covered by 95% isodose line

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Follow-Up A multidisciplinary team of oncologists, neurologist, endocrinologist, and psychologist is often necessary to assess tumor recurrence and late effects of therapy. Follow-up schedule and suggested examinations are detailed in Table 36.17.

Table 36.17 Follow-up schedule and examinations Schedule

Frequency

Years 0–2

 Every 3-4 months 

Years 2–5

 Every 6 months 

Examination History and physical

 Complete history and physical examination 

Imaging studies

 MRI of the brain   MRI of the spinal axis is also done for patients with initial lepto meningeal dissemination

37

Retinoblastoma David B. Mansur1

Key Points  Retinoblastoma is the tenth most common pediatric malignancy and the most common pediatric intraocular malignancy in the USA.  The most common presenting sign is leukocoria.  Multiple treatment modalities are routinely used including surgery, radiation therapy, and chemotherapy with the goal of maximizing cure rates while minimizing the need for enucleation or external-beam radiation therapy.  The current therapeutic approach stratifies patients based on the International Classification, and tailors therapy, based on disease extent.  While overall survival in patients with localized retinoblastoma is excellent, significant rates of second cancers in patients with heritable retinoblastoma (especially those treated with radiation therapy) is a persistent concern.

1

David B. Mansur, MD Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-16333-3_20 © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Risk Factors Epidemiology statistics and etiologic factors for retinoblastoma are presented in Table 37.1. Table 37.1 Statistics and etiology factors of retinoblastoma Type

Description Incidence of retinoblastoma has been stable in the past 30 years in USA, and retinoblastoma is the tenth most common pediatric cancer

Statistics

The mean age-adjusted incidence of retinoblastoma is ~12 per 1,000,000 children aged 0–4 years There is no age or gender-specific difference in retinoblastoma The overall incidence of bilaterality is 27%, although a higher proportion of bilateral tumors is seen in infants <1 year old (42%) than in children older than 5 years (4%) There are two forms, heritable (all bilateral cases, and approximately 15% of unilateral cases), which occurs after germline mutation in the retinoblastoma tumor suppressor gene, and nonheritable, which occurs after somatic mutation only

Etiologic factors

Family history of retinoblastoma is a risk factor for developing the disease, but most cases of retinoblastoma, even the heritable form, occur without a family history, indicating that the heritable form usually begins as a sporadic germline mutation Genetic testing can assist in determining if an individual has germline mutation (heritable form) and therefore have atrisk progeny. Heritable retinoblastoma behaves in an autosomal dominant pattern Low socioeconomic status is another risk factor

Sources: Gatta G, Capocaccia R, Coleman MP et al (2002) Childhood cancer survival in Europe and the United States. Cancer 95:1767–1772; Broaddus E, Topham A, Singh AD (2009) Incidence of retinoblastoma in the USA: 1975–2004. Br J Ophthalmol 93:21–23; Yandell DW, Campbell TA, Dayton SH et al (1989) Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling. N Engl J Med 321:1689–1695

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Anatomy The basic anatomy of the eye is presented in Figure 37.1. Of special note for treating retinal tumors with radiation therapy is the proximity of the lens to the anterior-most retina extent (ora serrata). This has implications when considering the use of lens-sparing techniques, which should only be used when disease is significantly posterior to the lens to prevent shielding of tumor.

Ora Serrata Retina

Vitreous Base

Limbus

Lens

Cornea

3- 4 mm 2-3 mm

16-23 mm

Figure 37.1 Anatomy of the eye. Note proximity of posterior lens to the anterior-most retina (ora serrata) Source: Halperin EC, Kirkpatrick JP (2005) Retinoblastoma. In: Halperin EC, Constine LS, Tarbell NJ et al Pediatric radiation oncology. 4th (edn). Lippincott, Williams & Wilkins, Philadelphia, pp. 135–177. Used with permission

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Patterns of Spread Tumors arise from the retina and typically grow either into the vitreous or subretinal space by direct extension. Vitreous seeds can also occur either to a limited or to an extensive degree. Extrascleral extension is rare in the USA, although invasion of the optic nerve is often seen in surgical specimens after enucleation of more advanced tumors.

Clinical Presentation The most common presentation is leukocoria (presence of a white pupillary light reflex). This is typically either seen by ophthalmoscopy during a screening physical examination, or noticed by family members in a flash photograph. Differential diagnosis and suggested work-up are listed in Table 37.2.

Table 37.2 Differential diagnosis and workup Type

Description

Differential diagnosis

 Astrocytic hamartoma  Toxocara canis  Coats’ disease  Retinopathy of prematurity  Persistent hyperplastic primary vitreous

Required workup

 History and physical examination including examination under anesthesia with scleral compression to evaluate the entire retinal surface  Imaging studies: ultrasonography, MRI of the brain and orbits, retinal diagram, fundus photography  Laboratory tests: complete blood count (CBC) and serum chemistry

Optional workup

 Bone scan (if abnormal chemistries or bone pain)  Bone marrow biopsy (if abnormal CBC)  LP/CSF cytology (if MRI demonstrates CNS disease, or if signs/symptoms of CNS disease are present)

Staging Although retinoblastoma can be staged according to the tumor, node, and metastasis (TNM) staging system, either the Reese-Ellsworth or the International Classification (Table 37.3) is more commonly used in most decision-making.

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Table 37.3 Reese-Ellsworth classification of retinoblastoma Type

Description

Group I

“Very favorable”

A B Group II A B Group III A B Group IV A B Group V A B

Solitary tumor, less than 4 dd in size, at or posterior to the equator Multiple tumors, none over 4 dd in size, all at or posterior to the equator “Favorable” Solitary tumor, 4–10 dd in size, at or posterior to the equator Multiple tumors, 4–10 dd in size, all posterior to the equator “Doubtful” Any lesion anterior to the equator Solitary tumors larger than 10 dd posterior to the equator “Unfavorable” Multiple tumors, some larger than 10 dd Any lesion extending to the ora serrata “Very unfavorable” Massive tumors involving over half the retina Vitreous seeding

dd: disc diameter, approximately 1.5 mm Source: Reese AB (1966) Tumors of the eye. 2nd edn. Harper & Row, New York

Historically, the likelihood of tumor response to external-beam radiation therapy (EBRT), and thereby the avoidance of enucleation has been categorized by the Reese-Ellsworth Classification. Enucleation is typically avoided in over 90% of group I eyes, but only 50% of group V eyes. The main limitation of the Reese-Ellsworth Classification is that it has less utility for modern approaches that utilize chemoreduction and local therapies. The success of chemoreduction is better predicted with the International Classification of Retinoblastoma (Table 37.4), which emphasizes vitreous and subretinal seeding extent, rather than tumor size and anterior tumor location. In the chemoreduction era, successful therapy is considered that which avoids both enucleation and EBRT.

Prognosis The Reese-Ellsworth and the International Classification Systems (Tables 37.3 and 37.4) are designed to predict the likelihood of avoiding enucleation and/or EBRT in patients with intraocular retinoblastoma. Overall survival of

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Table 37.4 International Classification of Retinoblastoma Risk group A

B

C

D

E

Description Small intraretinal tumors away from fovea and optic disc All tumors <3 mm in greatest dimension All tumors >3 from fovea and >1.5 mm from optic disc All other discrete intraretinal tumors Tumor associated subretinal fluid less than 3 mm from the tumor No subretinal seeding Discrete local disease including minimal subretinal or vitreous seeding Subretinal fluid involving up to 25% of retina without subretinal seeding Local fine vitreous seeding close to discrete tumor Local subretinal seeding <3 mm from tumor Diffuse or massive disease with significant vitreous or subretinal seeding Subretinal fluid without seeding involving up to total retinal detachment Diffuse or massive vitreous disease including “greasy” seeds or avascular tumor masses Diffuse subretinal seeding including subretinal plaques or tumors One or more of the following features Tumor touching lens Tumor involving ciliary body or anterior segment Diffuse infiltrating retinoblastoma Neovascular glaucoma Opaque media from hemorrhage Tumor necrosis with aseptic orbital cellulites Phthisis bulbi

Sources: Shields CL, Mashayekhi A, Demirci H et al (2004) Practical approach to management of retinoblastoma. Arch Ophthalmol 122:729–735; Shields CL, Mashayekhi A, Au AK et al (2006) The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113:2276–2280

patients with intraocular disease is typically greater than 90%. While rare in the USA, extraocular and disseminated disease is more prevalent in developing nations. Neither of the above classification systems is applicable to these patients. A staging system for retinoblastoma that takes into account all disease extents has been recently proposed (Table 37.5).

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Table 37.5 Proposed International Staging System for Retinoblastoma Stage

Description

0

Eye amenable to conservative treatment

I

Eye enucleated, negative surgical margins

II

Eye enucleated, positive surgical margins

III

Regional extension  Overt orbital disease  Regional lymph node involvement

IV

Metastatic disease  Hematogenous spread  CNS involvement (prechiasmatic disease, CNS mass, leptomeningeal disease)

Sources: Schipper J, Imhoff SM, Tan KE (1997) Precision megavoltage external beam radiation therapy for retinoblastoma. Front Radiat Ther Oncol 30:65–80; Chantada G, Doz F, Antoneli CB et al (2006) A proposal for an international retinoblastoma staging system. Pediatr Blood Cancer 47:801–805

Treatment The goal of treatment is maximizing cure rates while preserving vision and reducing late effects of therapy. To achieve this end, a multidisciplinary approach is required to rationally apply the various modalities available in treating this disease (Table 37.6). Close collaboration is required between ophthalmology, pediatric oncology, and pediatric radiation oncology. Historically, the primary eye-sparing modality was EBRT. However, with the development of modern focal therapies and effective systemic chemotherapy, the role of radiation therapy in this disease has become more limited. Table 37.6 Treatment modalities for retinoblastoma Modality

Description

Indication(s) and efficacy

Removal of globe (eyeball). To achieve negative surgical margins, a generous length (15 mm) of optic nerve is taken with the globe Removes the entire orbital contents including globe, lids, muscles, nerves, and fat

 For eyes with active tumor and no potential for useful vision or in the presence of tumor-related glaucoma. Local control is 95%

a

Surgery

Enucleation

Orbital exenteration

 Orbital extension of tumor or after orbital recurrence after enucleation ▶

1044 David B. Mansur Table 37.6 (continued) Modality

Description

Indication(s) and efficacy

Cryotherapyb

Trans-scleral freezing of tumor with a cryoprobe under general anesthesia

 Small anterior tumors (<2–3 dd) without vitreous seeding  Local control is 90%

Laser Photocoagulationc

Transpupillary ablation of tumor-feeding vessels under general anesthesia

 Small posterior tumors (<3 dd) without vitreous seeding  Local control is 70%

Transpupillary thermotherapy (TTT)d

Hyperthermia administered by transpupillary ophthalmic infrared laser under general anesthesia

 Small tumors (<2 dd) without vitreous seeds.  Local control is 90%

Multiple techniques available including photons (3D conformal, or IMRT), en face electrons, and protons. Dose is 36–45 Gy

 Generally used in eyes with potentially useful vision for more advanced tumors too large for brachytherapy, or if diffuse vitreous seeding.  Local control ranges from 100 to 50%, depending on Reese-Ellsworth group

Focal therapies

Radiation therapye

External beam

Episcleral plaque brachytherapy

 Localized tumors too large I or 106 Ru seeds defor focal therapies but <18 livers 35–40 Gy to tumor mm diameter apex as initial or salvage therapy  Local control is 80–90%

Postoperative radiation therapy

External beam or brachytherapy to orbital contents and proximal optic nerve surgical margin to 40–45 Gy

 Positive optic nerve margin  Scleral invasion  Extensive choroidal invasion  Post-laminar optic nerve involved (negative margin) and choroidal invasion  Local control is 90%

IV carboplatin, vincristine, and etoposide ×6 monthly cycles used alone or in combination with focal therapies or brachytherapy to avoid enucleation or externalbeam RT

 For eyes not amenable to treatment with focal therapies alone  Tumor control is 50% with chemotherapy alone, but 80% when combined with focal therapies

125

Chemotherapyf

Chemoreduction approach

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Table 37.6 (continued) Modality

Description

Indication(s) and efficacy

Chemotherapy (continued) f

Periocular

Adjuvant (after enucleation)

High dose with stem-cell transplant a

Subtenon or subconjunctival administration IV carboplatin, vincristine, etoposide, doxorubicin, cyclophosphamide High-dose thiotepa- or melphalan-based regimens with autologous stem cell rescue

Used less commonly than above for eyes not amenable to focal therapies alone Same indications as for postoperative RT above Used in cases of metastatic disease 40% disease-free survival

Source: Kim JW, Kathpalia V, Dunkel IJ et al (2009) Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93:463–467 b Source: Abramson DH, Ellsworth RM, Rozakis GW (1982) Cryotherapy for retinoblastoma. Arch Ophthalmol 100:1253–1256 c Source: Shields CL, Shields JA, Kiratli H et al (1995) Treatment of retinoblastoma with indirect ophthalmoscope laser photocoagulation. J Pediatr Ophthalmol Strabismus 32:317–322 d Source: Abramson DH, Schefler AC (2004) Transpupillary thermotherapy as initial treatment for small intraocular retinoblastoma: technique and predictors of success. Ophthalmology 111:984–991 e Sources: Schipper J, Imhoff SM, Tan KE (1997) Precision megavoltage external beam radiation therapy for retinoblastoma. Front Radiat Ther Oncol 30:65–80; Fontanesi J, Pratt CB, Kun LE et al (1996) Treatment outcome and dose-response relationship in infants younger than 1 year treated for retinoblastoma with primary irradiation. Med Pediatr Oncol 26:297–304; Scott IU, Murray TG, Feuer WJ et al (1999) External beam radiotherapy in retinoblastoma: tumor control and comparison of 2 techniques. Arch Ophthalmol 117:766– 770; Blach LE, McCormick B, Abramson DH (1996) External beam radiation therapy and retinoblastoma: long-term results in the comparison of two techniques. Int J Radiat Oncol Biol Phys 35:45–51; Abramson DH, Beaverson KL, Chang ST et al (2004) Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol 122:1316–1323; Merchant TE, Gould CJ, Wilson MW et al (2004) Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer 43:134–139; Schueler AO, Fluhs D, Anastassiou G et al (2006) Beta-ray brachytherapy with 106 Ru plaques for retinoblastoma. Int J Radiat Oncol Biol Phys 65:1212–1221; Abouzeid H, Moeckli R, Gaillard MC et al (2008) 106Ruthenium brachytherapy for retinoblastoma. Int J Radiat Oncol Biol Phys 71:821–828; Shields CL, Shields JA, Cater J et al (2001) Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 108:2116–2121; Chantada GL, Dunkel IJ, de Davila MT et al (2004) Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol 88:1069–1073 f Sources: Shields CL, Mashayekhi A, Cater J et al (2004) Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol 138:329–337; Chantada GL, Dunkel IJ, de Davila MT et al (2004) Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol 88:1069–1073; Dunkel IJ, Jubran RF, Gururangan S et al Trilateral retinoblastoma: potentially curable with intensive chemotherapy. Pediatr Blood Cancer 54:384–387; Rodriguez-Galindo C, Wilson MW, Haik BG et al (2003) Treatment of metastatic retinoblastoma. Ophthalmology 110:1237–1240

1046 David B. Mansur

The above modalities are usually used in combination. Optimal treatment depends on proper patient selection, which requires a comprehensive, multidisciplinary approach. The current Children’s Oncology Group (COG) approach is to use the International Classification and tailor therapy based on extent of disease (Table 37.7). Table 37.7 Current COG protocols for intraocular retinoblastoma stratified by international classification Class

Protocol Treatment

Comments

RT guidelines

A

No protocol

Focal therapy alone off study

None

None

ARET 0331

Chemotherapy response to be A “chemoreduction” assessed after approach with 6 cycles first cycle – prior of neoadjuvant cheto local therapy. motherapy (vincristine Primary endpoint and carboplatin) and is event-free surfocal therapy (either vival (i.e., need cryotherapy, photocofor non-protocol agulation, thermotherchemotherapy, apy, or brachytherapy) enucleation or external beam RT)

Eye plaque brachytherapy with 125 I or 106Ru. 30–35 Gy to tumor apex. Dose rate between 0.4 and 0.8 Gy/h

ARET 0231

Initial carboplatin, vincristine, and etoposide (CEV) ×6 cycles with subtenon carboplatin cycles 2–4 Focal tumor therapy with cycle 3

Due to more advanced disease, etoposide is added to the systemic therapy Primary endpoint is event-free survival, as defined above

As above, but total dose specified at 35 Gy

ARET 0332

Based on risk factors found following enucleation: (1) choroid invasion >3 mm, (2) any choroid invasion associated with any optic nerve involvement, and (3) any optic nerve involvement posterior to lamina cribrosa, Patients will receive adjuvant CEV (surgical margins must be negative). In the absence of risk factors, patients will be observed

To establish specific high-risk features and determine the efficacy of adjuvant chemotherapy in those patients, and to identify which patients can be treated with enucleation alone

No RT

B

C and D

Any eye enucleated as up front therapy

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The goals of these studies are to confirm chemotherapy response rates and efficacy described in single-institutional reports, to demonstrate the usefulness of the International Classification System in the modern era of retinoblastoma therapy, and to establish national collaboration in the therapy of retinoblastoma. All of this is directed toward improving outcomes of children with this disease.

