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

X


10

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

11

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

17

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

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

I1


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

23

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

24

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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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 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

32

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

35

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


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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

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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XX

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

VI

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

18

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).

1

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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James S. Butler

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)


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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

 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

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 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

Chapter 20 Testicular Cancer

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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


629

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


631

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


633

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 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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Keyur J. Mehta, Nikita Thawani and Subhakar Mutyala

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).

Chapter 21 Endometrial Cancer

643

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

644


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)


645

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.

646


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.


647

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

648


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).


649

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



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

Chapter 21 Endometrial Cancer 651

652


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 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.


653

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 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)

Chapter 22 Cervical Cancer

667

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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Nina Mayr, William Small Jr. and David K. Gaffney

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

686


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).


687

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]

688


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


689

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 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

 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

778 Maryse Bernard and Richard W. Tsang

Chapter 26 Hodgkin’s Lymphoma

779

Table 26.5 Advanced-stage HL: International Prognostic Score Risk factor

No. of risk factor

Freedom from progression at 5 years (%)

Serum albumin 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


793

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

794

Maryse Bernard and Richard W. Tsang

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.


795

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.

796


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 (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


797

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

798


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


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).

800


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.


801

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).

802


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.


803

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


805

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

806


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


807

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 ( 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]


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Wee Joo Chng and Ivan W.K. Tham

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-

Chapter 27 Multiple Myeloma and Plasmacytoma

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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 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 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 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

Chapter 28 Cutaneous T-Cell Lymphoma

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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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Ivan W.K. Tham

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


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


845

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


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


Yes

Refractory or Transformed

Skin-Directed Therapy


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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Ivan W.K. Tham


Stage III or SS

B0

B1

+/Skin Directed Therapies

Extracorporeal photophoresis

IFN-alpha

PUVA + IFN-alpha

Progression or Relapse?

Mainly Skin disease


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


847

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 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 60 years) when treated with MTX and WBRT have reported grade 5 neurotoxicity, as such, consider lowering the total dose or withholding radiation

862

Marnee M. Spierer and Evan M. Landau

Definitive Treatment KPS ≥ 40 Creatinine clearance 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

Chapter 29 Primary Central Nervous System Lymphoma

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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 ▶

866


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


867

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

868


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

870


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


Years 3–5


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

874

Allison M. Quick, Eric L. Chang and Simon S. Lo

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.

Chapter 30 Meningioma

875

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  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  ▶

884


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


885

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

– ▶

886


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


887

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

888

Allison M. Quick, Eric L. Chang and Simon S. Lo Figure 30.3 Left cavernous sinus meningioma demonstrated on axial T1 sequence with contrast

Figure 30.4 PTV (red) = GTV (cyan) plus 0.5 cm


889

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.

890

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:


891

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, 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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Heather McCarty, Colleen Dickie and Brian O’Sullivan

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.

Chapter 33 Soft Tissue Sarcoma

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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 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 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


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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José A. Peñagarícano and Vaneerat Ratanatharathorn

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 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).

Chapter 34 Cutaneous Malignant Melanoma

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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

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 (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


T0


Tis

Melanoma in situ

T1

Melanoma ≤1.0 mm in thickness with or without ulceration and 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


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


985

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.


987

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)

988


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 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 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


991

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

992


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.


993

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).

994


Table 34.13 Follow-up schedule and examinations Schedule

Frequency

First follow-up


Years 1–2

 Every 3–6 months (most recurrences occur within first 2 years after treatment)

Years 2+


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]


996


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

997

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

998


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.


999

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


T0


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


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


1001

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 4 mm or invading the reticular dermis and subcutis Tumor size: >4 cm in diameter Treatment: resection margins 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


Years 0–1


Years 2–5


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 (

Decision Making in Radiation Oncology: Volume 2

Decision Making in Radiation Oncology: Volume 1

Decision Making in Small Animal Oncology

New Technologies in Radiation Oncology

Radiation Oncology Management Decisions

Basic Radiation Oncology

Advances in Radiation Oncology in Lung Cancer

Treatment Planning in Radiation Oncology, 2 e 2006

Decision Making

Clinical Radiation Oncology, 3rd Edition

Pediatric Radiation Oncology, 4th Edition

Clinical Radiation Oncology, 3rd Edition

Decision-Making in Medieval Agriculture

Decision Making in Environmental Health

Decision-making in Complex Environments

Judgment in Managerial Decision Making

Handbook of Decision Making

The Decision-Making Pocketbook

Making the Antidepressant Decision

community decision making

Naive Decision Making

Gynecology decision making

Decision Making (Express Exec)

Decision Making Support Systems

Decision making and programming

Handbook of decision making

Organizational Decision Making (Cambridge Series on Judgment and Decision Making)

Radiation Oncology: Management Decisions (2nd Edition)

Radiation Oncology A Physicist’s-Eye View

Radiation Oncology: Rationale, Technique, Results, 9th Edition

Advances in Radiation Oncology in Lung Cancer, 2nd Edition

Decision Making in Radiation Oncology: Volume 2

Decision Making in Radiation Oncology: Volume 1

Decision Making in Small Animal Oncology

New Technologies in Radiation Oncology

Radiation Oncology Management Decisions

Basic Radiation Oncology

Advances in Radiation Oncology in Lung Cancer

Treatment Planning in Radiation Oncology, 2 e 2006

Decision Making

Clinical Radiation Oncology, 3rd Edition

Pediatric Radiation Oncology, 4th Edition

Clinical Radiation Oncology, 3rd Edition

Decision-Making in Medieval Agriculture

Decision Making in Environmental Health

Decision-making in Complex Environments

Judgment in Managerial Decision Making

Handbook of Decision Making

The Decision-Making Pocketbook

Making the Antidepressant Decision

community decision making

Naive Decision Making

Gynecology decision making

Decision Making (Express Exec)

Decision Making Support Systems

Decision making and programming

Handbook of decision making

Organizational Decision Making (Cambridge Series on Judgment and Decision Making)

Radiation Oncology: Management Decisions (2nd Edition)

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