Radiation Therapy Techniques External-Beam Radiation Therapy Patients who have disease too extensive to adequately treat with focal therapies including brachytherapy, are not responding to chemotherapy, and have useful vision in the affected eye are candidates for external-beam radiation therapy (EBRT). Retinoblastoma has been historically treated with lateral beams to encompass the affected retina(s), and spare the lens anteriorly, if possible. Figure 37.2 demonstrates a single, lateral D-shaped beam. The beam is oriented posteriorly a few degrees to avoid divergence through the contralateral lens. When considering the penumbra of the beam and the proximity of the ora serrata to the posterior aspect of the lens (Figure 37.1), meaningful lens sparing is feasible only if the entire retina is not targeted. In cases where there is disease more extensive such as vitreous seeding, it is necessary to treat a larger volume. Figure 37.3 is an example of intensity-modulated radiation therapy (IMRT) used to treat a single eye in a patient with diffuse vitreous seeding. The prescription dose is quite conformal at the expense of low doses delivered to a large, uninvolved area. Doses of up to 50 Gy have been used in the past. However, increasing evidence demonstrates that lower doses are as effective. Currently doses in the range of 35–40 Gy are utilized for EBRT.

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Figure 37.2 A single beam used to treat unilateral retinoblastoma

Figure 37.3 Intensity-modulated radiation therapy dose distribution used to treat the entire vitreous

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Brachytherapy 125

I or 106Ru is used for episcleral plaque therapy. The size of the plaque is chosen to allow a 2-mm margin on any side of the tumor. The plaque is sutured into place under general anesthesia and left in place for approximately 72 hours, depending on the activity of the seeds used. A typical isodose distribution for a 125I plaque is shown in Figure 37.4. Current protocols utilize doses of 30–35 Gy to the tumor apex.

Figure 37.4 Isodose distribution for an 125I episcleral brachytherapy plaque treatment

Protons The dosimetric advantage of the Bragg-Peak, which eliminates exit dose, results in less low dose to normal, uninvolved tissue. A proton plan is shown in Figure 37.5. The reduction in peripheral dose as compared with the IMRT plan is highly desirable in patients of this young age, many of whom carry a germline mutation, predisposing them to the development of secondary cancers. (Fontanesi J, Pratt CB, Kun LE et al (1996) Treatment outcome and dose–response relationship in infants younger than 1 year treated for retinoblastoma with primary irradiation. Med Pediatr Oncol 26:297–304).

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David B. Mansur Figure 37.5 Isodose distribution for a singlebeam proton plan Source: Lee CT, Bilton SD, Famiglietti RM et al (2005) Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques? Int J Radiat Oncol Biol Phys 63:362– 372. Used with permission

Treatment-Induced Complications and Second Cancer Risk Treatment-induced complications and their incidences observed in studies detailed above are presented in Table 37.8. Table 37.8 Treatment-induced complications, based on radiation therapy modalities and surgery Treatment modality and complications EBRT Cataracts (with lens-sparing technique) Retinopathy Xerophthalmia Mildly to moderately impaired orbital development Glaucoma Brachytherapy Cataracts Retinopathy Glaucoma Scleral necrosis Enucleation Chronic discharge Contraction of socket Extrusion of implant Mildly to moderately impaired orbital development

Incidence (%) 20–42% 2–12% 2% 80–90% 5% 31% 15–27% 11% 0% 11% 3% 10% 80–90%

Chapter 37 Retinoblastoma

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Patients with nonheritable retinoblastoma lack a germline mutation and therefore do not have an increased risk of second cancers in general (Figure 37.6).

Cumultative Incidence (%)

40 36% 95% Cl, 30.9% to 41.1% 30

20

10

5.69 % 95% Cl, 2.4% to 11.1%

0 0

10 20 30 40 Time After Retinoblastoma Diagnosis (years)

50

Hereditary 963

760

615

401

147

30

Nonhereditary 638

570

500

317

134

46

No. of Patients at Risk

Figure 37.6 Cumulative incidence of second cancers in patients with heritable versus non-heritable retinoblastoma Source: Kleinerman RA, Tucker MA, Tarone RE et al (2005) Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 23:2272–2279. Used with permission

However, patients with heritable retinoblastoma have a germline mutation in the retinoblastoma tumor suppressor gene, and they have been observed to have a sevenfold relative risk of second cancers, independent of the use of radiation therapy. Moreover, when these patients are irradiated, their second cancer relative risk further increases by a factor of three, with the highest relative risks occurring from bone or connective tissues within the irradiated volume (Figure 37.7).

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David B. Mansur

Cumultative Incidence (%)

40 38.2% 95% Cl, 32.6% to 43.8%

Radiotherapy 30

20 No Radiotherapy

10

21.0% 95% Cl, 9.42% to 35.6%

0 0 Radiotherapy 849

10 20 30 40 Time After Retinoblastoma Diagnosis (years) 658

No Radiotherapy 114 102

50

529

339

112

19

86

62

35

11

No. of Patients at Risk

Figure 37.7 Cumulative incidence of second cancers in patients with heritable retinoblastoma treated with or without radiotherapy Source: Kleinerman RA, Tucker MA, Tarone RE et al (2005) Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 23:2272-2279. Used with permission. Efendiemus ingulla ribute, nontiquam in

38

Neuroblastoma Natia Esiashvili1

Key Points  Neuroblastoma is the most common extracranial solid tumor in children.  About 70% of patients present with metastatic disease, with bone marrow and skeleton being the most common sites of metastases.  Patients may present with symptoms associated with adrenal masses, skeletal metastatic sites, ocular and skin involvement, neurological signs from paraspinal masses, etc. Additionally, constitutional symptoms with weight loss, anorexia, and fever are common with advanced disease stages.  Workup should include physical examinations, laboratory testing like urine cathecholamine homovanillic acid (HVA) and vanillylmandelic acid (VMA), bone marrow biopsy, radiological studies with abdominal computed tomography (CT) with contrast, metaiodobenzylguanidine (MIBG) scans, and Tc-99-diphosphonate bone scintigraphy.  Neuroblastoma staging has evolved from a surgical pathology–based to an image-based system.  Patients are divided into low-, intermediate-, and high-risk groups, based on their disease stage, tumor biology (MYCN amplification status, Shimada histology, and DNA ploidy), and age.  Chemotherapy plays a key role in the treatment of neuroblastoma, and its intensity increases from a few cycles of combination of drugs in low-risk cases to high-dose chemotherapy with stem cell rescue for high-risk group.  Surgical goals are based on disease risk groups: low-risk patients will need less aggressive resection, while intermediate- and high-risk patients should undergo gross total resection, when feasible.  Patients with low-risk disease usually have excellent outcomes with minimal therapy; the intermediate-risk group benefits from chemotherapy coupled with surgical tumor removal. High-risk group patients generally experience poor outcomes despite very intense treatment regimens.

1

Nitia Esiashvili, MD() Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_21, © Springer-Verlag Berlin Heidelberg 2011

1054 Natia Esiashvili

Epidemiology and Etiology Neuroblastoma (NB) is the most common extracranial solid childhood tumors, accounting for approximately 600 cases each year in the US population and approximately 15% of cancer-related deaths. NB is slightly more prevalent in white children, with a male predominance. The median age of diagnosis for NB is about 22 months, and almost 90% of cases are diagnosed before the age of 5 years. It is rarely diagnosed in adolescents and adults, who display a more indolent clinical course but have display poor outcomes. The etiology of NB is not clearly understood; however, both familial genetic predisposition and environmental exposures have been postulated as potential causes (Table 38.1). Table 38.1 Risk factors of NB Type

Description

Patient related

Age: most commonly diagnosed in infancy Gender: slightly more common in boys Familial/hereditary: ~1–2% is familial, with autosomal dominant inheritance Genetic predisposition: neurocristopathy, NF1

Environmental

Viruse(s): limited, unconfirmed data Drug(s): limited, unconfirmed data Industrial chemical(s): limited, unconfirmed data

NF1: neurofibromatosis type 1

Anatomy NB can arise anywhere there is sympathetic nervous tissue. The most common primary tumor location in the pediatric group is the abdomen, in the nervous tissue above the adrenal glands (~65% of NB cases, with infants accounting for 25% of these, and older children the remaining 40%). Tumors can also present along the paraspinal sympathetic chain in the neck, chest, and pelvis.

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Routes of Spread Metastatic spread of NB can happen by both lymphatic and hematogenous routes. Bone marrow, bone, liver, lymph nodes, and skin are common sties of spread (Table 38.2). Metastases to other organs such as the brain and lungs are rare, but as a greater number of high-risk patients are being treated, relapses in such rare locations are more commonly observed. Table 38.2 Routes of spread Type

Description

Regional lymph node metastasis

 Lymph node involvement is found in ~35% of cases at time of diagnosis  Abdominal lymph nodes are the most commonly involved with adrenal primary tumors

Distant metastasis

 ~70% of patients, regardless of age, will present with metastatic disease  Hematogenous metastasis is the most common route of spread  Bone marrow is the most common site of distant disease spread

Pathology NG belong to a small, round, blue-celled tumor family, which typically stain with immunohistochemical techniques for neuronal markers like synaptophysin and neuron-specific enolase. Ganglioneuromas, ganglioneuroblastomas, and NB are members of the neuroblastic tumor group at various stages of differentiation. Histological classification of NB, developed by H. Shimada and colleagues, is based on degree of neuroblast differentiation, schwannian stroma content, mitosis–karyorrhexis index, and age at diagnosis (Shimada H, Chatten J, Newton WA Jr et al (1984) Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst 73:405–416). The International Neuroblastoma Pathology classification system – developed based on the Shimada classification system – separates favorable histology (FH) from unfavorable histology (UF).

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Diagnosis, Staging, and Prognosis Screening Screening studies demonstrated an increased rate of diagnosis of NB but did not translate into decreased mortality, particularly in patients with advanced stage disease, and were thus not adopted into clinical practice.

Clinical Presentation The majority of patients present with metastatic disease; older children present with cases more disseminated as compared with infants, who are frequently found with localized disease. The symptoms of NB reflect the location of the primary tumor site, and regional and metastatic disease (Table 38.3). Table 38.3 Commonly observed signs and symptoms of NB Type

Description

Constitutional

Anorexia, weight loss, fevers

Site specific

Abdominal: distension, pain, bowel obstruction Face–neck–chest: Horner syndrome with unilateral ptosis, myositis, and anhydrosis; Pancoast tumor (tumor in the apex of the lung) Paraspinal: compression of nerve roots and spinal cord Orbital: ptosis and periorbital ecchymosis Bone and bone marrow: pain, limping

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Diagnosis The diagnosis of NB is based on clinical, laboratory, and imaging findings (Figure 38.1).

Diagnosis of NB Suspected

Figure 38.1

Complete History and Physical Examination

Laboratory Workup CBC, metabolic profile, serum ferritin, LDH, neuron-specific enolase, urine catecholamine

Imaging Studies CT, abdominal US, bone scan, MIBG scan

All patients should undergo laboratory testing including urine cathecholamine homovanillic acid (HVA) and vanillylmandelic acid (VMA) levels. Elevated levels of the serum marker–like serum ferritin (>142 ng/ml), lactic dehydrogenase (>1,500 IU/l), and neuron-specific enolase (>100 ng/ml) at time of diagnosis are associated with worse clinical outcomes.

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Computed tomography images are important in detecting tumor masses in primary and metastatic sites. The metaiodobenzylguanidine (MIBG) scintigraphy scan is a highly sensitive tool for initial tumor staging as well as assessment of treatment response and disease surveillance (Figure 38.2). Figure 38.2 A metaiodobenzylguanidine (MIBG) scintigraphy scan of a child with multiple skeletal metastases

Staging The International Neuroblastoma Staging System (INSS) is based on disease surgical pathology (Table 38.4); subsequently, the International Neuroblastoma Risk Group (INRG) panel of worldwide experts updated the staging system and developed a new INRG classification system, using pretreatment imaging for risk stratification (Tables 38.5 and 38.6).

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Table 38.4 International Neuroblastoma Staging System (INSS) Stage

Description

1

Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to, and removed with, the primary tumor may be positive)a

2

Localized tumor with incomplete gross resection; representative ipsilateral non-adherent lymph nodes negative for tumor microscopically

2A

Localized tumor with or without complete gross excision, with ipsilateral non-adherent lymph nodes positive for tumor; enlarged contralateral lymph nodes must be negative microscopically

3

Unresectable unilateral tumor infiltrating across the midline,b with or without regional lymph node involvement, or localized unilateral tumor with contralateral regional lymph node involvement, or midline tumor with bilateral extension by infiltration (unresectable), or by lymph node involvement

4

Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S)

4S

Localized primary tumor (as defined for stage 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrowc (limited to infants <1 year of age)

a

Multifocal primary tumors (e.g., bilateral adrenal primary tumors) should be staged according to the greatest extent of disease, as defined above, and succeeded by a subscript “M” (e.g., 3M) b The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to, or beyond, the opposite side of the vertebral column c Marrow involvement in stage 4S should be minimal, i.e., less than 10% of total nucleated cells identified as malignant on bone marrow biopsy or marrow aspirate. More extensive marrow involvement would be considered stage 4. The MIBG scan (if performed) should be negative in the marrow Source: Brodeur GM, Pritchard J, Berthold F et al (1993) Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466–1477

1060 Natia Esiashvili Table 38.5 Image-defined risk factors(IDRFs) Type

Description Neck  Tumor encasing carotid and/or vertebral artery and/or internal jugular vein  Tumor extending to the base of the skull  Tumor compressing the trachea Cervicothoracic junction  Tumor encasing brachial plexus roots  Tumor encasing subclavian vessels and/or vertebral and/or carotid artery  Tumor compressing the trachea

Ipsilateral tumor extension within 2 body compartments Neck–chest, chest–abdomen, abdomen–pelvis

Thorax  Tumor encasing the aorta and/or major branches  Tumor compressing the trachea and/or principal bronchi  Lower mediastinal tumor, infiltrating the costovertebral junction between T9 and T12  Thoraco-abdominal  Tumor encasing the aorta and/or vena cava Abdomen–pelvis  Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament  Tumor encasing branches of the superior mesenteric artery at the mesenteric root  Tumor encasing the origin of the celiac axis, and/or the superior mesenteric artery  Tumor invading one or both renal pedicles  Tumor encasing the aorta and/or vena cava  Tumor encasing the iliac vessels  Pelvic tumor crossing the sciatic notch

Intraspinal tumor extension whatever the location provided

More than a third of the spinal canal in the axial plane is invaded and/or the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal

Chapter 38 Neuroblastoma

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Table 38.5 (continued) Type

Description

Infiltration of adjacent organs/ structure

Pericardium, diaphragm, kidney, liver, duodenopancreatic block, and mesentery

Conditions to be recorded, but not a IDRFs

 Multifocal primary tumors  Pleural effusion, with or without malignant cells  Ascites, with or without malignant cells

Source: Monclair T, Brodeur GM, Ambros PF et al (2009) The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27:298–303

Table 38.6 International Neuroblastoma Risk Group (INRG) staging system Stage

Description

L1

Localized tumor not involving vital structures as defined by the list of IDRFs and confined to 1 body compartment

L2

Locoregional tumor with presence of 1 or more IDRFs

M

Distant metastatic disease (except stage MS)

MS

Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow

Source: Monclair T, Brodeur GM, Ambros PF et al (2009) The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27:298–303

Prognosis and Risk Stratification Prognostic factors affecting the outcome of patients diagnosed with NB are age, postsurgical staging, MYCN amplification, Shimada histology, and DNA ploidy. The MYCN oncogene is located on locus 2p24 and can be amplified in a subset of NB cases. It is strongly associated with unfavorable histology, with advanced stage disease, aggressive behavior, and high risk of relapse.

Any, except GN maturing or GNB intermixed

Any, except GN maturing or GNB intermixed

GBN nodular, NB

<18

≥18

L1

L2

Histologic category

GN maturing; GNB intermixed

Age (months)

L1/L2

INGR staging

Table 38.7 INRG Classification System

NA

Poorly differentiated or undifferentiated

Amp

NA

NA

H Intermediate

Yes

N High

E Low

G Intermediate

Yes No

D Low

No

K High

A Very Low

Treatment risk group

Amp

Ploidy

B Very Low

11q Aberration

NA

MYCN status

Differentiated

Grade of tumor differentiation

1062 Natia Esiashvili

Amp

<18

Amp

Source: Cohn SL, Pearson AD, London WB et al (2009) The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27:289–297

R High

Q High

Yes

P High

O High

J Intermediate

I Intermediate

F Low

Treatment risk group

C Very Low

Diploid

Diploid

Hyperdiploid

Ploidy

No

11q Aberration

GN: ganglioneuroma, GNB: ganglioneuroblastoma, NA: non-amplified, Amp: amplified

<18

NA

NA

12 to <18

MS

NA

<12

≥18

NA

MYCN status

<18

Grade of tumor differentiation

M

Histologic category

Age (months)

INGR staging

Table 38.7 (continued)

Chapter 38 Neuroblastoma

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1064 Natia Esiashvili

The INRG classification system is widely adopted in studies conducted worldwide. The risk classification scheme uses age, staging, MYCN amplification, Shimada histology, and DNA ploidy for assigning patients to low-, intermediate-, and high-risk groups in determining both prognosis and various treatment strategies (Table 38.7).

Treatment Principle and Practice The use of surgery, chemotherapy, and radiation therapy in the management of NB is presented in Table 38.8. Treatment of individual cases is determined by manifestation of disease (i.e., risk groups).

Table 38.8 Treatment modalities Type

Description

Surgery

Indications

 Limited role in infants with favorable biology tumors and in other low-risk group patients who have chances of spontaneous disease regression  High-risk disease should have safe maximal tumor resection for achieving adequate control of the primary tumor site

Facts/issues

 Special considerations are needed for patients with intraspinal tumors where initial aggressive surgical resection or radiotherapy will cause inferior functional outcome, especially that of late effects in young children  Patients generally respond favorably to upfront chemotherapy, with resolution of neurological symptoms, seen in most children

Radiation therapy

Indications

 No longer used for patients with low- and intermediate-risk disease, since tumor local control is excellent  Plays important role in multidisciplinary treatment of patients with high-risk disease

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Table 38.8 (continued) Type

Description

Techniques

 Techniques are site specific  Treatment goal is to achieve conformal dose coverage of clinical target volume (CTV), with sparing of nearby critical structures  For abdomen and majority of metastatic sites in skeleton, conventional opposing fields are usually feasible (Figure 38.2)  In cases where normal tissue constrains are difficult to meet, more conformal methods, such as intensity-modulated radiation therapy (IMRT), should be considered

Chemotherapy Indications

 Because of the systemic nature of disease spread, chemotherapy is the backbone of NB management  Response to standard cytotoxic drugs has prognostic significance, and patients with resistance disease are offered novel therapeutic agents on clinical trials

Medication

 Varies from few cycle of combination of drugs like carboplatin, etoposide, cyclophosphamide, and doxorubicin to intense, high-dose regimens as determined by disease risk category

The Low-Risk Group The low-risk group (Table 38.7) includes patients of any age with:  INSS stage 1 disease  Any MYCN  Any histology  Any DNA ploidy status  INSS stage 2 with >50% tumor resection  18 months of age with MYCN not-amplified (MYCN-NA)  Any histology  Any DNA ploidy status  Infants with stage 4S disease asymptomatic  (DI>1)  Favorable histology  MYCN-NA Figures 38.3 and 38.4 illustrate proposed treatment algorithms for patients with very low-risk and low-risk group disease.

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The Intermediate-Risk Group

Perinatally diagnosed NB (0–6 month)

Observation with abdominal sonograms, CT/MRI Urine VMA/HVA

Stable mass and catecholamines normalized

Mass is stable, but catecholamines remain elevated

Continue to observe

Proceed to surgical resection

Figure 38.3 A proposed treatment algorithm for very low-risk neuroblastoma

Stages 2A and 2B

>50 % resection

Stage 4S asymptomatic UF and/or DI>1

Observation

Observation

Low-Risk NB Stage 3 <18 months MYCN-NA

Stage 4 <1 year old MYCN-NA

Figure 38.4 A proposed treatment algorithm for low-risk neuroblastoma

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The intermediate-risk group (Table 38.7) includes the following:  INSS Stage 2 with MYCN-amp Stage 3  Any age with NMYC-amp, any histology  Stage 4  12 months old  Age >18 months with MYCN-NA, UH  Stage 4  12 to <18 months  MYCN-NA regardless of histology  FH  DI >1  Infants with stage 4S  MYCN-amp  Any ploidy, any unfavorable histology or presenting with symptomatic disease Figure 38.5 shows a proposed treatment algorithm for intermediate-risk group patients.

Biopsy only

Chemotherapy

< 50 % resection

Chemotherapy

Stages 2A and 2B

IntermediateRisk NB

Stage 4S UF and/or DI = 1

Chemotherapy

Stage 3 <18 months MYCN-NA

Chemotherapy

Stage 4 <12 month MYCN-NA, DI >1

Chemotherapy

Figure 38.5 A proposed treatment algorithm for intermediate-risk neuroblastoma

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The High-Risk Group The high-risk group (Table 38.7) includes the following:  INSS stage 2  MYCN-Amp  Stage 3  Any age with MYCN-Amp  >18 months of age with MYCN-NA and UH  Stage 4  MYCN-Amp  DI = 1 and/or UH  Infants with stage 4S  MYCN-Amp Figure 38.6 presents a suggested treatment algorithm for high-risk group patients.

Radiation Therapy The primary tumor site runs the main risk of relapse even after aggressive chemotherapy. Surgery and maximizing local control can favorably affect overall outcome for high-risk patients; thus, radiation continues to play an important role (Source: Haas-Kogan DA, Swift PS, Selch M, et al (2003) Impact of radiotherapy for high-risk neuroblastoma: a Children’s Cancer Group study. Int J Radiat Oncol Biol Phys 56:28–39; Bradfield SM, Douglas JG, Hawkins DS et al (2004) Fractionated low-dose radiotherapy after myeloablative stem cell transplantation for local control in patients with high-risk neuroblastoma. Cancer 100:1268–1275).

Stage 4S <1 year old MYCN-Amp

Stage 4 >18 months

Stage 4 12-18 month MYCN-Amp or DI >1 or UH

Induction Chemotherapy

Induction failure

Good response

Figure 38.6 A proposed treatment algorithm for intermediate-risk neuroblastoma

High-Risk NB

Stage 4 <1 year old MYCN-Amp

Stage 3 >18 months MYCN-NA UH

Stages 3 MYCN-Amp

Stages 2A and 2B MYCN-Amp

Experimental therapies

Maximal surgical resection of primary tumor

Consolidation with radiation therapy to primary and selected metatstatic sites

Meintenance with13-cisretionicacid and anti-DG2 antibody

Chapter 38 Neuroblastoma

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1070 Natia Esiashvili

Radiotherapy dose data was first derived from a study incorporating local tumor boost after total body irradiation (TBI) conditioning for bone marrow transplantation (BMT). For high-risk patients, an effective dose was found to be around 20–24 Gy. The dose to the primary tumor site was applied to subsequent high-risk protocols for local tumor control. However, later analysis revealed inferior outcomes in treated patients with gross residual disease. Radiotherapy dose escalation to 36 Gy is being tested in an ongoing cooperative group study. Additionally, persistent metastatic sites failing to respond to the initial chemotherapy phase and detectable on MIBG scan are now selected as radiotherapy targets during consolidation, and they are treated along with primary site to a dose 20–24 Gy (Figure 38.7).

Figure 38.7 The clinical target volume is outlined in red, encompassing post-induction chemotherapy adrenal tumor volume and adjacent involved para-aortic lymph nodes, and treated with anterior–posterior oppositional beams

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Treatment of Spinal Cord Compression Approximately 10% of patients present with paraspinal tumors that extend through vertebral foramina, with or without associated spinal cord compression (Figure 38.8). Prompt resolution of spinal cord compression should prevent the development of permanent neurologic damage in these children (Source: Katzenstein HM, Kent PM, London WB et al (2001) Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19:1047–1455).

Figure 38.8 A patient with an epidural tumor in the posterior spinal canal who presented with symptoms of spinal cord compression

The optimal treatment approach for cord decompression remains unknown; however, current therapeutic strategy is to relieve spinal cord compression with chemotherapy to avoid surgical interventions with laminectomy and radiation therapy, and to spare children from long-term toxicity. Laminectomy and/or radiation treatment are reserved for patients who progress with initial chemotherapy.

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Follow-Up Disease Surveillance The type of surveillance and frequency of NB is determined by disease risk group and delivered treatment intensity (Table 38.9). Low-risk disease diagnosed in infancy with minimal or no interventions can undergo spontaneous maturation and regression, and disease recurrence can usually be successfully salvaged.

Late Effects Children treated for NB are prone to late effects; however, the data are limited. One of the main goals for risk-adapted therapies is to decrease treatment intensity for children with less aggressive disease to decrease their risk of morbidity and mortality, and to reduce chance of long-term toxicities. Table 38.9 Recommendations for follow-up Risk group

Recommendations

Low; diagnosed in infancy; minimal or no interventions

 Active surveillance and monitoring required  Urine VMA and HVA are the sensitive for detecting recurrence  CT of abdomen and sonograms are preferred diagnostic modalities

High

 Continuous posttreatment monitoring required  Routine catecholamines and MIBG scan are highly acurate in assement of disease status

39

Ewing Sarcoma Daniel Indelicato1 and Robert B. Marcus Jr.2

Key Points  Ewing sarcoma family of tumors (ESFT) represents a diverse group of small, round, blue-cell tumors, which occur most frequently in the lower extremities.  The prognosis is dependent on primar y site, tumor volume, extent of disease, and location of metastases.  All patients require multiagent chemotherapy. Depending on tumor characteristics, local control may be obtained through surgery, radiotherapy, or a combination of the two.  Radiotherapy is typically started after 12 weeks of chemotherapy in patients with nonmetastatic disease. Radiation treatment volumes are determined both by pre- and post-induction chemotherapy tumor extent.  Careful radiotherapy planning is necessary to decrease the long-term visceral and musculoskeletal toxicit y in this pediatric and young-adult disease.

Epidemiology and Etiology The Ewing sarcoma family of tumors (ESFT) includes classic Ewing tumors of the bone and extraosseous Ewing sarcomas. The overall incidence of these tumors is approximately 1 per 1,000,000 in the U.S. population. The vast majority of patients are white adolescents. The etiology of ESFT is unclear. No definite patient or environmental factors have been identified.

Anatomy Ewing tumors can occur anywhere in the body, and they may be characterized by tumors with both an intraosseous component and extraosseous component (Figure 39.1a). Tumors in the thorax or abdomen may grow quite large and exhibit a “pushing margin” into body cavities. After good tumor response to chemotherapy, normal tissues within the cavity may return to their natural position (Figure 39.1b). 1

Daniel Indelicato, MD() Email: [email protected]

2

Robert B. Marcus Jr., MD. Email: [email protected]

J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_22, © Springer-Verlag Berlin Heidelberg 2011

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Daniel Indelicato and Robert B. Marcus Jr.

b

a

Figure 39.1 a, b a Ewing sarcoma of the femur with extraosseous soft tissue extension as indicated by arrows. b Ewing sarcoma of the posterior chest wall prior to chemotherapy demonstrating an intrathoracic “pushing margin”

Pathology and Cytogenetics Ewing tumors are small, round, blue-cell tumors arising from mesenchymal stem cells. Ninety-five percent have a translocation between the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11 (t[11:22][q24:q12]) or the ERG gene on chromosome 21 (t[21:22][q22:q12]). The translocations are present only in tumor cells and occur in bone and soft tissue Ewing tumors, primitive neuroectodermal tumors of bone and soft tissue, peripheral primitive neuroectodermal tumors (PNETs), Askin tumors, some esthesioneuroblastomas in children, and some central nervous system (CNS) tumors. The proto-oncogene c-myc is expressed in ESFT.

Routes of Spread Ewing tumors spread by direct extension from the primary lesion into the adjacent bone or soft tissue. Metastases generally spread through the blood stream, with the most common sites being the lung and nonadjacent bones, and approximately 25% are metastatic at diagnosis.

Chapter 39 Ewing Sarcoma

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Lymph node metastases are not common, except in peripheral PNETs, where they sometimes occur. Organ involvement, such as brain or liver, is rare and usually occurs only in end-stage disease.

Diagnosis, Staging, and Prognosis Ewing tumors arise most frequently in the lower extremity. The most common symptoms are pain and swelling in the primary site, whether it is bone or soft tissue. The symptoms often wax and wane, sometimes leading to a long delay in diagnosis. Ewing tumors have been shown to have the longest lag time in diagnosis for any pediatric solid tumor (mean of 146 days). Occasionally, a patient may present with systemic symptoms such as low-grade fever, malaise, or weakness, due to widespread metastases. There is no standard accepted staging system for the ESFT. Figure 39.2 presents a proposed algorithm for the diagnosis and staging of Ewing tumors.

Ewing or Other Bone Tumor Suspected

Complete History and Physical Examination

Imaging - CT + MRI of primary site - Chest X-ray - CT of chest - Bone scan - Consider PET scan

Pathology - Incisional biopsy or Complete resection - Cytogenetics on tissue material

Lab and other tests - Complete blood count (CBC) - Serum chemistry - Fertility consult

Figure 39.2 An algorithm for diagnosis and staging of Ewing tumor

Prognosis of Ewing Sarcoma of the Bone The prognosis of these tumors depends on the size and location of the primary tumor and whether there are metastases present at diagnosis:

1076 Daniel Indelicato and Robert B. Marcus Jr.

 Primary site: extremity primaries (particularly distal extremity) versus axial lesions (unfavorable).  Volume of tumor: small primary versus larger lesion (unfavorable). Both a maximum tumor size of approximately 8 cm has been used, as well as a volume cutoff of 200 cm3, per the European Intergroup Cooperative Ewing’s Sarcoma Study (EICESS) group.  Extent of disease: localized disease versus metastatic disease (unfavorable).  Site of metastasis: lung metastases versus bone/bone marrow (unfavorable) versus both bone and lung metastases (worst).  These prognostic factors are probably related, since axial lesions are usually larger than extremity lesions, particularly those in distal extremity bones. It is important to realize that most of the data for ESFT is based primarily on the prognosis of bone primary lesions (Table 39.1).

Table 39.1 Prognosis of ESFT Extent of disease

5-year survival (%)

Localized disease  Extremities  Axial

55% 58% 47%

Metastases at diagnosis  Lung metastases only  Bone metastases only  Bone and lung metastases

21% 29 (40% receiving whole-lung radiation) 19% 8%

Source: Cotterill SJ, Ahrens S, Paulussen M et al (2000) Prognostic factors in Ewing’s tumor of bone: analysis of 95 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 18:3108–3114

Treatment Table 39.2 outlines treatment modalities and Table 39.3 outlines trials and their results. Figure 39.3 presents a treatment schema.

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Table 39.2 Treatment by tumor resectability Surgical status

Example

Treatment

Unresectable lesions

Maxilla, base of skull, vertebral bodies

Radiotherapy alone

Lesions in expendable bones

Scapula, rib, clavicle, fi bula, ilium

Surgery with wide margins

Long bones, mandible

Can be treated with surgery alone and reconstruction; can also be treated with radiotherapy alone. Lesions with positive (and expected positive) or close margins should receive pre- or postoperative radiation

Borderline lesions

Table 39.3 Important trials in EFST Trial

Results

IESS-1 (1973–1978)a

 Randomized trial evaluating the addition of doxorubicin to the standard regimen at that time of vincristine, cyclophosphamide, and dactinomycin (VAC)  5-year survival was best in the VAC plus doxorubicin (VACA) arm at 65% versus 28% in the VAC arm  A third arm consisted of VAC plus whole-lung irradiation (WLI), which was better than VAC at 53%, but inferior to VACA  Doxorubicin has been the most important drug in Ewing sarcoma and ESFT since the results of this trial

POG 8346 (1983– 1988, U.S.)b

 Randomized trial evaluating the volume of the initial RT field  Conventional RT at that time was to treat the entire bone to about 39.6 Gy, then boost the gross tumor, with a 2-cm margin, to 55.8 Gy  The experimental arm (tailored field) consisted of treating what amounted to the boost field in the standard arm to 55.8 Gy  The LC and OS were equivalent. Since the results of this trial, a tailored field has been the standard of care for Ewing tumor, though the fields have evolved somewhat

1078 Daniel Indelicato and Robert B. Marcus Jr. Table 39.3 (continued) Trial

Results

CESS-86 (1986– 1991, Germany)c

 Studied intensifying chemotherapy for patients with large (>100 ml) primar y lesions and in smaller lesions. It also evaluated the choice of local therapy, though the local therapy was left to the choice of the institution  Intensifying chemotherapy for large lesions improved OS for patients with large primar y lesions  The LC was slightly better in the patients who received surgery alone for their local treatment, in contrast to those who received radiation alone or surgery plus radiation therapy. OS was equivalent, however

INT-0091 (1988– 1992, U.S.)d

 Randomized trial studying the addition of ifosphamide/ etoposide (IE) to the standard VACA regimen of that time  Survival in the VACA–IE arm was 69%, as compared with 54% for localized disease. There was no advantage for patients with metastatic disease  The major advantage in survival was for large axial lesions. Small primar y lesions fared similarly with the standard VACA regimen  The LC and OS in the pelvic lesions were equivalent for surgery alone, RT alone, and for surgery plus RT

LC: local control; OS: overall survival; RT: radiation therapy a

Source: Nesbit ME Jr, Gehan EA, Burgert EO Jr et al (1990) Multimodal therapy for the management of primary nonmetastatic Ewing’s sarcoma of bone: a long-term follow-up of the First Intergroup Study. J Clin Oncol 8:1664–1674 b Source: Donaldson SS, Torrey M, Link MP et al (1998) A multidisciplinary study investigating radiotherapy in Ewing’s Sarcoma: end results of POG #8346. Int J Radiat Oncol Biol Phys 42:125–135 c Source: Paulussen M, Ahrens S, Dunst W et al (2001) Localized Ewing tumor of bone: final results of the Cooperative Ewing’s Sarcoma Study (CESS) 86. J Clin Oncol 19:1818–1829 d Sources: Grier HE, Krailo MD, Tarbell NJ et al (2003) Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Eng J Med 348:694–701; Yock TI, Krailo M, Fryer CJ et al (2006) Local control in pelvic Ewing sarcoma: analysis from INT-0091 – a report from the Children’s Oncology Group. J Clin Oncol 24:3838–3843

Chapter 39 Ewing Sarcoma PRIMARY TREATMENT

Work-ups

Multiagent chemotherapy (category 1) for at least 6-24* weeks prior to local therapy

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RESTAGE For patients with localized disease Restage with: - Chest imaging - Local imaging - Consider PET scan or bone scan

For patients with metastatic disease ** Restage with: - Chest imaging - Local imaging - Consider PET scan or bone scan - Repeat other abnormal studies

Good Response (CR or PR) Proceed with local therapy, either RT or surgery; then continue present regimen *

Poor Response (NR or Progressive Disease) Extremely poor prognosis; proceed with local therapy but probably should switch chemotherapy regimen

* Most protocols now give 12 or more weeks of induction chemotherapy; however, some data indicate that the shorter the length of time before radiation therapy begins, the better the local control and survival. (Source: Dunst J, Schuck A. Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 2004; 42:465–470) # Patients who have less than a partial recovery to induction chemotherapy (50% shrinkage in the volume of soft tissue mass or poor histologic response at surgery) usually die. ** For patients with many metastic lesions, it may be preferable to wait until the end of chemotherapy to proceed with radiation therapy to the metastatic lesions, which may include lung irradiation if indicated.

Figure 39.3 Ewing tumor treatment schema (modified from NCCN guidelines)

1080 Daniel Indelicato and Robert B. Marcus Jr.

Radiation Therapy Techniques Imaging for Planning/Simulation A patient may be treated in the supine, prone, or lateral position. Volumetric computed tomography (CT)-based planning is necessary to optimize dose to the target volume while protecting normal tissues. Magnetic resonance imaging (MRI) fusion is recommended. If MRI is utilized, axial T1-gadolinium and T2-weighted sequences should cover the entire area of tumor (intra- and extraosseous) and the entire involved bone. Timing of Radiation Local control is typically undertaken at week 13 from the start of chemotherapy. The sequencing of radiation relative to surgery is variable (Tables 39.4 and 39.5). Table 39.4 Sequencing of RT Sequence

Pro(s)

Cons

Preoperative RT

 Lowest dose  Smaller fi eld size  May decrease tumor seeding at surgery

 Risk of overtreatment  Increased postoperative infection rate  Impaired bony union

Postoperative RT

 Allows pathologic  response and margin status to inform RT recommendations

 Intermediate dose  Larger field size  May be associated with inferior late functional outcome

Definitive RT

 Historical standard  Option for large, unresectable tumors  Less delays in chemotherapy

 Highest dose  May be associated with inferior local control, as compared with combined modality treatment

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Table 39.5 Target volumes Target volume

Defi nition

Margin

Definitive and preoperative radiation

Visible gross tumor consisting of prechemotherapy bone and soft tissue

NA

Postoperative radiation

Surgical tumor bed consisting of the margin of bone initially involved with tumor, the soft tissue tumor bed, and soft tissue contiguous with the tumor prior to surgical resection

NA

Definitive and preoperative radiation

Visible gross tumor consisting of (1) bone initially involved with tumor (prechemotherapy), and (2) residual soft-tissue tumor prior to radiotherapy (postchemotherapy), including the surfaces of normal tissues in contact with tumor, now returned to normal anatomic position (Figure 39.5)

NA

Standard-risk CTV

GTV1 plus a 2-cm anatomic margin of tissue, respecting anatomic barriers that limit tumor spread. Scar, drain site, and contaminated surgical sites should also be included

High-risk CTV

GTV2 plus a 1.5-cm anatomic margin of tissue, respecting anatomic barriers that limit tumor spread

Planning target volumes

CTV1/CTV2 plus an institutional specifi ed margin to account for day-today setup variation related to the ability to immobilize the patient and physiologic motion of the CTV1 /CTV2

GTV1

GTV2

CTV1

CTV2

PTV1/PTV2

NA: not applicable, GTV: gross tumor volume, CTV: clinical target volume, PTV: planning target volume

1082 Daniel Indelicato and Robert B. Marcus Jr.

Special Sites Vertebral Body Lesions Gross tumor volume (GTV)1 and GTV2 are defined as outlined in Table 39.5 and presented in Figure 39.4. At a minimum, clinical target volume (CTV)1 is defined as the entire vertebral body. For the field-reduction boost, CTV2 is defined as GTV2 plus an additional 1.5-cm margin to account for subclinical areas of residual disease but confined by anatomic boundaries (e.g., CTV2 does not enter the spinal canal if initial disease did not enter the canal). Figure 39.4 Schematic depiction of GTV1 (preinduction bone and preinduction soft tissue extent) and GTV2 (preinduction and postinduction soft tissue extent)

Prechemotherapy tumor

Postchemotherapy tumor

Tumors Within a Body Cavity (Abdominal, Pelvic, or Chest Wall) Regardless of GTV, CTV1 and CTV2 will be limited by the “pushing margin” of the tumor within the peritoneal or thoracic cavity where infiltration by microscopic disease is not suspected (Figure 39.5).

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Figure 39.5 Ewing sarcoma of the pelvis extending into the pelvic cavity. Note that CTV1 and CTV2 would both be defined by the postinduction disease extent along the peritoneal surface of the tumor

Radiation Dose Table 39.6 addresses various radiation doses, and Figure 39.6 illustrates a case of exceptional dose conformality.

Table 39.6 Recommended radiation doses Tumor site and presentation

PTV1 (Gy)

PTV2 (Gy)

Definitive RT or residual gross disease after incomplete resection

45

≤8 cm: 10.8

Definitive RT for vertebral body where spinal cord will receive the prescription dose (i.e., spinal cord cannot be avoided)

45

5.4

Definitive RT – unresected, involved lymph nodes

45

10.8

Preoperative RT

45

5.4

Postoperative RT – inadequate margins – microscopic residual

50.4–55.8

NA

>8 cm: 16.2

Doses above at 1.8 Gy per fraction daily using external beam radiotherapy Some practitioners advocate hyperfractionation at 1.2 Gy per fraction twice daily or lower doses (36–40 Gy) to PTV1 to decrease late effects Source: Indelicato DJ, Keole SR, Shahlaee AH et al (2008) Definitive radiotherapy for Ewing tumors of extremities and pelvis: long-term disease control, limb function, and treatment toxicity. Int J Radiat Oncol Biol Phys 72:871–877

1084 Daniel Indelicato and Robert B. Marcus Jr.

Figure 39.6 Three-year-old female with vertebral Ewing sarcoma with paraspinal soft tissue extension. The proton therapy plan is on the left and the IMRT plan is on the right. Note the reduction in low-intermediate cardiac, thyroid, pulmonary, and breast dose with the proton therapy plan. Table 39.7 Comparison of radiation therapy modalities 2-D and 3-D CRT (photon)

Brachytherapy

IMRT (photon)

Proton therapy

Historical standard in Ewing sarcoma

Excellent dose conformality

Improved highisodose conformality relative to 2-D and 3-D conformal therapy

Excellent dose conformality (Figure 39.6)

Technique utilized in the vast majority of randomized trials to date

Efficient and convenient

Heterogeneous dose distribution

Limited availability

Relatively homogeneous dose distribution

Risk of heterogeneous dose distribution

High integral body dose

Dose conformality often suboptimal for tumors near critical tissue

Limited to certain subsites and resectable tumors

Poor low-isodose conformality

CRT: conformal radiation therapy; IMRT: intensity- modulated radiation therapy

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Radiation Modality Table 39.7 compares different radiation therapy modalities.

Normal Tissue Tolerance Guidelines The childhood and pubescent skeleton (periods of active bone growth) is particularly sensitive to radiation effects. The following inline table presents the epiphyseal contributions to bone growth (Table 39.8). Table 39.9 details toxicities and recommendations for radiation therapy.

Table 39.8 Epiphyseal contributions to bone growth Proportional contribution to overall bone growth (%) Long bone Proximal epiphysis

Distal epiphysis

Femur

30%

70%

Tibia

60%

40%

Humerus

80%

20%

Table 39.9 Toxicities and recommendations for radiation therapy Toxicity

Recommendations

Long bone fracturea

Bone V40 < 64% Bone mean dose < 37 Gy 1-ml Dmax < 59 Gy

Flat-bone hypoplasiab

Minimize V35

Slippage of an upper femoral or humeral epiphysisc

Minimize epiphyseal V25

Muscular hypoplasia

Minimize compartmental V20

Scoliosis

“All or none” irradiation of vertebral body

Lymphedema

Keep dose to longitudinal 2- to 3-cm strip of extremity <15 Gy

Radiation-induced sarcomad Long-bone growth

e

Minimize normal tissue V60 Minimize growth plate V2f*

▶

1086 Daniel Indelicato and Robert B. Marcus Jr. Table 39.9 (continued) Vn: volume receiving nGy, Dmax maximum dose * The severity of this effect is dependent on the radiation dose, the patient’s age at irradiation, and the epiphysis irradiated. The skeleton is particularly sensitive to radiation effects during the periods of most active bone growth in early childhood and during puberty a Source: Dickie CI, Parent AL, Griffin AM et al (2009) Bone fractures following external beam radiotherapy and limb-preservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume, tumor location and dose. Int J Radiat Oncol Biol Phys 75:1119–1124 b Source: Krasin MJ, Xiong X, Wu S et al (2005) The effects of external beam irradiation on the growth of flat bones in children: modeling a dose–volume effect. Int J Radiat Oncol Biol Phys 62:1458–1463 c Source: Silverman CL, Thomas PR, McAlister WH et al (1981) Slipped femoral capital epiphyses in irradiated children: dose, volume and age relationships. Int J Radiat Oncol Biol Phys 7:1357–1363 d Source: Kuttesch JF Jr, Wexler LH, Marcus RB et al (1996) Second malignancies after Ewing’s sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 14:2818–2825 e Sources: Irwin CJ, Thomson E, Plowman PN (1993) Case report: paediatric radiotherapy—the avoidance of late radiation damage to the growing hip. Br J Radiol 66:369–374; Riseborough EJ, Grabias SL, Burton RI et al (1976) Skeletal alterations following irradiation for Wilms’ tumor: with particular reference to scoliosis and kyphosis. J Bone Joint Surg Am 58:526–536; Neuhauser EB, Wittenborg MH, Berman CZ et al (1952) Irradiation effects of roentgen therapy on the growing spine. Radiology 59:637–650

Follow-Up of Radiation Therapy Table 39.10 outlines recommendations for follow-up of radiation therapy. Table 39.10 Recommendations for follow-up Recommended baseline imaging after local control Site

Anatomic imaging

Functional imaging

Timing

Primary

AP and lateral radiographs

Within 2 weeks of surgery

Primary

MRI with gadolinium or CT with IV contrast (in patients without significant metallic artifact at primary tumor site)

3–4 months after local control

▶

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Table 39.10 (continued) Type

Description

Surveillance on chemotherapy and end-of-therapy evaluations Primary

AP and lateral radiographs

After 10 cycles of chemotherapy (~ 50% of way through)

Thorax

CT

After 10 cycles of chemotherapy (~ 50% way through)

Whole body

Whole body

MDP bone scintigraphy

At the end of cytotoxic chemotherapy (unless bone scintigraphy negative and FDGPET positive at presentation)

FDG-PET

At end of cytotoxic chemotherapy (unless bone scintigraphy positive and FDGPET negative at presentation)

Primary

MRI with gadolinium, or CT scan with IV contrast

If symptoms or abnormal imaging (and surgical intervention or radiation therapy contemplated)

Primary

AP and lateral radiographs

After 10 cycles of chemotherapy (~ 50% of way through)

Thorax

CT

After 10 cycles of chemotherapy (~ 50% of way through)

1088 Daniel Indelicato and Robert B. Marcus Jr. Table 39.10 (continued) Recommended postchemotherapy surveillance

Primary and chest

AP and lateral radiographs

Every 3 months ×8, then every 6 months ×6, then every 12 months ×5

Primary

MRI with gadolinium, or CT scan with IV contrast

If symptoms or abnormal imaging (and surgical intervention or radiation therapy contemplated)

Thorax

CT

If chest radiographs are abnormal

Whole body

Whole body

Primary and chest

AP and lateral radiographs

MDP bone scintigraphy

If symptoms or abnormal imaging (and primary tumor positive on prior bone scintigraphy and surgical or other intervention contemplated)

FDG-PET

If symptoms or abnormal imaging (and primary tumor positive on prior FDGPET and surgical or other intervention contemplated) Every 3 months ×8, then every 6 months ×6, then every 12 months ×5

AP: anteroposterior, IV: intravenous, FDG-PET: fluorodeoxyglucose–positronemission tomography, MDP: methyl diphosphate Source: Meyer JS, Nadel HR, Marina N et al (2008) Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 51:163–170

40

Wilms’ Tumor and Other Childhood Renal Tumors Arnold C. Paulino1

Key Points  Wilms’ tumor is the most common abdominal tumor of childhood.  Currently, approximately 90% of children with Wilms’ tumor are cured of disease.  Wilms’ tumor may be associated with congenital anomalies such as aniridia, hemihypertrophy, and genitourinary abnormalities.  Favorable histology Wilms’ tumor accounts for >90% of cases. Anaplastic Wilms’ tumors are divided into focal or diffuse.  Clear cell sarcoma and rhabdoid tumors are unfavorable types of renal neoplasms in children and have a propensity for bone and brain metastasis.  The standard treatment approach for Wilms’ tumor in North America is nephrectomy, followed by chemotherapy with and without radiotherapy  Children with stage III favorable histology Wilms’ tumor receive postoperative radiotherapy. The current recommended dose is 10.8 Gy in six fractions to the abdominal field.  Whole-abdominal radiotherapy is given to patients with preoperative rupture, peritoneal seeding, and diffuse spill of tumor during nephrectomy.  Patients requiring whole-lung radiation receive 12 Gy in 8 fractions to the lungs bilaterally for pulmonary metastasis.

1

Arnold C. Paulino, MD Email: [email protected] J. J. Lu, L. W. Brady (Eds.), Decision Making in Radiation Oncology DOI: 10.1007/978-3-642-16333-3_23, © Springer-Verlag Berlin Heidelberg 2011

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Epidemiology and Etiology Wilms’ tumor, or nephroblastoma, is the most common abdominal tumor of childhood and accounts for 5–6% of all childhood cancers. An estimated 450–500 new cases will be diagnosed in the USA annually. While the age standardized rates are 6–9 cases per million person years in Caucasian populations, the corresponding rates are less in East Asian (3–4 cases per million person years), and more in black (>10 cases per million person years) populations. Wilms’ tumor occurs equally in both boys and girls in most populations, but it is more common in girls than in boys in some parts of Asia. Paternal occupational exposure to hydrocarbon and lead exposure has been suggested to be a risk factor for Wilms’ tumor, but conclusive evidence is lacking. Certain congenital syndromes are associated with the development of Wilms’ tumor (Table 40.1). Table 40.1 Congenital syndromes associated with the development of Wilms’ tumor Syndrome

Description

WAGR

Associated with a mono-allelic deletion at chromosome 11p13 and characterized by aniridia, genitourinary malformations, and mental retardation; has a >30% incidence of Wilms’ tumor

Denys-Drash

Characterized by intersexual disorders and nephropathy, with a >90% incidence of Wilms’ tumor, and thought to arise from WT1 point mutation at 11p13

BeckwithWiedemann

Result of duplication of paternal allele at 11p15 and is characterized by macroglossia, organomegaly, hemihypertrophy, and neonatal hypoglycemia. While Wilms’ tumor can occur in about 10% of children with Beckwith-Wiedemann syndrome, these children are also at risk for other embryonal tumors such as hepatoblastoma and adrenocortical carcinoma

Source: Coppes MJ, Haber DA, Grundy PE (1994) Genetic events in the development of Wilms’ tumor. N Engl J Med 331:586–590

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Pathology Histological types of renal tumors in childhood is summarized in Table 40.2.

Table 40.2 Histology types of renal tumors in childhood and their characteristics Histology types

Histological and/or clinical features

Favorable histology Wilms’ tumor

 The most common renal tumor of childhood, and accounts for ~90% of all cases  On gross examination, Wilms’ tumor is often large, spherical, and well-demarcated. An inflammatory pseudocapsule is typically present, and cysts are not uncommon (Figure 40.1)  On microscopic examination, the classic nephroblastoma  contains three elements: blastemal, epithelial, and stromal cell types

Anaplastic (focal or diffuse)

 Accounts for <10% of primary renal tumors of childhood and can be further subdivided to focal or diffuse  Focal anaplasia corresponds to anaplastic nuclear changes  confined to ≥1 clearly defined loci within the primary tumor, without evidence of anaplasia or prominent nuclear atypia in extratumoral or extrarenal sites  A tumor with >1 anaplastic focus is acceptable when each is  small enough to be contained on a single microscopic section  Anaplastic changes that do not meet the criteria for focal anaplasia are called diffuse anaplasia

Clear cell sarcoma of the kidney

 Accounts for 4–5% of primary renal tumors of childhood  Also known as “bone metastasizing renal tumor of childhood” with a peak incidence at 1–4 years of age  Boys are more commonly affected than girls

Rhabdoid tumor

 Accounts for ~2% of all pediatric kidney tumors and is highly aggressive  More than half of the patients are diagnosed at <1 year of age  Has an association for synchronous or metachronous primary intracranial masses and brain metastasis  Boys are more commonly affected than girls

Renal cell carcinoma

 Reported in 7% of patients with kidney tumors manifesting in the first two decades of life  Can be associated with von Hippel–Lindau syndrome, in which tumors have a tendency to be multifocal

Mesoblastic nephroma

 The most common solid renal tumor in the neonate  Usually diagnosed within the first 3 months of life, with a benign course and treated with nephrectomy alone

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Arnold C. Paulino Figure 40.1 Gross nephrectomy specimen of a favorable histology Wilms’ tumor compressing a normal kidney which is marked by an arrow. The tumor is spherical with a pseudocapsule

Clinical Presentation, Diagnosis, and Staging Clinical Presentation The most common presentation in a child with Wilms’ tumor is a nonpainful abdominal mass (in ~75% of cases). Hematuria, abdominal pain, and varicocele have been reported in <30% of patients.

Diagnosis and Staging Figure 40.2 illustrates the diagnostic procedure of pediatric renal tumors, including suggested examination and tests.

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Renal Tumor(s) Suspected

Complete History and Physical Examination (with attention to abdominal mass/pain, hematuria, etc)

Recommended CT or MRI of Abdomen and Pelvis CT of Thorax

CBC Serum Chemistry

Rhabdoid Tumor, Clear Cell Sarcoma, and Renal Cell Carcinoma Bone Scan MRI of Brain

Metabolic Panel Hepatic Panel

Lab Studies

Imaging Studies

Nephrectomy (Renal Preservation for Bilateral Disease)

Staging, Histology, Potential Adj. Treatment In North America, patients with a unilateral renal mass undergo a nephrectomy In Europe, most patients are treated with preoperative chemotherapy for a presumptive Wilms’ tumor, followed by nephrectomy for histological diagnosis Biopsy of the renal mass violates the renal capsule and upstages the patient, requiring the use of radiation therapy

Figure 40.2 Proposed algorithm for diagnosis and staging of pediatric renal tumors

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Staging The staging system used for Wilms’ tumor, clear cell sarcoma, and rhabdoid tumor is presented in Table 40.3, and the staging system used for renal cell carcinoma is presented in Table 40.4. Table 40.3 Staging for Wilms’ tumor, rhabdoid tumor of the kidney and clear cell sarcoma of the kidney Stage

Description

I

Tumor limited to the kidney, completely resected. The renal capsule is intact. The tumor was not ruptured or biopsied prior to removal. The vessels of the renal sinus are not involved. There is no evidence of tumor at or beyond margin of resection

II

The tumor is completely resected, and there is no evidence of tumor at or beyond the margin of resection. The tumor extends beyond kidney, as indicated by one or both of the following:   There is regional extension of tumor (penetration of capsule or extensive invasion of the soft tissue of renal sinus)   Blood vessels within the nephrectomy specimen outside the renal parenchyma including those of renal sinus contain tumor

III

Residual nonhematogenous tumor present after surgery and confined to abdomen   Lymph nodes within the abdomen or pelvis are involved by tumor   Tumor has penetrated through the peritoneal surface   Gross or microscopic tumor remains postoperatively   The tumor is not completely resectable because of local infiltration into vital structures   Tumor spillage occurring either before or during surgery   The tumor is treated with preoperative chemotherapy (with or without biopsy regardless of type – Tru-Cut, open, or fine-needle aspiration) before removal   Tumor is removed greater than one piece. Extension of primary tumor within vena cava into thoracic vena cava and heart

IV

Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastasis outside abdomen or pelvis

V

Bilateral renal involvement by tumor is present at diagnosis

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Table 40.4 Staging for renal cell carcinoma Stage

Description

Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor ≤7.0 cm in greatest dimension, limited to the kidney

T2

Tumor >7.0 cm in greatest dimension, limited to the kidney

T3

Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota’s fascia

T3a

Tumor invades adrenal gland or perinephric tissues but not beyond Gerota’s fascia

T3b

Tumor grossly extends into renal vein or vena cava below diaphragm

T3c

Tumor grossly extends into vena cava above diaphragm

T4

Tumor invades beyond Gerota’s fascia

Regional lymph nodesa (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single regional lymph node

N2

Metastasis in >1 regional lymph node

Distant metastasis (M)

a

MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

Hilar, abdominal para-aortic, and paracaval nodes

Table 40.5 Stage grouping Stage Grouping T1

T2

T3

T4

N0

I

II

III

IV

N1

III

III

III

IV

N2

IV

IV

IV

IV

M1

IV

IV

IV

IV

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Prognostic Factors and Survival The most important prognostic factor for Wilms’ tumor is histology, with anaplastic tumors having a worse survival outcome as compared with favorable histology (FH) tumors (Table 40.6). Table 40.6 Four-year OS of children with Wilms’ tumor Stage

OS rates (%) FH

I

97%

II

92%

III

87%

IV

82%

FH LOH 91% 78%

Anaplastic 89% 68%

OS: overall survival; FH: favorable histology; LOH: loss of heterozygosity at 1p and 16q Sources: D’Angio GJ, Breslow N, Beckwith JB et al (1989) Treatment of Wilms’ tumor: results of the 3rd NWTS. Cancer 64:349–360; Grundy PE, Breslow NE, Li S et al (2005) Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 23:7312–7321

For bilateral Wilms’ tumor, children with synchronous tumors have a better 5-year overall survival than have those with metachronous presentation (73 versus 49%) (Source: Paulino AC, Thakkar B, Henderson WG [1998] Metachronous bilateral Wilms’ tumor: the importance of time interval to the development of a second tumor. Cancer 82:415–420; Montgomery BT, Kelalis PP, Blute ML et al [1991] Extended follow-up of bilateral Wilms’ tumor: results of NWTS. J Urol 46:514–518). The prognoses of patients with other renal tumors are detailed in Table 40.7.

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Table 40.7 Prognoses of other types of renal tumors, based on pathology types Pathology

Prognosis/prognoses

Clear cell sarcomaa OS of 83%, based on results from the 4th NWTS

Rhabdoid tumor of the kidneyb

 4 -year OS was 23%  Stage (stages I and II versus III and IV) and age at diagnosis (<1 versus ≥1 year old) were prognostic factors  Lower stage and age ≥1 year had better survival outcomes

Renal cell carcinomac

OS rate dependent on stage at 93, 85, 73, and 13% for stages I, II, III, and IV, respectively

Mesoblastic nephromad

Long-term OS was 98% with nephrectomy

NWTS: National Wilms’ Tumor Study; OS: overall survival a Source: Seibel NL, Li S, Breslow NE et al (2004) Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the NWTS Group. J Clin Oncol 22:468–473 b Source: Tomlinson GE, Breslow NE, Dome J et al (2005) Rhabdoid tumor of the kidney in NWTS: age at diagnosis as a prognostic factor. J Clin Oncol 23:7641–7645 c Source: Geller JI, Dome JS (2004) Local lymph node involvement does not predict poor outcome in pediatric renal cell carcinoma. Cancer 101:1575–1583 d Source: Howell CG, Othersen HB, Kiviat NE et al (1982) Therapy and outcome in 51 children with mesoblastic nephroma: a report from NWTS. J Pediatr Surg 17:826–831

Treatment Principle and Practice The treatment described in this chapter is based on the North American approach to Wilms’ tumor, wherein nephrectomy is performed at diagnosis, followed by adjuvant chemotherapy with or without radiation therapy. The current treatment strategy for adjuvant therapy is based on the current Children’s Oncology Group studies AREN 0532, AREN 03B2, and AREN 0533.

FH Wilms’ Tumor Adjuvant treatment strategies for FH Wilms’ tumor are detailed in Table 40.8. Figure 40.3 presents a left renal mass that revealed favorable histology post-nephrectomy.

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Table 40.8 Adjuvant treatment for FH Wilms’ tumor Stage

Treatment

I and II FH w/out LOH 1p and 16q

Adjuvant vincristine and actinomycin-D

I and II FH patients with LOH at 1p and 16q

Adjuvant vincristine, actinomycin-D, and doxorubicin

 No adjuvant treatment is recommended, as 85% of these I FH patients who patients are expected to be cured are <2 years of age with a tumor and  In the ≤15% who relapse and receive chemotherapy, most kidney weight of will be salvaged, with an overall survival rate of 95% using <550 g this approach III FH children without LOH at 1p and 16q

Actinomycin-D, vincristine, and doxorubicin, plus abdominal RT

III FH children with LOH at 1p and 16q

Actinomycin-D, vincristine, and doxorubicin, plus abdominal RT in addition to cyclophosphamide and etoposide

IV FH children without LOH at 1p and 16q

 Adjuvant actinomycin-D, vincristine, and doxorubicin are given  Abdominal RT is given if there is stage III local disease  For pulmonary metastasis only, 6 weeks of actinomycinD, vincristine, and doxorubicin is given, and an evaluation for pulmonary metastatic response is performed  If at 6 weeks, there is pulmonary metastasis, adjuvant whole-lung RT is delivered  If there are no pulmonary metastases at 6 weeks postchemotherapy, whole-lung RT is not given

IV FH children with LOH at 1p and 16q

 Actinomycin-D, vincristine, and doxorubicin chemotherapy is given  Pulmonary RT is given irrespective of response at 6 weeks

Bilateral Wilms’ tumor

 The general approach to bilateral Wilms’ tumor is the use of actinomycin-D, vincristine, and doxorubicin to shrink tumors and perform renal-preserving surgerya  Each kidney site is given a local stage  RT is only used for local stage III disease such as positive lymph nodes and microscopic margin of resection  In the current COG Study, AREN0534, bilateral Wilms’ tumor patients who had renal biopsies are not given RT to preserve functional renal parenchyma

RT: radiation therapy; FH: favorable histology; COG: Children’s Oncology Group a Source: Paulino AC, Wilimas J, Marina N et al (1996) Local control in synchronous bilateral Wilms’ tumor. Int J Radiat Oncol Biol Phys 36:541–548

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Figure 40.3 CT scan of the abdomen showing a left renal mass (arrow) and lymph node metastasis. Patient had a nephrectomy, which revealed a favorable histology Wilms’ tumor

Anaplastic Wilms’ Tumor Adjuvant treatment strategies for anaplastic Wilms’ tumor are detailed in Table 40.9. Table 40.9 Adjuvant treatment for anaplastic Wilms’ tumor Stage

Treatment

I–III focal anaplastic and stage I diffuse anaplasti

 Actinomycin-D, vincristine, and doxorubicin

II–III diffuse anaplastic and stage IV focal anaplastic

IV diffuse anaplastic

 RT doses and fields are similar to FH disease  Actinomycin-D, vincristine, doxorubicin, cyclophosphamide, etoposide, and carboplatin  RT doses are similar to favorable disease with the exception of stage III diffuse anaplasia, which receives 19.8 Gy in 11 fractions  In stage III diffuse anaplasia requiring whole-abdominal RT, the contralateral kidney is blocked at a dose of 14.4 Gy  Chemotherapy includes the 6 agents used for stages II and III diffuse anaplasia in addition to irinotecan  RT volumes and doses are similar to FH disease with the exception of a local stage III diffuse anaplastic tumor, which requires 19.8 Gy in 11 fractions

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Clear Cell Sarcoma Adjuvant treatment strategy for clear cell sarcoma is listed in Table 40.10. Adjuvant radiotherapy is given to all patients except for stage I clear cell sarcoma of the kidney. Table 40.10 Adjuvant treatment for clear cell sarcoma Stage

Treatment

I–III

 Actinomycin-D, vincristine, doxorubicin, cyclophosphamide, and  etoposide

IV

 Actinomycin-D, vincristine, doxorubicin, cyclophosphamide, eto poside, addition of carboplatin

Radiotherapy doses and volumes are similar to favorable histology Wilms’ tumor. An analysis of clear cell sarcoma cases from the NWTS 1 to 3 showed no radiotherapy dose response (Source: Green DM, Breslow NE, Beckwith JB et al (1994) Treatment of children with clear-cell sarcoma of the kidney: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 12:2132– 2137).

Rhabdoid Tumor Adjuvant treatment strategy for rhabdoid tumor is listed in Table 40.11. Table 40.11 Adjuvant treatment for rhabdoid tumor Stage

Treatment

I–III

 Actinomycin-D, vincristine, doxorubicin, cyclophosphamide, etoposide, and carboplatin   Abdominal radiotherapy

IV

 Above 6 drugs with irinotecan

Radiation therapy doses and volumes are similar to FH Wilms’ tumor if children are <1 year old. In children >1 year old, a dose of 19.8 Gy in 11 fractions is given to the primary site. Whole-lung irradiation dose in these older children is similar to FH Wilms’ tumor.

Chapter 40 Wilms’ Tumor and Other Childhood Renal Tumors

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Renal Cell Carcinoma Patients with completely resected renal cell carcinoma receive no adjuvant therapy. There are data reveal that even in nonmetastatic, completely resected tumors with lymph node involvement, the overall survival rates are good without adjuvant therapy (Source: Geller JI, Dome JS (2004) Local lymph node involvement does not predict poor outcome in pediatric renal cell carcinoma. Cancer 101:1575–1583). In children with unresectable stages III and IV disease, one can consider immunotherapy similar to the approach used in adults.

Mesoblastic Nephroma The standard treatment for mesoblastic nephroma is nephrectomy without adjuvant therapy.

Radiation Therapy Techniques Abdominal radiation therapy is delivered within 2 weeks of nephrectomy (Source: Kalapurakal JA, Li SM, Breslow NE et al (2003) Influence of RT delay on abdominal tumor recurrence in patients with FH histology Wilms’ tumor treated on NWTS-3 and NWTS-4: a report from the NWTS Group. Int J Radiat Oncol Biol Phys 57:495–499).

Radiation Therapy for FH Wilms’ Tumor For children who need local radiation, the clinical target volume (CTV) is the tumor bed (tumor and kidney) and adjacent paraaortic nodes with a 1-cm margin. The recommended dose is 10.8 Gy in six fractions. A previous study has shown that a dose of approximately 10 Gy is adequate if doxorubicin is used, and is equivalent to relapse-free survival rates achieved with approximately 20 Gy, without doxorubicin (Source: Thomas PR, Tefft M, Compaan PJ et al [1991] Results of two RT randomizations in the 3rd NWTS. Cancer 68:1703– 1707).

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Care should be taken to include the entire width of the vertebral body in the treatment field to prevent scoliosis. For children with preoperative rupture, peritoneal metastases, or diffuse spill during surgery, whole-abdominal radiotherapy is recommended at a dose of 10.5 Gy in seven fractions (Figure 40.4). Figure 40.4 Radiotherapy field including whole abdomen for a patient with diffuse spillage of tumor during a left nephrectomy. The whole abdomen was treated with AP/PA fields to a dose of 10.5 Gy in 7 fractions

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Pulmonary Radiation Therapy The entire lungs comprise the CTV. A 1-cm margin is added to create the planning target volume (PTV). A dose of 12 Gy in eight fractions is delivered (Figure 40.5). In the case in which local abdominal radiotherapy has been delivered for local stage III disease and pulmonary metastases did not completely respond to 6 weeks of three-drug chemotherapy, care should be taken to minimize overlap between the irradiated sites (abdominal and whole-lung fields). Figure 40.5 Radiotherapy field including whole lung and right hemi-abdomen for a patient with local stage III disease with a positive margin and para-aortic node, as well as pulmonary metastases. The right hemi-abdomen was treated with 10.5 Gy in 7 fractions, while the whole lung received an additional 1.5 Gy (total of 12 Gy in 8 fractions) by using AP/PA fields

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Follow-Up Schedule and suggested examinations during follow-up for children treated for renal tumors are presented in Table 40.12. Table 40.12 Follow-up schedule and examinations for children with Wilms’ tumor, clear cell sarcoma, and rhabdoid tumor Schedule

Frequency

First follow-up

 4 weeks after radiation therapy

Years 0–5

 Every 3 months

Examination History and physical

 Complete history and physical examination

Imaging studies

 Chest X-ray and abdominal ultrasound, alternating with CT of the thorax, abdomen, and pelvis every 3 months for 5 years  Bone scan and MRI of the brain for 2–3 years (clear cell sarcoma and rhabdoid tumors)

Because the survival rates of children with Wilms’ tumor have improved over the last 50 years, with approximately 85–90% of patients surviving, reduction of late effects has been a primary goal of cooperative studies. Reductions in the use and doses of radiotherapy as well as duration of chemotherapy have been investigated (Source: Green DM, Breslow NE, Beckwith JB et al (1998) Comparison between single- and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms’ tumor: a report from the NWTS Group. J Clin Oncol 16:237–245; D’Angio GJ, Breslow N, Beckwith JB et al [1989] Treatment of Wilms’ tumor: results of the 3rd NWTS. Cancer 64: 349–360). Late effects relating to the musculoskeletal system (scoliosis, kyphosis, bone, and soft tissue hypoplasia) have decreased with lower radiotherapy doses. Other long-term effects have included renal dysfunction, bowel obstruction, congestive heart failure, and secondary malignancy in a small minority of patients (Source: Paulino AC, Wen BC, Brown CK et al (2000) Late effects in children treated with RT for Wilms’ tumor. Int J Radiat Oncol Biol Phys 46:1239–1246; Breslow NE, Takashima JR, Whitton JA et al (1995) Second malignant neoplasms following treatment for Wilms’ tumor: a report from the NWTS Group. J Clin Oncol 13:1851–1859).

Foreword Index of Volumes 1 and 2

A Achalasia 330 Acromegaly 926, 933 – treatment 935 ACTH 924 Adenohypophysis 924 Adenoid cystic carcinoma 109, 113 ADH 924 Adrenocorticotropic hormone 924 Albinism 996 Anal canal – anatomy 513 – lymphatic drainage 515 Anal cancer 511–530 – chemotherapy 520 – classification 517, 518 – diagnosis 516, 517 – epidemiology 512 – etiology 512 – histology 514 – lymph nodes metastases 514, 515 – metastases 514, 515 – overall survival 519 – pathology 513, 514 – prognoses 519 – radiation therapy 522–530 – – dose 527 – – field arrangements 525–527 – – indications 520 – – intensity-modulated 528, 529 – – side effects 530 – – simulation 525 – – techniques 520, 525–527

– – – – – –

risk factors 512 salvage treatment 525 staging 516–518 surgery 520 symptoms 516 TNM-classification 517, 518 – treatment 520–530 – – adjuvant 525 – – algorithm 521 – – neoadjuvant 524 – – T2–4, N+ 522, 523 Androgen ablation 583, 589–595 Antidiuretic hormone 924 Astrocytoma – anaplastic 1015 – – treatment 908 – fibrillary 896, 900, 902, 1015, 1024 – high-grade 1019 – – radiation therapy 1030 – – treatment 1019, 1024, 1025 – low-grade fibrillary 896 – – radiation therapy 1030 – – treatment 1024 – pilocytic 896, 1012 – – diagnosis 900 – – juvenile 1024 – – prognosis 902 – – radiation therapy 919 – – treatment 911, 912 Autologous stem cell transplant 799, 821

B Bannayan–Riley–Ruvalcaba syndrome 209 Basal and squamous cell carcinoma see skin cancer, basal and squamous cell carcinoma Basal cell adenocarcinoma 109, 113 Basal cell carcinoma, skin see skin cancer, basal and squamous cell carcinoma B-cell lymphoma, CNS 855 B-cell prolymphocytic leukemia 747 Bilary system 449 Bile duct resection 457 Bisphosphonates, bone metastases 32 Bladder, anatomy 535, 536 Bladder cancer 533–566 – adenocarcinoma 537, 562 – bladder preservation 552 – brachytherapy 554 – chemoradiation therapy 555–560, 566 – chemotherapy 549–551 – classification 542 – diagnosis 541 – epidemiology 534 – etiology 534 – histology 537 – invasive 547 – lymph nodes metastases 538, 539

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Index of Volumes 1 and 2

– metastases 538–540 – – treatment 560 – non-urothelial 561, 562 – pathology 537 – prognosis 543, 544 – radiation therapy 552–566 – – dose 564 – – field arrangements 563 – – side effects 566 – – simulation 563 – recurrence 538, 539 – risk factos 534 – small cell carcinoma 561 – squamous cell carcinoma 537, 562 – staging 541–543 – superficial 545, 546 – surgery 548, 549 – symptoms 540 – TNM-classification 542 – transitional cell carcinoma 537 – treatment 544–566 – – algorithm 545, 547, 558 Blumer’s shelf 368 Bone metastases – chemotherapy 32 – diagnosis 28–30 – epidemiology 26 – etiology 26 – external-beam 33 – follow-up 41, 42 – fracture 39 – hormonal therapy 32 – pharmacotherapy 32 – prognosis 30 – radiation therapy 33–42 – spinal cord compression 39, 40 – surgery 33 – treatment 30–42 – – algorithm 31 Brachial plexus, radiation 73

Brain, development 1014 Brain metastases – diagnosis 5 – epidemiology 4 – management algorithm 11 – oligometastases 14 – pathophysiology 4 – prognosis 6 – radiation therapy 3–23 – single 11–13 – staging 5 – stereotactic radiosurgery 8, 12–18 – treatment 8–19 Brain radiation therapy 8, 12–18 Brain tumors – see also astrocytoma – see also central nervous system lymphoma – see also glioma – see also meningioma – diagnosis 1018–1021 – epidemiology 1012 – etiology 1012 – follow-up 1035 – metastases 1016, 1017 – pathology 1015, 1016 – pediatric 1011–1035 – prognosis 1022, 1023 – staging 1022 – symptoms 1018 – treatment 1024–1035 Brainstem glioma 1020, 1022 – diffuse 1025 – radiation therapy 1030 – treatment 1025 Brainstem radiation 73 BRCA-mutation 209 Breast – anatomy 210, 211 – lymphatic drainage 214 – quadrants 211 Breast cancer 207–258 – axillary nodes 212 – brachytherapy 245

– brain metastases 4 – chemotherapy 223 – – adjuvant 236–238 – – neoadjuvant 240, 241 – classification 218–220 – diagnosis 216–218 – epidemiology 208 – ER 221 – etiology 208 – genetic counseling 218 – genetic factors 209, 218 – HER2 221 – hormonal therapy 223 – – adjuvant 227, 228 – immunohistochemistry 221 – in situ carcinoma 224 – – ductal 228 – – lobular 228 – inflammatory 242–244 – internal mammary lymph nodes 212, 214 – invasive 214 – locally advanced 236, 237 – locally recurrent 245 – lumpectomy 233 – lymph nodes metastases 212–214 – male 257, 258 – mammography 210, 215 – metastases 212 – MRI 210 – pathology 212 – PR 221 – prognosis 221 – radiation therapy 223, 246–256 – – adjuvant 225, 226, 238, 239 – – dose fractionation 256 – – dosimetry 249 – – external-beam 193 – – fraction schedule 249 – – indications 246

Index of Volumes 1 and 2 – – partial-breast irradiation 232, 233 – – post-mastectomy 229–231 – – simulation 249 – – target volume 246, 247 – risk factors 209 – screening 210 – staging 216–218 – surgery 222, 229 – survival 220 – symptoms 214, 215 – targeted therapy 223 – TNM-classification 219, 220 – treatment 222–258 – – early stage 229 – – locally advanced 236, 237 – – systemic, adjuvant 238 Bronchial carcinoma see lung cancer bronchoscopy 268 Burkitt’s lymphoma 747, 748

C Carcinoma of unknown primary, head and neck 161–177 – chemotherapy 171 – diagnosis 165, 166 – follow-up 177 – pathology 163 – prognosis 167 – metastases 163, 164 – radiation therapy 168–177 – – dose 171 – – field arrangements 174 – – intensity-modulated 170, 174 – – side effects 177 – – simulation 171

– – target volume 168, 169, 171, 173 – – techniques 171–175 – – three-dimensional conformal 170 – staging 167 – treatment 168–177 Cementoplasty 33 Central nervous system lymphoma, primary 853–870 – chemotherapy 861 – diagnosis 857, 858 – epidemiology 854 – etiology 854 – follow-up 870 – metastases 856 – pathology 854 – prognosis 859 – radiation therapy – – dose 869 – – indications 861 – – techniques 869, 870 – risk factors 854 – staging 859 – surgery 860 – symptoms 857 – targeted therapy 861 – treatment 860–870 – – algorithm 862 – – definitive 863–866 – – response criteria 860 – – salvage 867–869 Central nervous systems tumors – see glioma – see meningioma – see pituitary tumors Cervical cancer 661–701 – brachytherapy 688–693 – – dose 690–693 – – image-guided 695 – – interstitial 689 – – timing 694 – chemotherapy 672, 674, 678–682 – diagnosis 667, 668 – epidemiology 662

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– etiology 662 – FIGO-classification 669, 670 – follow-up 696 – lymph nodes metastases 664, 665 – metastases 664, 665 – metastatic 683 – pathology 664 – prognosis 671, 672 – radiation therapy 672, 678–682 – – adjuvant 676 – – adjuvant 695, 696 – – definitive 683 – – dose 686 – – external-beam 683– 686 – – field arrangements 683–686 – – indications 674 – – intensity-modulated 687 – – para-aortic 682 – – postoperative 695, 696 – radiation therapy, side effects 697–701 – – simulation 683–686 – – target volume 683, 684 – – techniques 674, 683 – – timing 694, 695 – recurrent 682, 683 – resectable 675–678 – risk factors 663 – stage I–IIA 675–678 – stage IIB–IVA 678–682 – staging 667–670 – surgery 672, 673 – symptoms 666 – TNM-classification 669, 670 – treatment 672–701 – – adjuvant 676 – – algorithm 675

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Index of Volumes 1 and 2

– treatment, palliative 672 – – stage I–IIA 675–678 – – stage IIB–IVA 678– 682 Cervical lymph nodes 78 – metastases 163 Cervix, anatomy 663 Chamberlain procedure 268 Child–Pugh Score 429 Cholangiocarcinoma 447–467 – adenocarcinoma 450 – brachytherapy 458 – chemoembolization 458, 464 – chemotherapy – – adjuvant 460, 463 – – neoadjuvant 461 – – systemic 458 – classification 454, 455 – criteria for unresectability 457 – diagnosis 452–454 – embolization 458–464 – epidemiology 448 – etiology 448, 449 – hepatic 422 – histology 450 – intrahepatic 447 – liver transplantation 457, 462 – lymph nodes metastases 451 – metastases 451 – pathology 450 – prognosis 456 – radiation therapy – – dose 466 – – external-beam 458 – – field arrangements 465 – – simulation 465 – – target volume 465 – – techniques 465–467

– – unresectable disease 465, 466 – radioembolization 458, 464 – risk factors 449 – staging 454–456 – surgery 457, 458 – symptoms 452 – TNM-classification 454, 455 – treatment 457–467 – – adjuvant 460, 465, 466 – – neoadjuvant 461 – – unresectable disease 463, 465, 466 – unresectable disease 463, 465, 466 Cholecystectomy 477 Chondrosarcoma 946 Choriocarcinoma 615 Chronic lymphocytic leukaemia 748 Cigarette smoking, oral cavity and oropharynx cancer 84 Clear cell sarcoma 946 – kidney 1093 – prognosis 1099 – treatment 1102 Cochlea, radiation 73 Colorectal cancer see rectal cancer Cord compression 39, 56, 820, 1070 Craniopharnygioma 1021 – radiation therapy 1031 – treatment 1029 Cushing’s disease 926, 933 – treatment 935 Cushing’s syndrome 266 Cutaneous T-cell lymphoma 833–852 – advanced stage 842, 845, 846 – bexarotene 843 – chemotherapy 843

– – – – – – – – – – – – – –

classification 835, 838 diagnosis 837 early stage 842, 844 epidemiology 834 etiology 834 follow-up 852 histology 835 metastases 836 pathology 834, 835 phototherapy 842 primary 835, 838 prognosis 840, 841 PUVA 848 radiation therapy 847–852 – – dose 849 – – local 842 – – palliative 848 – – side effects 852 – – superficial 849 – – target volume 847, 848 – – techniques 847–851 – – total skin electron beam 842, 847–851 – recalcitrant 842 – staging 837–840 – symptoms 836 – treatment 841–852 – – advanced stage 845, 846 – – algorithm 844–846 – – early stage 842–844 – – topical 842 Cystadenocarcinoma 109 Cystectomy – partial 552 – radical 548, 549, 566

D Denys–Drash syndrome 1092 Dermatofibrosarcoma protuberans 945 Desmoplastic small cell tumor 946 Dysparenunia 700

Index of Volumes 1 and 2

E Elective neck irradiation 123, 127 endobronchial ultrasound (EBUS) 268 Endometrial cancer 641–660 – adenocarcinoma 644 – brachytherapy 658, 659 – – vaginal 650–652, 658, 659 – carcinosarcoma 654 – chemotherapy 649, 653 – diagnosis 646 – early stage 648–652 – epidemiology 642 – etiology 642 – follow-up 660 – histology 644 – hormonal therapy 649 – locoregionally advanced 653 – lymph nodes metastases 645 – metastases 645, 646 – pathology 644 – prognosis 648 – radiation therapy 655–660 – – adjuvant 650–653 – – dose 655, 656, 658 – – external-beam 649 – – field arrangements 655 – – indications 649 – – intensity-modulated 649, 656, 657 – – side effects 659 – – simulation 655 – – target volume 656, 657 – – three-dimensional conformal 656, 657 – risk factors 642 – staging 646, 647 – surgery 649 – symptoms 645 – techniques 649

– treatment 648–660 – – algorithm 650 endoscopic ultrasound 334, 335 Ependymoma – myxopapillary 1015 – prognosis 1022 – radiation therapy 1030 – symptoms 1020 – treatment 1027, 1028 Epididymo-orchitis 615 Epidural tumor 1071 Epithelioid hemangioendothelioma 946 Epithelioid leiomyosarcoma 945 Epithelioid sarcoma 946 Epstein–Barr–virus infection 162, 163 Erythroderma 848 Esophageal cancer 329– 358 – adenocarcinoma 336 – chemoradiotherapy – – adjuvant 350 – – definitive 347 – – palliative 351 – – postoperative 344–346 – – preoperative 344–346 – chemotherapy 340, 343, 344 – diagnosis 333, 334 – early stage 342 – endoscopic ultrasound 334 – epidemiology 329 – esophagegastroduodenoscopy 334 – etiology 329, 330 – inoperable 347 – locoregionally advanced disease 342, 347 – lymph nodes metastases 332 – metastases 332, 333

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– palliation 351 – pathology 332 – PET 357 – prognosis 337, 338 – radiation therapy – – 3D 340, 354 – – adjuvant 350 – – definitive 347 – – target volume 352 – – dose 354 – – external-beam 340 – – fractionation 354 – – immobilization 352 – – indications 340 – – intensity-modulated 340 – – palliative 351 – – planning 354 – – postoperative 344–346 – – preoperative 344–346 – – simulation 352 – – target volume 352, 353 – – techniques 340, 352–358 – – toxicity 355, 356 – recurrence 351 – risk factors 330 – staging 333, 334 – surgery 339, 343, 344, 349 – survival 337, 338 – symptoms 333 – targeted therapy 340 – TNM-classification 335, 336 – treatment 339–358 – – algorithm 341, 347 – – early stage 342 – – locoregionoally advanced disease 342, 347 Esophageal diverticuli 330 Esophageal webs 330 Esophagectomy 339

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Index of Volumes 1 and 2

Esophagegastroduodenoscopy 334 Esophagus – anatomy 330, 331 – lymphatic drainage 331 Ewing sarcoma 960, 1075–1090 – diagnosis 1077 – epidemiology 1075 – etiology 1075 – metastases 1076, 1077 – pathology 1076 – pediatric 1013 – prognosis 1077, 1078 – radiation therapy 1082–1090 – – dose 1085, 1086 – – follow-up 1088–1090 – – side effects 1087 – – simulation 1082 – – target volume 1083 – staging 1077 – surgery 1079 – treatment 1078–1090 – vertebral body lesions 1084 – within a body cavity 1084 Exenteration, orbital 1043 External-beam radiation – in bone metastases 33 – in breast cancer 193 – in cholangiocarcinoma 458 – in gallbladder carcinoma 479, 480 – in pancreatic cancer 399, 405, 412 – in prostate cancer 582, 583, 586, 590–593, 598–602 – in retinoblastoma 1044, 1047 – in thyroid cancer 193 Eye – anatomy 1039 – enucleation 1043, 1050 – exteration 1043

F Familial adenomatous polyposis 489 Fanconi anemia 996 α-fetoprotein 617, 620 Fibrous histiocytoma, malignant 945 Follicle-stimulating hormone 924 Follicular lymphoma 748 FSH 924

G Gallbladder, anatomy 449, 471 Gallbladder carcinoma 469–486 – chemotherapy 477 – classification 475, 476 – diagnosis 474 – epidemiology 470 – etiology 470 – genetic disposition 470 – lymph nodes metastases 472 – metastases 472 – pathology 471 – prognosis 476 – radiation therapy – – 3D 484 – – dose 483, 486 – – external-beam 479, 480 – – field arrangements 483 – – indications 477 – – intensity-modulated 482, 483 – – simulation 483, 485, 486 – – target volume 484–486 – – techniques 477, 483–485 – resectable 479–481 – risk factors 470 – staging 474, 475

– – – –

surgery 477–479 symptoms 473 targeted therapy 477 TNM-classification 475, 476 – treatment 477–486 – – adjuvant 481 – – algorithm 478 – – neoadjuvant 481 – – resectable disease 479–481 – – unresectable disease 481, 482, 485, 486 Gammopathy, monoclonal – see MGUS – see multiple myelom Ganglioneuroblastoma 1055, 1062, 1063 Ganglioneuroma 1055, 1062, 1063 Gastrectomy 372–374 Gastric cancer 361–387 – Borrmann’s classification 364 – chemotherapy 373, 375, 379 – – adjuvant 377, 378 – – infusional 377 – classification 364, 370, 371 – diagnosis 369 – early stage 375 – epidemiology 362 – etiology 362 – genetic factors 362 – histology 364, 365 – inoperable 378, 379 – Lauren’s classification 364 – localized 372 – locoregionally advanced 372, 375–378 – lymph node dissection 375 – lymph nodes metastases 365, 366

Index of Volumes 1 and 2 – metastases 365, 366, 370, 379, 380 – overall survival 372 – palliation 379, 380 – pathology 364 – prognosis 372 – radiation therapy 375, 379 – – adjuvant 378, 380, 381 – – complications 387 – – dose 382, 386 – – indications 373 – – intensity-modulated 382 – – palliative 382 – – side effects 387 – – simulation 380–382 – – target volume 382–385 – – techniques 373, 380–382 – – unresectable disease 382 – recurrence 379, 380 – risk factors 362 – staging 369–371 – surgery 372, 373 – symptoms 368 – targeted therapy 373 – TNM-classification 370, 371 – treatment 372–387 – – adjuvant 378 – – algorithm 374, 379 – – early stage 375–378 – – inoperable disease 378, 379 – – neoadjuvant 375, 376 – – palliative 380 Gastroesophageal reflux disease 330 Gastrointestinal stromal tumor 945, 946 – treatment 967, 968

Genitalurinary system, tumors – see bladder cancer – see prostate cancer – see testicular cancer Germ cell tumor 614, 1016 – symptoms 1020 – treatment 1028, 1029 Germinoma 1016 – radiation therapy 1030 – treatment 1028, 1029 Gleason score 571, 572 Glioblastoma multiforme 896, 1015 – diagnosis 899 – prognosis 902 – follow-up 922 Glioma 895–922 – anaplastic 896 – – diagnosis 899 – – prognosis 902 – chemotherapy 905, 913 – diagnosis 898 – epidemiology 895, 896 – etiology 895, 896 – treatment 906 – high grade 904–910 – – radiation therapy 919 – low grade 911–916, 1022 – – infiltrating 913–915, 919 – marker 903 – pathology 896 – pediatric 1012, 1015 – prognosis 901, 902 – radiation therapy – dose 917, 921 – – field arrangements 920 – – indications 905, 913 – – simulation 917, 918 – – techniques 905, 913, 917–921 – staging 901 – surgery 904, 913

1111

– symptomas 897 – targeted therapy 905, 913 – treatment 903–922 – – algorithm 907, 916 – – high grade 904–910 – – low grade 911–916 – – palliative 909, 910 Glomangiosarcoma 946 Glottis cancer 142, 144, 154 Gonadotropin-secreting adenoma 926 Gorlin’s syndrome 1013 Graded Prognostic Assessment (GPA) 8 Growth hormone 924

H Hairy cell leukemia 747, 748 Hemangiopericytoma 946 Hematopoietic stem cell transplant 759, 799 Hematuria 540 Hemibody irradiation 32, 34, 36–38 Hemochromatosis, hereditary 420 Hepatectomy 421, 431 – partial 457 Hepatocellular carcinoma 419–467 – advanced disease 434–438 – Child–Pugh score 429 – classification 427, 428 – clear cell type 422 – diagnosis 424–427 – epidemiology 420 – etiology 420 – fibrolamellar type 422 – histology 422 – liver transplant 431, 432 – lymph nodes metastases 423

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Index of Volumes 1 and 2

– metastases 422, 423, 427 – nonsurgical localized 433 – overall survival 430 – pathology 422 – percutaneous ethanol injection 433 – prognosis 429, 430 – radiation therapy 438–446 – – 3D 439 – – dose 442–444 – – image-guided 438 – – planning 441 – – side effects 446 – – simulation 438 – – target volume 438 – radiofrequency ablation 433 – risk factors 420 – staging 424–427 – surgery 431 – symptoms 424 – TNM-classification 427, 428 – treatment 430–446 – – adjuvant 433 – – advanced disease 434–438 – – neoadjuvant 433, 434 – – planning 441 Hepatoma see hepatocellular carcinoma Hereditary non-polyposis colorectal cancer 362, 390, 488, 489 – risk factors 489 Hodgkin’s lymphoma 747, 771–809 – advanced stage 779, 788–791 – cervical disease 805–807 – chemotherapy 780–782, 784–787 – classification 773, 774 – diagnosis 774, 775

– early stage 779–787 – – favorable disease 780 – – unfavorable disease 781–784 – epidemiology 772 – etiology 772 – follow-up 808 – lymphocyte-depleted 773 – lymphocyte-rich 773 – mediastinal disease 802–804 – nodular lymphocytepredominant 772, 773, 779, 787, 788 – nodular sclerosis 773 – pathology 772 – prognosis 777–779 – radiation therapy – – consolidation 789, 790 – – dose 781 – – extended-field 781, 782 – – involved-field 782, 783, 801–807 – – planning 803 – – salvage 799, 800 – – techniques 800–809 – refractory 798, 799 – relapsed 798, 799 – salvage high-dose therapy 799, 800 – side effects 809 – staging 774–776 – subtotal lymphoid irradiation 782 – symptoms 774 – treatment 779–809 – – response assessment 792–797 Horner’s syndrome 52 HPV-infection – cervical cancer 663 – oral cavity and oropharynx cancer 76 HTLV 746

β-human chorionic gonadotropin 617, 620 Human herpes virus infection 746 Human papilloma virus infection 162 Hürthle cell carcinoma 183 Hydrocele 615 Hydronephrosis 666 Hypogammaglobulinemia 313 Hypopharnx, anatomy 135 Hypopharynx cancer see larynx and hypopharynx cancer Hypophysis see pituitary gland Hysterectomy 649, 678, 734 – abdominal 651 – radical 667, 673 – vaginal 649

I Intratubular germ cell neoplasie 614

K Karnofsky Performance Status (KPS) 6 Klatskin tumor 449, 451 Krukenburg tumor 368 Kyphoplasty 33

L Lactate dehydrogenase 617, 620, 751 Lambert–Eaton myastenic syndrome 266 Larynx – anatomy 135 – radiation 73 Larynx and hypopharynx cancer 133–159 – diagnosis 138 – epidemiology 134

Index of Volumes 1 and 2 – – – –

etiology 134 follow-up 159 follow-up 159 lymph nodes metastases 136, 137 – metastases 136, 137, 142 – metastases 146, 147 – pathology 136 – prognosis 142 – radiation therapy 143–159 – – dose 145, 146, 149, 156 – – not suitable for organ preservation 154–159 – – organ preservation 151–154 – – simulation 144, 148, 153 – – target volume 144, 148, 153, 156 – – techniques 144, 145, 147, 148, 155, 156 – risk factors 134 – staging 138, 139 – surgery 147 – symptoms 138 – TNM-classification 139, 140 – treatment 141–159 – – algorithm 141 Leiomyosarcoma 945 Lentigo maligna 979 L’hermitte’s syndrome 809 Li–Fraumeni syndrome 209, 1013 Liposarcoma 945 Liver cancer carcinoma see hepatocellular carcinoma Liver – anatomy 420, 421, 449 – transplantation 431, 432, 457, 462 Lumpectomy 233

Lung – anatomy 263 – lobes 263 – lymph nodes 264 Lung cancer 261–307 – see also non-small cell lung cancer – see also small-cell lung cancer – adenocarcinoma 264 – brain metastases 4 – bronchoscopy 268 – chemotherapy 272, 273 – clinical treatment volume 297 – CT-guided biopsy 268 – diagnosis 267–269 – endobronchial brachytherapy 272 – endobronchial ultrasound 268 – epidemiology 262 – etiology 262 – gross tumor volume 297 – histology 264, 265 – imaging 268 – large cell lung cancer 264 – lymph nodes metastases 265 – mediastinoscopy 268 – metastases 265 – overall survival 270 – pathology 263, 264 – planning treatment volume 297 – prognosis 270 – radiation therapy – – indications 272 – – techniques 272 – risk factors 262 – squamous cell carcinoma 264 – staging 267–270 – surgery 268, 271 – symptoms 266

1113

– targeted therapy 272, 273 – TNM-classification 269, 270 – treatment 271–307 – – algorithm 273 – video assisted thorascopic surgery 268 Luteinizing-hormonereleasing hormone 589 Lymph nodes – cervical 45, 46, 78 – radiation 766 – regions 766, 777 Lymph nodes metastases – in anal cancer 514, 515 – in bladder cancer 538, 539 – in breast cancer 212–214 – in CUP of head and neck 163 – in gallbladder carcinoma 472 – in gastric cancer, lymph node metastases 365, 366 – in lymph node metastases 423 – in larynx and hypopharynx cancer 136, 137 – in lung cancer 265 – in melanoma, malignant, lymph node metastases 981 – in oral cavity and oropharynx cancer 79 – in pancreatic cancer, lymph node metastases 392, 393 – in prostate cancer, lymph node metastases 573, 574 – in rectal cancer, lymph node metastases 492

1114

Index of Volumes 1 and 2

– in soft tissue sarcoma, lymph node metastases 947 – in salivary glands cancer 110, 111 – in testicular cancer, lymph node metastases 613 – in vulva cancer, lymph node metastases 706 Lymphoplasmacytic lymphoma 748

M MALT 746 Mamma carcinoma see breast cancer Mammography 210, 215 Mandible, radiation 73 Mantle cell lymphoma 747, 748 Mediastinoscopy 268 Medulloblastoma 1012 – pediatric 1016, 1020 – prognosis 1023 – radiation therapy 1030–1034 – treatment 1025–1027 Melanoma, malignant – acral lentiginous 979 – adjuvant nodal irradiation 991 – brain metastases 4 – chemotherapy 988 – – adjuvant 991 – cutaneous 977–994 – desmoplastic 979 – diagnosis 981, 982 – epidemiology 978 – etiology 978 – follow-up 993, 994 – in-transitmetastases 990 – lymph nodes metastases 981 – metastases 980, 981 – metastatic 991, 992 – nodular 979

– pathology 978, 979 – prognosis 986 – radiation therapy – – dose fractionation 993 – – field arrangements 993 – – indications 988 – – nodal irradiation 991 – – simulation 993 – – techniques 988, 993 – recurrent 990 – sentinel lymph node biopsy 990 – staging 982–985 – superficial spreading 979 – surgery 988, 989 – symptoms 981 – targeted therapy 988 – TNM-classification 982, 983 – treatment 986–994 – – algorithm 987 – – metastatic stage 991, 992 – unresectable 990 Meningioma 873–893 – anaplastic 875 – benign 875, 881, 882 – chemotherapy 879 – epidemiology 874 – etiology 874 – follow up 893 – malignant 875, 883, 884 – metastases 876 – pathology 875 – prognosis 877 – radiation therapy – – adjuvant 881, 882 – – dose 890, 891 – – indications 878 – – side effects 892 – – simulation 887 – – target volume 887, 888

– – techniques 878, 887–892 – recurrent 885, 886 – risk factors 874 – surgery 878, 879 – symptoms 876, 877 – treatment 878–893 – – algorithm 880 – unresectable 885, 886 Menorrhagia 645 MGUS 812, 813 – diagnosis 817, 818 Mitosis-karyorrhexis index 1055 Monoclonal gammopathy of undetermined significance see MGUS Mucinous adenocarcinoma 109, 113 Mucoepidermoid carcinoma 109, 113 Mucosa-associated lymphoid tissue 746 Multiple endocrine neoplasia 180 Multiple myeloma 811– 832 – anemia 815, 816 – asymptomatic 817 – chemotherapy 821–823, 829 – cord compression 820 – diagnosis 816, 817 – epidemiology 812 – etiology 812 – follow-up 832 – hypercalcemia 815, 816, 820 – non-secretory 817 – pathology 814 – prognosis 819 – progressive disease 824 – radiation therapy 825, 826 – – dose 826, 832 – – indications 826, 827 – – side effects 826

Index of Volumes 1 and 2 – – target volume 828–830 – – techniques 826–832 – recurrent 823 – relaps 825 – renal failure 815, 820 – risk factors 812 – smoldering 813, 816 – staging 819 – stem cell transplant 821 – surgery 828 – symptoms 814–816 – treatment 820–832 – – response 823–825 – – supportive 823 – – transplant-eligible patients 821 – – transplant-ineligible patients 822 Myasthenia gravis 313 Mycosis fungoides 835 Myoepithelial carcinoma 109, 113 Myxoid liposarcoma 945

N Nasopharyngeal carcinoma 45–74, 163 – chemoradiation 61–63 – chemotherapy 59 – – adjuvant 66 – – neoadjuvant 64–66 – diagnosis 54, 55 – epidemiology 46 – etiology 46 – follow-up 74 – gross volume 69 – high risk 69, 70 – metastases 52, 53 – pathology 52 – prognostic factors 58 – radiation therapy 59–72 – – dose 70–73 – – fractionation 70, 71 – – target volume 67 – – techniques 67, 68 – staging 55, 56

– surgery 59 – symptoms 54, 55 – TNM-classification 55, 56 – treatment 58–72 – – algorithm 60 Nasopharynx, anatomy 46, 47 Neck lymph nodes 47, 48 – levels 49–51 Nelson’s syndrome 926 Nephroblastoma, see Wilms’ tumor Nephroma, mesoblastic 1093, 1099, 1103 Neuroblastoma 1053–1072 – chemotherapy 1065 – diagnosis 1057, 1058 – epidemiology 1054 – etiology 1054 – metastases 1055 – pathology 1055 – pediatric 1013 – prognosis 1061, 1062 – radiation therapy 1067–1072 – – Indications 1064 – – techniques 1065 – risk factors 1054, 1060, 1061 – staging 1058, 1059, 1061 – surgery 1064 – symptoms 1056 – treatment 1064–1072 – – algorithm 1066, 1068, 1069 – – high-risk group 1067 – – intermediate-risk group 1066–1069 – – low-risk group 1065 – – side effects 1072 Neurofibromatosis 1013 Neuron-specific enolase 1055 NK-cell neoplasma 747 Non-germ cell tumor 614

1115

Non-Hodgkin’s lymphoma 745–768 – aggressive – – advanced-stage 762, 763 – – limited-stage 760–762 – biopsy 750 – chemotherapy 759 – classification 747 – diagnosis 750, 751 – epidemiology 746 – etiology 746 – follow-up 767, 768 – immunotherapy 759 – indolent – – advanced-stage 756–759 – – limited-stage 754, 755 – prognosis 752, 753 – radiation therapy – – advanced stage 756– 759, 762, 763 – – extended field 764, 765 – – involved-field 765, 766 – – limited stage 760–762 – – low-dose 758 – – mantle field 764, 767 – – palliative 757 – – techniques 764–768 – radioimmunotherapy 759 – risk factors 746 – staging 750–752 – stem cell transplant 759, 799 – symptoms 749 – treatment 754–768 – – algorithm 754 Non-small cell lung cancer 263 – chemotherapy 302 – – adjuvant 277

1116

Index of Volumes 1 and 2

– – concurrent 283–285 – – sequential 283–285 – early-stage 270 – endobronchial brachytherapy 304 – induction therapy 286–288 – locally advanced 270, 278, 300 – prognosis 270 – radiation therapy 278–304 – – 3D 302 – – adjuvant 304 – – continuous hyperfractionated accelerated 281 – – dose escalation 289 – – dose 280, 281, 300, 301, 304 – – fractionation scheme 300, 301, 304 – – hyperfractionated accelerated 281, 282 – – immobilization 297 – – intensitymodulated 302, 303 – – planning 297–299 – – postoperative 278, 279, 304 – – simulation 296–299 – – target volume 302, 305 – – techniques 296–300 – staging 266–270 – stereotactic body radiation 274–276, 300 – surgery 274, 275, 286–288 – symptoms 266 – targeted therapy 289 – TNM-classification 269, 270 – treatment 274–289

O Oat cell cancer 264 Oligoastrocytoma 908, 909 Oligodendroglioma 896, 1015 – diagnosis 899 – prognosis 902 – treatment 908 Optic nerve, radiation 73 Oral cavity, anatomy 77 Oral cavity and oropharynx cancer 75–103 – chemoradiation 90, 91 – – adjuvant 92, 93 – chemotherapy 86 – diagnosis 80–82 – epidemiology 76 – etiology 76 – follow-up 103 – lymph nodes metastases 79 – metastases 78, 79, 82 – pathology 78 – prognosis 84 – radiation therapy 86–103 – – dose 94, 100 – radiation therapy – – field setup 94 – – fractionation 88, 89 – – intensity-modulated 98 – – postoperative 96 – – simulation 94, 99 – – target volume 94, 99 – – techniques 94, 95 – risk factors 76 – staging 81–84 – surgery 86 – symptoms 79, 80 – targeted therapy 86 – TNM-classification 83 – treatment 85–103 – – algorithm 85 Orbital exenteration 1043 Orchiectomy 583, 625 Oropharynx, anatomy 77

Oropharnynx cancer see Oral cavity and oropharynx cancer Osteosarcoma, pediatric 1013 Oxytocin 924

P Pancreas – anatomy 391, 449 – lymph nodes 393, 394 Pancreatectomy 401–405 Pancreatic cancer 389–417 – chemoradiation 404–412 – chemotherapy 399, 405–411 – – indications 399 – – definitive 399 – classification 397, 398 – diagnosis 396 – epidemiology 390 – etiology 390 – genetic factors 390 – head 395 – locoregionally advanced 410, 412 – lymph nodes metastases 392, 393 – metastases 392, 393 – overall survival 398 – pathology 392 – prognosis 398 – radiation therapy – – 3D 399 – – adjuvant 399, 412, 413 – – dose 414, 416 – – external-beam 399, 405, 412 – – field arrangements 413 – – indications 399 – – intensity-modulated 414 – – intraoperative 399 – – palliative 399 – – side effects 416

Index of Volumes 1 and 2 – – simulation 413, 414 – – target volume 414, 415 – – techniques 399, 413, 414 – – unresectable disease 414, 415 – resectable 401–405 – risk factors 390 – staging 396 – surgery 401–405 – symptoms 394, 395 – targeted therapy 412 – TNM-classification 397, 398 – treatment 399–416 – – adjuvant 401–404 – – algorithm 400, 405 – – neoadjuvant 404, 405 – – palliative 412 – – resectable disease 401–405 – – unresectable disease 405–411, 414, 415 – unresectable 405–411 Parotid gland 108, 111 Partial-breast irradiation 232, 233 Percutaneous ethanol injection 433 Petrosphenoidal syndrome of Jacod 54 Pituitary gland, anatomy 924, 925 Pituitary tumor 923–940 – classification 931 – diagnosis 928, 929 – epidemiology 924 – etiology 924 – follow-up 939 – metastases 927 – pathology 925, 926 – pediatric 1012 – pharmacotherapy 933 – prognosis 931 – radiation therapy 934–939

– – dose 938 – – field arrangements 936, 937 – – indications 933 – – simulation 934 – – target volume 934, 935 – – techniques 933–939 – risk factors 924 – staging 929–931 – surgery 932 – symptoms 927 – treatment 932–940 – – algorithm 934 – – side effects 940 Plasma cell myeloma 747 Plasmacytoma – see also multiple myeloma – extramedullary 817, 829, 830 – solitary of the bone 747, 817, 827, 828, 830 Precursor B-cell lymphoblastic leukemia 747, 748 Precursor T-cell lymphoblastic leukemia 747, 748 Primitive neuroectodermal tumor 946, 1016 – radiation therapy 1030 – supratentorial 1020, 1022, 1030 Prolactin 924 Prolactinoma 925, 933 – treatment 934 Prophylactic cranial irradiation 292, 294, 295 Prostate – anatomy 535, 568, 569 – lymphatic drain 573, 574 Prostate cancer 567–609 – active surveillance 582 – adenocarcinoma 571

1117

– androgen ablation 583, 589–595 – brachytherapy – – instititial 583 – – low-dose rate 594, 595 – – permanent 585 – chemotherapy 593, 594 – diagnosis 574–577 – epidemiology 568 – etiology 568 – follow up 609 – high risk 594 – intermediate risk 593 – localized 581–598 – lymph nodes metastases 573, 574 – metastases 572–574, 578 – metastatic 598 – pathology 571, 572 – prognosis 580, 581 – radiation therapy 598–609 – – adjuvant 596–598, 605–608 – – brachytherapy, interstitial 602–604 – – dose 602, 603, 608 – – dose escalation 586– 589 – – external-beam 582, 583, 586, 590–593, 598–602 – – postoperative 605–607 – – simulation 599 – – target volume 600– 602 – radioactive seed implantation 596 – recurrence 598 – risk factors 568 – screening 568, 575 – staging 576–579 – symptoms 574 – TNM-classification 578, 579

1118

Index of Volumes 1 and 2

– treatment 581–609 – – algorithm 584 – TRUS-guided needle biopsy 575 Prostatectomy 582 Prostate-specific antigen 568 – serum 575 Proteus-like syndrome 209 PSA see Prostate-specific antigen PTEN hamartoma tumor syndrome 209 Pyspareunia 666

R Radiation therapy – external-beam 32 – multiple fraction 35 – palliative 25–42 – side effects 42, 73 – single fraction 35 Radiofrequency ablation 433 Radionuclides 33, 38 Rectal cancer 487–509 – chemoradiation – – adjuvant 501, 501 – – neoadjuvant 501, 501 – chemotherapy 498 – classification 494 – diagnosis 492, 493 – epidemiology 488 – etiology 488 – lymph nodes metastases 492 – metastases 491,492 – pathology 490 – prognosis 496 – radiation therapy 497–507 – – 3D 506 – – dose 506 – – field arrangements 504–506 – – indications 497

– – intensity-modulated 507 – – side effects 509 – – simulation 504 – – techniques 497 – – techniques 504–507 – risk factors 488, 489 – staging 492–495 – surgery 497 – symptoms 492 – targeted therapy 498 – TNM-classification 494 – treatment 497–509 – – algorithm 499 – – stage I 500 – – stage II-IIIc 500–503 – – stage IV 503 Rectum, anatomy 490 Renal cell carcinoma 1093, 1097, 1099, 1103 Retinoblastoma 1037–1052 – brachytherapy 1044, 1049 – chemotherapy 1044–1046 – classification 1042 – cryotherapy 1044 – epidemiology 1038 – episcleral plaque brachytherapy 1044 – laser photocoagulation 1044 – metastases 1040 – prognosis 1041 – radiation therapy – – brachytherapy 1044, 1049 – – external-beam 1044, 1047 – – postoperative 1044 – – proton therapy 1049, 1050 – – techniques 1047–1052

– – – – –

risk factors 1038 staging 1040–1042 surgery 1043 symptoms 1040 transpupillary thermotherapy 1044 – treatment 1043–1052 – – side effects 1050–1052 Rhabdoid tumor 1093 – kidney 1099, 1102 Rhabdomyosarcoma 946, 960 – pediatric 1013 Robbins-classification 47, 48 Rothmund–Thomsonsyndrome 996 Roux-en-Y hepaticojejunostomy 457

S Salivary duct carcinoma 109 Salivary glands – anatomy 107 – major 107, 108 – parotid 108 – sublingual 108 – submandibular 108 Salivary glands cancer 105–131 – chemotherapy 117 – diagnosis 114 – elective neck irradiation 123, 127 – epidemiology 106 – etiology 106 – follow-up 131 – inoperable 124 – lymph nodes metastases 110, 111 – metastases 110–112 – metastatic 125 – pathology 109 – prognosis 116 – radiation therapy 117–131

Index of Volumes 1 and 2 – – dose 126 – – field arrangements 128 – – indications 126 – – intensity-modulated 129 – – simulation 125 – – target volume 126 – – techniques 125–130 – risk factors 106 – staging 114–116 – surgery 117 – symptoms 113 – targeted therapy 117 – TNM-classification 115 – treatment 116–131 – – adjuvant 120, 121 – – algorithm 118 Salpingo-oophorectomy 649, 651 Sclerosis tuberous 1013 Score Index for Radiosurgery (SIR) 7 Seminoma 614, 616 – see also testicular cancer – classification 619, 620 Sentinel lymph node biopsy – malignant melanoma 990 – vulva cancer 712, 714 Sézary syndrome 835 Skin cancer – see also melanoma, malignant – basal and squamous cell carcinoma 995–1008 – – diagnosis 998, 999 – – epidemiology 996 – – etiologly 996 – – metastases 998–1000 – – pathology 997, 998 – – prognosis 1001 – – radiation therapy 1005–1008

–– –– –– –– –– ––

recurrence 1002 risk factors 996 staging 999–1001 surgery 1005 symptoms 998, 999 TNM-classification 1000, 1001 – – treatment 1002–1008 Small-cell lung cancer 263 – see also lung cancer – chemotherapy 290–292 – extensive-stage 296 – limited stage 293 – prognosis 270 – prophylactic cranial irradiation 292, 294, 295 – radiation therapy 290–296 – – consolidative 296 – – dose 295, 305 – – early 293 – – fractionation schemes 305 – – techniques 305 – – toxicities 306 – staging 266–270 – symptoms 266 – TNM-classification 269, 270 – treatment 290–307 Smoldering multiple myeloma 813, 816 Soft palate tumors 80 Soft tissue sarcoma 943–976 – advanced stage 962, 963 – brachytherapy 957–959 – chemotherapy 952, 960, 961 – diagnosis 949 – epidemiology 944 – etiology 944 – follow-up 975, 976 – localized deep 954, 955

1119

– localized superficial small 954 – locally recurrent 962 – lymph nodes metastases 947 – metastases 947 – pathology 945 – prognosis 951 – radiation therapy 957–959, 969–975 – – dose 969–973 – – indications 952 – – intensitymodulated 974 – – preoperative 964 – – simulation 969, 974 – – target volume 969, 974 – – techniques 952 – retroperitoneal 962, 971 – risk factors 944 – staging 949–951 – surgery 952, 954–956, 964 – symptoms 948 – targeted therapy 952 – TNM-classification 950 – treatment 952–976 – – algorithm 953, 966 Spermatogenesis, after radiation therapy 635 Spinal cord – compression 39, 56, 820, 1070 – radiation 73 Squamous cell carcinoma – see skin cancer, basal and squamous cell carcinoma – of unknown head and neck primary 161–177 Stem cell transplant 759, 799, 821 Stereotactic radiosurgery 8, 12–18, 21, 22 – adjuvant-treatment modality 18, 19

1120

Index of Volumes 1 and 2

Stomach – anatomy 362, 363 – lymph nodes 367 Subependymoma 1015 Sublingual gland 108, 111 Submandibular gland 108, 111 Superior sulcus syndrome 266 Superior vena cava syndrome 266 Supraglottis cancer 147 Synovial sarcoma 946

T Tamoxifen 227 Targeted therapy – breast cancer 223 – central nervous system lymphoma, primary 861 – esophageal cancer 340 – gallbladder carcinoma 477 – gastric cancer 373 – glioma 905, 913 – lung cancer 272, 273 – malignant melanoma 988 – non-small cell lung cancer 289 – oral cavity and oropharynx cancer 86 – pancreatic cancer 412 – rectal cancer 498 – salivary glands cancer 117 – soft tissue sarcoma 952 T-cell lymphoma – see also cutaneous T-cell lymphoma – central nervous system lymphoma 855 T-cell lymphotropic virus 746 T-cell prolymphocytic leukemia 747 Teratoma 615

Testicular cancer – chemotherapy 623, 627 – choriocarcinoma 615 – diagnosis 616, 617 – epidemiology 612 – etiology 612 – follow up 636 – lymph nodes metastases 613 – lymphadenopathy 622 – metastases 613 – non-seminoma 615, 627 – pathology 614 – prognosis 622 – radiation therapy 628–637 – – adjuvant 634 – – dose 629–632 – – indications 623 – – prophylactic 633 – – side effects 635, 637 – – simulation 628 – – spermatogenesis 635 – – sterility 637 – – target volume 629–632 – – techniques 623, 628 – risk factors 612 – seminoma 614 – stage I/II 625, 626 – stage II–IV 627 – staging 618–621 – surveillance 623 – symptoms 615 – teratoma 615 – TNM-classification 619, 620 – treatment 622–637 – – adjuvant 624 – – algorithm 624 Testis, anatomy 613 Thymectomy 316, 317 Thymoma 309–328 – chemotherapy 321–324 – – consolidation 321–324 – – induction 321–324

– – neoadjuvant 316 – – postoperative 323 – classification 312 – consolidation chemotherapy 321–324 – cortical 312 – diagnosis 315 – epidemiology 309 – etiology 310 – induction chemotherapy 321–324 – medullary 312 – metastases 312, 313 – pathology 311, 312 – prognosis 315 – radiation therapy 316–328 – – 3D 325 – – adjuvant 316, 325 – – clinical target volume 324, 325 – – dose 325 – – field arrangements 325 – – gross tumor volume 324, 325 – – intensity-modulated 316, 325–327 – – planning target volume 324, 325 – – postoperative 319 – – resectable thymoma 318, 319 – – side effects 328 – – target volume 324, 325 – – techniques 324–328 – – unresectable thymoma 320–324 – resectable 318, 319 – risk factors 310 – spindle cell 312 – staging 314 – surgery 316–319, 321–324 – symptoms 313 – treatment 316–328

Index of Volumes 1 and 2 – – algorithm 317, 320–322 – unresectable 320–324 – video-assisted thoracic surgery 316 Thymus – anatomy 310 – imaging 311 Thyroid cancer 179–203 – anaplastic 181, 183, 185, 190 – – radiation therapy 198–200 – diagnosis 186–188 – epidemiology 180 – etiology 180 – excisional biopsy 187 – fine-needle aspiration 187 – follicular 181, 182, 185 – follow-up 202, 203 – genetic testing 188 – medullary 180, 181, 183, 185, 190 – – radiation treatment 193, 195–198 – metastases 184 – papillary 181, 182, 185, 190, 193 – pathology 181 – prognosis 191, 192 – radiation therapy 193–203 – – adjuvant 194, 195 – – dose 201 – – external-beam 193 – – indications 193, 194, 197, 199 – – intensity-modulated 201 – – simulation 200, 201 – – target volume 200, 201 – – techniques 200–202 – risk factors 180 – staging 188, 189 – surgery 192, 193

– symptoms 184, 185 – TNM-classification 189 – treatment 192–203 Thyroid gland – radiation 73 – anatomy 181 Thyroidectomy 200 Thyroid-stimulating hormone 924 TNM-classification – anal cancer 517, 518 – bladder cancer 542 – breast cancer 219, 220 – cervical cancer, TNMclassification 669, 670 – cholangiocarcinoma, TNM-classification 454, 455 – esophageal cancer, TNM-classification 335, 336 – gallbladder carcinoma, TNM-classification 475, 476 – gastric cancer 370, 371 – hepatocellular carcinoma 427, 428 – larynx and hypopharynx cancer 139, 140 – lung cancer 269, 270 – malignant melanoma 982, 983 – nasopharyngeal carcinoma 55, 56 – non-small cell lung cancer 269, 270 – oral cavity and oropharynx cancer 83 – pancreatic cancer 397, 398 Tongue cancer 80, 101, 102 Transmandibular joint, radiation 73 Transpupillary thermotherapy 1044 Trismus 54 TSH 924

1121

TSH-secreting adenoma 926 Tuberous sclerosis 1013 Turcot’s syndrome 996, 1013

U Urachus, anatomy 535 Ureter, anatomy 535 Urogenital system – anatomy 535, 536 – tumors – – see bladder cancer – – see prostate cancer – – see testicular cancer Uterine papillary serous carcinoma 655 Uterus – adenomatoid tumor 644 – anatomy 642, 643, 663 – blood supply 643 – leiomyoma 644 – leiomyosarcoma 644 – lymphatic drain 643

V Vagina, anatomy 726 Vaginal cancer 725–743 – adenocarcinoma 741 – brachytherapy – – high-dose rate 733, 740 – – low-dose rate 733, 740 – chemotherapy 733, 734 – clear cell adenocarcinoma 727 – diagnosis 729 – early stage 737 – FIGO-classification 730 – follow-up 741 – intermediate stage 737 – invasive 733–736 – locally advanced 737 – malignant melanoma 727, 741 – metastases 728

1122

Index of Volumes 1 and 2

– pathology 727 – prognosis 731, 732 – radiation therapy – – clinical target volume 739 – – dose 737, 738 – – external-beam 738 – – gross tumor volume 739 – – indications 734 – – planning target volume 739 – – simulation 738 – – target volume 738–740 – – techniques 734, 737–740 – – three-dimensional conformal 739 – risk factors 727 – sarcoma 727 – squamous cell carcinoma 727 – staging 729, 730 – surgery 733, 734 – symptoms 728 – TNM-classification 730 – treatment 732–743 – – algorithm 736 – – side effects 740 Vaginal intraepithelial neoplasia 727 Vaginal stenosis 700 Vaginectomy 734 Vertebroplasty 33 Video assisted thorascopic surgery (VATS) 268 Villaret’s syndrome 54 Virchow’s node 368 Von Hippel-Lindau syndrome 1013 Vulva, anatomy 704, 705 Vulva cancer 703–724 – chemoradiation 716, 717 – chemotherapy 712 – diagnosis 707, 708 – early stage 712–716

– epidemiology 704 – etiology 704 – FIGO-classification 709 – fine-needle aspiration 706 – follow-up 723, 724 – locally advanced 716 – lymph nodes metastases 706 – metastases 705, 706 – pathology 705 – prognosis 710, 711 – radiation therapy 714, 715 – – adjuvant 714, 715 – – dose 723 – – external-beam 712 – – field arrangements 720, 721 – – indications 712 – – intensitymodulated 722 – – postoperative 714 – – preoperative 714 – – side effects 724 – – simulation 719, 720 – – techniques 712, 719–723 – resectable 714, 715 – risk factors 704 – sentinel node biopsy 712, 714 – staging 707–710 – surgery 711, 717 – symptoms 707 – TNM-classification 709 – treatment 711–724 – – algorithm 718 – – early stage 712–716 – unresectable 717, 718 Vulvectomy 711 – radical 715

W WAGR syndrome 1092

Waldenström’s macroglobulinemia 747 Whole-brain radiation therapy 9, 19 – adverse effects 22, 23 – dose 21 – simulation 19 Wilms’ tumor 1013, 1091–1106 – anaplastic 1093, 1101 – bilateral 1100 – diagnosis 1094, 1095 – epidemiology 1092 – etiology 1092 – follow-up 1106 – pathology 1093 – prognosis 1098, 1099 – radiation therapy 1100 – – pulmonary 1105 – – techniques 1103–1105 – staging 1095–1097 – symptoms 1094 – TNM-classification 1097 – treatment 1099–1106 – – adjuvant 1099, 1100

X Xanthoastrocytoma, pleomorphic 1015, 1024 Xeroderma pigmentosum 996